Bedford Laboratories

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Bedford Laboratories Drugs

Amifostine

Amifostine

For Reduction of Cumulative Renal Toxicity with Chemotherapy:

The recommended starting dose of Amifostine for Injection is 910 mg/m2 administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior to chemotherapy.

The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.

Patients should be adequately hydrated prior to Amifostine for Injection infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.

The infusion of Amifostine for Injection should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
Guideline for Interrupting Amifostine for Injection Infusion Due to Decrease in Systolic Blood Pressure Baseline Systolic Blood Pressure (mm Hg) <100 100-119 120-139 140-179 ≥180 Decrease in systolic blood pressure during infusion of Amifostine for Injection (mm Hg) 20 25 30 40 50
If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted so that the full dose of Amifostine for Injection may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine for subsequent chemotherapy cycles should be 740 mg/m2.

It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor antagonist, be administered prior to and in conjunction with Amifostine for Injection. Additional antiemetics may be required based on the chemotherapy drugs administered.

For Reduction of Moderate to Severe Xerostomia from Radiation of the Head and Neck:

The recommended dose of Amifostine for Injection is 200 mg/m2 administered once daily as a 3-minute i.v. infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).

Patients should be adequately hydrated prior to Amifostine for Injection infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.

It is recommended that antiemetic medication be administered prior to and in conjunction with Amifostine for Injection. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.

Reconstitution

Amifostine for Injection is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.

Prior to intravenous injection, Amifostine for Injection is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) is chemically stable for up to 5 hours at room temperature (approximately 25°C) or up to 24 hours under refrigeration (2°C to 8°C).

Amifostine for Injection prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5 mg/mL to 40 mg/mL is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C) or up to 24 hours when stored under refrigeration (2°C to 8°C).

CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate is observed.

Incompatibilities

The compatibility of Amifostine for Injection with solutions other than 0.9% Sodium Chloride for Injection, or Sodium Chloride solutions with other additives, has not been examined. The use of other solutions is not recommended.
Topotecan Hydrochloride...

Topotecan Hydrochloride

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

Prior to administration of the first course of topotecan hydrochloride for injection, patients must have a baseline neutrophil count of >1,500 cells/mm

3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage:
The recommended dose of topotecan hydrochloride for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed and median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.Dosage Modification Guidelines: In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses.
2.2 Cervical Cancer

Recommended Dosage: The recommended dose of topotecan hydrochloride for injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines: Dosage adjustments for subsequent courses of topotecan hydrochloride for injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.
In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of topotecan hydrochloride for injection to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride for injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride for injection to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses.
2.3 Dosage Adjustment in Specific Populations

Renal Impairment: No dosage adjustment of topotecan hydrochloride for injection appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of topotecan hydrochloride for injection to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride for injection [see Use in Specific Populations (8.6) and ClinicalPharmacology (12.3)].

Topotecan hydrochloride for injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride for injection after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Adminstration

Handling: Topotecan hydrochloride for injection is a cytotoxic anticancer drug. Prepare topotecan hydrochloride for injection under a vertical laminar flow hood while wearing gloves and protective clothing. If topotecan hydrochloride for injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If topotecan hydrochloride for injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4

Preparation and Administration: Each 4 mg vial of topotecan hydrochloride for injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability: Unopened vials of topotecan hydrochloride for injection are stable until the date indicated on the package when stored at 20°-25°C (68°-77°F); [See USP Controlled Room Temperature] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of topotecan hydrochloride for injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.
Leucovorin Calcium

Leucovorin Calcium

Advanced Colorectal Cancer

Either of the following two regimens is recommended:
1. Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. 2. Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5-fluorouracil at 425 mg/m 2 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 alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 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
NormalMethotrexate Elimination

Serum methotrexate level approximately 10 micromo-molar 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 micrommolar at 72 hours, and more than 0.05 micromolar 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 alkalization, 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 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 x 10-6 M or the 48 hour level is greater than 9 x 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 7.0 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 50, 100, and 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 5, 10, and 20 mL, respectively, 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 per mL. Leucovorin Calcium for Injection contains no preservative. Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection (benzyl alcohol preserved), or Sterile Water for Injection. When reconstituted with Bacteriostatic Water for Injection, the resulting solution must be used within 7 days. If the product is reconstituted with Sterile Water for Injection, use immediately and discard any unused portion.

Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, 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.
Acyclovir

Acyclovir

CAUTION - RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS).

INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED (seeWARNINGS).

Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections.

A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.

DOSAGE

HERPES SIMPLEX INFECTIONS: MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 AND HSV-2) INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

Adults and Adolescents (12 years of age and older): 5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Pediatrics (Under 12 years of age): 10 mg/kg infused at a constant rate over

1 hour, every 8 hours for 7 days.

SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

Adults and Adolescents (12 years of age and older): 5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

HERPES SIMPLEX ENCEPHALITIS:

Adults and Adolescents (12 years of age and older): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

Pediatrics (3 months to 12 years of age): 20 mg/kg infused at a constant rate over at least 1 hour, every 8 hours for 10 days.

Neonatal Herpes Simplex Virus Infections (Birth to 3 months): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days. In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

VARICELLA ZOSTER INFECTIONS: ZOSTER IN IMMUNOCOMPROMISED PATIENTS:

Adults and Adolescents (12 years of age and older): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Pediatrics (Under 12 years of age): 20 mg/kg infused at a constant rate over

1 hour, every 8 hours for 7 days.

Obese Patients: Obese patients should be dosed at recommended adult dose using Ideal Body Weight.

Patients with Acute or Chronic Renal Impairment: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.
Table 5: Dosage Adjustments for Patients with Renal Impairment
Creatinine Clearance

(mL/min/1.73 m2)

Percent of Recommended Dose

Dosing Interval

(hours)

> 5025 – 5010 – 250 – 10

100%100%100%50%

8122424

Hemodialysis

For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6 hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

Peritoneal Dialysis

No supplemental dose appears to be necessary after adjustment of the dosing interval.

Method of Preparation

Each 10 mL vial contains acyclovir sodium equivalent to 500 mg of acyclovir. Each 20 mL vial contains acyclovir sodium equivalent to 1000 mg of acyclovir. The contents of the vial should be dissolved in Sterile Water for Injection as follows:

Contents of Vial

Amount of Diluent

500 mg

10 mL

1000 mg

20 mL

The resulting solution in each case contains 50 mg acyclovir per mL (pH approximately 11). Shake the vial well to assure complete dissolution before measuring and transferring each individual dose. The reconstituted solution should be used within 12 hours. Refrigeration of reconstituted solution may result in the formation of a precipitate which will redissolve at room temperature.

DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING BENZYL ALCOHOL OR PARABENS.

ADMINISTRATION

The calculated dose should then be removed and added to any appropriate intravenous solution at a volume selected for administration during each 1 hour infusion. Infusion concentrations of approximately 7 mg/mL or lower are recommended. In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose. Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation. Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

Once diluted for administration, each dose should be used within 24 hours.

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

Prochlorperazine Edisylate

Notes on Injection

For intramuscular administration, inject deeply into the upper, outer quadrant of the buttock. Subcutaneous administration is not advisable because of local irritation.

Stability

This solution should be protected from light. A slight yellowish discoloration will not alter potency. If markedly discolored, solution should be discarded.

Compatibility

It is recommended that prochlorperazine injection not be mixed with other agents in the syringe.

ADULTS

(For children's dosage and administration, see below.) Dosage should be increased more gradually in debilitated or emaciated patients.

Elderly Patients

In general, dosages in the lower range are sufficient for most elderly patients. Since they appear to be more susceptible to hypotension and neuromuscular reactions, such patients should be observed closely. Dosage should be tailored to the individual, response carefully monitored and dosage adjusted accordingly. Dosage should be increased more gradually in elderly patients.

To Control Severe Nausea and Vomiting: Adjust dosage to the response of the individual. Begin with the lowest recommended dosage.I.M. Dosage: Initially 5 to 10 mg (1 to 2 mL) injected deeply into the upper outer quadrant of the buttock. If necessary, repeat every 3 or 4 hours. Total I.M. dosage should not exceed 40 mg per day. I.V. Dosage: 2.5 to 10 mg (0.5 to 2 mL) by slow I.V. injection or infusion at a rate not to exceed 5 mg per minute. Prochlorperazine edisylate injection may be administered either undiluted or diluted in isotonic solution. A single dose of the drug should not exceed 10 mg; total I.V. dosage should not exceed 40 mg per day. When administered I.V., do not use bolus injection. Hypotension is a possibility if the drug is given by I.V. injection or infusion. Subcutaneous administration is not advisable because of local irritation.

Adult Surgery (for severe nausea and vomiting): Total parenteral dosage should not exceed 40 mg per day. Hypotension is a possibility if the drug is given by I.V. injection or infusion. I.M. Dosage: 5 to 10 mg (1 to 2 mL) 1 to 2 hours before induction of anesthesia (repeat once in 30 minutes, if necessary), or to control acute symptoms during and after surgery (repeat once if necessary). I.V. Dosage: 5 to 10 mg (1 to 2 mL) as a slow I.V. injection or infusion 15 to 30 minutes before induction of anesthesia, or to control acute symptoms during or after surgery. Repeat once if necessary. Prochlorperazine may be administered either undiluted or diluted in isotonic solution, but a single dose of the drug should not exceed 10 mg. The rate of administration should not exceed 5 mg per minute. When administered I.V., do not use bolus injection.

In Adult Psychiatric Disorders: Adjust dosage to the response of the individual and according to the severity of the condition. Begin with the lowest recommended dose. Although response ordinarily is seen within a day or 2, longer treatment is usually required before maximal improvement is seen.I.M. Dosage: For immediate control of adult schizophrenic patients with severe symptomatology, inject an initial dose of 10 to 20 mg (2 to 4 mL) deeply into the upper outer quadrant of the buttock. Many patients respond shortly after the first injection. If necessary, however, repeat the initial dose every 2 to 4 hours (or, in resistant cases, every hour) to gain control of the patient. More than three or four doses are seldom necessary. After control is achieved, switch patient to an oral form of the drug at the same dosage level or higher. If, in rare cases, parenteral therapy is needed for a prolonged period, give 10 to 20 mg (2 to 4 mL) every 4 to 6 hours. Pain and irritation at the site of injection have seldom occurred.Subcutaneous administration is not advisable because of local irritation.

CHILDREN

DO NOT USE IN PEDIATRIC SURGERY.

Children seem more prone to develop extrapyramidal reactions, even on moderate doses. Therefore, use lowest effective dosage. Tell parents not to exceed prescribed dosage, since the possibility of adverse reactions increases as dosage rises.

Occasionally the patient may react to the drug with signs of restlessness and excitement; if this occurs, do not administer additional doses. Take particular precaution in administering the drug to children with acute illnesses or dehydration (see under PRECAUTIONS and Dystonia).

Severe Nausea and Vomiting in Children: Prochlorperazine should not be used in pediatric patients under 20 pounds in weight or 2 years of age. It should not be used in conditions for which children's dosages have not been established. Dosage and frequency of administration should be adjusted according to the severity of the symptoms and the response of the patient. The duration of activity following intramuscular administration may last up to 12 hours. Subsequent doses may be given by the same route if necessary.I.M. Dosage: Calculate each dose on the basis of 0.06 mg of the drug per lb of body weight; give by deep I.M. injection. Control is usually obtained with one dose.

Children with Schizophrenia: I.M. Dosage: For ages under 12, calculate each dose on the basis of 0.06 mg of prochlorperazine per lb of body weight; give by deep I.M. injection. Control is usually obtained with one dose. After control is achieved, switch the patient to an oral form of the drug at the same dosage level or higher.

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

Metoprolol Tartrate

Myocardial Infarction

Early Treatment

During the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol tartrate as soon as possible after the patient’s arrival in the hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the patient’s hemodynamic condition has stabilized.

Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of metoprolol tartrate each; give the injections at approximately 2 minute intervals. During the intravenous administration of metoprolol tartrate, monitor blood pressure, heart rate, and electrocardiogram.

In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the maintenance dosage is 100 mg orally twice daily.

Start patients who appear not to tolerate the full intravenous dose on metoprolol tartrate tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance, discontinue metoprolol tartrate (see WARNINGS).

Special populations

Pediatric patients: No pediatric studies have been performed. The safety and efficacy of metoprolol tartrate in pediatric patients have not been established.

Renal impairment: No dose adjustment of metoprolol tartrate is required in patients with renal impairment.

Hepatic impairment: Metoprolol tartrate blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, metoprolol tartrate should be initiated at low doses with cautious gradual dose titration according to clinical response.

Geriatric patients (>65 years): In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Method of administration:

Parenteral administration of metoprolol tartrate should be done in a setting with intensive monitoring.

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

Amikacin Sulfate

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 micrograms per mL and trough concentrations (just prior to the next dose) above 10 micrograms per 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 gram/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

5 mg/kg

q12h

OR

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 administrating 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:

Maintenance Dose = observed CC in mL/min X Calculated loading dose Every 12 Hours normal CC in mL/min in mg (CC-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 of the 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 ordered for the patient. It should be a sufficient amount to infuse the Amikacin Sulfate Injection 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 5.0 mg/mL in the following solutions:

5% Dextrose Injection

5% Dextrose and 0.2% Sodium Chloride Injection

5% Dextrose and 0.45% Sodium Chloride Injection

0.9% Sodium Chloride Injection

Lactated Ringer’s Injection

Normosol® M in 5% Dextrose Injection (or Plasma-Lyte 56 Injection in 5% Dextrose in Water)

Normosol® R in 5% Dextrose Injection (or Plasma-Lyte 148 Injection in 5% Dextrose in Water)

In the above solutions with Amikacin Sulfate Injection 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 the 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.
Valproate Sodium

Valproate Sodium

2.1 Epilepsy

Valproate sodium injection is for intravenous use only.

Use of valproate sodium injection for periods of more than 14 days has not been studied. Patients should be switched to oral valproate products as soon as it is clinically feasible.

Valproate sodium injection should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.

In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma levels of valproate were given single infusions of valproate sodium injection (up to 15 mg/kg and mean dose of 1184 mg) over 5 to 10 minutes (1.5 to 3 mg/kg/min). Patients generally tolerated the more rapid infusions well [see AdverseReactions (6.1)]. This study was not designed to assess the effectiveness of these regimens. For pharmacokinetics with rapid infusions, see Clinical Pharmacology (12.3).

Initial Exposure to Valproate

The following dosage recommendations were obtained from studies utilizing oral divalproex sodium products.

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Valproate sodium injection has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of valproate sodium injection therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Valproate sodium injection may be added to the patient’s regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see ClinicalStudies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [seeClinical Pharmacology (12.3)].

As the valproate sodium injection dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Replacement Therapy

When switching from oral valproate products, the total daily dose of valproate sodium injection should be equivalent to the total daily dose of the oral valproate product [see Clinical Pharmacology (12)], and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary. Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be monitored more closely. If the total daily dose exceeds 250 mg, it should be given in a divided regimen. There is no experience with more rapid infusions in patients receiving valproate sodium injection as replacement therapy. However, the equivalence shown between valproate sodium injection and oral valproate products (divalproex sodium) at steady state was only evaluated in an every 6 hour regimen. Whether, when valproate sodium injection is given less frequently (i.e., twice or three times a day), trough levels fall below those that result from an oral dosage form given via the same regimen, is unknown. For this reason, when valproate sodium injection is given twice or three times a day, close monitoring of trough plasma levels may be needed.

2.2 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific Populations (8.5) andClinical Pharmacology (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Administration

Rapid infusion of valproate sodium injection has been associated with an increase in adverse reactions. There is limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min in patients with epilepsy [see Adverse Reactions (6)].

Valproate sodium injection should be administered intravenously as a 60 minute infusion, as noted above. It should be diluted with at least 50 mL of a compatible diluent. Any unused portion of the vial contents should be discarded.

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

Compatibility and Stability

Valproate sodium injection was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature 15 to 30°C (59 to 86°F).
• dextrose (5%) injection, USP • sodium chloride (0.9%) injection, USP • lactated ringer’s injection, USP
Cafcit

Cafcit

Prior to initiation of CAFCIT (caffeine citrate), baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta.

The recommended loading dose and maintenance doses of CAFCIT follow.

Dose of CAFCIT (caffeine citrate) Volume

Dose of CAFCIT (caffeine citrate) mg/kg

Route

Frequency

Loading Dose

1 mL/kg

20 mg/kg

Intravenous* (over 30 minutes)

One Time

Maintenance Dose

0.25 mL/kg

5 mg/kg

Intravenous*

(over 10 minutes) or Orally

Every 24 hours**

*using a syringe infusion pump

**beginning 24 hours after the loading dose

NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base).

Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. Serious toxicity has been associated with serum levels greater than 50 mg/L.

CAFCIT should be inspected visually for particulate matter and discoloration prior to administration. Vials containing discolored solution or visible particulate matter should be discarded.

Drug Compatibility

To test for drug compatibility with common intravenous solutions or medications, 20 mL of CAFCIT (caffeine citrate) Injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid® admixture, which was combined as 80 mL/80 mL. The physical appearance of the combined solutions was evaluated for precipitation. The admixtures were mixed for 10 minutes and then assayed for caffeine. The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.

Based on this testing, CAFCIT (caffeine citrate) Injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.

• Dextrose Injection, USP 5%

• 50% Dextrose Injection USP

• Intralipid® 20% IV Fat Emulsion

• Aminosyn® 8.5% Crystalline Amino Acid Solution

• Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5% • Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL)

• Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5%

• Fentanyl Citrate Injection, USP 50 μg/mL diluted to 10 μg/mL with Dextrose Injection, USP 5%
Rifampin

Rifampin

Rifampin for Injection is administered by IV infusion (see INDICATIONS AND USAGE).

See CLINICAL PHARMACOLOGY for dosing information in patients with renal failure.

Tuberculosis

Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, IV.

Pediatric Patients: 10 to 20 mg/kg, not to exceed 600 mg/day, IV.

Rifampin is indicated in the treatment of all forms of tuberculosis. A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide (e.g., RIFATER®) is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE®) for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Preparation of Solution for IV Infusion

Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for 24 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 4 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 24 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

Incompatibilities

Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem hydrochloride and rifampin (6 mg/mL in normal saline) during simulated Y-site administration.

Meningococcal Carriers

Adults: For adults, it is recommended that 600 mg rifampin be administered twice daily for two days.

Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to exceed 600 mg per dose) every 12 hours for two days.

Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.
Levocarnitine

Levocarnitine

Levocarnitine Injection is administered intravenously. The recommended dose is 50 mg/kg given as a slow 2 to 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 level 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 level should be between 35 and 60 micromoles/liter) and overall clinical condition.

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

Compatibility and Stability

Levocarnitine Injection USP is compatible and stable when mixed in parenteral solutions of Sodium Chloride 0.9% or Lactated Ringer's in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8.0 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags.
Phentolamine Mesylate

Phentolamine Mesylate

The reconstituted solution should be used upon preparation and should not be stored.
1. Prevention or control of hypertensive episodes in the patient with pheochromo-cytoma. For preoperative reduction of elevated blood pressure, 5 mg of phentolamine mesylate (1 mg for children) is injected intravenously or intramuscularly 1 or 2 hours before surgery, and repeated if necessary. During surgery, phentolamine mesylate (5 mg for adults, 1 mg for children) is administered intravenously as indicated, to help prevent or control paroxysms of hypertension, tachycardia, respiratory depression, convulsions, or other effects of epinephrine intoxication. (Postoperatively, norepinephrine may be given to control the hypotension that commonly follows complete removal of a pheochromocytoma.) 2. Prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. For Prevention: 10 mg of phentolamine mesylate is added to each liter of solution containing norepinephrine. The pressor effect of norepinephrine is not affected. For Treatment: 5 to 10 mg of phentolamine mesylate in 10 mL of saline is injected into the area of extravasation within 12 hours. 3. Diagnosis of pheochromocytoma - phentolamine blocking test. The test is most reliable in detecting pheochromocytoma in patients with sustained hypertension and least reliable in those with paroxysmal hypertension. False-positive tests may occur in patients with hypertension without pheochromocytoma.
a. Intravenous

Preparation

The CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections should be reviewed. Sedatives, analgesics, and all other medications except those that might be deemed essential (such as digitalis and insulin) are withheld for at least 24 hours, and preferably 48 to 72 hours, prior to the test. Antihypertensive drugs are withheld until blood pressure returns to the untreated, hypertensive level. This test is not preformed on a patient who is normotensive.

Procedure

The patient is kept at rest in a supine position throughout the test, preferably in a quiet, darkened room. Injection of phentolamine is delayed until blood pressure is stabilized, as evidenced by blood pressure readings taken every 10 minutes for at least 30 minutes.

Five milligrams of phentolamine mesylate is dissolved in 1 mL of Sterile Water for Injection. The dose for adults is 5 mg; for children, 1 mg.

The syringe needle is inserted into the vein, and injection is delayed until pressor response to venipuncture has subsided.

Phentolamine is injected rapidly. Blood pressure is recorded immediately after injection, at 30-second intervals for the first 3 minutes, and at 60-second intervals for the next 7 minutes.

Interpretation

A positive response, suggestive of pheochromocytoma, is indicated when the blood pressure is reduced more than 35 mm Hg systolic and 25 mm Hg diastolic. A typical positive response is a reduction in pressure of 60 mm Hg systolic and 25 mm Hg diastolic. Usually, maximal effect is evident within 2 minutes after injection. A return to preinjection pressure commonly occurs within 15 to 30 minutes but may occur more rapidly.

If blood pressure decreases to a dangerous level, the patient should be treated as outlined under OVERDOSAGE.

A positive response should always be confirmed by other diagnostic procedures, preferably by measurement of urinary catecholamines or their metabolites.

A negative response is indicated when the blood pressure is elevated, unchanged, or reduced less than 35 mm Hg systolic and 25 mm Hg diastolic after injection of phentolamine. A negative response to this test does not exclude the diagnosis of pheo-chromocytoma, especially in patients with paroxysmal hypertension in whom the incidence of false-negative responses is high.

b. Intramuscular

If the intramuscular test for pheochromocytoma is preferred, preparation is the same as for the intravenous test. Five milligrams of phentolamine mesylate is then dissolved in 1 mL of Sterile Water for Injection. The dose for adults is 5 mg intramuscularly; for children, 3 mg. Blood pressure is recorded every 5 minutes for 30 to 45 minutes following injection. A positive response is indicated when the blood pressure is reduced 35 mm Hg systolic and 25 mm Hg diastolic, or more, within 20 minutes following injection.

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

Diltiazem Hydrochloride

Direct Intravenous Single Injections (Bolus)

The initial dose of diltiazem hydrochloride injection should be 0.25 mg/kg actual body weight as a bolus administered over 2 minutes (20 mg is a reasonable dose for the average patient). If response is inadequate, a second dose may be administered after 15 minutes. The second bolus dose of diltiazem hydrochloride injection should be 0.35 mg/kg actual body weight administered over 2 minutes (25 mg is a reasonable dose for the average patient). Subsequent intravenous bolus doses should be individualized for each patient. Patients with low body weights should be dosed on a mg/kg basis. Some patients may respond to an initial dose of 0.15 mg/kg, although duration of action may be shorter. Experience with this dose is limited.

Continuous Intravenous Infusion

For continued reduction of the heart rate (up to 24 hours) in patients with atrial fibrillation or atrial flutter, an intravenous infusion of diltiazem hydrochloride may be administered. Immediately following bolus administration of 20 mg (0.25 mg/kg) or 25 mg (0.35 mg/kg) diltiazem hydrochloride injection and reduction of heart rate, begin an intravenous infusion of diltiazem hydrochloride. The recommended initial infusion rate of diltiazem hydrochloride is 10 mg/h. Some patients may maintain response to an initial rate of 5 mg/h. The infusion rate may be increased in 5 mg/h increments up to 15 mg/h as needed, if further reduction in heart rate is required. The infusion may be maintained for up to 24 hours.

Diltiazem shows dose-dependent, non-linear pharmacokinetics. Duration of infusion longer than 24 hours and infusion rates greater than 15 mg/h have not been studied. Therefore, infusion duration exceeding 24 hours and infusion rates exceeding 15 mg/h are not recommended.

Dilution: To prepare diltiazem hydrochloride injection for continuous intravenous infusion, aseptically transfer the appropriate quantity (see chart) of diltiazem hydrochloride injection to the desired volume of either Normal Saline, D5W, or D5W/0.45% NaCl. Mix thoroughly. Use within 24 hours. Keep refrigerated until use.
* 5 mg/h may be appropriate for some patients
Diluent Volume

Quantity of

Diltiazem HCl

Injection to Add

Final

Concentration

Administration Dose*

Infusion Rate

100 mL

125 mg (25 mL)

Final Volume 125 mL

1 mg/mL

10 mg/h

15 mg/h

10 mL/h

15 mL/h

250 mL

250 mg (50 mL)

Final Volume 300 mL

0.83 mg/mL

10 mg/h

15 mg/h

12 mL/h

18 mL/h

500 mL

250 mg (50 mL)

Final Volume 550 mL

0.45 mg/mL

10 mg/h

15 mg/h

22 mL/h

33 mL/h

Compatibility: Diltiazem hydrochloride injection was tested for compatibility with three commonly used intravenous fluids at a maximal concentration of 1 mg diltiazem hydrochloride per milliliter. Diltiazem hydrochloride injection was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinylchloride (PVC) bags at controlled room temperature 15° to 30°C (59° to 86°F) or under refrigeration 2° to 8°C (36° to 46°F).
• dextrose (5%) injection • sodium chloride (0.9%) injection • dextrose (5%) and sodium chloride (0.45%) injection
Physical Incompatibilities: Because of potential physical incompatibilities, it is recommended that diltiazem hydrochloride not be mixed with any other drugs in the same container. If possible, it is recommended that diltiazem hydrochloride not be co-infused in the same intravenous line.

Physical incompatibilities (precipitate formation or cloudiness) were observed when diltiazem hydrochloride injection was infused in the same intravenous line with the following drugs: acetazolamide, acyclovir, aminophylline, ampicillin, ampicillin sodium/sulbactam sodium, cefamandole, cefoperazone, diazepam, furosemide, hydrocortisone sodium succinate, insulin (regular: 100 units/mL), methylprednisolone sodium succinate, mezlocillin, nafcillin, phenytoin, rifampin, and sodium bicarbonate.

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

Transition to Further Antiarrhythmic Therapy.

Transition to other antiarrhythmic agents following administration of diltiazem hydrochloride injection is generally safe. However, reference should be made to the respective agent manufacturer’s package insert for information relative to dosage and administration.

In controlled clinical trials, therapy with antiarrhythmic agents to maintain reduced heart rate in atrial fibrillation or atrial flutter or for prophylaxis of PSVT was generally started within 3 hours after bolus administration of diltiazem hydrochloride. These antiarrhythmic agents were intravenous or oral digoxin, Class 1 antiarrhythmics (e.g., quinidine, procainamide), calcium channel blockers, and oral beta-blockers.

Experience in the use of antiarrhythmic agents following maintenance infusion of diltiazem hydrochloride injection is limited. Patients should be dosed on an individual basis and reference should be made to the respective manufacturer’s package insert for information relative to dosage and administration.
Octreotide Acetate

Octreotide Acetate

Octreotide acetate may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of octreotide acetate 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 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 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 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 reevaluated at 6 month intervals.

Octreotide acetate 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 therapy may be resumed.

Carcinoid Tumors

The suggested daily dosage of octreotide acetate 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.
Milrinone Lactate

Milrinone Lactate

Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines:

LOADING DOSE

50 mcg/kg: Administer slowly over 10 minutes

The table below shows the loading dose in milliliters (mL) of milrinone (1mg/mL) by patient body weight (kg).
Loading Dose (mL) Using 1 mg/mL Concentration
Patient Body Weight (kg)

kg

30

40

50

60

70

80

90

100

110

120

mL

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (see Maintenance Dose for diluents) may simplify the visualization of the injection rate.

MAINTENANCE DOSE

Infusion Rate

Total Daily Dose (24 hours)

Minimum

0.375 mcg/kg/min

0.59 mg/kg

Administer as a continuous intravenous infusion.

Standard

0.50 mcg/kg/min

0.77 mg/kg

Maximum

0.75 mcg/kg/min

1.13 mg/kg

Milrinone drawn from vials should be diluted prior to maintenance dose administration. The diluents that may be used are 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The table below shows the volume of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL concentration for infusion, and the resultant total volumes.

Desired Infusion

Concentration

mcg/mL

Milrinone

1 mg/mL

(mL)

Diluent

(mL)

Total Volume

(mL)

200

10

40

50

300

20

80

100

The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.

Note: See "Dosage Adjustment in Renally Impaired Patients." Dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day. Duration of therapy should depend upon patient responsiveness.

The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.
Milrinone Infusion Rate (mL) Using 200 mcg/mL Concentration
Maintenance Dose (mcg/kg/min)

Patient Body Weight (kg)

30

40

50

60

70

80

90

100

110

120

0.375

3.4

4.5

5.6

6.8

7.9

9.0

10.1

11.3

12.4

13.5

0.400

3.6

4.8

6.0

7.2

8.4

9.6

10.8

12.0

13.2

14.4

0.500

4.5

6.0

7.5

9.0

10.5

12.0

13.5

15.0

16.5

18.0

0.600

5.4

7.2

9.0

10.8

12.6

14.4

16.2

18.0

19.8

21.6

0.700

6.3

8.4

10.5

12.6

14.7

16.8

18.9

21.0

23.1

25.2

0.750

6.8

9.0

11.3

13.5

15.8

18.0

20.3

22.5

24.8

27.0

When administering milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device.

Dosage Adjustment in Renally Impaired Patients

Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:

Creatinine Clearance

(mL/min/1.73 m2)

Infusion Rate

(mcg/kg/min)

5

0.20

10

0.23

20

0.28

30

0.33

40

0.38

50

0.43

Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.
Gemcitabine

Gemcitabine

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

2.1 Ovarian Cancer

Recommended Dose and Schedule

The recommended dose of gemcitabine for injection is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine for injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.

Dose Modifications

Recommended gemcitabine for injection dose modifications for myelosuppression are described Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.

Table 1: Dosage Reduction Guidelines for Gemcitabine For Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
Treatment Day Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose Day 1 ≥1500 and ≥100,000 100% <1500 or <100,000 Delay Treatment Cycle Day 8 ≥1500 and ≥100,000 100 1000 to 1499 or 75,000 to 99,999 50 <1000 or <75,000 Hold
Table 2: Gemcitabine For Injection Dose Modification for Myelosuppression in Previous Cycle In Ovarian Cancer
Occurrence Myelosuppression During Treatment Cycle Dose Modification Initial Occurrence Absolute granulocyte count less than 500 x 106/L for more than 5 days Absolute granulocyte count less than 100 x 106/L for more than 3 days Febrile neutropenia Platelets less than 25,000x106/L Cycle delay of more than one week due to toxicity Permanently reduce gemcitabine for injection to 800 mg/m2 on Days 1 and 8 Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction Permanently reduce gemcitabine for injection dose to 800 mg/m2on Day 1 only
2.2 Breast Cancer

Recommended Dose and Schedule

The recommended dose of gemcitabine for injection is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before gemcitabine for injection administration.

Dose Modifications Recommended dose modifications for gemcitabine for injection for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.

Table 3: Recommended Dose Reductions for Gemcitabine For Injection for Myelosuppression on Day of Treatment in Breast Cancer
Treatment Day Absolute granulocyte count (x 106/L) Platelet count(x 106/L) % of full dose Day 1 ≥1500 and ≥ 100,000 100% less than1500 or less than 100,000 Hold Day 8 ≥ 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
2.3 Non-Small Cell Lung Cancer

Recommended Dose and Schedule

Every 4-week schedule The recommended dose of gemcitabine for injection is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection.

Every 3-week schedule

The recommended dose of gemcitabine for injection is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection.

Dose Modifications

Recommended dose modifications for gemcitabine for injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine for injection recommendations for non-hematologic adverse reactions.

2.4 Pancreatic Cancer

Recommended Dose and Schedule

The recommended dose of gemcitabine for injection is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule

• Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one week rest.

• After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.

Dose Modifications

Recommended dose modifications for gemcitabine for injection for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.

Patients receiving gemcitabine for injection 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 4.

Table 4: Recommended Dose Reductions for Gemcitabine For Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer
Absolute granulocyte count (x 106/L) Platelet count(x 106/L) % of full dose ≥1000 And ≥100,000 100 500 to 999 Or 50,000 to 99,999 75 <500 Or <50,000 Hold

2.5 Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue gemcitabine for injection for any of the following
Unexplained dyspnea or other evidence of severe pulmonary toxicity Severe hepatic toxicity Hemolytic-Uremic Syndrome Capillary Leak Syndrome Posterior reversible encephalopathy syndrome
Withhold gemcitabine for injection or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

2.6 Preparation and Administration Precautions

Exercise caution and wear gloves when preparing gemcitabine for injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine for injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine for injection go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

2.7 Preparation for Intravenous Infusion Administration

Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives. Add 5 mL to the 200 mg vial or 25 mL to the 1 g vial. These dilutions each yield a gemcitabine for injection concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine for injection. 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 for injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine for injection solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.

No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Fluconazole

Fluconazole

Dosage and Administration in Adults

Multiple Dose

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 candidema, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration 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 of 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:
* Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended.
Pediatric Patients

Adults

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. (See CLINICAL 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 3mg/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 one 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 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

Percent of

(mL/min)

Recommended Dose

>50

100%

≤ (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 x 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 injection is 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 injection in glass container is intended only for intravenous administration using sterile equipment.

Parental 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.
Glucagen

Glucagen

For GlucaGen HypoKit:

2.1 Treatment of severe hypoglycemia
1. Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing GlucaGen powder and inject all the liquid from the syringe into the vial. 2. Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency. 3. The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL glucagon. 4. The reconstituted GlucaGen should be used immediately after reconstitution. 5. Inject 1 mL (adults and children, weighing more than 55 lbs (25 kg)) or 0.5 mL (children weighing less than 55 lbs (25 kg)) subcutaneously, intramuscularly, or intravenously. If the weight is not known: children younger than 6 years should be given a 0.5 mL and children 6 years and older should be given 1 mL. 6. Discard any unused portion. 7. Emergency assistance should be sought immediately after subcutaneous or intramuscular injection of glucagon. 8. The glucagon injection may be repeated using a new kit while waiting for emergency assistance. 9. Intravenous glucose MUST be administered if the patient fails to respond to glucagon. 10. When the patient has responded to the treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia.
For GlucaGen Diagnostic Kit and the GlucaGen 10-pack:

2.2 Use as a diagnostic aid
1. GlucaGen should be reconstituted with 1 mL of Sterile Water for Reconstitution (if supplied) or 1 mL of Sterile Water for Injection, USP. Using a syringe, withdraw all of the Sterile Water for Reconstitution (if supplied) or 1 mL Sterile Water for Injection, USP and inject into the GlucaGen vial. 2. Shake the vial gently until the powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency. 3. The reconstituted GlucaGen gives a concentration of approximately 1 mg/mL glucagon. 4. The reconstituted GlucaGen should be used immediately after reconstitution. 5. GlucaGen must be administered by medical personnel. 6. Discard any unused portion. 7. Onset of action after an injection will depend on the organ under examination and route of administration [see Pharmacodynamics (12.2)]. 8. The usual diagnostic dose for relaxation of the stomach, duodenal bulb, duodenum, and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly; the usual dose to relax the colon is 0.5 mg to 0.75 mg intravenously and 1 mg to 2 mg intramuscularly [see Pharmacodynamics (12.2)]. 9. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure applied.
The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are intended only for use by healthcare providers as a diagnostic aid. The GlucaGen Diagnostic Kit and the GlucaGen 10-pack presentations are not intended for use by patients to treat severe hypoglycemia because they are not packaged with a syringe and diluent necessary for rapid preparation and administration during an emergency outside of a healthcare facility.
Ceftriaxone

Ceftriaxone

Ceftriaxone may be administered intravenously or intramuscularly.

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line.

Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions,including continuous calcium-containing infusions such as parenteral nutrition via a Y-site.However, in patients other than neonates, ceftriaxone and calcium-containing solutions may beadministered sequentially of one another if the infusion lines are thoroughly flushed betweeninfusions with a compatible fluid (see WARNINGS).

NEONATES:

Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone (see CONTRAINDICATIONS).

Ceftriaxone is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).

PEDIATRIC PATIENTS:

For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams.

For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).

For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.

In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

ADULTS:

The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 grams, in order to achieve > 90% target attainment. The total daily dose should not exceed 4 grams.

If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 12 to 2 hours before surgery is recommended.

Generally, ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

No dosage adjustment is necessary for patients with impairment of renal or hepatic functio..

DIRECTIONS FOR USE:

Intramuscular Administration:

Reconstitute ceftriaxone powder with the appropriate diluent (see COMPATIBILITY AND STABILITY: ).

Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose.

After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to, the amount of diluent indicated below. If required, more dilute solutions could be utilized. A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents.

As with all intramuscular preparations, ceftriaxone should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.

Vial Dosage Size

Amount of Diluent to be Added

250 mg/mL

350 mg/mL

250 mg

0.9 mL

__

500 mg

1.8 mL

1.0 mL

1 g

3.6 mL

2.1 mL

2 g

7.2 mL

4.2 mL

Intravenous Administration:

Ceftriaxone should be administered intravenously by infusion over a period of 30 minutes. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluent (see COMPATIBILITY AND STABILITY: ).

Vial Dosage Size

Amount of Diluent to be Added

250 mg

2.4 mL

500 mg

4.8 mL

1 g

9.6 mL

2 g

19.2 mL

After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.

COMPATIBILITY AND STABILITY:

Ceftriaxone has been shown to be compatible with Flagyl®* IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.

*Registered trademark of G.D. Searle & Co.

Vancomycin, amsacrine, aminoglycosides, and fl uconazole are physically incompatible with ceftriaxone in admixtures. When any of these drugs is to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone or to further dilute a reconstituted vial for IV administration. Particulate formation can result.

Ceftriaxone solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (se WARNINGS).

Ceftriaxone sterile powder should be stored at room temperature—77°F (25°C)—or below and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

Ceftriaxone intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods:

Storage

Diluent

Concentration

mg/mL

Room Temp.

(25°C)

Refrigerated

(4°C)

Sterile Water for Injection

100

250, 350

2 days

24 hours

10 days

3 days

0.9% Sodium Chloride

Solution

100

250, 350

2 days

24 hours

l0 days

3 days

5% Dextrose Solution

100

250, 350

2 days

24 hours

10 days

3 days

Bacteriostatic Water + 0.9%

Benzyl Alcohol

100

250, 350

24 hours

24 hours

10 days

3 days

1% Lidocaine Solution

(without epinephrine)

100

250, 350

24 hours

24 hours

10 days

3 days

Ceftriaxone intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:

Diluent

Storage

Room Temp.

(25°C)

Refrigerated

(4°C)

Sterile Water

0.9% Sodium Chloride Solution

5% Dextrose Solution

10% Dextrose Solution

5% Dextrose + 0.9% Sodium Chloride Solution*

5% Dextrose + 0.45% Sodium Chloride Solution

2 days

2 days

2 days

2 days

2 days

2 days

10 days

10 days

10 days

10 days

Incompatible

Incompatible

*Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.

The following intravenous ceftriaxone solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).

After the indicated stability time periods, unused portions of solutions should be discarded.

NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.

Ceftriaxone reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state ((-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.

Frozen solutions of ceftriaxone should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

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