Teva Parenteral Medicines, Inc.

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Teva Parenteral Medicines, Inc. Drugs

Naproxen Sodium

Naproxen Sodium

Octreotide acetate injection may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of octreotide acetate injection for control of symptoms. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination. Octreotide acetate injection is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

Octreotide acetate injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50 to 200 mL and infused intravenously over 15 to 30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g., carcinoid crisis) it may be given by rapid bolus.

The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose titration is frequently required. Dosage information for patients with specific tumors follows.

Acromegaly

Dosage may be initiated at 50 mcg t.i.d. Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses. IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone levels at 0 to 8 hours after octreotide acetate injection administration permit more rapid titration of dose. The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females. The dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to 500 mcg t.i.d. for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. IGF-I (somatomedin C) or growth hormone levels should be re-evaluated at 6 month intervals.

Octreotide acetate injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, octreotide acetate injection therapy may be resumed.

Carcinoid Tumors

The suggested daily dosage of octreotide acetate injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited.

VIPomas

Daily dosages of 200 to 300 mcg in 2 to 4 divided doses are recommended during the initial 2 weeks of therapy (range 150 to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required.
Irinotecan Hydrochlorid...

Irinotecan Hydrochloride

2.2 Colorectal Single Agent Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin > 2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.
Table 3. Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications a Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 (weekly)a

125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest

Starting Dose and Modified Dose Levelsc (mg/m2)

Starting Dose

Dose Level -1

Dose Level -2

125

100

75

Regimen 2 (every 3 weeks)b

350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeksc

Starting Dose and Modified Dose Levels (mg/m2)

Starting Dose

Dose Level -1

Dose Level -2

350

300

250

Dose Modifications

Based on recommended dose-levels described in Table 3, Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.
Table 4: Recommended Dose Modifications for Single-Agent Schedulesa a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1500/mm3, and the platelet count has recovered to ≥ 100,000/mm3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection.

Worst Toxicity NCI Gradeb (Value)

During a Cycle of Therapy

At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cyclea

Weekly

Weekly

Once Every 3 Weeks

No toxicity

Maintain dose level

↑ 25 mg/m2 up to a maximum dose of 150 mg/m2

Maintain dose level

Neutropenia

1 (1500 to

1999/mm3)

Maintain dose level

Maintain dose level

Maintain dose level

2 (1000 to

1499/mm3)

↓ 25 mg/m2

Maintain dose level

Maintain dose level

3 (500 to 999/mm3)

Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

4 (< 500/mm3)

Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

Neutropenic fever

Omit dose until resolved, then ↓ 50 mg/m2 when resolved

↓ 50 mg/m2

↓ 50 mg/m2

Other hematologic toxicities

Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.

Diarrhea

1 (2 to 3 stools/day > pretxc)

Maintain dose level

Maintain dose level

Maintain dose level

2 (4 to 6 stools/day > pretx)

↓ 25 mg/m2

Maintain dose level

Maintain dose level

3 (7 to 9 stools/day > pretx)

Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

4 (≥ 10 stools/day > pretx)

Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

Other nonhematologicd toxicities

1

Maintain dose level

Maintain dose level

Maintain dose level

2

↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

3

Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

4

Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

2.3 Dosage in Patients with Reduced UGT1A1 Activity

When administered in as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see Tables 1 to 4).

2.4 Premedication

It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride injection. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.

2.5 Preparation of Infusion Solution

Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.

Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded.

Irinotecan hydrochloride injection must be diluted prior to infusion. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution.

The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided.

The irinotecan hydrochloride injection solution should be used immediately after reconstitution as it contains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g., on Laminar Air Flow bench), irinotecan hydrochloride injection solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

2.6 Safe Handling

Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

2.7 Extravasation

Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.
Asprisol

Asprisol

Each 250 mL polyolefin bag contains 250 mg of argatroban (1 mg/mL); and, as supplied, is ready for intravenous infusion. Dilution is not required.

Argatroban Injection is a clear, colorless to pale yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy, contains precipitates, or if the flip-off seal is not intact.

2.1 Dosing in Patients with Heparin-Induced Thrombocytopenia

Initial Dosage

Before administering Argatroban Injection, discontinue heparin therapy and obtain a baseline aPTT. The recommended initial dose of Argatroban Injection for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 1).
Table 1. Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban Injection for Patients With HITa and Without Hepatic Impairment (1 mg/mL Concentration)
Body Weight (kg)

Dose (mcg/min)

Infusion Rate (mL/hr)

50

100

6

60

120

7

70

140

8

80

160

10

90

180

11

100

200

12

110

220

13

120

240

14

130

260

16

140

280

17

Monitoring Therapy

For use in HIT, therapy with Argatroban Injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of Argatroban Injection. Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment

After the initiation of Argatroban Injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range [see Clinical Studies(14.1)].

2.2 Dosing in Patients Undergoing Percutaneous Coronary Intervention

Initial Dosage

Initiate an infusion of Argatroban Injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes (see Table 2). Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed. The PCI procedure may proceed if the ACT is greater than 300 seconds.

Dosage Adjustment

If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later (see Table 2).

If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later (Table 3).

Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.

In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min. Check the ACT after each additional bolus or change in the rate of infusion.
Table 2. Recommended Starting and Maintenance Doses (Within the Target ACT Range) of Argatroban Injection in Patients Undergoing PCI Without Hepatic Impairment (1 mg/mL Concentration) NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs
Body Weight (kg)

Starting Bolus Dose

(350 mcg/kg)

Starting and Maintenance Continuous Infusion Dosing

For ACT 300 to 450 seconds

25 mcg/kg/min

Bolus Dose (mcg)

Bolus Volume (mL)

Continuous Infusion Dose (mg/min)

Continuous Infusion Rate (mL/hr)

50

17500

18

1250

75

60

21000

21

1500

90

70

24500

25

1750

105

80

28000

28

2000

120

90

31500

32

2250

135

100

35000

35

2500

150

110

38500

39

2750

165

120

42000

42

3000

180

130

45500

46

3250

195

140

49000

49

3500

210
Table 3. Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment (1 mg/mL Concentration)
Body Weight (kg)

If ACT

Less than 300 seconds

Dosage Adjustment†

30 mcg/kg/min

If ACT

Greater than 450 seconds Dosage Adjustment*

15 mcg/kg/min

Additional Bolus

Dose (mcg)

Bolus Volume (mL)

Continuous Infusion Dose (mcg/min)

Continuous Infusion Rate (mL/hr)

Continuous Infusion Dose (mcg/min)

Continuous Infusion Rate (mL/hr)

50

7500

8

1500

90

750

45

60

9000

9

1800

108

900

54

70

10500

11

2100

126

1050

63

80

12000

12

2400

144

1200

72

90

13500

14

2700

162

1350

81

100

15000

15

3000

180

1500

90

110

16500

17

3300

198

1650

99

120

18000

18

3600

216

1800

108

130

19500

20

3900

234

1950

117

140

21000

21

4200

252

2100

126
NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs †Additional intravenous bolus dose of 150 mcg/kg should be administered if ACT less than 300 seconds. * No bolus dose is given if ACT greater than 450 seconds
Monitoring Therapy

For use in PCI, therapy with Argatroban Injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure. Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure.

Continued Anticoagulation after PCI

If a patient requires anticoagulation after the procedure, Argatroban Injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range [see Dosage and Administration (2.1)].

2.3 Dosing in Patients with Hepatic Impairment

For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in argatroban clearance relative to those with normal hepatic function. Monitor the aPTT closely, and adjust the dosage as clinically indicated.

Monitoring Therapy

Achievement of steady-state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.

For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate Argatroban Injection until the desired level of anticoagulation is achieved. Use of Argatroban Injection in PCI patients with clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)].

2.4 Dosing in Pediatric Patients with Heparin-Induced Thrombocytopenia/Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

Initial Dosage

Initial argatroban infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function [see Use in Specific Populations(8.4)].

Monitoring Therapy

In general, therapy with argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of argatroban in patients without hepatic impairment [see Warnings and Precautions (5.2)]. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment: [see Use in Specific Populations (8.4)]

2.5 Conversion to Oral Anticoagulant Therapy

Initiating Oral Anticoagulant Therapy

When converting patients from argatroban to oral anticoagulant therapy, consider the potential for combined effects on International Normalized Ratio (INR). To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, overlap Argatroban Injection and warfarin therapy. There are insufficient data available to recommend the duration of the overlap. Initiate therapy using the expected daily dose of warfarin. A loading dose of warfarin should not be used.

The relationship between INR and bleeding risk is altered when argatroban and warfarin are coadministered. The combination of argatroban and warfarin does not cause further reduction in the vitamin K–dependent factor Xa activity than that which is seen with warfarin alone. The relationship between INR obtained on combined therapy and INR obtained on warfarin alone is dependent on both the dose of argatroban and the thromboplastin reagent used. The INR value on warfarin alone (INRW) can be calculated from the INR value on combination argatroban and warfarin therapy [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].

Coadministration of Warfarin and Argatroban Injection at Doses Up to 2 mcg/kg/min

Measure INR daily while Argatroban Injection and warfarin are coadministered. In general, with doses of Argatroban Injection up to 2 mcg/kg/min, Argatroban Injection can be discontinued when the INR is greater than 4 on combined therapy. After Argatroban Injection is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of Argatroban Injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

Coadministration of Warfarin and Argatroban Injection at Doses Greater than 2 mcg/kg/min

For doses greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Argatroban Injection to a dose of 2 mcg/kg/min. Repeat the INR on Argatroban Injection and warfarin 4 to 6 hours after reduction of the Argatroban Injection dose and follow the process outlined above for administering Argatroban Injection at doses up to 2 mcg/kg/min.
Carboplatin

Carboplatin

NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin injection.

Single Agent Therapy

Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Combination Therapy with Cyclophosphamide

In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing).

Cyclophosphamide - 600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (see CLINICAL STUDIES).

Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Dose Adjustment Recommendations

Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.
Platelets Neutrophils Adjusted Dose1 (From Prior Course)
> 100,000

> 2,000

125%

50 to 100,000

500 to 2,000

No Adjustment

< 50,000

< 500

75%

Carboplatin injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

Patients with Impaired Kidney Function

Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single agent carboplatin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.
Baseline Creatinine Clearance Recommended Dose on Day 1
41 to 59 mL/min

250 mg/m2

16 to 40 mL/min

200 mg/m2

The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance based on the degree of bone marrow suppression.

Formula Dosing

Another approach for determining the initial dose of carboplatin injection is the use of mathematical formulae, which are based on a patient's pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin (see CLINICAL PHARMACOLOGY). The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

A simple formula for calculating dosage, based upon a patient's glomerular filtration rate (GFR in mL/min) and carboplatin injection target area under the concentration versus time curve (AUC in mg/mL∙min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

_____________________________________________________________________________________

CALVERT FORMULA FOR CARBOPLATIN DOSING

Total Dose (mg) = (target AUC) x (GFR + 25)

Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.

_____________________________________________________________________________________

The target AUC of 4 mg/mL∙min to 6 mg/mL∙min using single agent carboplatin appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent carboplatin administered to previously treated patients and the likelihood of developing toxicity.
% Actual Toxicity in Previously Treated Patients AUC (mg/mL∙min) Gr 3 or Gr 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia
4 to 5

16%

13%

6 to 7

33%

34%

Geriatric Dosing

Because renal function is often decreased in elderly patients, formula dosing of carboplatin injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin injection AUCs and thereby minimize the risk of toxicity.
Oxacillin

Oxacillin

The penicillinase-resistant penicillins are available for oral administration and for intramuscular and intravenous injection. The sodium salts of methicillin, oxacillin, and nafcillin may be administered parenterally and the sodium salts of cloxacillin, dicloxacillin, oxacillin, and nafcillin are available for oral use.

Bacteriologic studies to determine the causative organisms and their susceptibility to oxacillin should always be performed. Duration of therapy varies with the type of severity of infection as well as the overall condition of the patient; therefore, it should be determined by the clinical and bacteriological response of the patient. In severe staphylococcal infections, therapy with oxacillin should be continued for at least 14 days. Therapy should be continued for at least 48 hours after the patient has become afebrile, asymptomatic, and cultures are negative. Treatment of endocarditis and osteomyelitis may require a longer duration of therapy.

Concurrent administration of oxacillin and probenecid increases and prolongs serum penicillin levels. Probenecid decreases the apparent volume of distribution and slows the rate of excretion by competitively inhibiting renal tubular secretion of penicillin. Penicillin-probenecid therapy is generally limited to those infections where very high serum levels of penicillin are necessary.

Oral preparations of the penicillinase-resistant penicillins should not be used as initial therapy in serious, life-threatening infections (See PRECAUTIONS-General). Oral therapy with the penicillinase-resistant penicillins may be used to follow-up the previous use of a parenteral agent as soon as the clinical condition warrants. For intramuscular gluteal injections, care should be taken to avoid sciatic nerve injury.

With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.
RECOMMENDED DOSAGES FOR OXACILLIN FOR INJECTION, USP
Drug

Adults

Infants and Children < 40 kg (88 lbs)

Other Recommendat ons

Oxacillin

250 to 500 mg IM or IV every 4 to 6hours (mild to moderate infections)

50 mg/kg/day IM or IV in equally divideddoses every 6 hours (mild to moderate infections)

1 gram IM or IVevery 4 to 6 hours (severe infections)

100 mg/kg/day IM or IV in equally divided dosesevery 4 to 6 hours (severe infections)

Premature and Neonates 25 mg/kg/day IM or IV

Directions for use

For Intramuscular Use

Use Sterile Water for Injection, USP. Add 5.7 mL to the 1 gram vial and 11.5 mL to the 2 gram vial. Shake well until a clear solution is obtained. After reconstitution, vials will contain 250 mg of active drug per 1.5 mL of solution. The reconstituted solution is stable for 3 days at 70°F or for one week under refrigeration (40° F).

For Direct Intravenous Use

Use Sterile Water for Injection, USP or Sodium Chloride Injection, USP. Add 10 mL to the 1 gram vial and 20 mL to the 2 gram vial. Withdraw the entire contents and administer slowly over a period of approximately10 minutes.

For Administration by Intravenous Drip

Reconstitute as directed above (For Direct Intravenous Use) prior to diluting with Intravenous Solution.
STABILITY PERIODS FOR OXACILLIN FOR INJECTION, USP
Concentration mg/mL

Sterile water for Injection

0.9% sodium chloride Injection, USP

M/6 Molar Sodium Lactate Solution

5% Dextrose in water

5% Dextrose in 0.45% sodium chloride

10% Invert Sugar Injection, USP

Lactated Ringers Solution

ROOM TEMPERATURE (25° C)

10 to100

4 Days

4 Days

10 to 30

24 Hrs

24 Hrs

0.5 to 2

6 Hrs

6 Hrs

6 Hrs

REFRIGERATION (4° C)

10 to 100

7 Days

7 Days

10 to 30

4 Days

4 Days

4 Days

4 days

4 Days

FROZEN (-15° C)

50 to 100

30 Days

250/1.5 mL

30 Days

100

30 Days

10 to 100

30 Days

30 Days

30 Days

30 days

30 Days

Stability studies on oxacillin sodium at concentrations of 0.5 mg/mL and 2 mg/mL in various intravenous solutions listed below indicate the drug will lose less than 10% activity at room temperature (70°F) during a 6-hour period.

IV Solution

5% Dextrose in Normal Saline

10% D-Fructose in Water

10% D-Fructose in Normal Saline

Lactated Potassic Saline Injection

10% Invert Sugar in Normal Saline

10% Invert Sugar Plus 0.3% Potassium Chloride in Water

Travert 10% Electrolyte #1

Travert 10% Electrolyte #2

Travert 10% Electrolyte #3

Only those solutions listed above should be used for the intravenous infusion of oxacillin sodium. The concentration of the antibiotic should fall within the range specified. The drug concentration and the rate and volume of the infusion should be adjusted so that the total dose of oxacillin is administered before the drug loses its stability in the solution in use.

If another agent is used in conjunction with oxacillin therapy, it should not be physically mixed with oxacillin but should be administered separately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not add supplementary medication to Oxacillin for Injection, USP.
Metoclopramide

Metoclopramide

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis)

If only the earliest manifestations of diabetic gastric stasis are present, oral administration of metoclopramide may be initiated. However, if severe symptoms are present, therapy should begin with metoclopramide injection USP (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

Administration of metoclopramide injection USP up to 10 days may be required before symptoms subside, at which time oral administration of metoclopramide may be instituted. The physician should make a thorough assessment of the risks and benefits prior to prescribing further metoclopramide treatment.

For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose may be adequate.

For doses in excess of 10 mg, metoclopramide injection USP should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with metoclopramide injection USP, can be stored frozen for up to 4 weeks. Metoclopramide injection USP is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide injection USP diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

If acute dystonic reactions should occur, inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and the symptoms usually will subside.

For the Prevention of Postoperative Nausea and Vomiting

Metoclopramide injection USP should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation

If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2-minute period.

The recommended single dose is: Pediatric patients above 14 years of age and adults — 10 mg metoclopramide base. Pediatric patients (6-14 years of age) — 2.5 to 5 mg metoclopramide base; (under 6 years of age) — 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations

In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over a 1- to 2-minute period.

For dosage, see intubation above.

Use in Patients With Renal or Hepatic Impairment

Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

See OVERDOSAGE section for information regarding dialysis.

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ADMIXTURES COMPATIBILITIES

Metoclopramide injection USP is compatible for mixing and injection with the following dosage forms to the extent indicated below:

Physically and Chemically Compatible Up to 48 Hours

Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex).

Physically Compatible Up to 48 Hours

Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).

Physically Compatible Up to 24 Hours

(Do not use if precipitation occurs)

Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly).

Conditionally Compatible

(Use within one hour after mixing or may be infused directly into the same running IV line)

Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle).

Incompatible

(Do Not Mix)

Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Abbott).
Sumatriptan Succinate

Sumatriptan Succinate

The maximum single recommended adult dose of sumatriptan succinate injection is 6 mg injected subcutaneously. If side effects are dose limiting, then lower doses may be used (see Table 1).

The maximum recommended dose that may be given in 24 hours is two 6-mg injections separated by at least 1 hour. Controlled clinical trials have failed to show that clear benefit is associated with the administration of a second 6-mg dose in patients who have failed to respond to a first injection.

In patients receiving MAO inhibitors, decreased doses of sumatriptan should be considered (see WARNINGS: Concomitant Drug Use and CLINICAL PHARMACOLOGY: Drug Interactions: Monoamine Oxidase Inhibitors).

Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery should be avoided. Patients should be directed to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

In patients receiving doses other than 4 or 6 mg, only the 6-mg single-dose vial dosage form should be used.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.
Alprostadil

Alprostadil

The preferred route of administration for alprostadil injection, USP is continuous intravenous infusion into a large vein. Alternatively, alprostadil injection may be administered through an umbilical artery catheter placed at the ductal opening. Increases in blood pO2 (torr) have been the same in neonates who received the drug by either route of administration.

Begin infusion with 0.05 to 0.1 micrograms alprostadil per kilogram of body weight per minute. A starting dose of 0.1 micrograms per kilogram of body weight per minute is the recommended starting dose based on clinical studies; however, adequate clinical response has been reported using a starting dose of 0.05 micrograms per kilogram of body weight per minute. After a therapeutic response is achieved (increased pO2 in infants with restricted pulmonary blood flow or increased systemic blood pressure and blood pH in infants with restricted systemic blood flow), reduce the infusion rate to provide the lowest possible dosage that maintains the response. This may be accomplished by reducing the dosage from 0.1 to 0.05 to 0.025 to 0.01 micrograms per kilogram of body weight per minute. If response to 0.05 micrograms per kilogram of body weight per minute is inadequate, dosage can be increased up to 0.4 micrograms per kilogram of body weight per minute although, in general, higher infusion rates do not produce greater effects.

Dilution Instructions

To prepare infusion solutions, dilute 1 mL of alprostadil injection, USP with sodium chloride injection, USP or dextrose injection, USP. Undiluted alprostadil injection may interact with the plastic sidewalls of volumetric infusion chambers causing a change in the appearance of the chamber and creating a hazy solution. Should this occur, the solution and the volumetric infusion chamber should be replaced.

When using a volumetric infusion chamber, the appropriate amount of intravenous infusion solution should be added to the chamber first. The undiluted alprostadil injection should then be added to the intravenous infusion solution, avoiding direct contact of the undiluted solution with the walls of the volumetric infusion chamber.

Dilute to volumes appropriate for the pump delivery system available. Prepare fresh infusion solutions every 24 hours. Discard any solution more than 24 hours old.
Sample Dilutions and Infusion Rates to Provide a Dosage of 0.1 Micrograms per Kilogram of Body Weight per Minute Add 1 vial (500 micrograms) alprostadil to: Approximate Concentration of resulting solution (micrograms/mL) lnfusion rate (mL/min per kg) (of body weight) 250 mL 2 0.05 100 mL 5 0.02 50 mL 10 0.01 25 mL 20 0.005 Example: To provide 0.1 micrograms/kilogram of body weight per minute to an infant weighing 2.8 kilograms using a solution of 1 vial alprostadil injection, USP in 100 mL of saline or dextrose: INFUSION RATE = 0.02 mL/min per kg × 2.8 kg = 0.056 mL/min or mL/hr.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Natroba

Natroba

Rocuronium bromide injection is for intravenous use only. This drug should only be administered by experienced clinicians or trained individuals supervised by an experienced clinician familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents. Doses of rocuronium bromide injection should be individualized and a peripheral nerve stimulator should be used to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered.

The dosage information which follows is derived from studies based upon units of drug per unit of body weight. It is intended to serve as an initial guide to clinicians familiar with other neuromuscular blocking agents to acquire experience with rocuronium bromide injection.

In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose adjustment should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.9, 5.12), Drug Interactions (7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.10), and Use in Specific Populations (8.6)].

2.1 Dose for Tracheal Intubation

The recommended initial dose of rocuronium bromide injection, regardless of anesthetic technique, is 0.6 mg/kg. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1 (0.4 to 6) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 3 minutes. This dose may be expected to provide 31 (15 to 85) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug Interactions (7.3)].

A lower dose of rocuronium bromide injection (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1.3 (0.8 to 6.2) minute(s), and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 4 minutes. This dose may be expected to provide 22 (12 to 31) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15 minutes.

A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology (12.2)].

2.2 Rapid Sequence Intubation

In appropriately premedicated and adequately anesthetized patients, rocuronium bromide injection 0.6 to 1.2 mg/kg will provide excellent or good intubating conditions in most patients in less than 2 minutes [see Clinical Studies (14.1)].

2.3 Maintenance Dosing

Maintenance doses of 0.1, 0.15, and 0.2 mg/kg rocuronium bromide injection, administered at 25% recovery of control T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2 to 31), 17 (6 to 50), and 24 (7 to 69) minutes of clinical duration under opioid/nitrous oxide/oxygen anesthesia [see Clinical Pharmacology (12.2)]. In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until recovery of neuromuscular function is evident. A clinically insignificant cumulation of effect with repetitive maintenance dosing has been observed [see Clinical Pharmacology (12.2)].

2.4 Use by Continuous Infusion

Infusion at an initial rate of 10 to 12 mcg/kg/min of rocuronium bromide injection should be initiated only after early evidence of spontaneous recovery from an intubating dose. Due to rapid redistribution [see Clinical Pharmacology (12.3)] and the associated rapid spontaneous recovery, initiation of the infusion after substantial return of neuromuscular function (more than 10% of control T1) may necessitate additional bolus doses to maintain adequate block for surgery.

Upon reaching the desired level of neuromuscular block, the infusion of rocuronium bromide injection must be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as monitored with the use of a peripheral nerve stimulator. In clinical trials, infusion rates have ranged from 4 to 16 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane, may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion by 30% to 50%, at 45 to 60 minutes after the intubating dose.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide injection infusion may be expected to proceed at rates comparable to that following comparable total doses administered by repetitive bolus injections [see Clinical Pharmacology (12.2)].

Infusion solutions of rocuronium bromide injection can be prepared by mixing rocuronium bromide injection with an appropriate infusion solution such as 5% glucose in water or lactated Ringers [see Dosage and Administration (2.6)]. These infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

Infusion rates of rocuronium bromide injection can be individualized for each patient using the following tables for 3 different concentrations of rocuronium bromide injection solution as guidelines:
Table 1: Infusion Rates Using Rocuronium Bromide Injection (0.5 mg/mL)* Patient Weight Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 9 10 12 14 16 (kg) (lbs) Infusion Delivery Rate (mL/hr) * 50 mg rocuronium bromide injection in 100 mL solution.
10

22

4.8

6

7.2

8.4

9.6

10.8

12

14.4

16.8

19.2

15

33

7.2

9

10.8

12.6

14.4

16.2

18

21.6

25.2

28.8

20

44

9.6

12

14.4

16.8

19.2

21.6

24

28.8

33.6

38.4

25

55

12

15

18

21

24

27

30

36

42

48

35

77

16.8

21

25.2

29.4

33.6

37.8

42

50.4

58.8

67.2

50

110

24

30

36

42

48

54

60

72

84

96

60

132

28.8

36

43.2

50.4

57.6

64.8

72

86.4

100.8

115.2

70

154

33.6

42

50.4

58.8

67.2

75.6

84

100.8

117.6

134.4

80

176

38.4

48

57.6

67.2

76.8

86.4

96

115.2

134.4

153.6

90

198

43.2

54

64.8

75.6

86.4

97.2

108

129.6

151.2

172.8

100

220

48

60

72

84

96

108

120

144

168

192
Table 2: Infusion Rates Using Rocuronium Bromide Injection (1 mg/mL)* Patient Weight Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 9 10 12 14 16 (kg) (lbs) Infusion Delivery Rate (mL/hr) * 100 mg rocuronium bromide injection in 100 mL solution.
10

22

2.4

3

3.6

4.2

4.8

5.4

6

7.2

8.4

9.6

15

33

3.6

4.5

5.4

6.3

7.2

8.1

9

10.8

12.6

14.4

20

44

4.8

6

7.2

8.4

9.6

10.8

12

14.4

16.8

19.2

25

55

6

7.5

9

10.5

12

13.5

15

18

21

24

35

77

8.4

10.5

12.6

14.7

16.8

18.9

21

25.2

29.4

33.6

50

110

12

15

18

21

24

27

30

36

42

48

60

132

14.4

18

21.6

25.2

28.8

32.4

36

43.2

50.4

57.6

70

154

16.8

21

25.2

29.4

33.6

37.8

42

50.4

58.8

67.2

80

176

19.2

24

28.8

33.6

38.4

43.2

48

57.6

67.2

76.8

90

198

21.6

27

32.4

37.8

43.2

48.6

54

64.8

75.6

86.4

100

220

24

30

36

42

48

54

60

72

84

96
Table 3: Infusion Rates Using Rocuronium Bromide Injection (5 mg/mL)* Patient Weight Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 9 10 12 14 16 (kg) (lbs) Infusion Delivery Rate (mL/hr) * 500 mg rocuronium bromide injection in 100 mL solution.
10

22

0.5

0.6

0.7

0.8

1

1.1

1.2

1.4

1.7

1.9

15

33

0.7

0.9

1.1

1.3

1.4

1.6

1.8

2.2

2.5

2.9

20

44

1

1.2

1.4

1.7

1.9

2.2

2.4

2.9

3.4

3.8

25

55

1.2

1.5

1.8

2.1

2.4

2.7

3

3.6

4.2

4.8

35

77

1.7

2.1

2.5

2.9

3.4

3.8

4.2

5

5.9

6.7

50

110

2.4

3

3.6

4.2

4.8

5.4

6

7.2

8.4

9.6

60

132

2.9

3.6

4.3

5

5.8

6.5

7.2

8.6

10.1

11.5

70

154

3.4

4.2

5

5.9

6.7

7.6

8.4

10.1

11.8

13.4

80

176

3.8

4.8

5.8

6.7

7.7

8.6

9.6

11.5

13.4

15.4

90

198

4.3

5.4

6.5

7.6

8.6

9.7

10.8

13

15.1

17.3

100

220

4.8

6

7.2

8.4

9.6

10.8

12

14.4

16.8

19.2

2.5 Dosage in Specific Populations

Pediatric Patients

The recommended initial intubation dose of rocuronium bromide injection is 0.6 mg/kg; however, a lower dose of 0.45 mg/kg may be used depending on anesthetic technique and the age of the patient.

For sevoflurane (induction) rocuronium bromide injection doses of 0.45 mg/kg and 0.6 mg/kg in general produce excellent to good intubating conditions within 75 seconds. When halothane is used, a 0.6 mg/kg dose of rocuronium bromide injection resulted in excellent to good intubating conditions within 60 seconds.

The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months) and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants.

When sevoflurane is used for induction and isoflurane/nitrous oxide for maintenance of general anesthesia, maintenance dosing of rocuronium bromide injection can be administered as bolus doses of 0.15 mg/kg at reappearance of T3 in all pediatric age groups. Maintenance dosing can also be administered at the reappearance of T2 at a rate of 7 to 10 mcg/kg/min, with the lowest dose requirement for neonates (birth to less than 28 days) and the highest dose requirement for children (greater than 2 years up to 11 years).

When halothane is used for general anesthesia, patients ranging from 3 months old through adolescence can be administered rocuronium bromide injection maintenance doses of 0.075 to 0.125 mg/kg upon return of T1 to 0.25% to provide clinical relaxation for 7 to 10 minutes. Alternatively, a continuous infusion of rocuronium bromide injection initiated at a rate of 12 mcg/kg/min upon return of T1 to 10% (one twitch present in train-of-four) may also be used to maintain neuromuscular blockade in pediatric patients.

Additional information for administration to pediatric patients of all age groups is presented elsewhere in the label [see Clinical Pharmacology (12.2)].

The infusion of rocuronium bromide injection must be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as monitored with the use of a peripheral nerve stimulator. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide injection infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [see Clinical Pharmacology (12.2)].

Rocuronium bromide injection is not recommended for rapid sequence intubation in pediatric patients.

Geriatric Patients

Geriatric patients (65 years or older) exhibited a slightly prolonged median (range) clinical duration of 46 (22 to 73), 62 (49 to 75), and 94 (64 to 138) minutes under opioid/nitrous oxide/oxygen anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively. No differences in duration of neuromuscular blockade following maintenance doses of rocuronium bromide injection were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.2 and Clinical Studies (14.2)]. [See also Warnings and Precautions (5.4)].

Patients With Renal or Hepatic Impairment

No differences from patients with normal hepatic and kidney function were observed for onset time at a dose of 0.6 mg/kg rocuronium bromide injection. When compared to patients with normal renal and hepatic function, the mean clinical duration is similar in patients with end-stage renal disease undergoing renal transplant, and is about 1.5 times longer in patients with hepatic disease. Patients with renal failure may have a greater variation in duration of effect [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

Obese Patients

In obese patients, the initial dose of rocuronium bromide injection 0.6 mg/kg should be based upon the patient's actual body weight [see Clinical Studies (14.1)].

An analysis across all US controlled clinical studies indicates that the pharmacodynamics of rocuronium bromide injection are not different between obese and nonobese patients when dosed based upon their actual body weight.

Patients With Reduced Plasma Cholinesterase Activity

Rocuronium metabolism does not depend on plasma cholinesterase so dosing adjustments are not needed in patients with reduced plasma cholinesterase activity.

Patients With Prolonged Circulation Time

Because higher doses of rocuronium bromide injection produce a longer duration of action, the initial dosage should usually not be increased in these patients to reduce onset time; instead, in these situations, when feasible, more time should be allowed for the drug to achieve onset of effect [see Warnings and Precautions (5.7)].

Patients With Drugs or Conditions Causing Potentiation of Neuromuscular Block

The neuromuscular blocking action of rocuronium bromide injection is potentiated by isoflurane and enflurane anesthesia. Potentiation is minimal when administration of the recommended dose of rocuronium bromide injection occurs prior to the administration of these potent inhalation agents. The median clinical duration of a dose of 0.57 to 0.85 mg/kg was 34, 38, and 42 minutes under opioid/nitrous oxide/oxygen, enflurane and isoflurane maintenance anesthesia, respectively. During 1 to 2 hours of infusion, the infusion rate of rocuronium bromide injection required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia [see Drug Interactions (7.3)].

2.6 Preparation for Administration of Rocuronium Bromide Injection

Diluent Compatibility

Rocuronium bromide injection is compatible in solution with:

0.9% NaCl solution

sterile water for injection

5% glucose in water

lactated Ringers

5% glucose in saline

Rocuronium bromide injection is compatible in the above solutions at concentrations up to 5 mg/mL for 24 hours at room temperature in plastic bags, glass bottles, and plastic syringe pumps.

Drug Admixture Incompatibility

Rocuronium bromide injection is physically incompatible when mixed with the following drugs:

amphotericin

hydrocortisone sodium succinate

amoxicillin

insulin

azathioprine

Intralipid

cefazolin

ketorolac

cloxacillin

lorazepam

dexamethasone

methohexital

diazepam

methylprednisolone

erythromycin

thiopental

famotidine

trimethoprim

furosemide

vancomycin

If rocuronium bromide injection is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed between administration of rocuronium bromide injection and drugs for which incompatibility with rocuronium bromide injection has been demonstrated or for which compatibility with rocuronium bromide injection has not been established.

Infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

Rocuronium bromide injection should not be mixed with alkaline solutions [see Warnings and Precautions (5.10)].

Visual Inspection

Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit. Do not use solution if particulate matter is present.
Mitoxantrone

Mitoxantrone

(See also WARNINGS.)

Multiple Sclerosis

The recommended dosage of mitoxantrone injection (concentrate) is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of mitoxantrone injection (concentrate) and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with mitoxantrone injection (concentrate). Mitoxantrone injection (concentrate) should not be administered to multiple sclerosis patients with an LVEF < 50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of > 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of mitoxantrone injection (concentrate) and in the event that signs or symptoms of infection develop. Mitoxantrone injection (concentrate) generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. Mitoxantrone injection (concentrate) therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because mitoxantrone injection (concentrate) clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of mitoxantrone injection (concentrate) (see WARNINGS, Pregnancy).

Hormone-Refractory Prostate Cancer

Based on data from two Phase 3 comparative trials of mitoxantrone injection (concentrate) plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone injection (concentrate) is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.

Combination Initial Therapy for ANLL in Adults

For induction, the recommended dosage is 12 mg/m2 of mitoxantrone injection (concentrate) daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24 hour infusion on Days 1 to 7.

Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone injection (concentrate) should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.

If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.

Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone injection (concentrate), 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24 hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred (seeCLINICAL PHARMACOLOGY).

Hepatic Impairment

For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment).

Preparation and Administration Precautions

MITOXANTRONE INJECTION CONCENTRATE MUST BE DILUTED PRIOR TO USE.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The dose of mitoxantrone injection (concentrate) should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone injection (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.

Mitoxantrone injection (concentrate) should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone injection (concentrate) not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted mitoxantrone injection concentrate should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.

Care in the administration of mitoxantrone injection (concentrate) will reduce the chance of extravasation. Mitoxantrone injection (concentrate) should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone injection (concentrate) with the skin, mucous membranes, or eyes. MITOXANTRONE INJECTION (CONCENTRATE) SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of mitoxantrone injection (concentrate) extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.

Skin accidentally exposed to mitoxantrone injection (concentrate) should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Cisplatin

Cisplatin

Cisplatin Injection is administered by slow intravenous infusion. CISPLATIN INJECTION SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

Note: Needles or intravenous sets containing aluminum parts that may come in contact with Cisplatin Injection should not be used for preparation or administration. Aluminum reacts with Cisplatin Injection, causing precipitate formation and a loss of potency.

Metastatic Testicular Tumors

The usual Cisplatin Injection dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.

Metastatic Ovarian Tumors

The usual Cisplatin Injection dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every four weeks (DAY 1).

The dose of cyclophosphamide when used in combination with Cisplatin Injection is 600 mg/m2 IV once every 4 weeks (DAY 1).

For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.

In combination therapy, Cisplatin Injection and cyclophosphamide are administered sequentially.

As a single agent, Cisplatin Injection should be administered at a dose of 100 mg/m2 IV per cycle once every four weeks.

Advanced Bladder Cancer

Cisplatin Injection should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.

All Patients

Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a Cisplatin Injection dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in ½ or ⅓ normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute Cisplatin Injection in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours.

A repeat course of Cisplatin Injection should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm3, WBC ≥ 4000/mm3). Subsequent doses of Cisplatin Injection should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
Haloperidol Decanoate

Haloperidol Decanoate

Haloperidol decanoate injection 50 mg/mL and haloperidol decanoate injection 100 mg/mL should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Haloperidol decanoate injection 50 mg/mL and haloperidol decanoate injection 100 mg/mL are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting haloperidol in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol.

The dose of haloperidol decanoate injection 50 mg/mL or haloperidol decanoate injection 100 mg/mL should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient's age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g., up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10 to 15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate.

Initial Therapy

Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents.

In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g., up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion.

In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections.

The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e., a maximum of 100 mg initially followed by the balance in 3 to 7 days.

Maintenance Therapy

The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient.
HALOPERIDOL DECANOATE DOSING RECOMMENDATIONS Patients Monthly 1st Month Maintenance
Stabilized on low daily oral doses(up to 10 mg/day)Elderly or Debilitated

10 to 15 × Daily Oral Dose

10 to 15 × Previous Daily Oral Dose

High dose Risk of relapseTolerant to oral haloperidol

20 × Daily Oral Dose

10 to 15 × Previous Daily Oral Dose

Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (see CLINICAL PHARMACOLOGY).

Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited.
Levocarnitine

Levocarnitine

Levocarnitine injection is administered intravenously.

Metabolic Disorders

The recommended dose is 50 mg/kg given as a slow 2–3 minute bolus injection or by infusion. Often a loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. It should be administered q3h or q4h, and never less than q6h either by infusion or by intravenous injection. All subsequent daily doses are recommended to be in the range of 50 mg/kg or as therapy may require. The highest dose administered has been 300 mg/kg.

It is recommended that a plasma carnitine concentration be obtained prior to beginning this parenteral therapy. Weekly and monthly monitoring is recommended as well. This monitoring should include blood chemistries, vital signs, plasma carnitine concentrations (the plasma free carnitine concentration should be between 35 and 60 μmol/L) and overall clinical condition.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Fluconazole

Fluconazole

Dosage and Administration in Adults

SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy.

The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.

Oropharyngeal candidiasis

The recommended dosage of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.

Esophageal candidiasis

The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.

Systemic Candida infections

For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used.

Urinary tract infections and peritonitis

For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50 to 200 mg have been used in open, noncomparative studies of small numbers of patients.

Cryptococcal meningitis

The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily.

Prophylaxis in patients undergoing bone marrow transplantation.

The recommended fluconazole daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm.

Dosage and Administration in Children

The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients:
Pediatric Patients Adults * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. 3 mg/kg 100 mg 6 mg/kg 200 mg 12 * mg/kg 400 mg
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. (SeeCLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding fluconazole pharmacokinetics in full-term newborns is available.

Oropharyngeal candidiasis

The recommended dosage of fluconazole for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.

Esophageal candidiasis

For the treatment of esophageal candidiasis, the recommended dosage of fluconazole in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.

Systemic Candida infections

For the treatment of candidemia and disseminated Candida infections, daily doses of 6 to 12 mg/kg/day have been used in an open, noncomparative study of a small number of children.

Cryptococcal meningitis

For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.

Dosage In Patients With Impaired Renal Function

Fluconazole is cleared primarily by renal excretion as unchanged drug. In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:
Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition.

When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults:
Males: Weight (kg) × (140-age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children:
K × linear length or height (cm) serum creatinine (mg/100 mL)
(Where K = 0.55 for children older than 1 year and 0.45 for infants.)

Administration

Fluconazole may be administered by intravenous infusion. Fluconazole can be taken with or without food. Fluconazole injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of fluconazole should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion.

Fluconazole injections in glass and plastic containers are intended only for intravenous administration using sterile equipment.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not use if the solution is cloudy or precipitated or if the seal is not intact.

Directions for IV Use of Fluconazole in Plastic Containers

Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

To Open

Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.

DO NOT ADD SUPPLEMENTARY MEDICATION.

Preparation for Administration:
Suspend container from eyelet support. Remove plastic protector from outlet port at bottom of container. Attach administration set. Refer to complete directions accompanying set.
Verapamil Hydrochloride...

Verapamil Hydrochloride

Ifosfamide injection should be administered intravenously at a dose of 1.2 grams per m2 per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity.

In order to prevent bladder toxicity, ifosfamide injection should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. Mesna should be used to reduce the incidence of hemorrhagic cystitis. Ifosfamide injection should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Studies of ifosfamide injection in patients with hepatic or renal impairment have not been conducted [see Use in Specific Populations 8.6, 8.7)].

Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP

Lactated Ringer’s Injections, USP

Sterile Water for Injection, USP

Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, VIAFLEX bags or PAB bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.

Constituted or constituted and further diluted solutions of ifosfamide injection should be refrigerated and used within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of ifosfamide.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Fludarabine Phosphate

Fludarabine Phosphate

2.1 Recommended Dose

The recommended adult dose of fludarabine phosphate injection is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5-day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from fludarabine phosphate injection. These include advanced age, renal impairment, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of fludarabine phosphate injection be administered following the achievement of a maximal response and then the drug should be discontinued.

2.2 Renal Impairment

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine phosphate injection should not be administered to patients with creatinine clearance less than 30 mL/min.

Starting Dose Adjustment for Renal Impairment

Creatinine Clearance

Starting Dose

> 80 mL/min

25 mg/m2 (full dose)

50 to 79 mL/min

20 mg/m2

30 to 49 mL/min

15 mg/m2

< 30 mL/min

Do not administer

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

2.3 Use of Infusion Solutions

Fludarabine phosphate injection contains no antimicrobial preservative and should be used within 8 hours of opening. Care must be taken to assure sterility of infusion solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Fludarabine phosphate injection should not be mixed with other drugs.
Medroxyprogesterone Ace...

Medroxyprogesterone Acetate

2.1 Prevention of Pregnancy

The 1 mL vial of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension. The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep IM injection in the gluteal or deltoid muscle. Medroxyprogesterone acetate injectable suspension should not be used as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate. Dosage does not need to be adjusted for body weight [see Clinical Studies (14.1)].

To ensure the patient is not pregnant at the time of the first injection, the first injection should be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of medroxyprogesterone acetate injectable suspension depends on adherence to the dosage schedule of administration.

2.2 Switching from other Methods of Contraception

When switching from other contraceptive methods, medroxyprogesterone acetate injectable suspension should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of medroxyprogesterone acetate injectable suspension on the day after the last active tablet or at the latest, on the day following the final inactive tablet).
Gemcitabine Hydrochlori...

Gemcitabine Hydrochloride

Gemcitabine for Injection is for intravenous use only. Gemcitabine may be administered on an outpatient basis.

2.1 Ovarian Cancer

Gemcitabine for Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 × 106/L and a platelet count ≥100,000 × 106/L prior to each cycle.

Dose Modifications

Gemcitabine for Injection dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to guidelines in Table 1.
Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin Absolutegranulocyte count(× 106/L) Platelet count(× 106/L) % offull dose ≥1500 And ≥100,000 100 1000 to 1499 and/or 75,000 to 99,999 50 <1000 and/or <75,000 Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer's prescribing information.

Dose adjustment for gemcitabine for injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of gemcitabine for injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:
Absolute granulocyte count <500 × 106/L for more than 5 days Absolute granulocyte count <100 × 106/L for more than 3 days Febrile neutropenia Platelets <25,000 × 106/L Cycle delay of more than one week due to toxicity
If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, gemcitabine for injection should be given on Day 1 only at 800 mg/m2.

2.2 Breast Cancer

Gemcitabine for Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 × 106/L and a platelet count ≥100,000 × 106/L prior to each cycle.

Dose Modifications

Gemcitabine dosage adjustments for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine dosage should be modified according to the guidelines in Table 2.
Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine in Combination with Paclitaxel Absolutegranulocyte count(× 106/L) Platelet count(× 106/L) % offull dose ≥1200 And >75,000 100 1000 to 1199 Or 50,000 to 75,000 75 700 to 999 And ≥50,000 50 <700 Or <50,000 Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer's prescribing information.

2.3 Non-Small Cell Lung Cancer

Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, gemcitabine should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine. With the 3-week schedule, gemcitabine should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of gemcitabine on Day 1. See prescribing information for cisplatin administration and hydration guidelines.

Dose Modifications

Dosage adjustments for hematologic toxicity may be required for gemcitabine and for cisplatin. Gemcitabine dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer's prescribing information.

In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine plus cisplatin was 5% versus 2% for cisplatin alone).

2.4 Pancreatic Cancer

Gemcitabine for Injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.

Dose Modifications

Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology(12.3)].

Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.
Table 3: Dosage Reduction Guidelines Absolutegranulocyte count(× 106/L) Platelet count(× 106/L) % offull dose ≥1000 And ≥100,000 100 500 to 999 Or 50,000 to 99,999 75 <500 Or <50,000 Hold
Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine for Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

Patients treated with gemcitabine who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 × 106/L and 100,000 × 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of gemcitabine at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 × 106/L and 100,000 × 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

2.5 Preparation and Administration Precautions

Caution should be exercised in handling and preparing gemcitabine solutions. The use of gloves is recommended. If gemcitabine solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published [see References (15)].

2.6 Preparation for Intravenous Infusion Administration

The recommended diluent for reconstitution of gemcitabine is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for gemcitabine upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.

To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200 mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1 g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200 mg vial or 1.3 mL for the 1 g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.

Reconstituted gemcitabine is a clear, colorless to light straw-colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer.

When prepared as directed, gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion. Solutions of reconstituted gemcitabine should not be refrigerated, as crystallization may occur.

The compatibility of gemcitabine with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Toposar

Toposar

Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used withundiluted etoposide injection.

TOPOSAR

The usual dose of TOPOSAR in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5.

In small cell lung cancer, the TOPOSAR dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days.

For recommended dosing adjustments in patients with renal impairment see PRECAUTIONS section.

Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.

The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Administration Precautions

As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of TOPOSAR. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If TOPOSAR solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.

Preparation for Intravenous Administration

TOPOSAR must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the TOPOSAR solution be administered over a 30- to 60-minute period. A longer duration of administration may be used if the volume of fluid to be infused is a concern. TOPOSAR should not be given by rapid intravenous injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration (see DESCRIPTION section) prior to administration whenever solution and container permit.

Stability

Unopened vials of TOPOSAR are stable until the date indicated on the package at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Enalaprilat

Enalaprilat

FOR INTRAVENOUS ADMINISTRATION ONLY

The dose in hypertension is 1.25 mg every six hours administered intravenously over a five minute period. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after dosing. The peak effects of the second and subsequent doses may exceed those of the first.

No dosage regimen for enalaprilat injection has been clearly demonstrated to be more effective in treating hypertension than 1.25 mg every six hours. However, in controlled clinical studies in hypertension, doses as high as 5 mg every six hours were well tolerated for up to 36 hours. There has been inadequate experience with doses greater than 20 mg per day.

In studies of patients with hypertension, enalaprilat injection has not been administered for periods longer than 48 hours. In other studies, patients have received enalaprilat injection for as long as seven days.

The dose for patients being converted to enalaprilat injection from oral therapy for hypertension with enalapril maleate is 1.25 mg every six hours. For conversion from intravenous to oral therapy, the recommended initial dose of oral enalapril maleate, is 5 mg once a day with subsequent dosage adjustments as necessary.

Patients On Diuretic Therapy

For patients on diuretic therapy the recommended starting dose for hypertension is 0.625 mg administered intravenously over a five minute period; also see below, Patients at Risk of Excessive Hypotension. A clinical response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after dosing, although most of the effect is usually apparent within the first hour. If after one hour there is an inadequate clinical response, the 0.625 mg dose may be repeated. Additional doses of 1.25 mg may be administered at six hour intervals.

For conversion from intravenous to oral therapy, the recommended initial dose of oral enalapril maleate for patients who have responded to 0.625 mg of enalaprilat injection every six hours is 2.5 mg once a day with subsequent dosage adjustment as necessary.

Dosage Adjustment in Renal Impairment

The usual dose of 1.25 mg of enalaprilat injection every six hours is recommended for patients with a creatinine clearance > 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≤ 30 mL/min (serum creatinine ≥ 3 mg/dL), the initial dose is 0.625 mg (see WARNINGS).

If after one hour there is an inadequate clinical response, the 0.625 mg dose may be repeated. Additional doses of 1.25 mg may be administered at six hour intervals.

For dialysis patients, see below, Patients at Risk of Excessive Hypotension.

For conversion from intravenous to oral therapy, the recommended initial dose of oral enalapril maleate is 5 mg once a day for patients with creatinine clearance > 30 mL/min and 2.5 mg once daily for patients with creatinine clearance ≤ 30 mL/min. Dosage should then be adjusted according to blood pressure response.

Patients at Risk of Excessive Hypotension

Hypertensive patients at risk of excessive hypotension include those with the following concurrent conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology (see WARNINGS). Single doses of enalaprilat injection as low as 0.2 mg have produced excessive hypotension in normotensive patients with these diagnoses. Because of the potential for an extreme hypotensive response in these patients, therapy should be started under very close medical supervision. The starting dose should be no greater than 0.625 mg administered intravenously over a period of no less than five minutes and preferably longer (up to one hour).

Patients should be followed closely whenever the dose of enalaprilat injection is adjusted and/or diuretic is increased.

Administration

Enalaprilat injection should be administered as a slow intravenous infusion, as indicated above. It may be administered as provided or diluted with up to 50 mL of a compatible diluent.

Compatibility and Stability

Enalaprilat injection as supplied and mixed with the following intravenous diluents has been found to maintain full activity for 24 hours at room temperature:
5 percent Dextrose Injection 0.9 percent Sodium Chloride Injection 0.9 percent Sodium Chloride Injection in 5 percent Dextrose 5 percent Dextrose in Lactated Ringer's Injection B. Braun ISOLYTE***E
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.
Adrucil

Adrucil

General Instructions

ADRUCIL Injection should be administered only intravenously, using care to avoid extravasation. No dilution is required.

All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of ADRUCIL.

Dosage

Twelve mg/kg are given intravenously once daily for 4 successive days. The daily dose should not exceed 800 mg. If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs. No therapy is given on the 5th, 7th, 9th or 11th days. Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent. (See WARNINGS and PRECAUTIONS sections.)

Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days. If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs. No therapy is given on the 4th, 6th or 8th days. The daily dose should not exceed 400 mg.

A sequence of injections on either schedule constitutes a "course of therapy."

Maintenance Therapy

In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:
Repeat dosage of first course every 30 days after the last day of the previous course of treatment. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose. Do not exceed 1 gm per week.
The patient's reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly. Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Although the fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected. If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.
Adrucil

Adrucil

General Instructions

ADRUCIL Injection should be administered only intravenously, using care to avoid extravasation. No dilution is required.

All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of ADRUCIL.

Dosage

Twelve mg/kg are given intravenously once daily for four successive days. The daily dose should not exceed 800 mg. If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs. No therapy is given on the 5th, 7th, 9th or 11th days. Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent. (See WARNINGS and PRECAUTIONS sections.)

Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for three days. If no toxicity is observed, 3 mg/kg may be given on the 5th, 7 th and 9 th days unless toxicity occurs. No therapy is given on the 4 th, 6 th or 8 th days. The daily dose should not exceed 400 mg.

A sequence of injections on either schedule constitutes a "course of therapy."

Maintenance Therapy

In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:
Repeat dosage of first course every 30 days after the last day of the previous course of treatment. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose. Do not exceed 1 g per week.
The patient's reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly. Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

Directions for proper use of pharmacy bulk package

(Not for Direct Infusion)

The 50 mL and 100 mL Pharmacy Bulk Packages are for use in a Pharmacy Admixture Service only. They should be inserted into a plastic hanging device and suspended as a unit in a laminar flow hood. Use only if clear and seal is intact and undamaged.

Use of this product is restricted to a suitable work area, such as a laminar flow hood. Use only if clear and seal is intact and undamaged. Prior to entering the vial, remove the flip-off seal and cleanse the rubber closure with a suitable antiseptic agent. The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. The date and time the vial was initially opened should be recorded in the space provided on the vial label. Transfer individual dose(s) to appropriate intravenous infusion solutions. Use of a syringe with a needle is not recommended. Multiple entries increase the potential of microbial and particulate contamination.

The withdrawal of container contents should be accomplished without delay using aseptic technique.However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations. It is recommended that the transferred fluids be used promptly.

Recommended Storage Conditions After Opening

Keep under laminar flow hood at room temperature.
Vecuronium Bromide

Vecuronium Bromide

Vecuronium bromide for injection is for intravenous use only.

This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium bromide by volatile anesthetics and by prior use of succinylcholine (see PRECAUTIONS - Drug Interactions).

To obtain maximum clinical benefits of vecuronium bromide and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.

The recommended initial dose of vecuronium bromide is 0.08 to 0.1 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium bromide is enhanced. If vecuronium bromide is first administered more than 5 minutes after the start of inhalation agent or when steady-state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.06 to 0.085 mg/kg.

Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium bromide. If intubation is performed using succinylcholine, a reduction of initial dose of vecuronium bromide to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required.

During prolonged surgical procedures, maintenance doses of 0.01 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium bromide injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.

Since vecuronium bromide lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)

Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see CLINICAL PHARMACOLOGY-Pharmacokinetics).

Use by Continuous Infusion

After an intubating dose of 0.08 to 0.1 mg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 min later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations. (See PRECAUTIONS-Long-Term Use in ICU.)

The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60%, 45 to 60 minutes after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see CLINICAL PHARMACOLOGY).

Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer's Injection.

Unused portions of infusion solutions should be discarded.

Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
Drug Delivery Rate Infusion Delivery Rate (mcg/kg/min) (mL/kg/min) 0.1 mg/mL* 0.2 mg/mL† * 10 mg of Vecuronium bromide in 100 mL solution † 20 mg of Vecuronium bromide in 100 mL solution
0.7

0.007

0.0035

0.8

0.008

0.0040

0.9

0.009

0.0045

1.0

0.010

0.0050

1.1

0.011

0.0055

1.2

0.012

0.0060

1.3

0.013

0.0065

The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
VECURONIUM BROMIDE INFUSION RATE - mL/min Amount of Drug mcg/kg/min Patient Weight - kg 40 50 60 70 80 90 100
0.7

0.28

0.35

0.42

0.49

0.56

0.63

0.70

0.8

0.32

0.40

0.48

0.56

0.64

0.72

0.80

0.9

0.36

0.45

0.54

0.63

0.72

0.81

0.90

1.0

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1.1

0.44

0.55

0.66

0.77

0.88

0.99

1.10

1.2

0.48

0.60

0.72

0.84

0.96

1.08

1.20

1.3

0.52

0.65

0.78

0.91

1.04

1.17

1.30

NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half.

Use in Pediatrics

Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.

Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 1½ times as long to recover. (See PRECAUTIONS - Pediatric Use.) Information presently available does not permit recommendation on usage in pediatric patients less than 7 weeks of age (see PRECAUTIONS-Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.

COMPATIBILITY

Vecuronium bromide is compatible in solution with:
Sodium Chloride 0.9% Injection Dextrose 5% Injection Sterile Water for Injection Dextrose 5% in Sodium Chloride 0.9% Injection Lactated Ringer's Injection
Use within 24 hours of mixing with the above solutions.

Vecuronium bromide is also compatible in solution with: bacteriostatic water for injection (NOT FOR USE IN NEWBORNS)

Use within 5 days of mixing with the above solution.

Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.

After Reconstitution

See DOSAGE AND ADMINISTRATION – Compatibility for diluents compatible with Vecuronium Bromide for Injection.
• When reconstituted with bacteriostatic water for injection: CONTAINS BENZYL ALCOHOL, WHICH IS NOT INTENDED FOR USE IN NEWBORNS. Use within 5 days. May be stored at room temperature or refrigerated. • When reconstituted with sterile water for injection or other compatible intravenous solutions: Refrigerate vial. Use within 24 hours. Single use only. Discard unused portion.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Pamidronate Disodium

Pamidronate Disodium

2.1 Hypercalcemia of Malignancy

Vigorous saline hydration, should be initiated promptly along with pamidronate therapy and if possible the urine output should be about 2 L/day throughout treatment [see Warnings and Precautions (5.2)].

Patients who receive pamidronate disodium injection should have serum creatinine assessed prior to each treatment [see Warnings and Precautions (5.1)]. Treatment should be withheld for renal deterioration.

Moderate Hypercalcemia

The recommended dose of pamidronate disodium injection in moderate hypercalcemia (corrected serum calcium* of approximately 12 mg/dL to 13.5 mg/dL) is 60 mg to 90 mg given as a single-dose, intravenous infusion over 2 hours to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal impairment.

Severe Hypercalcemia

The recommended dose of pamidronate disodium injection in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a single-dose, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency/impairment.

*Albumin-corrected serum calcium = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL).

Retreatment

Retreatment with pamidronate disodium injection in patients who show complete or partial response initially may be carried out if serum calcium does not return to normal or remain normal after initial treatment. A minimum of 7 days between treatments is recommended to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.

2.2 Paget’s Disease

The recommended dose of pamidronate disodium injection in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg. When clinically indicated, patients should be retreated at the dose of initial therapy.

2.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

Osteolytic Bone Metastases of Breast Cancer

The recommended dose of pamidronate disodium injection in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

In a clinical study, renal deterioration was defined as follows:
• With normal baseline creatinine, an increase of 0.5 mg/dL. • With abnormal baseline creatinine, an increase of 1 mg/dL.
In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

The optimal duration of therapy is not known; however, in two breast cancer studies, final analyses performed after 24 months of therapy demonstrated overall benefits [see Clinical Studies (14.3)].

Osteolytic Bone Lesions of Multiple Myeloma

The recommended dose of pamidronate disodium injection in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion administered every four weeks.

Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to pamidronate disodium injection infusion.

Limited information is available on the use of pamidronate disodium injection in multiple myeloma patients with a serum creatinine greater than or equal to 3 mg/dL.

Patients who receive pamidronate disodium injection should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration.

In a clinical study, renal deterioration was defined as follows:
• With normal baseline creatinine, an increase of 0.5 mg/dL. • With abnormal baseline creatinine, an increase of 1 mg/dL.
In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

The optimal duration of therapy is not known. However, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits [see Clinical Studies (14.3)].

2.5 Dilution for Administration

Hypercalcemia of Malignancy

The daily dose must be administered as an intravenous infusion over at least 2 hours and up to 24 hours for the 60 mg and 90 mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% sodium chloride injection or 5% dextrose injection. This infusion solution is stable for up to 24 hours at room temperature.

Paget’s Disease

The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection and administered over a 4-hour period daily for 3 consecutive days.

Osteolytic Bone Metastases of Breast Cancer

The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% sodium chloride injection or 5% dextrose injection and administered over a 2-hour period once every 3 to 4 weeks.

Osteolytic Bone Lesions of Multiple Myeloma

The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection, and administered over a 4-hour period every four weeks.

2.6 Incompatibilities, Inspection before Use

Pamidronate disodium injection must not be mixed with calcium-containing infusion solutions such as Ringer’s solution. Administer as a single intravenous solution and infuse using an intravenous line reserved for pamidronate alone.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Zanosar

Zanosar

ZANOSAR sterile powder should be administered intravenously by rapid injection or short/prolonged infusion. It is not active orally. Although it has been administered intraarterially, this is not recommended pending further evaluation of the possibility that adverse renal effects may be evoked more rapidly by this route of administration.

Two different dosage schedules have been employed successfully with ZANOSAR.

Daily Schedule—The recommended dose for daily intravenous administration is 500 mg/m2 of body surface area for five consecutive days every six weeks until maximum benefit or until treatment-limiting toxicity is observed. Dose escalation on this schedule is not recommended.

Weekly Schedule—The recommended initial dose for weekly intravenous administration is 1000 mg/m2 of body surface area at weekly intervals for the first two courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a therapeutic response and who have not experienced significant toxicity with the previous course of treatment. However, A SINGLE DOSE OF 1500 mg/m2 BODY SURFACE AREA SHOULD NOT BE EXCEEDED as a greater dose may cause azotemia. When administered on this schedule, the median time to onset of response is about 17 days and the median time to maximum response is about 35 days. The median total dose to onset of response is about 2000 mg/m2 body surface area and the median total dose to maximum response is about 4000 mg/m2 body surface area.

The ideal duration of maintenance therapy with ZANOSAR has not yet been clearly established for either of the above schedules.

For patients with functional tumors, serial monitoring of fasting insulin levels allows a determination of biochemical response to therapy. For patients with either functional or nonfunctional tumors, response to therapy can be determined by measurable reductions of tumor size (reduction of organomegaly, masses, or lymph nodes).

Reconstitute ZANOSAR with 9.5 mL of dextrose injection, USP, or 0.9% sodium chloride injection, USP. The resulting pale-gold solution will contain 100 mg of streptozocin and 22 mg of citric acid per mL. Where more dilute infusion solutions are desirable, further dilution in the above vehicles is recommended. The total storage time for streptozocin after it has been placed in solution should not exceed 12 hours. This product contains no preservatives and is not intended as a multiple-dose vial.

Caution in the handling and preparation of the powder and solution should be exercised, and the use of gloves is recommended. If the sterile powder of ZANOSAR or a solution prepared from ZANOSAR contacts the skin or mucosae, immediately wash the affected area with soap and water.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Desmopressin Acetate

Desmopressin Acetate

Hemophilia A and von Willebrand's Disease (Type I)

Desmopressin acetate injection is administered as an intravenous infusion at a dose of 0.3 mcg desmopressin acetate/kg body weight diluted in sterile physiological saline and infused slowly over 15 to 30 minutes. In adults and children weighing more than 10 kg, 50 mL of diluent is recommended; in children weighing 10 kg or less, 10 mL of diluent is recommended. Blood pressure and pulse should be monitored during infusion. If desmopressin acetate injection is used preoperatively, it should be administered 30 minutes prior to the scheduled procedure.

The necessity for repeat administration of desmopressin acetate or use of any blood products for hemostasis should be determined by laboratory response as well as the clinical condition of the patient. The tendency toward tachyphylaxis (lessening of response) with repeated administration given more frequently than every 48 hours should be considered in treating each patient.

Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.)

Diabetes Insipidus

This formulation is administered subcutaneously or by direct intravenous injection. Desmopressin acetate injection 4 mcg/mL dosage must be determined for each patient and adjusted according to the pattern of response. Response should be estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover.

The usual dosage range in adults is 0.5 mL (2 mcg) to 1 mL (4 mcg) daily, administered intravenously or subcutaneously, usually in two divided doses. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. For patients who have been controlled on intranasal desmopressin acetate and who must be switched to the injection form, either because of poor intranasal absorption or because of the need for surgery, the comparable antidiuretic dose of the injection is about one-tenth the intranasal dose.

Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Geriatric Use

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics, CONTRAINDICATIONS, and PRECAUTIONS, Geriatric Use.)
Pancuronium Bromide

Pancuronium Bromide

NOTE: CONTAINS BENZYL ALCOHOL (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS: Pediatric Use)

Pancuronium bromide injection is for intravenous use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. DOSAGE MUST BE INDIVIDUALIZED IN EACH CASE. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only. Since potent inhalational anesthetics or prior use of succinylcholine may enhance the intensity and duration of pancuronium bromide (see PRECAUTIONS—Drug Interactions), the lower end of the recommended initial dosage range may suffice when pancuronium bromide is first used after intubation with succinylcholine and/or after maintenance doses of volatile liquid inhalational anesthetics are started. To obtain maximum clinical benefits of pancuronium bromide injection and to minimize the possibility of overdosage, the monitoring of muscle twitch response to a peripheral nerve stimulator is advised.

In adults under balanced anesthesia the initial intravenous dosage range is 0.04 to 0.1 mg/kg. Later incremental doses starting at 0.01 mg/kg may be used. These increments slightly increase the magnitude of the blockade and significantly increase the duration of blockade, because a significant number of myoneural junctions are still blocked when there is clinical need for more drug.

If pancuronium bromide injection is used to provide skeletal muscle relaxation for endotracheal intubation, a bolus dose of 0.06 to 0.1 mg/kg is recommended. Conditions satisfactory in intubation are usually present within 2 to 3 minutes. (SeePRECAUTIONS.)

Dosage in Children

Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Due to the potential toxicity of benzyl alcohol in neonates, solutions containing benzyl alcohol must not be used in this patient population (see CONTRAINDICATIONS).

Caesarean Section

The dosage to provide relaxation for intubation and operation is the same as for general surgical procedures. The dosage to provide relaxation, following usage of succinylcholine for intubation (see PRECAUTIONS—Drug Interactions), is the same as for general surgical procedures.

Compatibility

Pancuronium bromide injection is compatible in solution with:
0.9% sodium chloride injection 5% dextrose injection 5% dextrose and sodium chloride injection Lactated Ringer's Injection
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

When mixed with the above solutions in glass or plastic containers, pancuronium bromide injection will remain stable in solution for 48 hours with no alteration in potency or pH; no decomposition is observed and there is no absorption to either the glass or plastic container.
3098-20 Continuous Epid...

3098-20 Continuous Epidural 18g Hustead

The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid.

Follow the pictorial directions on the reverse side of this package insert for administration.

NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use.
Daunorubicin Hydrochlor...

Daunorubicin Hydrochloride

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.

Principles

In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.

It is recommended that the dosage of daunorubicin hydrochloride be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:
Serum Bilirubin Serum Creatinine Dose Reduction 1.2 to 3 mg% — 25% > 3 mg% — 50% — > 3 mg% 50%
Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Nonlymphocytic Leukemia

In Combination

For patients under age 60, daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.

For patients 60 years of age and above, daunorubicin hydrochloride 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This daunorubicin hydrochloride dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.

The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.

Representative Dose Schedule and Combination for the Approved Indication of Remission Induction in Pediatric Acute Lymphocytic Leukemia

In Combination

Daunorubicin hydrochloride 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.

In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the daunorubicin hydrochloride dosage calculation should be based on weight (1 mg/kg) instead of body surface area.

Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Lymphocytic Leukemia

In Combination

Daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day X 10 days IV on days 22 through 32.

The sterile 4 mL vial contents provide 20 mg of daunorubicin with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% sodium chloride injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% dextrose injection, USP or 0.9% sodium chloride injection, USP. Daunorubicin hydrochloride should not be administered mixed with other drugs or heparin.
Ifosfamide And Mesna Ki...

Ifosfamide And Mesna Kit

Ifosfamide injection should be administered intravenously at a dose of 1.2 grams per m2 per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity.

In order to prevent bladder toxicity, ifosfamide injection should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. Mesna should be used to reduce the incidence of hemorrhagic cystitis. Ifosfamide injection should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Studies of ifosfamide injection in patients with hepatic or renal impairment have not been conducted [see Use in Specific Populations (8.6, 8.7)].

Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

5% dextrose injection, USP

0.9% sodium chloride injection, USP

Lactated ringer’s injections, USP

Sterile water for injection, USP

Because essentially identical stability results were obtained for sterile water admixtures as for the other admixtures (5% dextrose injection, 0.9% sodium chloride injection, and lactated ringer’s injection), the use of large volume parenteral glass bottles, viaflex bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% dextrose injection, 0.45% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection) is also acceptable.

Constituted or constituted and further diluted solutions of ifosfamide injection should be refrigerated and used within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of ifosfamide.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Methotrexate

Methotrexate

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection (preservative free) injectable products may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.

Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

Leukemia

Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

Meningeal Leukemia

In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
Age (years) Dose (mg) < 1 6 1 8 2 10 3 or older 12
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.

Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

Lymphomas

In Burkitt's Tumor, Stages I to II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

Mycosis Fungoides (Cutaneous T Cell Lymphoma)

Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

Osteosarcoma

An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.
Drug* Dose* Treatment Week After Surgery * Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No. 25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, 45 Leucovorin 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion - - - Doxorubicin† as a single drug 30 mg/ m2 day IV × 3 days 8, 17 Doxorubicin† Cisplatin† 50 mg/m2 IV100 mg/m2 IV 20, 23, 33, 3620, 23, 33, 36 Bleomycin† Cyclophosphamide† Dactinomycin† 15 units/m2 IV × 2 days 600 mg/m2 IV × 2 days 0.6 mg/m2 IV × 2 days 2, 13, 26, 39, 422, 13, 26, 39, 422, 13, 26, 39, 42
When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE
Administration of methotrexate should be delayed until recovery if: the WBC count is less than 1500/microliter the neutrophil count is less than 200/microliter the platelet count is less than 75,000/microliter the serum bilirubin level is greater than 1.2 mg/dL the SGPT level is greater than 450 U mucositis is present, until there is evidence of healing persistent pleural effusion is present; this should be drained dry prior to infusion. Adequate renal function must be documented. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. Alkalinize urine to maintain pH above 7 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 × 10-8 mol/L (0.05 micromolar). The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels (see table below‡).Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.
CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

Adult Rheumatoid Arthritis

Recommended Starting Dosage Schedules
Single oral doses of 7.5 mg once weekly.† Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.†
† Methotrexate Sodium Tablets for oral administration are available.

Polyarticular-Course Juvenile Rheumatoid Arthritis

The recommended starting dose is 10 mg/m2 given once weekly.

For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see Information for Patients under PRECAUTIONS). Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy (see PRECAUTIONS). Appropriate steps should be taken to avoid conception during methotrexate therapy (see PRECAUTIONS and CONTRAINDICATIONS).

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see ADVERSE REACTIONS). Maximal myelosuppression usually occurs in seven to ten days.

Psoriasis

Recommended Starting Dose Schedule
Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.† Divided oral dose schedule: 2.5 mg at 12 hour intervals for three doses.†
† Methotrexate Sodium Tablets for oral administration are available.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

DILUTION INSTRUCTIONS FOR METHOTREXATE INJECTION USP

Methotrexate Injection USP, Isotonic Liquid, Preservative Free, for Single Use Only

If desired, the solution may be further diluted immediately prior to use with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP.
Epoprostenol Sodium

Epoprostenol Sodium

Important Note: Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for epoprostenol sodium for injection. Do not dilute reconstituted solutions of epoprostenol for injection or administer with other parenteral solutions or medications (see WARNINGS).

Dosage

Administer continuous chronic infusion of epoprostenol sodium for injection through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of epoprostenol sodium for injection at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then decrease the infusion rate until epoprostenol sodium for injection is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, identify a lower dose that is tolerated by the patient.

In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

Dosage Adjustments

Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of epoprostenol sodium for injection. In general, expect increases in dose from the initial chronic dose.

Consider increments in dose if symptoms of PAH persist or recur. Increase the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of epoprostenol sodium for injection or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of epoprostenol sodium for injection only under the direction of a physician.

In patients receiving lung transplants, doses of epoprostenol sodium for injection were tapered after the initiation of cardiopulmonary bypass.

Administration

Epoprostenol sodium for injection is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, epoprostenol sodium for injection may be administered peripherally.

The ambulatory infusion pump used to administer epoprostenol sodium for injection should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver epoprostenol sodium for injection. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

To facilitate extended use at ambient temperatures exceeding 20° to 25°C (68° to 77°F), a cold pouch with frozen gel packs was used in clinical trials (see DOSAGE AND ADMINISTRATION: Storage and Stability). The cold pouches and gel packs used in clinical trials were obtained from Palco Labs, Palo Alto, California. Any cold pouch used must be capable of maintaining the temperature of reconstituted epoprostenol sodium for injection between 2° and 8°C for 12 hours.

Reconstitution

Epoprostenol sodium for injection is stable only when reconstituted with STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol sodium for injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

Select a concentration for the solution of epoprostenol sodium for injection that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. When administered chronically, prepare epoprostenol sodium for injection in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of STERILE DILUENT for epoprostenol sodium for injection for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of epoprostenol sodium for injection.
Table 6. Reconstitution and Dilution Instructions * Higher concentrations may be required for patients who receive epoprostenol sodium for injection long-term. To make 100 mL ofsolutionwith Final Concentration(ng/mL) of: Directions: 3,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw 3 mL and add to sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL. 5,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw entire vial contents and add sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL. 10,000 ng/mL Dissolve contents of two 0.5-mg vials each with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw entire vial contents and add sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL. 15,000 ng/mL* Dissolve contents of one 1.5-mg vial with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw entire vial contents and add sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL.
Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Infusion rates may be calculated using the following formula:
Infusion Rate (mL/hr) = [Dose (ng/kg/min) × Weight (kg) × 60 min/hr] Final Concentration (ng/mL)
Tables 7 through 10 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of epoprostenol sodium for injection to be used. These tables may be used to select the most appropriate concentration of epoprostenol sodium for injection that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of epoprostenol sodium for injection.
Table 7. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 3,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 2 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 10 ---- ---- 1.2 1.6 2.0 2.4 2.8 3.2 20 ---- 1.6 2.4 3.2 4.0 4.8 5.6 6.4 30 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6 40 1.6 3.2 4.8 6.4 8.0 9.6 11.2 12.8 50 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 60 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2 70 2.8 5.6 8.4 11.2 14.0 16.8 19.6 22.4 80 3.2 6.4 9.6 12.8 16.0 19.2 22.4 25.6 90 3.6 7.2 10.8 14.4 18.0 21.6 25.2 28.8 100 4.0 8.0 12.0 16.0 20.0 24.0 28.0 32.0 Table 8. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 5,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 2 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 10 ---- ---- ---- 1.0 1.2 1.4 1.7 1.9 20 ---- 1.0 1.4 1.9 2.4 2.9 3.4 3.8 30 ---- 1.4 2.2 2.9 3.6 4.3 5.0 5.8 40 1.0 1.9 2.9 3.8 4.8 5.8 6.7 7.7 50 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6 60 1.4 2.9 4.3 5.8 7.2 8.6 10.1 11.5 70 1.7 3.4 5.0 6.7 8.4 10.1 11.8 13.4 80 1.9 3.8 5.8 7.7 9.6 11.5 13.4 15.4 90 2.2 4.3 6.5 8.6 10.8 13.0 15.1 17.3 100 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2 Table 9. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 10,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 20 ---- ---- 1.0 1.2 1.4 1.7 1.9 30 ---- 1.1 1.4 1.8 2.2 2.5 2.9 40 1.0 1.4 1.9 2.4 2.9 3.4 3.8 50 1.2 1.8 2.4 3.0 3.6 4.2 4.8 60 1.4 2.2 2.9 3.6 4.3 5.0 5.8 70 1.7 2.5 3.4 4.2 5.0 5.9 6.7 80 1.9 2.9 3.8 4.8 5.8 6.7 7.7 90 2.2 3.2 4.3 5.4 6.5 7.6 8.6 100 2.4 3.6 4.8 6.0 7.2 8.4 9.6 Table 10. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 15,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 30 ---- ---- 1.0 1.2 1.4 1.7 1.9 40 ---- 1.0 1.3 1.6 1.9 2.2 2.6 50 ---- 1.2 1.6 2.0 2.4 2.8 3.2 60 1.0 1.4 1.9 2.4 2.9 3.4 3.8 70 1.1 1.7 2.2 2.8 3.4 3.9 4.5 80 1.3 1.9 2.6 3.2 3.8 4.5 5.1 90 1.4 2.2 2.9 3.6 4.3 5.0 5.8 100 1.6 2.4 3.2 4.0 4.8 5.6 6.4
Storage and Stability

Unopened vials of epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] and protected from light in the carton. Unopened vials of STERILE DILUENT for epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Prior to use, reconstituted solutions of epoprostenol sodium for injection must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately. Do not freeze reconstituted solutions of epoprostenol sodium for injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 48 hours.

During use, a single reservoir of reconstituted solution of epoprostenol sodium for injection can be administered at room temperature for a total duration of 8 hours, or it can be used with a cold pouch and administered up to 24 hours with the use of 2 frozen 6 oz gel packs in a cold pouch. When stored or in use, insulate reconstituted epoprostenol sodium for injection from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.

Use at Room Temperature

Prior to use at room temperature, 15° to 25°C (59° to 77°F), reconstituted solutions of epoprostenol sodium for injection may be stored refrigerated at 2° to 8°C (36° to 46°F) for no longer than 40 hours. When administered at room temperature, reconstituted solutions may be used for no longer than 8 hours. This 48-hour period allows the patient to reconstitute a 2-day supply (200 mL) of epoprostenol sodium for injection. Each 100 mL daily supply may be divided into 3 equal portions. Two of the portions are stored refrigerated at 2° to 8°C (36° to 46°F) until they are used.

Use with a Cold Pouch

Prior to infusion with the use of a cold pouch, solutions may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours. When a cold pouch is employed during the infusion, reconstituted solutions of epoprostenol sodium for injection may be used for no longer than 24 hours. Change gel packs every 12 hours. Reconstituted solutions may be kept at 2° to 8°C (36° to 46°F), either in refrigerated storage or in a cold pouch or a combination of the two, for no more than 48 hours.

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.
Daunorubicin Hydrochlor...

Daunorubicin Hydrochloride

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.

Principles

In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.

It is recommended that the dosage of daunorubicin hydrochloride be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:
Serum Bilirubin Serum Creatinine Dose Reduction 1.2 to 3 mg% — 25% > 3 mg% — 50% — > 3 mg% 50%
Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Nonlymphocytic Leukemia

In Combination

For patients under age 60, daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.

For patients 60 years of age and above, daunorubicin hydrochloride 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This daunorubicin hydrochloride dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.

The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.

Representative Dose Schedule and Combination for the Approved Indication of Remission Induction in Pediatric Acute Lymphocytic Leukemia

In Combination

Daunorubicin hydrochloride 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.

In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the daunorubicin hydrochloride dosage calculation should be based on weight (1 mg/kg) instead of body surface area.

Representative Dose Schedules and Combination for the Approved Indication of Remission Induction in Adult Acute Lymphocytic Leukemia

In Combination

Daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day X 10 days IV on days 22 through 32.

The sterile 4 mL vial contents provide 20 mg of daunorubicin with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% sodium chloride injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% dextrose injection, USP or 0.9% sodium chloride injection, USP. Daunorubicin hydrochloride should not be administered mixed with other drugs or heparin.
Haldol

Haldol

There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control.

To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less haloperidol. The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels.

Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. The maximum dose is 20 mg/day.

Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Switchover Procedure

An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient’s clinical status, the first oral dose should be given within 12 to 24 hours following the last parenteral dose.
Hydromorphone Hydrochlo...

Hydromorphone Hydrochloride

Parenteral: HYDROMORPHONE HYDROCHLORIDE INJECTION (HIGH POTENCY FORMULATION) SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF OPIOIDS. Hydromorphone hydrochloride injection (high potency formulation) is indicated for relief of moderate-to-severe pain in opioid-tolerant patients. Thus, these patients will already have been treated with other opioid analgesics. If the patient is being changed from regular hydromorphone hydrochloride to high potency formulation, similar doses should be used, depending on the patient's clinical response to the drug. If hydromorphone hydrochloride injection (high potency formulation) is substituted for a different opioid analgesic, the following equivalency table should be used as a guide to determine the appropriate dose of hydromorphone hydrochloride injection (high potency formulation). Patients with hepatic and renal impairment should be started on a lower starting dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
Opioid Analgesic Equivalents with Approximately Equianalgesic Potency* Drug Substance IM or SC** Dose Oral Dose
Morphine Sulfate

10 mg

40 – 60 mg

Hydromorphone HCl

1.3 – 2 mg

6.5 – 7.5 mg

Oxymorphone HCl

1 – 1.1 mg

6.6 mg

Levorphanol tartrate

2 – 2.3 mg

4 mg

Meperidine HCl

(pethidine HCl)

75 – 100 mg

300 – 400 mg

Methadone HCl

10 mg

10 – 20 mg

Nalbuphine HCl

12 mg

–

Butorphanol tartrate

1.5 – 2.5 mg

–

* Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references comparing opioid analgesics in cancer and severe pain.

**IM = intramuscular; SC = subcutaneous

Experience with administration of hydromorphone hydrochloride injection (high potency formulation) by the intravenous route is limited. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes.

A gradual increase in dose may be required if analgesia is inadequate, tolerance occurs, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in hydromorphone hydrochloride injection (high potency formulation) vials. No loss of potency has been demonstrated. Hydromorphone hydrochloride injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.

500 mg/50 mL Vial: To use this single dose presentation, do not penetrate the stopper with a syringe. Instead, remove both the aluminum flipseal and rubber stopper in a suitable work area such as under a laminar flow hood (or equivalent clean air compounding area). The contents may then be withdrawn for preparation of a single, large volume parenteral solution. Any unused portion should be discarded in an appropriate manner.
Individualization of Dosage
The dosage of opioid analgesics like hydromorphone hydrochloride should be individualized for any given patient, since adverse events can occur at doses that may not provide complete freedom from pain.

Safe and effective administration of opioid analgesics to patients with acute or chronic pain depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency, etiology, and pathophysiology), as well as the concurrent medical status of the patient, will affect selection of the starting dosage.

In patients receiving opioids, both the dose and duration of analgesia will vary substantially depending on the patient's opioid tolerance. The dose should be selected and adjusted so that at least 3-4 hours of pain relief may be achieved. In patients taking opioid analgesics, the starting dose of hydromorphone hydrochloride injection (high potency formulation) should be based on prior opioid usage. This should be done by converting the total daily usage of the previous opioid to an equivalent total daily dosage of hydromorphone hydrochloride injection (high potency formulation) using an equianalgesic table (see above). For opioids not in the table, first estimate the equivalent total daily usage of oral morphine, then use the table to find the equivalent total daily dosage of hydromorphone hydrochloride injection (high potency formulation).

Once the total daily dosage of hydromorphone hydrochloride injection (high potency formulation) has been estimated, it should be divided into the desired number of doses. Since there is individual variation in response to different opioid drugs, only 1/2 to 2/3 of the estimated dose of hydromorphone hydrochloride injection (high potency formulation) calculated from equivalence tables should be given for the first few doses, then increased as needed according to the patient's response.

Since the pharmacokinetics of hydromorphone are affected in hepatic and renal impairment with a consequent increase in exposure, patients with hepatic and renal impairment should be started on a lower starting dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

In chronic pain, doses should be administered around-the-clock. A supplemental dose of 5-15% of the total daily usage may be administered every two hours on an "as-needed" basis.

Periodic reassessment after the initial dosing is always required. If pain management is not satisfactory, and in the absence of significant opioid-induced adverse events, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early in the dosing interval, the hydromorphone hydrochloride dose should be reduced. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided more by the need for analgesia than the absolute dose of opioid employed.
Low Dose Aspirin

Low Dose Aspirin

2.1 General Dosage and Administration

The recommended dosage for linezolid injection formulations for the treatment of infections is described in Table 1.
Table 1. Dosage Guidelines for Linezolid Injection * Due to the designated pathogens [see Indications and Usage (1)] † Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. ‡ Oral dosing using either linezolid tablets or linezolid for oral suspension [see How Supplied/Storage and Handling (16)].
Infection*

Dosage and Route of Administration

Recommended Duration of Treatment (consecutive days)

Pediatric Patients† (Birth through 11 Years of Age)

Adults and Adolescents(12 Years and Older)

Nosocomial pneumonia

10 mg/kg intravenously or oral‡ every 8 hours

600 mg intravenously or oral‡ every 12 hours

10 to 14

Community-acquired pneumonia, including concurrent bacteremia

Complicated skin and skin structure infections

Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia

10 mg/kg intravenously or oral‡ every 8 hours

600 mg intravenously or oral‡ every 12 hours

14 to 28

Uncomplicated skin and skin structure infections

less than 5 yrs: 10 mg/kg oral‡ every 8 hours5 to 11 yrs: 10 mg/kg oral‡ every12 hours

Adults: 400 mg oral‡ every 12 hoursAdolescents: 600 mg oral‡ every 12 hours

10 to 14

No dose adjustment is necessary when switching from intravenous to oral administration.

2.2 Intravenous Administration

Linezolid injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid injection may exhibit a yellow color that can intensify over time without adversely affecting potency.

Linezolid injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If linezolid injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of linezolid injection with an infusion solution compatible with linezolid injection and with any other drug(s) administered via this common line.

2.3 Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.

2.4 Incompatibilities

Physical incompatibilities resulted when linezolid injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when linezolid injection was combined with ceftriaxone sodium.
Vincasar Pfs

Vincasar Pfs

This preparation is for intravenous use only (see WARNINGS).

Neurotoxicity appears to be dose related. Extreme care must be used in calculating and administering the dose of VINCASAR PFS, since overdosage may have a very serious or fatal outcome.

The usual dose of VINCASAR PFS for pediatric patients is 1.5 to 2 mg/m2. For pediatric patients weighing 10 kg or less, the starting dose should be 0.05 mg/kg, administered once a week. The usual dose of VINCASAR PFS for adults is 1.4 mg/m2. A 50% reduction in the dose of VINCASAR PFS is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.

The drug is administered intravenously at weekly intervals.

TO REDUCE THE POTENTIAL FOR FATAL MEDICATION ERRORS DUE TO INCORRECT ROUTE OF ADMINISTRATION, VINCASAR PFS SHOULD BE DILUTED IN A FLEXIBLE PLASTIC CONTAINER AND PROMINENTLY LABELED FOR INTRAVENOUS USE ONLY (see WARNINGS).

The concentration of VINCASAR PFS is 1 mg/mL. Do not add extra fluid to the vial prior to removal of the dose. Withdraw the solution of VINCASAR PFS into an accurate dry syringe, measuring the dose carefully. Do not add extra fluid to the vial in an attempt to empty it completely.

Preparation for flexible plastic container

VINCASAR PFS when diluted with 0.9% sodium chloride injection in concentrations from 0.0015 mg/mL to 0.08 mg/mL is stable for up to 24 hours when protected from light or 8 hours under normal light at 25°C.

Preparation for syringe

Special Dispensing Information

When dispensing VINCASAR PFS in a syringe, it is imperative that it be packaged in the provided overwrap which bears the following statement: “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES”(see WARNINGS).A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.”

Caution: It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during intravenous administration of VINCASAR PFS may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.

VINCASAR PFS must be administered via an intact, free-flowing intravenous needle or catheter. Care should be taken that there is no leakage or swelling occurring during administration (see boxed WARNINGS).

The solution may be injected either directly into a vein or into the tubing of a running intravenous infusion (see Drug Interactions below). Injection of VINCASAR PFS should be accomplished within 1 minute.

Patients Receiving Radiation Therapy

VINCASAR PFS should not be given to patients while they are receiving radiation therapy through ports that include the liver. When VINCASAR PFS is used in combination with L-asparaginase, VINCASAR PFS should be given 12 to 24 hours before administration of the enzyme in order to minimize toxicity; administering L-asparaginase before VINCASAR PFS may reduce hepatic clearance of vincristine.

Drug Interactions

VINCASAR PFS should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything other than normal saline or glucose in water.

Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Bleomycin

Bleomycin

BECAUSE OF THE POSSIBILITY OF AN ANAPHYLACTOID REACTION, LYMPHOMA PATIENTS SHOULD BE TREATED WITH 2 UNITS OR LESS FOR THE FIRST TWO DOSES. IF NO ACUTE REACTION OCCURS, THEN THE REGULAR DOSAGE SCHEDULE MAY BE FOLLOWED.

The following dose schedule is recommended:

Squamous cell carcinoma, non-Hodgkin's lymphoma, testicular carcinoma- 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

Hodgkin's Disease - 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.

Pulmonary toxicity of bleomycin appears to be dose related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.

Note: When bleomycin is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.

Improvement of Hodgkin's Disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.

Malignant Pleural Effusion - 60 units administered as a single dose bolus intrapleural injection (see Administration, Intrapleural).

Use in Patients with Renal Insufficiency

The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:

Patient CrCL
(mL/min)
Bleomycin for Injection, USP
Dose (%) 50 and above 100 40 to 50 70 30 to 40 60 20 to 30 55 10 to 20 45 5 to 10 40

CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:

Males CrCL = [weight x (140 – Age)]/(72 x Scr)

Females CrCL = 0.85 x [weight x (140 – Age)]/(72 x Scr)

Where CrCL in mL/min/1.73m2, weight in kg, age in years, and Scr in mg/dL.

Administration

Bleomycin for injection may be given by the intramuscular, intravenous, subcutaneous, or intrapleural routes.

Administration Precautions

Caution should be exercised when handling bleomycin for injection. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing bleomycin for injection. If bleomycin for injection contacts the skin, immediately wash the skin thoroughly with soap and water. If contact with mucous membranes occurs, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

Intramuscular or Subcutaneous

The bleomycin for injection USP 15 units vial should be reconstituted and dissolved with 1 to 5 mL of sterile water for injection, USP, sodium chloride injection, 0.9%, USP, or bacteriostatic water for injection, USP. The bleomycin for injection USP 30 units vial should be reconstituted and dissolved with 2 to 10 mL of the above diluents.

Intravenous

The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively, of Sodium Chloride for Injection, 0.9%, USP, and administered slowly over a period of 10 minutes.

Intrapleural

60 units of bleomycin are dissolved in 50 to 100 mL Sodium Chloride for Injection, 0.9%, USP and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and reestablishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of bleomycin. Although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 mL in a 24-hour period prior to sclerosis. However, bleomycin instillation may be appropriate when drainage is between 100 to 300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after bleomycin instillation. The patient is moved from the supine to the left and right lateral positions several times during the next four hours. The clamp is then removed and suction reestablished. The amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation.

The intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Epirubicin Hydrochlorid...

Epirubicin Hydrochloride

When possible, to reduce the risk of developing cardiotoxicity in patients receiving epirubicin hydrochloride injection after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, epirubicin hydrochloride injection-based therapy should be delayed until the other agents have cleared from the circulation [see Warnings and Precautions (5.3)].

Administer epirubicin hydrochloride injection by intravenous infusion. Give epirubicin hydrochloride injection in repeated 3 to 4 week cycles. The total dose of epirubicin hydrochloride injection may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of epirubicin hydrochloride injection are as follows:

2.1 Recommended Dose

The recommended dose of epirubicin hydrochloride injection is 100 to 120 mg/m2. The following regimens are recommended:

CEF-120:

Cyclophosphamide

75 mg/m2 PO D 1 to 14

Epirubicin Hydrochloride Injection

60 mg/m2 IV D 1, 8

5-Fluorouracil

500 mg/m2 IV D 1, 8

Repeated every 28 days for 6 cycles

FEC-100:

5-Fluorouracil

500 mg/m2

Epirubicin Hydrochloride Injection

100 mg/m2

Cyclophosphamide

500 mg/m2

All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles

Patients administered the 120 mg/m2 regimen of epirubicin hydrochloride injection should receive prophylactic antibiotic therapy.

2.2 Dose Modifications

Epirubicin hydrochloride injection dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts < 50,000/mm3, absolute neutrophil counts (ANC) < 250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce epirubicin hydrochloride injection Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥ 100,000/mm3, ANC ≥ 1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1.

Bone Marrow Dysfunction

Consider administering a lower starting dose (75 to 90 mg/m2) for heavily pretreated patients, patients with preexisting bone marrow depression, or in the presence of neoplastic bone marrow infiltration [see Warnings and Precautions (5)]. For patients receiving a divided dose of epirubicin hydrochloride injection (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000 to 100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are < 75,000/mm3, ANC < 1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.

Hepatic Impairment

Recommendations regarding use of epirubicin hydrochloride injection in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended:
• Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose • Bilirubin > 3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose
Renal Impairment

While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

2.3 Preparation and Administration Precautions

Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15 to 25°C).

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing epirubicin hydrochloride injection. Several guidelines on this subject have been published1-4 [see References (15)].

Protective Measures

Take the following protective measures when handling epirubicin hydrochloride injection:
• Train personnel in appropriate techniques for reconstitution and handling. • Exclude pregnant staff from working with this drug. • Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling epirubicin hydrochloride injection. • Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. • Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. • Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves.
Incompatibilities

Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix epirubicin hydrochloride injection with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

Epirubicin hydrochloride injection can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.

Preparation of Infusion Solution

Administer epirubicin hydrochloride injection into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100 to 120 mg/m2 should generally have epirubicin hydrochloride injection infused over 15 to 20 minutes. For patients who require lower epirubicin hydrochloride injection starting doses due to organ dysfunction or who require modification of epirubicin hydrochloride injection doses during therapy, the epirubicin hydrochloride injection infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein [see Warnings and Precautions (5.9)]. Use epirubicin hydrochloride injection within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
Amlodipine Besylate

Amlodipine Besylate

(See WARNINGS)

For induction therapy in adult patients with AML the following dose schedule is recommended:

Idarubicin hydrochloride injection 12 mg/m2 daily for 3 days by slow (10 to 15 min) intravenous injection in combination with cytarabine. The cytarabine may be given as 100 mg/m2 daily by continuous infusion for 7 days or as cytarabine 25 mg/m2 intravenous bolus followed by cytarabine 200 mg/m2 daily for 5 days continuous infusion. In patients with unequivocal evidence of leukemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experience severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended. In patients with hepatic and/or renal impairment, a dose reduction of idarubicin hydrochloride injection should be considered. Idarubicin hydrochloride injection should not be administered if the bilirubin level exceeds 5 mg%. (See WARNINGS.)

The benefit of consolidation in prolonging the duration of remissions and survival is not proven. There is no consensus regarding optional regimens to be used for consolidation. (See CLINICAL STUDIES for doses used in U.S. Clinical studies.)

Preparation and Administration Precautions

Caution in handling the solution must be exercised as skin reactions associated with idarubicin hydrochloride injection may occur. Skin accidentally exposed to idarubicin hydrochloride injection should be washed thoroughly with soap and water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Care in the administration of idarubicin hydrochloride injection will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. During intravenous administration of idarubicin hydrochloride injection extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs (1/2 hour immediately, then 1/2 hour 4 times per day for 3 days) be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained early if there is any sign of a local reaction such as pain, erythema, edema or vesication. If ulceration begins or there is severe persistent pain at the site of extravasation, early wide excision of the involved area should be considered.

Idarubicin hydrochloride injection should be administered slowly (over 10 to 15 minutes) into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP (0.9%) or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.

Incompatibility

Unless specific compatibility data are available, idarubicin hydrochloride injection should not be mixed with other drugs. Precipitation occurs with heparin. Prolonged contact with any solution of an alkaline pH will result in degradation of the drug.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and containers permit.

Handling and Disposal

Procedures for handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Toposar

Toposar

Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used withundiluted etoposide injection.

TOPOSAR

The usual dose of TOPOSAR in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5.

In small cell lung cancer, the TOPOSAR dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days.

For recommended dosing adjustments in patients with renal impairment see PRECAUTIONS section.

Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.

The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Administration Precautions

As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of TOPOSAR. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If TOPOSAR solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.

Preparation for Intravenous Administration

TOPOSAR must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the TOPOSAR solution be administered over a 30- to 60-minute period. A longer duration of administration may be used if the volume of fluid to be infused is a concern. TOPOSAR should not be given by rapid intravenous injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration (see DESCRIPTION section) prior to administration whenever solution and container permit.

Stability

Unopened vials of TOPOSAR are stable until the date indicated on the package at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Methotrexate

Methotrexate

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection (preservative free) injectable products may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.

Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

Leukemia

Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

Meningeal Leukemia

In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
Age (years) Dose (mg) < 1 6 1 8 2 10 3 or older 12
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.

Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

Lymphomas

In Burkitt's Tumor, Stages I to II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

Mycosis Fungoides (Cutaneous T Cell Lymphoma)

Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

Osteosarcoma

An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.
Drug* Dose* Treatment Week After Surgery * Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No. 25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, 45 Leucovorin 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion - - - Doxorubicin† as a single drug 30 mg/ m2 day IV × 3 days 8, 17 Doxorubicin† Cisplatin† 50 mg/m2 IV100 mg/m2 IV 20, 23, 33, 3620, 23, 33, 36 Bleomycin† Cyclophosphamide† Dactinomycin† 15 units/m2 IV × 2 days 600 mg/m2 IV × 2 days 0.6 mg/m2 IV × 2 days 2, 13, 26, 39, 422, 13, 26, 39, 422, 13, 26, 39, 42
When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE
Administration of methotrexate should be delayed until recovery if: the WBC count is less than 1500/microliter the neutrophil count is less than 200/microliter the platelet count is less than 75,000/microliter the serum bilirubin level is greater than 1.2 mg/dL the SGPT level is greater than 450 U mucositis is present, until there is evidence of healing persistent pleural effusion is present; this should be drained dry prior to infusion. Adequate renal function must be documented. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. Alkalinize urine to maintain pH above 7 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 × 10-8 mol/L (0.05 micromolar). The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels (see table below‡).Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.
CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

Adult Rheumatoid Arthritis

Recommended Starting Dosage Schedules
Single oral doses of 7.5 mg once weekly.† Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.†
† Methotrexate Sodium Tablets for oral administration are available.

Polyarticular-Course Juvenile Rheumatoid Arthritis

The recommended starting dose is 10 mg/m2 given once weekly.

For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see Information for Patients under PRECAUTIONS). Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy (see PRECAUTIONS). Appropriate steps should be taken to avoid conception during methotrexate therapy (see PRECAUTIONS and CONTRAINDICATIONS).

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see ADVERSE REACTIONS). Maximal myelosuppression usually occurs in seven to ten days.

Psoriasis

Recommended Starting Dose Schedule
Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.† Divided oral dose schedule: 2.5 mg at 12 hour intervals for three doses.†
† Methotrexate Sodium Tablets for oral administration are available.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

DILUTION INSTRUCTIONS FOR METHOTREXATE INJECTION USP

Methotrexate Injection USP, Isotonic Liquid, Preservative Free, for Single Use Only

If desired, the solution may be further diluted immediately prior to use with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP.
Vinorelbine

Vinorelbine

Single-Agent Vinorelbine Injection

The usual initial dose of single-agent vinorelbine injection is 30 mg/m2 administered weekly. The recommended method of administration is an intravenous injection over 6 to 10 minutes. In controlled trials, single-agent vinorelbine injection was given weekly until progression or dose-limiting toxicity.

Vinorelbine Injection in Combination with Cisplatin

Vinorelbine injection may be administered weekly at a dose of 25 mg/m2 in combination with cisplatin given every 4 weeks at a dose of 100 mg/m2.

Blood counts should be checked weekly to determine whether dose reductions of vinorelbine injection and/or cisplatin are necessary. In the SWOG study, most patients required a 50% dose reduction of vinorelbine injection at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3.

Vinorelbine injection may also be administered weekly at a dose of 30 mg/m2 in combination with cisplatin, given on days 1 and 29, then every 6 weeks at a dose of 120 mg/m2.

Dose Modifications for Vinorelbine Injection

The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose for the corresponding starting dose of vinorelbine injection (see Table 5).

Dose Modifications for Hematologic Toxicity

Granulocyte counts should be ≥1000 cells/mm3 prior to the administration of vinorelbine injection. Adjustments in the dosage of vinorelbine injection should be based on granulocyte counts obtained on the day of treatment according to Table 5.
Table 5 Dose Adjustments Based on Granulocyte Counts Granulocytes on Day of Treatment (cells/mm3) Percentage of Starting Dose of Vinorelbine Injection ≥1500 100% 1000 to 1499 50% <1000 Do not administer. Repeat granulocyte count in 1 week. If 3 consecutive weekly doses are held because granulocyte count is <1000 cells/mm3, discontinue vinorelbine injection. Note: For patients who, during treatment with vinorelbine injection, experienced fever and/or sepsis while granulocytopenic or had 2 consecutive weekly doses held due to granulocytopenia, subsequent doses of vinorelbine injection should be: ≥1500 75% 1000 to 1499 37.5% <1000 See above
Dose Modifications for Hepatic Insufficiency

Vinorelbine injection should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with vinorelbine injection, the dose should be adjusted for total bilirubin according toTable 6.
Table 6 Dose Modification Based on Total Bilirubin Total Bilirubin(mg/dL) Percentage of Starting Dose of Vinorelbine Injection ≤2.0 100% 2.1 to 3.0 50% >3.0 25%
Dose Modifications for Concurrent Hematologic Toxicity and Hepatic Insufficiency

In patients with both hematologic toxicity and hepatic insufficiency, the lower of the doses based on the corresponding starting dose of vinorelbine injection determined fromTable 5andTable 6should be administered.

Dose Modifications for Renal Insufficiency

No dose adjustments for vinorelbine injection are required for renal insufficiency. Appropriate dose reductions for cisplatin should be made when vinorelbine injection is used in combination.

Dose Modifications for Neurotoxicity

If grade ≥2 neurotoxicity develops, vinorelbine injection should be discontinued.

Administration Precautions

Caution—vinorelbine injection must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any vinorelbine injection is injected. Leakage into surrounding tissue during intravenous administration of vinorelbine injection may cause considerable irritation, local tissue necrosis, and/or thrombophlebitis. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Since there are no established guidelines for the treatment of extravasation injuries with vinorelbine injection, institutional guidelines may be used. The ONS Chemotherapy Guidelines provide additional recommendations for the prevention of extravasation injuries.1

As with other toxic compounds, caution should be exercised in handling and preparing the solution of vinorelbine injection. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the solution of vinorelbine injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Severe irritation of the eye has been reported with accidental contamination of the eye with another vinca alkaloid. If this happens with vinorelbine injection, the eye should be flushed with water immediately and thoroughly.

Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.2–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Vinorelbine injection is a clear, colorless to pale yellow solution. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, vinorelbine injection should not be administered.

Preparation for Administration

Vinorelbine injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted vinorelbine injection should be administered over 6 to 10 minutes into the side port of a free-flowing IV closest to the IV bag followed by flushing with at least 75 to 125 mL of one of the solutions. Diluted vinorelbine injection may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F)

Syringe

The calculated dose of vinorelbine injection should be diluted to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:

  5% Dextrose Injection, USP

  0.9% Sodium Chloride Injection, USP

IV Bag

The calculated dose of vinorelbine injection should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:

  5% Dextrose Injection, USP

  0.9% Sodium Chloride Injection, USP

  0.45% Sodium Chloride Injection, USP

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  Ringer's Injection, USP

  Lactated Ringer's Injection, USP

Stability

Unopened vials of vinorelbine injection are stable until the date indicated on the package when stored under refrigeration at 2° to 8°C (36° to 46°F) and protected from light in the carton. Unopened vials of vinorelbine injection are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product should not be frozen.
Sulfamethoxazole And Tr...

Sulfamethoxazole And Trimethoprim

SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION ISCONTRAINDICATED IN PEDIATRIC PATIENTS LESS THAN 2 MONTHS OF AGE. CAUTION—SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION MUST BE DILUTED IN 5% DEXTROSE IN WATER SOLUTION PRIOR TO ADMINISTRATION. DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION WITH OTHER DRUGS OR SOLUTIONS. RAPID INFUSION OR BOLUS INJECTION MUST BE AVOIDED.

Dosage

Children and Adults

PneumocystisJiroveci Pneumonia

Total daily dose is 15 to 20 mg/kg (based on the trimethoprim component) given in 3 or 4 equally divided doses every 6 to 8 hours for up to 14 days. One investigator noted that a total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function.10

Severe Urinary Tract Infections and Shigellosis

Total daily dose is 8 to 10 mg/kg (based on the trimethoprim component) given in 2 or 4 equally divided doses every 6, 8 or 12 hours for up to 14 days for severe urinary tract infections and 5 days for shigellosis. The maximum recommended daily dose is 60 mL per day.

For Patients With Impaired Renal Function

When renal function is impaired, a reduced dosage should be employed using the following table:

Creatinine
Clearance (mL/min)
Recommended
Dosage Regimen Above 30 Usual standard regimen 15 to 30 1⁄2 the usual regimen Below 15 Use not recommended
Method of Preparation

Sulfamethoxazole and trimethoprim injection must be diluted. EACH 5 ML SHOULD BE ADDED TO 125 ML OF 5% DEXTROSE IN WATER. After diluting with 5% dextrose in water the solution should not be refrigerated and should be used within 6 hours. If a dilution of 5 mL per 100 mL of 5% dextrose in water is desired, it should be used within 4 hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

Multidose Vials

After initial entry into the vial, the remaining contents must be used within 48 hours.

The following infusion systems have been tested and found satisfactory: unit-dose glass containers; unit-dose polyvinyl chloride and polyolefin containers. No other systems have been tested and therefore no others can be recommended.

Dilution

EACH 5 ML OF SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION SHOULD BE ADDED TO 125 ML OF 5% DEXTROSE IN WATER.

Note: In those instances where fluid restriction is desirable, each 5 mL may be added to 75 mL of 5% dextrose in water. Under these circumstances the solution should be mixed just prior to use and should be administered within 2 hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION 5% DEXTROSE IN WATER WITH DRUGS OR SOLUTIONS IN THE SAME CONTAINER.

Administration

The solution should be given by intravenous infusion over a period of 60 to 90 minutes. Rapid infusion or bolus injection must be avoided. Sulfamethoxazole and trimethoprim injection should not be given intramuscularly.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
Chloraprep One-step

Chloraprep One-step

2.2 Colorectal Single Agent Regimens 1 and 2

Administer irinotecan hydrochloride injection as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 3.

A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin > 2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.
Table 3. Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications a Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance. b Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance. c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
Regimen 1 (weekly)a

125 mg/m2 intravenous infusion over 90 minutes, days 1,8,15,22 then 2-week rest

Starting Dose and Modified Dose Levelsc (mg/m2)

Starting Dose

Dose Level -1

Dose Level -2

125

100

75

Regimen 2 (every 3 weeks)b

350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeksc

Starting Dose and Modified Dose Levels (mg/m2)

Starting Dose

Dose Level -1

Dose Level -2

350

300

250

Dose Modifications

Based on recommended dose-levels described in Table 3, Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 4, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.
Table 4: Recommended Dose Modifications for Single-Agent Schedulesa a All dose modifications should be based on the worst preceding toxicity b National Cancer Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1500/mm3, and the platelet count has recovered to ≥ 100,000/mm3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection.

Worst Toxicity NCI Gradeb (Value)

During a Cycle of Therapy

At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cyclea

Weekly

Weekly

Once Every 3 Weeks

No toxicity

Maintain dose level

↑ 25 mg/m2 up to a maximum dose of 150 mg/m2

Maintain dose level

Neutropenia

1 (1500 to

1999/mm3)

Maintain dose level

Maintain dose level

Maintain dose level

2 (1000 to

1499/mm3)

↓ 25 mg/m2

Maintain dose level

Maintain dose level

3 (500 to 999/mm3)

Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

4 (< 500/mm3)

Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

Neutropenic fever

Omit dose until resolved, then ↓ 50 mg/m2 when resolved

↓ 50 mg/m2

↓ 50 mg/m2

Other hematologic toxicities

Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.

Diarrhea

1 (2 to 3 stools/day > pretxc)

Maintain dose level

Maintain dose level

Maintain dose level

2 (4 to 6 stools/day > pretx)

↓ 25 mg/m2

Maintain dose level

Maintain dose level

3 (7 to 9 stools/day > pretx)

Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

4 (≥ 10 stools/day > pretx)

Omit dose until resolved to ≤ grade 2 then ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

Other nonhematologicd toxicities

1

Maintain dose level

Maintain dose level

Maintain dose level

2

↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

3

Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2

↓ 25 mg/m2

↓ 50 mg/m2

4

Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

2.3 Dosage in Patients with Reduced UGT1A1 Activity

When administered in as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see Tables 1 to 4).

2.4 Premedication

It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride injection. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.

2.5 Preparation of Infusion Solution

Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.

Irinotecan hydrochloride injection 20 mg/mL is intended for single use only and any unused portion should be discarded.

Irinotecan hydrochloride injection must be diluted prior to infusion. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution.

The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided.

The irinotecan hydrochloride injection solution should be used immediately after reconstitution as it contains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g., on Laminar Air Flow bench), irinotecan hydrochloride injection solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

2.6 Safe Handling

Care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

2.7 Extravasation

Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.
Cyclobenzaprine Hydroch...

Cyclobenzaprine Hydrochloride

2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

Ondansetron Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

Adults

The recommended adult intravenous dosage of ondansetron hydrochloride is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology12.2]. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron hydrochloride.

Pediatrics

For pediatric patients 6 months through 18 years of age, the intravenous dosage of ondansetron hydrochloride is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1), Clinical Pharmacology (12.2,12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron hydrochloride. The drug should be infused intravenously over 15 minutes.

2.2 Prevention of Postoperative Nausea and Vomiting

Ondansetron Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.

Adults

The recommended adult intravenous dosage of ondansetron hydrochloride is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

Pediatrics

For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1 mg/kg dose for patients weighing 40 kg or less, or a single 4 mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ondansetron hydrochloride.

2.3 Stability and Handling

After dilution, do not use beyond 24 hours. Although Ondansetron Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

Ondansetron Injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.

2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].
Donnatal

Donnatal

The patient’s pretreatment body weight should be obtained for calculation of correct dosage. Amikacin sulfate injection may be given intramuscularly or intravenously.

The status of renal function should be estimated by measurement of the serum creatinine concentration or calculation of the endogenous creatinine clearance rate. The blood urea nitrogen (BUN) is much less reliable for this purpose. Reassessment of renal function should be made periodically during therapy.

Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels. It is desirable to measure both peak and trough serum concentrations intermittently during therapy. Peak concentrations (30 to 90 minutes after injection) above 35 mcg/mL and trough concentrations (just prior to the next dose) above 10 mcg/mL should be avoided. Dosage should be adjusted as indicated.

Intramuscular Administration for Patients with Normal Renal Function

The recommended dosage for adults, children and older infants (see WARNINGS box) with normal renal function is 15 mg/kg/day divided into 2 or 3 equal doses administered at equally divided intervals, i.e., 7.5 mg/kg q12h or 5 mg/kg q8h. Treatment of patients in the heavier weight classes should not exceed 1.5 grams/day.

When amikacin is indicated in newborns (see WARNINGS box), it is recommended that a loading dose of 10 mg/kg be administered initially to be followed with 7.5 mg/kg every 12 hours.

The usual duration of treatment is 7 to 10 days. It is desirable to limit the duration of treatment to short-term whenever feasible. The total daily dose by all routes of administration should not exceed 15 mg/kg/day. In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin should be reevaluated. If continued, amikacin serum levels and renal, auditory and vestibular functions should be monitored. At the recommended dosage level, uncomplicated infections due to amikacin-sensitive organisms should respond in 24 to 48 hours. If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked. Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.

When amikacin is indicated in uncomplicated urinary tract infections, a dose of 250 mg twice daily may be used.
DOSAGE GUIDELINES ADULTS AND CHILDREN WITH NORMAL RENAL FUNCTION Patient Weight Dosage lbs kg 7.5 mg/kg OR 5 mg/kg q12h q8h
99

45

337.5 mg

225 mg

110

50

375 mg

250 mg

121

55

412.5 mg

275 mg

132

60

450 mg

300 mg

143

65

487.5 mg

325 mg

154

70

525 mg

350 mg

165

75

562.5 mg

375 mg

176

80

600 mg

400 mg

187

85

637.5 mg

425 mg

198

90

675 mg

450 mg

209

95

712.5 mg

475 mg

220

100

750 mg

500 mg

Intramuscular Administration for Patients with Impaired Renal Function

Whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures. Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed interval.

Both methods are based on the patient’s creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function. These dosage schedules must be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. Neither method should be used when dialysis is being performed.

Normal Dosage at Prolonged Intervals

If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage interval in hours for the normal dose can be calculated by multiplying the patient’s serum creatinine by 9, e.g., if the serum creatinine concentration is 2 mg/100 mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

Reduced Dosage at Fixed Time Intervals

When renal function is impaired and it is desirable to administer amikacin at a fixed time interval, dosage must be reduced. In these patients, serum amikacin concentrations should be measured to assure accurate administration of amikacin and to avoid concentrations above 35 mcg/mL. If serum assay determinations are not available and the patient’s condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as a guide for dosage.

First, initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose. This loading dose is the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above.

To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient’s creatinine clearance rate:

An alternate rough guide for determining reduced dosage at 12 hour intervals (for patients whose steady state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

The above dosage schedules are not intended to be rigid recommendations but are provided as guides to dosage when the measurement of amikacin serum levels is not feasible.

Intravenous Administration

The individual dose, the total daily dose, and the total cumulative dose of amikacin sulfate are identical to the dose recommended for intramuscular administration. The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 or 200 mL of sterile diluent such as 0.9% sodium chloride injection or 5% dextrose injection or any other compatible solutions listed below.

The solution is administered to adults over a 30 to 60 minute period. The total daily dose should not exceed 15 mg/kg/day and may be divided into either 2 or 3 equally-divided doses at equally-divided intervals.

In pediatric patients, the amount of fluid used will depend on the amount of amikacin sulfate ordered for the patient. It should be a sufficient amount to infuse the amikacin over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion.

Amikacin should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

Stability in IV Fluids

Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in the following solutions:

5% Dextrose Injection USP

5% Dextrose USP and 0.2% Sodium Chloride Injection USP

5% Dextrose USP and 0.45% Sodium Chloride Injection USP

0.9% Sodium Chloride Injection USP

Lactated Ringer’s Injection USP

Normosol® M in 5% Dextrose Injection USP(or Plasma-Lyte 56 injection in 5% Dextrose USP in water).

Normosol® R in 5% Dextrose Injection USP (or Plasma-Lyte 148 injection in 5% Dextrose USP in water).

In the above solutions with amikacin sulfate concentrations of 0.25 and 5 mg/mL, solutions aged for 60 days at 4°C and then stored at 25°C had utility times of 24 hours.

At the same concentrations, solutions frozen and aged for 30 days at -15°C, thawed, and stored at 25°C had utility times of 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Aminoglycosides administered by any of the above routes should not be physically premixed with other drugs but should be administered separately.

Because of the potential toxicity of aminoglycosides, “fixed dosage” recommendations which are not based upon body weight are not advised. Rather, it is essential to calculate the dosage to fit the needs of each patient.
Doxorubicin Hydrochlori...

Doxorubicin Hydrochloride

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin hydrochloride injection is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles [see Clinical Studies (14)].

Metastatic Disease, Leukemia, or Lymphoma
The recommended dose of doxorubicin hydrochloride injection when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days. The recommended dose of doxorubicin hydrochloride injection, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days. Consider use of the lower doxorubicin dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1)].
2.2 Dose Modifications

Cardiac Impairment

Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Doxorubicin hydrochloride injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin > 5 mg/dL) [see Contraindications (4)].

Decrease the dose of doxorubicin hydrochloride injection in patients with elevated serum total bilirubin concentrations as follows:
Serum bilirubin concentration Doxorubicin HCl Dose reduction 1.2 to 3 mg/dL 50 % 3.1 to 5 mg/dL 75 % greater than 5 mg/dL
Do not initiate doxorubicin HCl
Discontinue doxorubicin HCl
[see Warnings and Precautions (5.5) and Use in Specific Population (8.7)]

2.3 Preparation and Administration

Preparation for Continuous Intravenous Infusion

Dilute doxorubicin hydrochloride injection solution or reconstituted solution in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

Storage of vials of doxorubicin hydrochloride injection following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Administration by Intravenous Injection:
Administer doxorubicin hydrochloride injection as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Administer doxorubicin hydrochloride injection intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride injection administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.

Administration by Continuous Intravenous Infusion:
Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride injection administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Protect from light from preparation for infusion until completion of infusion.

Management of Suspected Extravasation

Discontinue doxorubicin hydrochloride injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:
Do not remove the needle until attempts are made to aspirate extravasated fluid. Do not flush the line. Avoid applying pressure to the site. Apply ice to the site intermittently for 15 min 4 times a day for 3 days. If the extravasation is in an extremity, elevate the extremity. In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3)].

Incompatibility with Other Drugs

Do not admix doxorubicin hydrochloride injection with other drugs. If doxorubicin hydrochloride injection is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride injection.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin hydrochloride injection consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.
Ciprofloxacin

Ciprofloxacin

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis)

If only the earliest manifestations of diabetic gastric stasis are present, oral administration of metoclopramide may be initiated. However, if severe symptoms are present, therapy should begin with metoclopramide injection USP (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

Administration of metoclopramide injection USP up to 10 days may be required before symptoms subside, at which time oral administration of metoclopramide may be instituted. The physician should make a thorough assessment of the risks and benefits prior to prescribing further metoclopramide treatment.

For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose may be adequate.

For doses in excess of 10 mg, metoclopramide injection USP should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with metoclopramide injection USP, can be stored frozen for up to 4 weeks. Metoclopramide injection USP is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide injection USP diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

If acute dystonic reactions should occur, inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and the symptoms usually will subside.

For the Prevention of Postoperative Nausea and Vomiting

Metoclopramide injection USP should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation

If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2-minute period.

The recommended single dose is: Pediatric patients above 14 years of age and adults — 10 mg metoclopramide base. Pediatric patients (6-14 years of age) — 2.5 to 5 mg metoclopramide base; (under 6 years of age) — 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations

In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over a 1- to 2-minute period.

For dosage, see intubation above.

Use in Patients With Renal or Hepatic Impairment

Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

See OVERDOSAGE section for information regarding dialysis.

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ADMIXTURES COMPATIBILITIES

Metoclopramide injection USP is compatible for mixing and injection with the following dosage forms to the extent indicated below:

Physically and Chemically Compatible Up to 48 Hours

Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex).

Physically Compatible Up to 48 Hours

Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).

Physically Compatible Up to 24 Hours

(Do not use if precipitation occurs)

Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly).

Conditionally Compatible

(Use within one hour after mixing or may be infused directly into the same running IV line)

Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle).

Incompatible

(Do Not Mix)

Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Abbott).
Ondansetron

Ondansetron

2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

Ondansetron Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

Adults

The recommended adult intravenous dosage of ondansetron hydrochloride is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron hydrochloride.

Pediatrics

For pediatric patients 6 months through 18 years of age, the intravenous dosage of ondansetron hydrochloride is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1), Clinical Pharmacology (12.2, 12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron hydrochloride. The drug should be infused intravenously over 15 minutes.

2.2 Prevention of Postoperative Nausea and Vomiting

Ondansetron Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.

Adults

The recommended adult intravenous dosage of ondansetron hydrochloride is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

Pediatrics

For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1 mg/kg dose for patients weighing 40 kg or less, or a single 4 mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ondansetron hydrochloride.

2.3 Stability and Handling

After dilution, do not use beyond 24 hours. Although Ondansetron Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

Ondansetron Injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.

2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].
Promethazine Hydrochlor...

Promethazine Hydrochloride

Important Notes on Administration

Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues regardless of the route of administration. Irritation and damage can result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration (see WARNINGS-Severe Tissue Injury, Including Gangrene).
The preferred parenteral route of administration for promethazine hydrochloride injection is by deep intramuscular injection. Under no circumstances should promethazine hydrochloride injection be given by intra-arterial injection due to likelihood of severe arteriorospasm and the possibility of resultant gangrene (see WARNINGS-Severe Tissue Injury, Including Gangrene). Subcutaneous injection is contraindicated as it may result in tissue necrosis. When administered intravenously, promethazine hydrochloride injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute. It is preferable to inject through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intravenous injection of promethazine hydrochloride injection, the injection should be stopped immediately to evaluate for possible arterial injection or perivascular extravasation.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use promethazine hydrochloride injection if solution has developed color or contains precipitate.

To avoid the possibility of physical and/or chemical incompatibility, consult specialized literature before diluting with any injectable solution or combining with any other medication. Do not use if there is a precipitate or any sign of incompatibility.

Allergic Conditions

The average adult dose is 25 mg. This dose may be repeated within two hours if necessary, but continued therapy, if indicated, should be via the oral route as soon as existing circumstances permit. After initiation of treatment, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The average adult dose for amelioration of allergic reactions to blood or plasma is 25 mg.

Sedation

In hospitalized adult patients, nighttime sedation may be achieved by a dose of 25 to 50 mg of promethazine hydrochloride injection.

Nausea and Vomiting

For control of nausea and vomiting, the usual adult dose is 12.5 to 25 mg, not to be repeated more frequently than every four hours. When used for control of postoperative nausea and vomiting, the dosage of analgesics and barbiturates should be reduced accordingly (see PRECAUTIONS-Drug Interactions).

Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see PRECAUTIONS-Pediatric Use).

Preoperative and Postoperative Use

As an adjunct to preoperative or postoperative medication, 25 to 50 mg of promethazine hydrochloride injection in adults may be combined with appropriately reduced doses of analgesics and atropine-like drugs as desired. Dosage of concomitant analgesic or hypnotic medication should be reduced accordingly. (see PRECAUTIONS-Drug Interactions.)

Promethazine hydrochloride is contraindicated for use in pediatric patients less than two years of age.

Obstetrics

Promethazine hydrochloride injection in doses of 50 mg will provide sedation and relieve apprehension in the early stages of labor. When labor is definitely established, 25 to 75 mg (average dose, 50 mg) promethazine hydrochloride injection may be given with an appropriately reduced dose of any desired narcotic (see PRECAUTIONS-Drug Interactions). If necessary, promethazine hydrochloride injection with a reduced dose of analgesic may be repeated once or twice at four-hour intervals in the course of a normal labor. A maximum total dose of 100 mg of promethazine hydrochloride injection may be administered during a 24-hour period to patients in labor.

Pediatric Patients

Promethazine hydrochloride injection is contraindicated for use in pediatric patients less than 2 years of age (see WARNINGS-Respiratory Depression). Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age or older. It is recommended that the lowest effective dose of promethazine hydrochloride be used in pediatric patients 2 years of age and older and concomitant administration of other drugs with respiratory depressant effects be avoided (see WARNINGS-Respiratory Depression).

In pediatric patients 2 years of age and older, the dosage should not exceed half that of the suggested adult dose. As an adjunct to premedication, the suggested dose is 1.1 mg per kg of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug. (see PRECAUTIONS-Drug Interactions.) Antiemetics should not be used in vomiting of unknown etiology in pediatric patients.
Leucovorin Calcium

Leucovorin Calcium

Advanced Colorectal Cancer

Either of the following two regimens is recommended:
Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.
5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28 day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests). For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosages may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

Leucovorin Rescue After High-Dose Methotrexate Therapy

The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).

Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalinization (pH of 7 or greater) should be continued until the methotrexate level is below 5 × 10-8 M (0.05 micromolar). The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:
GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY
Clinical

Situation
Laboratory Findings
Leucovorin Dosage

and Duration

Normal

Methotrexate Elimination
Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. 15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.
Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Impaired Methotrexate Elimination or Inadvertent Overdosage

Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS). Leucovorin 10 mg/m2 should be administered IV, IM, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 × 10-6 M or the 48 hour level is greater than 9 × 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7 or greater.

Megaloblastic Anemia Due to Folic Acid Deficiency

Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

Each 100 mg vial of leucovorin calcium for injection when reconstituted with 10 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL. Each 350 mg vial of leucovorin calcium for injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg leucovorin per mL. Leucovorin calcium for injection contains no preservative. Reconstitute the lyophilized vial products with bacteriostatic water for injection, USP, (benzyl alcohol preserved), or sterile water for injection, USP. When reconstituted with bacteriostatic water for injection, USP, the resulting solution must be used within 7 days. If the product is reconstituted with sterile water for injection, USP, use immediately and discard any unused portion.

Because of the benzyl alcohol contained in bacteriostatic water for injection, USP, when doses greater than 10 mg/m2 are administered, leucovorin calcium for injection should be reconstituted with sterile water for injection, USP, and used immediately (see WARNINGS). Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.
Leucovorin Calcium

Leucovorin Calcium

Advanced Colorectal Cancer

Either of the following two regimens is recommended:
Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.
5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28 day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests). For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosages may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

Leucovorin Rescue After High-Dose Methotrexate Therapy

The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).

Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalinization (pH of 7 or greater) should be continued until the methotrexate level is below 5 × 10-8 M (0.05 micromolar). The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:
GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY
Clinical

Situation
Laboratory Findings
Leucovorin Dosage

and Duration

Normal

Methotrexate Elimination
Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. 15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.
Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Impaired Methotrexate Elimination or Inadvertent Overdosage

Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS). Leucovorin 10 mg/m2 should be administered IV, IM, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 × 10-6 M or the 48 hour level is greater than 9 × 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7 or greater.

Megaloblastic Anemia Due to Folic Acid Deficiency

Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

Each 350 mg vial of leucovorin calcium for injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg leucovorin per mL. Leucovorin calcium for injection contains no preservative. Reconstitute the lyophilized vial products with bacteriostatic water for injection, USP, (benzyl alcohol preserved), or sterile water for injection, USP. When reconstituted with bacteriostatic water for injection, USP, the resulting solution must be used within 7 days. If the product is reconstituted with sterile water for injection, USP, use immediately and discard any unused portion.

Because of the benzyl alcohol contained in bacteriostatic water for injection, USP, when doses greater than 10 mg/m2 are administered, leucovorin calcium for injection should be reconstituted with sterile water for injection, USP, and used immediately (see WARNINGS). Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.
Diclofenac Sodium And M...

Diclofenac Sodium And Misoprostol

Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel injection solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to paclitaxel injection administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel injection, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel injection, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel injection.

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES, Ovarian Carcinoma):
1. For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS, Disease-Specific Adverse Event Experiences). 1.%2. Paclitaxel injection administered intravenously over 3 hours at a dose of 175 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2; or 2.%2. Paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2. 2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel injection has been used at several doses and schedules; however, the optimal regimen is not yet clear (see CLINICAL STUDIES, Ovarian Carcinoma). The recommended regimen is paclitaxel injection 135 mg/m 2 or 175 mg/m 2 administered intravenously over 3 hours every 3 weeks.
For patients with carcinoma of the breast, the following is recommended (see CLINICAL STUDIES, Breast Carcinoma):
1. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel injection, at a dose of 175 mg/m 2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES, Breast Carcinoma). 2. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel injection at a dose of 175 mg/m 2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.
For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel injection administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:
1. Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); 2. Initiate or repeat treatment with paclitaxel injection only if the neutrophil count is at least 1000 cells/mm 3; 3. Reduce the dose of subsequent courses of paclitaxel injection by 20% for patients who experience severe neutropenia (neutrophil < 500 cells/mm 3 for a week or longer); and 4. Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.
For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel injection should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel injection should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil < 500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel injection therapy should have dosage reduced by 20% for subsequent courses of paclitaxel injection. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Preparation and Administration Precautions

Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Hepatic Impairment

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3 and 24 hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.
TABLE 17: RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATAa
Degree of Hepatic Impairment

Recommended Paclitaxel Injection Dosec

Transaminase Levels

Bilirubin Levelsb

24 hour infusion

< 2 × ULN

and

≤ 1.5 mg/dL

135 mg/m2

2 to < 10 × ULN

and

≤ 1.5 mg/dL

100 mg/m2

< 10 × ULN

and

1.6 to 7.5 mg/dL

50 mg/m2

≥ 10 × ULN

or

> 7.5 mg/dL

Not recommended

3 hour infusion

< 10 × ULN

and

≤ 1.25 × ULN

175 mg/m2

< 10 × ULN

and

1.26 to 2 × ULN

135 mg/m2

< 10 × ULN

and

2.01 to 5 × ULN

90 mg/m2

≥ 10 × ULN

or

> 5 × ULN

Not recommended

a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (e.g., for AIDS-related Kaposi’s sarcoma).

b Differences in criteria for bilirubin levels between the 3 and 24 hour infusion are due to differences in clinical trial design.

c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel injection. If paclitaxel injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel injection contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see PRECAUTIONS, Injection Site Reaction).

Preparation for Intravenous Administration

Paclitaxel injection must be diluted prior to infusion. Paclitaxel injection should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel injection solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

Paclitaxel injection should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel injection since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel injection solution.

Stability

Unopened vials of paclitaxel injection are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel injection vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.
Topotecan

Topotecan

Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)].

2.1 Small Cell Lung Cancer

Recommended Dosage: The recommended dose of Topotecan Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily on days 1 to 5 of each 21-day cycle until disease progression.

Dosage Modification Guidelines: Recommended dose modifications in patients with bone marrow suppression or renal impairment are provided in the table below [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Table 1. Recommended Dose Modifications in Patients with Small Cell Lung Cancer Adverse Reaction or Laboratory Values Recommended Dose Modification
On Day 1 of first cycle

--neutrophil count of ≤ 1,500 cells/mm3or

--platelet count ≤ 100,000 cells/mm3or
--serum creatinine > 1.5 mg/dL Delay initiation of Topotecan Injection until hematologic or renal recovery
On Day 1 of subsequent cycles (cycle 2 and beyond)

--neutrophil count of ≤ 1,000 cells/mm3or

--platelet count ≤ 100,000 cells/mm3or

--hemoglobin < 9.0 gm/dL or
--serum creatinine > 1.5 mg/dL Delay next cycle of Topotecan Injection until hematologic or renal recovery For neutropenia < 500 cells/mm3 in preceding cycle Permanently reduce Topotecan Injection dose to 1.25 mg/m2 or administer prophylactic granulocyte colony-stimulating factor during subsequent cycles. For platelets < 25,000 cells/mm3 in preceding cycle Permanently reduce Topotecan Injection dose to 1.25 mg/m2 For creatinine clearance 20-39 mL/min Reduce the Topotecan Injection dose to 0.75 mg/m2
2.2 Cervical Cancer

Recommended Dosage: The recommended dose of Topotecan Injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3 of each 21-day cycle. Administer cisplatin 50 mg/m2 by intravenous infusion on day 1 of each 21-day cycles.

Dosage Modification Guidelines: Recommended dose modifications in patients with bone marrow suppression or renal impairment are provided in the table below [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.
Table 2. Recommended Dose Modifications in Patients with Cervical Cancer Adverse Reaction or Laboratory Values Recommended Dose Modification
On Day 1 of first cycle

--neutrophil count of ≤ 1,500 cells/mm3or

--platelet count ≤ 100,000 cells/mm3or
--serum creatinine > 1.5 mg/dL Delay initiation of Topotecan Injection until hematologic or renal recovery
On Day 1 of subsequent cycles (cycle 2 and beyond)

--neutrophil count of ≤ 1,000 cells/mm3or

--platelet count ≤ 100,000 cells/mm3or

--hemoglobin < 9.0 gm/dL or
--serum creatinine > 1.5 mg/dL Delay next cycle of Topotecan Injection until hematologic or renal recovery For the first occurrence of febrile neutropenia [ < 1,000 neutrophils/mm3 with fever ≥ 38.0°C (≥ 100.4°F) in preceding cycle Permanently reduce the daily Topotecan Injection dose to 0.60 mg/m2 or administer prophylactic granulocyte colony-stimulating factor (G-CSF) during subsequent cycles. For re-occurrence of febrile neutropenia [< 1,000 neutrophils/mm3 with fever ≥ 38.0°C (≥ 100.4°F) in preceding cycle despite use of G-CSF Permanently reduce the daily Topotecan Injection dose to 0.45 mg/m2 For platelet nadir < 25,000 cells/mm3 in preceding cycle Permanently reduce the daily Topotecan Injection dose to 0.60 mg/m2 For serum creatinine > 1.5 mg/dL in subsequent cycles Permanently discontinue cisplatin and Topotecan Injection
2.3 Instructions for Handling, and Preparation for Intravenous Administration

Use procedures for proper handling and disposal of anticancer drugs [see References (15)].

Dilute Topotecan Injection in either 0.9% Sodium Chloride USP or 5% Dextrose USP. Store diluted Topotecan Injection solutions at approximately 20°C to 25°C (68°F to 77°F) for no more than 4 hours or under refrigerated (2°C to 8°C) conditions for no more than 12 hours.
Metoclopramide

Metoclopramide

For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis)

If only the earliest manifestations of diabetic gastric stasis are present, oral administration of metoclopramide may be initiated. However, if severe symptoms are present, therapy should begin with metoclopramide injection USP (IM or IV). Doses of 10 mg may be administered slowly by the intravenous route over a 1- to 2-minute period.

Administration of metoclopramide injection USP up to 10 days may be required before symptoms subside, at which time oral administration of metoclopramide may be instituted. The physician should make a thorough assessment of the risks and benefits prior to prescribing further metoclopramide treatment.

For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30 minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then every 3 hours for three doses.

The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose may be adequate.

For doses in excess of 10 mg, metoclopramide injection USP should be diluted in 50 mL of a parenteral solution.

The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when combined with metoclopramide injection USP, can be stored frozen for up to 4 weeks. Metoclopramide injection USP is degraded when admixed and frozen with Dextrose-5% in Water. Metoclopramide injection USP diluted in Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride, Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without freezing) after preparation if protected from light. All dilutions may be stored unprotected from light under normal light conditions up to 24 hours after preparation.

If acute dystonic reactions should occur, inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and the symptoms usually will subside.

For the Prevention of Postoperative Nausea and Vomiting

Metoclopramide injection USP should be given intramuscularly near the end of surgery. The usual adult dose is 10 mg; however, doses of 20 mg may be used.

To Facilitate Small Bowel Intubation

If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose (undiluted) may be administered slowly by the intravenous route over a 1- to 2-minute period.

The recommended single dose is: Pediatric patients above 14 years of age and adults — 10 mg metoclopramide base. Pediatric patients (6-14 years of age) — 2.5 to 5 mg metoclopramide base; (under 6 years of age) — 0.1 mg/kg metoclopramide base.

To Aid in Radiological Examinations

In patients where delayed gastric emptying interferes with radiological examination of the stomach and/or small intestine, a single dose may be administered slowly by the intravenous route over a 1- to 2-minute period.

For dosage, see intubation above.

Use in Patients With Renal or Hepatic Impairment

Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

See OVERDOSAGE section for information regarding dialysis.

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ADMIXTURES COMPATIBILITIES

Metoclopramide injection USP is compatible for mixing and injection with the following dosage forms to the extent indicated below:

Physically and Chemically Compatible Up to 48 Hours

Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex), Potassium Phosphate, USP (Invenex).

Physically Compatible Up to 48 Hours

Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn), Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP (Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI), Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).

Physically Compatible Up to 24 Hours

(Do not use if precipitation occurs)

Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP (Lilly).

Conditionally Compatible

(Use within one hour after mixing or may be infused directly into the same running IV line)

Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP (Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb), Tetracycline Hydrochloride, USP (Lederle).

Incompatible

(Do Not Mix)

Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium Bicarbonate, USP (Abbott).
Nafcillin Sodium

Nafcillin Sodium

Nafcillin for Injection is available for intramuscular and intravenous use. The penicillinase-resistant penicillins are available for oral administration and for intramuscular and intravenous injection. The sodium salts of methicillin, oxacillin, and nafcillin may be administered parenterally and the sodium salts of cloxacillin, dicloxacillin, oxacillin, and nafcillin are available for oral use. The usual I.V dosage for adults is 500 mg every 4 hours. For severe infections, 1 gram every 4 hours is recommended. Administer slowly over at least 30 to 60 minutes to minimize the risk of vein irritation and extravasation.
RECOMMENDED DOSAGE FOR NAFCILLIN FOR INJECTION, USP Drug Adults Infants and Children <40 kg (88 lbs) Other Recommendations Nafcillin 500 mg IM every 4 to 6 hours.IV every 4 hours 25 mg/kg IM twice daily Neonates 10 mg/kg IM twice daily Nafcillin 1 gram IM or IV every 4 hours (severe infections)
Bacteriologic studies to determine the causative organisms and their susceptibility to nafcillin should always be performed. Duration of therapy varies with the type and severity of infection as well as the overall condition of the patient; therefore, it should be determined by the clinical and bacteriological response of the patient. In severe staphylococcal infections, therapy with nafcillin should be continued for at least 14 days. Therapy should be continued for at least 48 hours after the patient has become afebrile, asymptomatic, and cultures are negative. The treatment of endocarditis and osteomyelitis may require a longer duration of therapy.

Concurrent administration of the penicillinase- resistant penicillins and probenecid increases and prolongs serum penicillin levels. Probenecid decreases the apparent volume of distribution and slows the rate of excretion by competitively inhibiting renal tubular secretion of penicillin. Nafcillin-probenecid therapy is generally limited to those infections where very high serum levels of nafcillin are necessary.

No dosage alterations are necessary for patients with renal dysfunction, including those on hemodialysis. Hemodialysis does not accelerate nafcillin clearance from the blood.

For patients with hepatic insufficiency and renal failure, measurement of nafcillin serum levels should be performed and dosage adjusted accordingly.

With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not add supplementary medication to Nafcillin.

Oral preparations of the penicillinase-resistant penicillins should not be used as initial therapy in serious life-threatening infections (see PRECAUTIONS, General ). Oral therapy with the penicillinase-resistant penicillins may be used to follow-up the previous use of a parenteral agent as soon as the clinical condition warrants. For intramuscular gluteal injections, care should be taken to avoid sciatic nerve injury. With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.

DIRECTIONS FOR USE

For Intramuscular Use

Reconstitute with Sterile Water for Injection, USP, 0.9% Sodium Chloride Injection, USP or Bacteriostatic Water for Injection, USP (with benzyl alcohol or parabens); add 3.4 mL to the 1 g vial for 4 mL resulting solution and 6.6 mL to the 2 g vial for 8 mL resulting solution. All reconstituted vials have a concentration of 250 mg per mL.

The clear solution should be administered by deep intragluteal injection immediately after reconstitution.

Reconstituted Stability

Reconstitute with the required amount of Sterile Water for Injection, USP, 0.9% Sodium Chloride Injection, USP or Bacteriostatic Water for Injection, USP (with benzyl alcohol or parabens). The resulting solutions are stable for 3 days at room temperature or 7 days under refrigeration and 90 days frozen.

For Direct Intravenous Use

The required amount of drug should be diluted in 15 to 30 mL of Sterile Water for Injection, USP or Sodium Chloride Injection, USP and injected over a 5- to 10- minute period. This may be accomplished through the tubing of an intravenous infusion if desirable.

For Administration by Intravenous Drip

Reconstitute as directed above (For Intravenous Use) prior to diluting with intravenous solution.
STABILITY PERIODS FOR NAFCILLIN FOR INJECTION, USP*
*IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that a product should be used as soon after preparation as feasible.
Concentration Sterile water Sodium Sodium Dextrose Dextrose and Invert Sugar Lactated mg/mL for Injection, Chloride Lactate injection sodium Injection Ringer’s USP Injection Solution USP (5%) chloride USP (10%) Injection USP (0.9%) USP (M/6 injection USP USP Molar) (5% Dextrose and 0.45% Sodium Chloride) ROOM TEMPERATURE (25° C) 10-200 24 Hrs 24 Hrs 30 24 Hrs 2-30 24 Hrs 24 Hrs 10-30 24 Hrs 24 Hrs REFRIGERATION (4° C) 10-200 7 Days 7 Days 10-30 7 Days 7 Days 7 Days 7 Days 7 Days FROZEN (-15° C) 250 90 Days 90 Days 10-250 90 Days 90 Days 90 Days 90 Days 90 Days
Only those solutions listed above should be used for the intravenous infusion of nafcillin sodium, USP. The concentration of the antibiotic should fall within the range specified. The drug concentration and the rate and volume of the infusion should be adjusted so that the total dose of nafcillin is administered before the drug loses its stability in the solution in use.

There is no clinical experience available on the use of this agent in neonates or infants for this route of administration.

This route of administration should be used for relatively short-term therapy (24 to 48 hours) because of the occasional occurrence of thrombophlebitis particularly in elderly patients.

If another agent is used in conjunction with nafcillin therapy, it should not be physically mixed with nafcillin but should be administered separately.
Topcare Mucus Relief Co...

Topcare Mucus Relief Cold Flu And Sore Throat

2.1 Intravenous Dosing

Mesna Injection may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

Mesna injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.
* The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.
Table 1. Recommended Intravenous Dosing Schedule

0 Hours

4 Hours

8 Hours

Ifosfamide

1.2 g/m2

--

--

Mesna Injection*

240 mg/m2

240 mg/m2

240 mg/m2

2.3 Monitoring for Hematuria

Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when mesna injection is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.

2.4 Preparation of Intravenous Administration and Stability

Preparation

Determine the volume of mesna injection for the intended dose.

Dilute the volume of mesna injection for the dose in any of the following fluids to obtain a final concentration of 20 mg/mL:
• 5% Dextrose Injection, USP • 5% Dextrose and 0.2% Sodium Chloride Injection, USP • 5% Dextrose and 0.33% Sodium Chloride Injection, USP • 5% Dextrose and 0.45% Sodium Chloride Injection, USP • 0.9% Sodium Chloride Injection, USP • Lactated Ringer’s Injection, USP
Stability

The mesna injection multidose vials may be stored and used for up to 8 days after initial puncture.

Store diluted solutions at 25°C (77°F). Use diluted solutions within 24 hours.

Do not mix mesna injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard.

The benzyl alcohol contained in mesna injection vials can reduce the stability of ifosfamide. Ifosfamide and mesna may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL. Higher concentrations of ifosfamide may not be compatible with mesna and may reduce the stability of ifosfamide.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.
Olanzapine

Olanzapine

Norepinephrine bitartrate injection is a concentrated, potent drug which must be diluted in dextrose containing solutions prior to infusion. An infusion of norepinephrine bitartrate injectionshould be given into a large vein (see PRECAUTIONS).

Restoration of Blood Pressure in Acute Hypotensive States

Blood volume depletion should always be corrected as fully as possible before any vasopressor is administered. When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or coronary artery ischemia, norepinephrine bitartrate injection can be administered before and concurrently with blood volume replacement.

Diluent

Norepinephrine bitartrate injection should be diluted in 5 percent dextrose injection or 5 percent dextrose and sodium chloride injections. These dextrose containing fluids are protection against significant loss of potency due to oxidation. Administration in saline solution alone is not recommended. Whole blood or plasma, if indicated to increase blood volume, should be administered separately (for example, by use of a Y-tube and individual containers if given simultaneously).

Average Dosage

Add the content of the vial (4 mg/4 mL) of norepinephrine bitartrate injection to 1,000 mL of a 5 percent dextrose containing solution. Each mL of this dilution contains 4 mcg of the base of norepinephrine bitartrate injection. Give this solution by intravenous infusion. Insert a plastic intravenous catheter through a suitable bore needle well advanced centrally into the vein and securely fixed with adhesive tape, avoiding, if possible, a catheter tie-in technique as this promotes stasis. An IV drip chamber or other suitable metering device is essential to permit an accurate estimation of the rate of flow in drops per minute. After observing the response to an initial dose of 2 mL to 3 mL (from 8 mcg to 12 mcg of base) per minute, adjust the rate of flow to establish and maintain a low normal blood pressure (usually 80 mm Hg to 100 mm Hg systolic) sufficient to maintain the circulation to vital organs. In previously hypertensive patients, it is recommended that the blood pressure should be raised no higher than 40 mm Hg below the preexisting systolic pressure. The average maintenance dose ranges from 0.5 mL to 1 mL per minute (from 2 mcg to 4 mcg of base).

High Dosage

Great individual variation occurs in the dose required to attain and maintain an adequate blood pressure. In all cases, dosage of norepinephrine bitartrate injection should be titrated according to the response of the patient. Occasionally much larger or even enormous daily doses (as high as 68 mg base or 17 vials) may be necessary if the patient remains hypotensive, but occult blood volume depletion should always be suspected and corrected when present. Central venous pressure monitoring is usually helpful in detecting and treating this situation.

Fluid Intake

The degree of dilution depends on clinical fluid volume requirements. If large volumes of fluid (dextrose) are needed at a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution more dilute than 4 mcg per mL should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration greater than 4 mcg per mL may be necessary.

Duration of Therapy

The infusion should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. Infusions of norepinephrine bitartrate injection should be reduced gradually, avoiding abrupt withdrawal. In some of the reported cases of vascular collapse due to acute myocardial infarction, treatment was required for up to six days.

Adjunctive Treatment in Cardiac Arrest

Infusions of norepinephrine bitartrate injection are usually administered intravenously during cardiac resuscitation to restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means. [Norepinephrine bitartrate injection’s powerful beta-adrenergic stimulating action is also thought to increase the strength and effectiveness of systolic contractions once they occur.]

Average Dosage

To maintain systemic blood pressure during the management of cardiac arrest, norepinephrine bitartrate injection is used in the same manner as described under Restoration of Blood Pressure in Acute Hypotensive States.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit.

Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

Avoid contact with iron salts, alkalis, or oxidizing agents.
Sleep Aid

Sleep Aid

The recommended adenosine injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).
• Administer adenosine injection only as a continuous peripheral intravenous infusion • Inject Thallium-201 at the midpoint of the adenosine injection infusion (i.e., after the first three minutes of adenosine injection) • Thallium-201 is physically compatible with adenosine injection and may be injected directly into the adenosine injection infusion set • Inject Thallium-201 as close to the venous access as possible to prevent an inadvertent increase in the dose of adenosine injection (the contents of the intravenous tubing) being administered
Visually inspect adenosine injection for particulate matter and discoloration prior to administration. Do not administer adenosine injection if it contains particulate matter or is discolored

There are no data on the safety or efficacy of alternative adenosine injection infusion protocols. The safety and efficacy of adenosine injection administered by the intracoronary route have not been established.

Table 1 Dosage Chart for Adenosine Injection

Patient Weight(kilograms)

Infusion Rate(mL per minute over 6 minutes for total dose of

0.84 mg/kg)

45

2.1

50

2.3

55

2.6

60

2.8

65

3

70

3.3

75

3.5

80

3.8

85

4

90

4.2

The nomogram displayed in Table 1 was derived from the following general formula:
Oxaliplatin

Oxaliplatin

Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

2.1 Dosage

Administer oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as a 22 hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as a 22 hour continuous infusion.

Figure 1

The administration of oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on 5-fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients With Stage III Colon Cancer

Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from Grade 3/4 gastrointestinal (despite prophylactic treatment) or Grade 4 neutropenia or Grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 × 109/L and platelets ≥ 75 × 109/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients With Advanced Colorectal Cancer

Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22 hour infusion) is recommended for patients after recovery from Grade 3/4 gastrointestinal (despite prophylactic treatment) or Grade 4 neutropenia or Grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 × 109/L and platelets ≥ 75 × 109/L.

Dose Modifications in Therapy for Patients With Renal Impairment

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended oxaliplatin dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Preparation of Infusion Solution

Do not freeze and protect from light the concentrated solution.

A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

The solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection.

After dilution with 250 to 500 mL of 5% Dextrose Injection, the shelf life is 6 hours at room temperature [20° to 25°C (68° to 77°F)] or up to 24 hours under refrigeration [2° to 8°C (36° to 46°F)]. After final dilution, protection from light is not required.

Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection prior to administration of any concomitant medication.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

Needles or intravenous administration sets containing aluminum parts that may come in contact with oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
Carboplatin

Carboplatin

NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin injection.

Single Agent Therapy

Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Combination Therapy with Cyclophosphamide

In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing).

Cyclophosphamide - 600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (see CLINICAL STUDIES).

Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Dose Adjustment Recommendations

Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.
Platelets Neutrophils Adjusted Dose* (From Prior Course) * Percentages apply to carboplatin injection as a single agent or to both carboplatin and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies. > 100,000 > 2,000 125% 50 to 100,000 500 to 2,000 No Adjustment < 50,000 < 500 75%
Carboplatin injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

Patients with Impaired Kidney Function

Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single agent carboplatin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.
Baseline Creatinine Clearance Recommended Dose on Day 1 41 to 59 mL/min 250 mg/m2 16 to 40 mL/min 200 mg/m2
The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance based on the degree of bone marrow suppression.

Formula Dosing

Another approach for determining the initial dose of carboplatin injection is the use of mathematical formulae, which are based on a patient's pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin (see CLINICAL PHARMACOLOGY). The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

A simple formula for calculating dosage, based upon a patient's glomerular filtration rate (GFR in mL/min) and carboplatin injection target area under the concentration versus time curve (AUC in mg/mL•min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

CALVERT FORMULA FOR CARBOPLATIN DOSING

Total Dose (mg) = (target AUC) × (GFR + 25)

Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.

The target AUC of 4 mg/mL•min to 6 mg/mL•min using single agent carboplatin appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent carboplatin administered to previously treated patients and the likelihood of developing toxicity.
% Actual Toxicity in Previously Treated Patients AUC (mg/mL∙min) Gr 3 or Gr 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia 4 to 5 16% 13% 6 to 7 33% 34%
Geriatric Dosing

Because renal function is often decreased in elderly patients, formula dosing of carboplatin injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin injection AUCs and thereby minimize the risk of toxicity.

PREPARATION OF INTRAVENOUS SOLUTIONS

Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin.

Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.

When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution.
Carboplatin

Carboplatin

NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin injection.

Single Agent Therapy

Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Combination Therapy with Cyclophosphamide

In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing).

Cyclophosphamide - 600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (see CLINICAL STUDIES).

Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Dose Adjustment Recommendations

Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.
Platelets Neutrophils Adjusted Dose* (From Prior Course) * Percentages apply to carboplatin injection as a single agent or to both carboplatin and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies. > 100,000 > 2,000 125% 50 to 100,000 500 to 2,000 No Adjustment < 50,000 < 500 75%
Carboplatin injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

Patients with Impaired Kidney Function

Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single agent carboplatin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.
Baseline Creatinine Clearance Recommended Dose on Day 1 41 to 59 mL/min 250 mg/m2 16 to 40 mL/min 200 mg/m2
The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance based on the degree of bone marrow suppression.

Formula Dosing

Another approach for determining the initial dose of carboplatin injection is the use of mathematical formulae, which are based on a patient's pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin (see CLINICAL PHARMACOLOGY). The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

A simple formula for calculating dosage, based upon a patient's glomerular filtration rate (GFR in mL/min) and carboplatin injection target area under the concentration versus time curve (AUC in mg/mL∙min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

CALVERT FORMULA FOR CARBOPLATIN DOSING

Total Dose (mg) = (target AUC) × (GFR + 25)

Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.

The target AUC of 4 mg/mL∙min to 6 mg/mL∙min using single agent carboplatin appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent carboplatin administered to previously treated patients and the likelihood of developing toxicity.
% Actual Toxicity in Previously Treated Patients AUC (mg/mL∙min) Gr 3 or Gr 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia 4 to 5 16% 13% 6 to 7 33% 34%
Geriatric Dosing

Because renal function is often decreased in elderly patients, formula dosing of carboplatin injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin injection AUCs and thereby minimize the risk of toxicity.
Propofol

Propofol

Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

Shake well before use. Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised. Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

When administering propofol injectable emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing propofol injectable emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of propofol injectable emulsion.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate propofol injectable emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of propofol injectable emulsion and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of propofol injectable emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction of General Anesthesia

Adult Patients

Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of propofol injectable emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, propofol injectable emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of propofol injectable emulsion.

Elderly, Debilitated, or ASA-PS III or IV Patients

It is important to be familiar and experienced with the intravenous use of propofol injectable emulsion before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of propofol injectable emulsion for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of propofol injectable emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of propofol injectable emulsion. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering propofol injectable emulsion to pediatric patients. Boluses of propofol injectable emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of propofol injectable emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Cardiac Anesthesia

Propofol injectable emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other anesthetic and sedative-hypnotic agents, propofol injectable emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with propofol injectable emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, propofol injectable emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injectable emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of propofol injectable emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.

A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when propofol injectable emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, propofol injectable emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of propofol injectable emulsion will reduce the opioid requirements (see Table 4). When propofol injectable emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).
Table 4. Cardiac Anesthesia Techniques Primary Agent Rate Secondary Agent/Rate (Following Induction with Primary Agent)
Propofol Injectable Emulsion

OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

Preinduction

Anxiolysis

25 mcg/kg/min

Induction

0.5 to 1.5 mg/kg over 60 sec

Maintenance (Titrated to Clinical Response)

100 to 150 mcg/kg/min

OPIOIDb

Propofol Injectable Emulsion/50 to 100 mcg/kg/min (no bolus)

Induction

25 to 50 mcg/kg

Maintenance

0.2 to 0.3 mcg/kg/min

aOPIOID is defined in terms of fentanyl equivalents, i.e.,1 mcg of fentanyl = 5 mcg of alfentanil (for bolus) = 10 mcg of alfentanil (for maintenance) or = 0.1 mcg of sufentanil

bCare should be taken to ensure amnesia.

Maintenance of General Anesthesia

Propofol injectable emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Adult Patients

In adults, anesthesia can be maintained by administering propofol injectable emulsion by infusion or intermittent IV bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

Propofol injectable emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of propofol injectable emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus

Increments of propofol injectable emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

Propofol injectable emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of propofol injectable emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed. Propofol injectable emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients (see Table 2 Clinical Trials).

Monitored Anesthesia Care (MAC) Sedation

Adult Patients

When propofol injectable emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of propofol injectable emulsion administration will be in the range of 25 to 75 mcg/kg/min.

During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

Initiation of MAC Sedation

For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing propofol injectable emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses. When propofol injectable emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration should be over 3 to 5 minutes and the dosage of propofol injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Maintenance of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of propofol injectable emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of propofol injectable emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration and the dosage of propofol injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Propofol injectable emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When propofol injectable emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of propofol injectable emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

ICU Sedation

(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

Abrupt discontinuation of propofol injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of propofol injectable emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION). With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient's underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

Propofol injectable emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation). For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). Dosages of propofol injectable emulsion should be reduced in patients who have received large dosages of narcotics. The propofol injectable emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES). Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of propofol injectable emulsion required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

SUMMARY OF DOSAGE GUIDELINES

Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older.

For complete dosage information, see DOSAGE AND ADMINISTRATION.
INDICATION DOSAGE AND ADMINISTRATION
Induction of General Anesthesia:

Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).

Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

Pediatric Patients - healthy, from 3 years to 16 years of age: 2.5 to 3.5 mg/kg administered over 20 to 30 seconds (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics).

Maintenance of General Anesthesia:

Infusion

Healthy Adults Less Than 55 Years of Age: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

Elderly, Debilitated, ASA-PS III or IV Patients: 50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

Cardiac Anesthesia: Most patients require: Primary propofol injectable emulsion with Secondary Opioid – 100 to 150 mcg/kg/min. Low-Dose propofol injectable emulsion with Primary Opioid – 50 to 100 mcg/kg/min (see DOSAGE AND ADMINISTRATION, Table 4).

Neurosurgical Patients: 100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

Pediatric Patients - healthy, from 2 months of age to 16 years of age: 125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h) Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics).

Maintenance of General Anesthesia:

Intermittent Bolus

Healthy Adults Less Than 55 Years of Age: Increments of 20 to 50 mg as needed.

Initiation of MAC Sedation:

Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.

Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS).

Maintenance of MAC Sedation:

Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS).

Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of propofol injectable emulsion required for sedation.

The tubing and any unused propofol injectable emulsion drug product should be discarded after 12 hours because propofol injectable emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION).

Administration with Lidocaine

If lidocaine is to be administered to minimize pain on injection of propofol injectable emulsion, it is recommended that it be administered prior to propofol injectable emulsion administration or that it be added to propofol injectable emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg propofol injectable emulsion.

Compatibility and Stability

Propofol injectable emulsion should not be mixed with other therapeutic agents prior to administration.

Dilution Prior to Administration

Propofol injectable emulsion is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration with Other Fluids

Compatibility of propofol injectable emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS). When administered using a y-type infusion set, propofol injectable emulsion has been shown to be compatible with the following intravenous fluids.
- 5% Dextrose Injection, USP - Lactated Ringers Injection, USP - Lactated Ringers and 5% Dextrose Injection - 5% Dextrose and 0.45% Sodium Chloride Injection, USP - 5% Dextrose and 0.2% Sodium Chloride Injection, USP
Handling Procedures

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clinical experience with the use of in-line filters and propofol injectable emulsion during anesthesia or ICU/MAC sedation is limited. Propofol injectable emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of propofol injectable emulsion and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

Do not use if there is evidence of separation of the phases of the emulsion.

Rare cases of self-administration of propofol injectable emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

Strict aseptic technique must always be maintained during handling. Propofol injectable emulsion is a single access parenteral product (single patient infusion vial) which contains sodium metabisulfite (0.25 mg/mL) to retard the rate of growth of microorganisms in the event of accidental extrinsic contamination. However, propofol injectable emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person.

Propofol injectable emulsion, with sodium metabisulfite, inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

Propofol injectable emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. Propofol injectable emulsion should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing propofol injectable emulsion from vials, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

Propofol injectable emulsion must be prepared for single-patient use only. Any unused propofol injectable emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing propofol injectable emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual propofol injectable emulsion.

Guidelines for Aseptic Technique for ICU Sedation

Propofol injectable emulsion must be prepared for single-patient use only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of propofol injectable emulsion. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused propofol injectable emulsion drug product must be discarded after 12 hours.

If propofol injectable emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing propofol injectable emulsion from a vial, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. Propofol injectable emulsion should be discarded and administration lines changed after 12 hours.
V-max

V-max

Usual Dose

The recommended adult dose of fludarabine phosphate for injection is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from fludarabine phosphate for injection. These include advanced age, renal impairment, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of fludarabine phosphate for injection be administered following the achievement of a maximal response and then the drug should be discontinued.

Renal Impairment

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine phosphate for injection should not be administered to patients with creatinine clearance less than 30 mL/min.

Starting Dose Adjustment for Renal Impairment

Creatinine Clearance

Starting Dose

≥ 80 mL/min

25 mg/m2(full dose)

50 to 79 mL/min

20 mg/m2

30 to 49 mL/min

15 mg/m2

< 30 mL/min

do not administer

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

Preparation of Solutions

Fludarabine phosphate for injection should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 to 8.2. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP or 0.9% Sodium Chloride, USP.

Reconstituted fludarabine phosphate for injection contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Fludarabine phosphate for injection should not be mixed with other drugs.

Handling and Disposal

Procedures for proper handling and disposal should be considered. Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published. 1-4

Caution should be exercised in the handling and preparation of fludarabine phosphate for injection solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.
Methylprednisolone Acet...

Methylprednisolone Acetate

Because of possible physical incompatibilities, methylprednisolone acetate injectable suspension should not be diluted or mixed with other solutions.

The initial dosage of parenterally administered methylprednisolone acetate injectable suspension will vary from 4 to 120 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

It Should Be Emphasized that Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation, it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

A. Administration for Local Effect

Therapy with methylprednisolone acetate injectable suspension does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.

1. Rheumatoid Arthritis and Osteoarthritis

The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks, depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide:

Size of Joint

Examples

Range of Dosage

Large

KneesAnklesShoulders

20 to 80 mg

Medium

ElbowsWrists

10 to 40 mg

Small

MetacarpophalangealInterphalangealSternoclavicularAcromioclavicular

4 to 10 mg

Procedure: It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti-inflammatory effect, it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of methylprednisolone acetate injectable suspension. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing.

Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile.

If a local anesthetic is used prior to injection of methylprednisolone acetate injectable suspension, the anesthetic package insert should be read carefully and all the precautions observed.

2. Bursitis

The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied.

3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis

In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken, following application of a suitable antiseptic to the overlying skin, to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection.

The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary.

4. Injections for Local Effect in Dermatologic Conditions

Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60 mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection.

B. Administration for Systemic Effect

The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each 24 hour period of a dose of the suspension equal to the total daily oral dose of methylprednisolone tablets is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection.

In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated. Dosage must be individualized according to the severity of the disease and response of the patient. The recommended dosage may be reduced for pediatric patients, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight.

In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120 mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80 to 120 mg. In chronic contact dermatitis, repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition.

Following intramuscular administration of 80 to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks. Similarly, in patients with allergic rhinitis (hay fever), an intramuscular dose of 80 to 120 mg may be followed by relief of coryzal symptoms within six hours persisting for several days to three weeks.

If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated.

In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective.

For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids:

Cortisone, 25

Triamcinolone, 4

Hydrocortisone, 20

Paramethasone, 2

Prednisolone, 5

Netamethasone, 0.75

Prednisone, 5

Dexamethasone, 0.75

Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.
Methylprednisolone Acet...

Methylprednisolone Acetate

NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS, Pediatric Use).

Because of possible physical incompatibilities, methylprednisolone acetate injectable suspension should not be diluted or mixed with other solutions.

The initial dosage of parenterally administered methylprednisolone acetate injectable suspension will vary from 4 to 120 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

It Should Be Emphasized that Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation, it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient's condition. If after long term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

A. Administration for Local Effect

Therapy with methylprednisolone acetate injectable suspension does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.

1. Rheumatoid Arthritis and Osteoarthritis

The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks, depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide:
Size of Joint Examples Range of Dosage
Large

KneesAnklesShoulders

20 to 80 mg

Medium

ElbowsWrists

10 to 40 mg

Small

Metacarpophalangeal InterphalangealSternoclavicular Acromioclavicular

4 to 10 mg

Procedure: It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti-inflammatory effect, it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of methylprednisolone acetate injectable suspension. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing.

Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile.

If a local anesthetic is used prior to injection of methylprednisolone acetate injectable suspension, the anesthetic package insert should be read carefully and all the precautions observed.

2. Bursitis

The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied.

3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis

In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken following application of a suitable antiseptic to the overlying skin to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection.

The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary.

4. Injections for Local Effect in Dermatologic Conditions

Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60 mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection.

When multidose vials are used, special care to prevent contamination of the contents is essential. (See WARNINGS.)

B. Administration for Systemic Effect

The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each 24 hour period of a dose of the suspension equal to the total daily oral dose of methylprednisolone tablets is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection.

In pediatric patients, the initial dose of methylprednisolone may vary depending upon the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day. Dosage must be individualized according to the severity of the disease and response of the patient.

In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120 mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80 to 120 mg. In chronic contact dermatitis, repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition.

Following intramuscular administration of 80 to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks. Similarly, in patients with allergic rhinitis (hay fever), an intramuscular dose of 80 to 120 mg may be followed by relief of coryzal symptoms within six hours persisting for several days to three weeks.

If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated.

In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective.

For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids:

Cortisone, 25

Triamcinolone, 4

Hydrocortisone, 20

Paramethasone, 2

Prednisolone, 5

Netamethasone, 0.75

Prednisone, 5

Dexamethasone, 0.75

Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.
Enoxaparin Sodium

Enoxaparin Sodium

All patients should be evaluated for a bleeding disorder before administration of enoxaparin sodium injection USP, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring enoxaparin sodium injection USP activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9)].

For subcutaneous use, enoxaparin sodium injection USP should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), enoxaparin sodium injection USP can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

Enoxaparin sodium injection USP is not intended for intramuscular administration.

2.1 Adult Dosage

Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of enoxaparin sodium injection USP is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of enoxaparin sodium injection USP is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with enoxaparin sodium injection USP 40 mg once a day be administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of enoxaparin sodium injection USP is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of enoxaparin sodium injection USP has been administered in the controlled clinical trial.

Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of enoxaparin sodium injection USP is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of enoxaparin sodium injection USP is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of enoxaparin sodium injection USP). Enoxaparin sodium injection USP should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of enoxaparin sodium injection USP administration has been administered in controlled clinical trials.

Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of enoxaparin sodium injection USP is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with enoxaparin sodium injection USP should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of enoxaparin sodium injection USP has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].

Treatment of Acute ST-Segment Elevation Myocardial Infarction:In patients with acute ST-segment elevation myocardial infarction, the recommended dose of enoxaparin sodium injection USP is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥ 75 years of age [see Dosage and Administration (2.3)]. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated.

When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), enoxaparin sodium injection USP should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. In the pivotal clinical study, the enoxaparin sodium injection USP treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.

For patients managed with percutaneous coronary intervention (PCI): If the last enoxaparin sodium injection USP SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last enoxaparin sodium injection USP SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin sodium injection USP should be administered [see Warnings and Precautions (5.2)].

2.2 Renal Impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30 to 50 mL/min) and mild (creatinine clearance 50 to 80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.

The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance < 30 mL/min) are described in Table 1 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Table 1: Dosage Regimens for Patients With Severe Renal Impairment (Creatinine Clearance < 30 mL/Minute)
Indication

Dosage Regimen

Prophylaxis in abdominal surgery

30 mg administered SC once daily

Prophylaxis in hip or knee replacement surgery

30 mg administered SC once daily

Prophylaxis in medical patients during acute illness

30 mg administered SC once daily

Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium

1 mg/kg administered SC once daily

Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium

1 mg/kg administered SC once daily

Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin

1 mg/kg administered SC once daily

Treatment of acute ST-segment elevation myocardial infarction in patients < 75 years of age, when administered in conjunction with aspirin

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily.

Treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥ 75 years of age, when administered in conjunction with aspirin

1 mg/kg administered SC once daily (no initial bolus)

2.3 Geriatric Patients With Acute ST-Segment Elevation Myocardial Infarction

For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥ 75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2)].

2.4 Administration

Enoxaparin sodium injection USP is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

Enoxaparin sodium injection USP must not be administered by intramuscular injection. Enoxaparin sodium injection USP is intended for use under the guidance of a physician.

For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.

Subcutaneous Injection Technique: Patients should be lying down and enoxaparin sodium injection USP administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.

Enoxaparin sodium injection USP prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection.

Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister. Do not remove by pulling on the plunger as this may damage the syringe.

1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.

Figure A

Figure A

2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B).

Figure B

Figure B

3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C).

Figure C

Figure C

4. Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation (see Figure D).

Figure D

Figure D

5. Immediately dispose of the syringe in the nearest sharps container (see Figure E).

Figure E

Figure E

NOTE:
• The safety system can only be activated once the syringe has been emptied. • Activation of the safety system must be done only after removing the needle from the patient’s skin. • Do not replace the needle shield after injection. • The safety system should not be sterilized.
Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others.

Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should be used. Enoxaparin sodium injection USP should be administered through an intravenous line. Enoxaparin sodium injection USP should not be mixed or coadministered with other medications. To avoid the possible mixture of enoxaparin sodium injection USP with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of enoxaparin sodium injection USP to clear the port of drug. Enoxaparin sodium injection USP may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.

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