E.r. Squibb & Sons, L.l.c.

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E.r. Squibb & Sons, L.l.c. Drugs

Medique Diotame

Medique Diotame

2.1 Recommended Dosage

EVOTAZ is a fixed-dose combination product containing 300 mg of atazanavir and 150 mg of cobicistat. In treatment-naive and -experienced adults, the recommended dosage of EVOTAZ is one tablet taken once daily orally with food. Administer EVOTAZ in conjunction with other antiretroviral agents [see Drug Interactions (7)].

When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Drug Interactions (7)].

2.2 Laboratory Testing Prior to Initiation of EVOTAZ

Prior to starting EVOTAZ, assess estimated creatinine clearance because cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3)]. When coadministering EVOTAZ with tenofovir disoproxil fumarate (tenofovir DF) assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions 5.4].

2.3 Dosage in Patients with Renal Impairment

EVOTAZ is not recommended in HIV-1 treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

EVOTAZ coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

2.4 Dosage in Patients with Hepatic Impairment

EVOTAZ is not recommended in patients with hepatic impairment. [See Warnings and Precautions (5.6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3).]
Droxia

Droxia

2.1 Dosing Information
Table 1:     Dosing Recommendation Based on Blood Count
Dosing Regimen

Dose

Dose Modification Criteria

Monitoring Parameters

Initial RecommendedDosing

15 mg/kg/day as a single dose

Base dosage on the patient’s actual or ideal weight, whichever is less.

Monitor the patient’s blood count every 2 weeks [see Warnings and Precautions (5.1)].

Dosing Based on Blood Counts

  In an acceptable  range

Increase dose5 mg/kg/day every 12 weeks

Maximal dose:35 mg/kg/day*

*Maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks.

Increase dosing only if blood counts are in an acceptable range.

Do not increase if myelosuppression occurs.

Blood Counts Acceptable Range

neutrophils ≥2500 cells/mm3

platelets ≥95,000/mm3

hemoglobin >5.3 g/dL

reticulocytes ≥95,000/mm3 if     the hemoglobin    concentration <9 g/dL

  Between acceptable  and toxic range

Do not increase dose.

If blood counts are considered toxic, discontinue DROXIA until hematologic recovery.

Blood Counts Toxic Range

neutrophils <2000 cells/mm3

platelets <80,000/mm3

hemoglobin <4.5 g/dL

reticulocytes <80,000/mm3 if     the hemoglobin     concentration <9 g/dL

Dosing After Hematologic Recovery

Reduce dose by2.5 mg/kg/day.

Reduce the dose from the dose associated with hematologic toxicity.

May titrate up or down every 12 weeks in 2.5 mg/kg/day increments.

The patient should be at a stable dose with no hematologic toxicity for 24 weeks.

Discontinue the treatment permanently if a patient develops hematologic toxicity twice.

Patients must be able to follow directions regarding drug administration and their monitoring and care.

Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of DROXIA in clinical use. Obtain HbF levels every three to four months. Monitor for an increase in HbF of at least two-fold over the baseline value.

DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

DROXIA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

2.2 Dose Modifications for Renal Impairment

Reduce the dose of DROXIA by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Creatinine clearance values were obtained using 24-hour urine collections.
*  On dialysis days, administer DROXIA to patients with ESRD following hemodialysis.
Creatinine Clearance

(mL/min)

Recommended DROXIA Initial Dose

(mg/kg daily)

≥60

15

<60 or ESRD*

7.5

Monitor the hematologic parameters closely in these patients.
Hydrea

Hydrea

2.1 Dosing Information

HYDREA is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.

Base all dosage on the patient’s actual or ideal weight, whichever is less.

HYDREA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.7)].

2.2 Dose Modifications for Toxicity

Monitor for the following and reduce the dose or discontinue HYDREA accordingly:
• Myelopression [seeWarnings and Precautions (5.1)] • Cutaneous vasculitis [seeWarnings and Precautions (5.4)]
Monitor blood counts at least once a week during HYDREA therapy. Severe anemia must be corrected before initiating therapy with HYDREA. Consider dose modifications for other toxicities.

2.3 Dose Modifications for Renal Impairment

Reduce the dose of HYDREA by 50% in patients with measured creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Creatinine Clearance(mL/min) Recommended HYDREA Initial Dose(mg/kg daily)
≥60

15

<60 or ESRD*

7.5

* On dialysis days, administer HYDREA to patients following hemodialysis.

Close monitoring of hematologic parameters is advised in these patients.
Ixempra

Ixempra

2.1 General Dosing Information

The recommended dosage of IXEMPRA is 40 mg/m2 administered intravenously over 3 hours every 3 weeks. Doses for patients with body surface area (BSA) greater than 2.2 m2 should be calculated based on 2.2 m2.

2.2 Dose Modification

Dose Adjustments During Treatment

Patients should be evaluated during treatment by periodic clinical observation and laboratory tests including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing adjustment guidelines for monotherapy and combination therapy are shown in Table 1. If toxicities recur, an additional 20% dose reduction should be made.
Table 1: Dose Adjustment Guidelinesa IXEMPRA (Monotherapy or Combination Therapy) IXEMPRA Dose Modification a  Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).
Nonhematologic:

Grade 2 neuropathy (moderate) lasting ≥7 days

Decrease the dose by 20%

Grade 3 neuropathy (severe) lasting <7 days

Decrease the dose by 20%

Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy

Discontinue treatment

Any grade 3 toxicity (severe) other than neuropathy

Decrease the dose by 20%

Transient grade 3 arthralgia/myalgia or fatigue

No change in dose of IXEMPRA

Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)

Any grade 4 toxicity (disabling)

Discontinue treatment

Hematologic:

Neutrophil <500 cells/mm3 for ≥7 days

Decrease the dose by 20%

Febrile neutropenia

Decrease the dose by 20%

Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding

Decrease the dose by 20%

Capecitabine(when used in combination with IXEMPRA)

CapecitabineDose Modification

Nonhematologic:

Follow Capecitabine Label

Hematologic:

Platelets <25,000/mm3 or <50,000/mm3 with bleeding

Hold for concurrent diarrhea or stomatitis until platelet count >50,000/mm3, then continue at same dose.

Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia

Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

Re-treatment Criteria: Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.

Dose Adjustments in Special Populations - Hepatic Impairment

Combination Therapy:

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × ULN may receive the standard dose of ixabepilone (40 mg/m2) [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].

Monotherapy:

Patients with hepatic impairment should be dosed with IXEMPRA based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. Use in patients with AST or ALT >10 × ULN or bilirubin >3 × ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 × ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
Table 2: Dose Adjustments for IXEMPRA as Monotherapy in Patients with Hepatic Impairment Transaminase Levels Bilirubin Levelsa IXEMPRAb (mg/m2) a  Excluding patients whose total bilirubin is elevated due to Gilbert’s disease.b  Dosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance.
Mild

AST and ALT ≤2.5 × ULN

and

≤1 × ULN

40

AST and ALT ≤10 × ULN

and

≤1.5 × ULN

32

Moderate

AST and ALT ≤10 × ULN

and

>1.5 × ULN - ≤3 × ULN

20 - 30

Strong CYP3A4 Inhibitors

The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of IXEMPRA and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the IXEMPRA dose is adjusted upward to the indicated dose [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of IXEMPRA may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, IXEMPRA should be given as a 4-hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with IXEMPRA. If the strong inducer is discontinued, the IXEMPRA dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.1)].

2.3 Premedication

To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with:
• An H 1 antagonist (eg, diphenhydramine 50 mg orally or equivalent) and • An H 2 antagonist (eg, ranitidine 150 - 300 mg orally or equivalent).
Patients who experienced a hypersensitivity reaction to IXEMPRA require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously, 30 minutes before infusion or orally, 60 minutes before infusion) in addition to pretreatment with H1 and H2 antagonists.

2.4 Instructions for Preparation and IV Administration

IXEMPRA Kit contains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Only supplied DILUENT must be used for constituting IXEMPRA (ixabepilone) for injection. IXEMPRA Kit must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting IXEMPRA for injection, the Kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature. To allow for withdrawal losses, the vial labeled as 15 mg IXEMPRA for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg IXEMPRA for injection contains 47 mg of ixabepilone. The 15-mg IXEMPRA Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg IXEMPRA Kit is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.

Please refer to Preparation and Handling Precautions [see Dosage and Administration (2.5)] before preparation.

A. To constitute:
1. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is constituted with 8 mL of DILUENT and the 45-mg IXEMPRA is constituted with 23.5 mL of DILUENT. 2. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved.
B. To dilute:

Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.

The following infusion fluids have been qualified for use in the dilution of IXEMPRA:
• Lactated Ringer’s Injection, USP • 0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP) • When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted IXEMPRA solution. • PLASMA-LYTE A Injection pH 7.4 ®
For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used.

The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
Total Infusion Volume = mL of Constituted Solution + mL of infusion fluid Final Infusion Concentration = Dose of IXEMPRA (mg)/Total Infusion Volume (mL) 1. Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL. 2. Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA. 3. Thoroughly mix the infusion bag by manual rotation.
The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion containers and administration sets must be used. Any remaining solution should be discarded according to institutional procedures for antineoplastics.

Stability

After constituting IXEMPRA, the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted IXEMPRA must be completed within this 6-hour period. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain IXEMPRA stability. Other infusion fluids should not be used with IXEMPRA.

2.5 Preparation and Handling Precautions

Procedures for proper handling and disposal of antineoplastic drugs [see References (15)] should be followed. To minimize the risk of dermal exposure, impervious gloves should be worn when handling vials containing IXEMPRA, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.

2.1 General Dosing Information

The recommended dosage of IXEMPRA is 40 mg/m2 administered intravenously over 3 hours every 3 weeks. Doses for patients with body surface area (BSA) greater than 2.2 m2 should be calculated based on 2.2 m2.

2.2 Dose Modification

Dose Adjustments During Treatment

Patients should be evaluated during treatment by periodic clinical observation and laboratory tests including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing adjustment guidelines for monotherapy and combination therapy are shown in Table 1. If toxicities recur, an additional 20% dose reduction should be made.
Table 1: Dose Adjustment Guidelinesa IXEMPRA (Monotherapy or Combination Therapy) IXEMPRA Dose Modification a  Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).
Nonhematologic:

Grade 2 neuropathy (moderate) lasting ≥7 days

Decrease the dose by 20%

Grade 3 neuropathy (severe) lasting <7 days

Decrease the dose by 20%

Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy

Discontinue treatment

Any grade 3 toxicity (severe) other than neuropathy

Decrease the dose by 20%

Transient grade 3 arthralgia/myalgia or fatigue

No change in dose of IXEMPRA

Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)

Any grade 4 toxicity (disabling)

Discontinue treatment

Hematologic:

Neutrophil <500 cells/mm3 for ≥7 days

Decrease the dose by 20%

Febrile neutropenia

Decrease the dose by 20%

Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding

Decrease the dose by 20%

Capecitabine(when used in combination with IXEMPRA)

CapecitabineDose Modification

Nonhematologic:

Follow Capecitabine Label

Hematologic:

Platelets <25,000/mm3 or <50,000/mm3 with bleeding

Hold for concurrent diarrhea or stomatitis until platelet count >50,000/mm3, then continue at same dose.

Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia

Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

Re-treatment Criteria: Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.

Dose Adjustments in Special Populations - Hepatic Impairment

Combination Therapy:

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × ULN may receive the standard dose of ixabepilone (40 mg/m2) [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].

Monotherapy:

Patients with hepatic impairment should be dosed with IXEMPRA based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. Use in patients with AST or ALT >10 × ULN or bilirubin >3 × ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 × ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
Table 2: Dose Adjustments for IXEMPRA as Monotherapy in Patients with Hepatic Impairment Transaminase Levels Bilirubin Levelsa IXEMPRAb (mg/m2) a  Excluding patients whose total bilirubin is elevated due to Gilbert’s disease.b  Dosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance.
Mild

AST and ALT ≤2.5 × ULN

and

≤1 × ULN

40

AST and ALT ≤10 × ULN

and

≤1.5 × ULN

32

Moderate

AST and ALT ≤10 × ULN

and

>1.5 × ULN - ≤3 × ULN

20 - 30

Strong CYP3A4 Inhibitors

The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of IXEMPRA and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the IXEMPRA dose is adjusted upward to the indicated dose [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of IXEMPRA may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, IXEMPRA should be given as a 4-hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with IXEMPRA. If the strong inducer is discontinued, the IXEMPRA dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.1)].

Dose Adjustments During Treatment

Patients should be evaluated during treatment by periodic clinical observation and laboratory tests including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing adjustment guidelines for monotherapy and combination therapy are shown in Table 1. If toxicities recur, an additional 20% dose reduction should be made.
Table 1: Dose Adjustment Guidelinesa IXEMPRA (Monotherapy or Combination Therapy) IXEMPRA Dose Modification a  Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).
Nonhematologic:

Grade 2 neuropathy (moderate) lasting ≥7 days

Decrease the dose by 20%

Grade 3 neuropathy (severe) lasting <7 days

Decrease the dose by 20%

Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy

Discontinue treatment

Any grade 3 toxicity (severe) other than neuropathy

Decrease the dose by 20%

Transient grade 3 arthralgia/myalgia or fatigue

No change in dose of IXEMPRA

Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)

Any grade 4 toxicity (disabling)

Discontinue treatment

Hematologic:

Neutrophil <500 cells/mm3 for ≥7 days

Decrease the dose by 20%

Febrile neutropenia

Decrease the dose by 20%

Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding

Decrease the dose by 20%

Capecitabine(when used in combination with IXEMPRA)

CapecitabineDose Modification

Nonhematologic:

Follow Capecitabine Label

Hematologic:

Platelets <25,000/mm3 or <50,000/mm3 with bleeding

Hold for concurrent diarrhea or stomatitis until platelet count >50,000/mm3, then continue at same dose.

Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia

Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

Re-treatment Criteria: Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.

Dose Adjustments in Special Populations - Hepatic Impairment

Combination Therapy:

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × ULN may receive the standard dose of ixabepilone (40 mg/m2) [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].

Monotherapy:

Patients with hepatic impairment should be dosed with IXEMPRA based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. Use in patients with AST or ALT >10 × ULN or bilirubin >3 × ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 × ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
Table 2: Dose Adjustments for IXEMPRA as Monotherapy in Patients with Hepatic Impairment Transaminase Levels Bilirubin Levelsa IXEMPRAb (mg/m2) a  Excluding patients whose total bilirubin is elevated due to Gilbert’s disease.b  Dosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance.
Mild

AST and ALT ≤2.5 × ULN

and

≤1 × ULN

40

AST and ALT ≤10 × ULN

and

≤1.5 × ULN

32

Moderate

AST and ALT ≤10 × ULN

and

>1.5 × ULN - ≤3 × ULN

20 - 30

Strong CYP3A4 Inhibitors

The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of IXEMPRA and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the IXEMPRA dose is adjusted upward to the indicated dose [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of IXEMPRA may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, IXEMPRA should be given as a 4-hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with IXEMPRA. If the strong inducer is discontinued, the IXEMPRA dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.1)].

2.3 Premedication

To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with:
• An H 1 antagonist (eg, diphenhydramine 50 mg orally or equivalent) and • An H 2 antagonist (eg, ranitidine 150 - 300 mg orally or equivalent).
Patients who experienced a hypersensitivity reaction to IXEMPRA require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously, 30 minutes before infusion or orally, 60 minutes before infusion) in addition to pretreatment with H1 and H2 antagonists.

2.4 Instructions for Preparation and IV Administration

IXEMPRA Kit contains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Only supplied DILUENT must be used for constituting IXEMPRA (ixabepilone) for injection. IXEMPRA Kit must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting IXEMPRA for injection, the Kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature. To allow for withdrawal losses, the vial labeled as 15 mg IXEMPRA for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg IXEMPRA for injection contains 47 mg of ixabepilone. The 15-mg IXEMPRA Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg IXEMPRA Kit is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.

Please refer to Preparation and Handling Precautions [see Dosage and Administration (2.5)] before preparation.

A. To constitute:
1. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is constituted with 8 mL of DILUENT and the 45-mg IXEMPRA is constituted with 23.5 mL of DILUENT. 2. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved.
B. To dilute:

Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.

The following infusion fluids have been qualified for use in the dilution of IXEMPRA:
• Lactated Ringer’s Injection, USP • 0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP) • When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted IXEMPRA solution. • PLASMA-LYTE A Injection pH 7.4 ®
For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used.

The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
Total Infusion Volume = mL of Constituted Solution + mL of infusion fluid Final Infusion Concentration = Dose of IXEMPRA (mg)/Total Infusion Volume (mL) 1. Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL. 2. Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA. 3. Thoroughly mix the infusion bag by manual rotation.
The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion containers and administration sets must be used. Any remaining solution should be discarded according to institutional procedures for antineoplastics.

Stability

After constituting IXEMPRA, the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted IXEMPRA must be completed within this 6-hour period. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain IXEMPRA stability. Other infusion fluids should not be used with IXEMPRA.

Stability

After constituting IXEMPRA, the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted IXEMPRA must be completed within this 6-hour period. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain IXEMPRA stability. Other infusion fluids should not be used with IXEMPRA.

2.5 Preparation and Handling Precautions

Procedures for proper handling and disposal of antineoplastic drugs [see References (15)] should be followed. To minimize the risk of dermal exposure, impervious gloves should be worn when handling vials containing IXEMPRA, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.
Megace

Megace

The recommended adult initial dosage of MEGACE Oral Suspension is 800 mg/day (20 mL/day). Shake container well before using.

In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective.

A plastic dosage cup with 10 mL and 20 mL markings is provided for convenience.
Complete Allery And Sin...

Complete Allery And Sinus Multi-symptom

2.1 Recommended Dosage

The recommended dosage of DAKLINZA is 60 mg, taken orally, once daily in combination with sofosbuvir for 12 weeks. DAKLINZA may be taken with or without food.

The optimal duration of DAKLINZA and sofosbuvir for patients with cirrhosis has not been established [see Clinical Studies (14)].

For specific dosage recommendations for sofosbuvir, refer to the respective prescribing information.

2.2 Dosage Modification Due to Drug Interactions

Refer to the drug interactions and contraindication sections for other drugs before coadministration with DAKLINZA.

Strong inhibitors of cytochrome P450 enzyme 3A (CYP3A): Reduce the dosage of DAKLINZA to 30 mg once daily when coadministered with strong CYP3A inhibitors using the 30 mg tablet [see Drug Interactions (7)].

Moderate CYP3A inducers: Increase the dosage of DAKLINZA to 90 mg once daily using an appropriate combination of tablets (three 30 mg tablets or one 60 mg and one 30 mg tablet) when coadministered with moderate CYP3A inducers [see Drug Interactions (7)].

Strong CYP3A inducers: DAKLINZA is contraindicated in combination with strong CYP3A inducers [see Contraindications (4)].

Dosage reduction of DAKLINZA for adverse reactions is not recommended.

2.3 Discontinuation of Therapy

If sofosbuvir is permanently discontinued in a patient receiving DAKLINZA with sofosbuvir, then DAKLINZA should also be discontinued.
Ceenu

Ceenu

The recommended dose of CeeNU in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks (see PRECAUTIONS: Information for Patients and HOW SUPPLIED: Directions to the Pharmacist). In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When CeeNU is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. All doses of CeeNU must be rounded to the nearest 10 mg by the prescriber (see HOW SUPPLIED).

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:
Nadir After Prior Dose Percentage of Prior Doseto be Given Leukocytes (/mm3) Platelets (/mm3) ≥4000 ≥100,000 100% 3000–3999 75,000–99,999 100% 2000–2999 25,000–74,999 70% <2000 <25,000 50%
A repeat course of CeeNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.
Vumon

Vumon

NOTE: Contact of undiluted VUMON with plastic equipment or devices used to prepare solutions for infusion may result in softening or cracking and possible drug product leakage. This effect has not been reported with diluted solutions of VUMON.

In order to prevent extraction of the plasticizer DEHP [di(2-ethylhexyl) phthalate], solutions of VUMON should be prepared in non-DEHP containing LVP containers such as glass or polyolefin plastic bags or containers.

VUMON solutions should be administered with non-DEHP containing intravenous administration sets.

In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of VUMON 165 mg/m2 and cytarabine 300 mg/m2 intravenously, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of VUMON 250 mg/m2 and vincristine 1.5 mg/m2 intravenously, weekly for 4 to 8 weeks and prednisone 40 mg/m2 orally for 28 days.

Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment.

Preparation and Administration Precautions

Caution should be exercised in handling and preparing the solution of VUMON. Several guidelines on proper handling and disposal of anticancer drugs have been published.1–4 Skin reactions associated with accidental exposure to VUMON may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing VUMON. If VUMON solution contacts the skin, immediately wash the skin thoroughly with soap and water. If VUMON contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

Preparation for Intravenous Administration

VUMON must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. VUMON solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of VUMON solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers.

Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of VUMON diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of VUMON.

Hypotension has been reported following rapid intravenous administration; it is recommended that the VUMON solution be administered over at least a 30- to 60-minute period. VUMON should not be given by rapid intravenous injection.

In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP [di(2-ethylhexyl) phthalate] from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended.

Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient’s exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured.

Stability

Unopened ampules of VUMON are stable until the date indicated on the package when stored under refrigeration (2°-8°C) in the original package. Freezing does not adversely affect the product.

Preparation and Administration Precautions

Caution should be exercised in handling and preparing the solution of VUMON. Several guidelines on proper handling and disposal of anticancer drugs have been published.1–4 Skin reactions associated with accidental exposure to VUMON may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing VUMON. If VUMON solution contacts the skin, immediately wash the skin thoroughly with soap and water. If VUMON contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

Preparation for Intravenous Administration

VUMON must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. VUMON solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of VUMON solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers.

Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of VUMON diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of VUMON.

Hypotension has been reported following rapid intravenous administration; it is recommended that the VUMON solution be administered over at least a 30- to 60-minute period. VUMON should not be given by rapid intravenous injection.

In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP [di(2-ethylhexyl) phthalate] from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended.

Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient’s exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured.

Stability

Unopened ampules of VUMON are stable until the date indicated on the package when stored under refrigeration (2°-8°C) in the original package. Freezing does not adversely affect the product.
Desipramine Hydrochlori...

Desipramine Hydrochloride

The recommended starting dosage of SPRYCEL for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole. SPRYCEL can be taken with or without a meal, either in the morning or in the evening.

In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR) is not known.

2.1 Dose Modification

Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma concentrations and should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital). St. John’s wort may decrease dasatinib plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a SPRYCEL dose increase should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2)].

Concomitant Strong CYP3A4 inhibitors: CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) may increase dasatinib plasma concentrations. Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided.

Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible, is recommended. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered. Based on pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for patients taking SPRYCEL 100 mg daily. For patients taking SPRYCEL 140 mg daily, a dose decrease to 40 mg daily should be considered. These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors. However, there are no clinical data with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose reduction, either the strong CYP3A4 inhibitor must be discontinued, or SPRYCEL should be stopped until treatment with the inhibitor has ceased. When the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the SPRYCEL dose is increased [see Drug Interactions (7.1)].

2.2 Dose Escalation

In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended starting dosage.

2.3 Dose Adjustment for Adverse Reactions

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications are summarized in Table 1.
Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia * ANC: absolute neutrophil count
Chronic Phase CML(starting dose 100 mg once daily)

ANC* <0.5 × 109/LorPlatelets <50 × 109/L
1. Stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥50 × 10 9/L. 2. Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days. 3. If platelets <25 × 10 9/L or recurrence of ANC <0.5 × 10 9/L for >7 days, repeat Step 1 and resume SPRYCEL at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue SPRYCEL (for patients resistant or intolerant to prior therapy including imatinib).
Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily)

ANC* <0.5 × 109/LorPlatelets <10 × 109/L
1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥20 × 10 9/L and resume at the original starting dose. 3. If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode). 4. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.
Non-hematological Adverse Reactions

If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event [see Warnings and Precautions (5.1)].

2.1 Dose Modification

Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma concentrations and should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital). St. John’s wort may decrease dasatinib plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a SPRYCEL dose increase should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2)].

Concomitant Strong CYP3A4 inhibitors: CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) may increase dasatinib plasma concentrations. Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided.

Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible, is recommended. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered. Based on pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for patients taking SPRYCEL 100 mg daily. For patients taking SPRYCEL 140 mg daily, a dose decrease to 40 mg daily should be considered. These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors. However, there are no clinical data with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose reduction, either the strong CYP3A4 inhibitor must be discontinued, or SPRYCEL should be stopped until treatment with the inhibitor has ceased. When the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the SPRYCEL dose is increased [see Drug Interactions (7.1)].

2.2 Dose Escalation

In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended starting dosage.

2.3 Dose Adjustment for Adverse Reactions

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications are summarized in Table 1.
Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia * ANC: absolute neutrophil count
Chronic Phase CML(starting dose 100 mg once daily)

ANC* <0.5 × 109/LorPlatelets <50 × 109/L
1. Stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥50 × 10 9/L. 2. Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days. 3. If platelets <25 × 10 9/L or recurrence of ANC <0.5 × 10 9/L for >7 days, repeat Step 1 and resume SPRYCEL at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue SPRYCEL (for patients resistant or intolerant to prior therapy including imatinib).
Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily)

ANC* <0.5 × 109/LorPlatelets <10 × 109/L
1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥20 × 10 9/L and resume at the original starting dose. 3. If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode). 4. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.
Non-hematological Adverse Reactions

If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event [see Warnings and Precautions (5.1)].

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications are summarized in Table 1.
Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia * ANC: absolute neutrophil count
Chronic Phase CML(starting dose 100 mg once daily)

ANC* <0.5 × 109/LorPlatelets <50 × 109/L
1. Stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥50 × 10 9/L. 2. Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days. 3. If platelets <25 × 10 9/L or recurrence of ANC <0.5 × 10 9/L for >7 days, repeat Step 1 and resume SPRYCEL at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue SPRYCEL (for patients resistant or intolerant to prior therapy including imatinib).
Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily)

ANC* <0.5 × 109/LorPlatelets <10 × 109/L
1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥20 × 10 9/L and resume at the original starting dose. 3. If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode). 4. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.
Non-hematological Adverse Reactions

If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event [see Warnings and Precautions (5.1)].
Hydrochlorothiazide

Hydrochlorothiazide

2.1 Recommended Dosage

The dosage of KOMBIGLYZE XR should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability. KOMBIGLYZE XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The following dosage forms are available:
• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/500 mg • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/1000 mg • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 2.5 mg/1000 mg
The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.

In patients treated with metformin, the dosage of KOMBIGLYZE XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.

Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with KOMBIGLYZE XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are either metformin naive or who require a dose of metformin higher than 1000 mg should use the individual components.

The maximum daily recommended dosage is 5 mg for saxagliptin and 2000 mg for metformin extended-release.

No studies have been performed specifically examining the safety and efficacy of KOMBIGLYZE XR in patients previously treated with other antihyperglycemic medications and switched to KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

2.2 Dosage Adjustments with Concomitant Use of Strong CYP3A4/5 Inhibitors

The maximum recommended dosage of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the KOMBIGLYZE XR dosage to 2.5 mg/1000 mg once daily. [See Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3).]

2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When KOMBIGLYZE XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dosage of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. [See Warnings and Precautions (5.9).]

2.1 Recommended Dosage

The dosage of KOMBIGLYZE XR should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability. KOMBIGLYZE XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The following dosage forms are available:
• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/500 mg • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/1000 mg • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 2.5 mg/1000 mg
The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.

In patients treated with metformin, the dosage of KOMBIGLYZE XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.

Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with KOMBIGLYZE XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are either metformin naive or who require a dose of metformin higher than 1000 mg should use the individual components.

The maximum daily recommended dosage is 5 mg for saxagliptin and 2000 mg for metformin extended-release.

No studies have been performed specifically examining the safety and efficacy of KOMBIGLYZE XR in patients previously treated with other antihyperglycemic medications and switched to KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

2.2 Dosage Adjustments with Concomitant Use of Strong CYP3A4/5 Inhibitors

The maximum recommended dosage of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the KOMBIGLYZE XR dosage to 2.5 mg/1000 mg once daily. [See Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3).]

2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When KOMBIGLYZE XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dosage of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. [See Warnings and Precautions (5.9).]
Onglyza

Onglyza

2.1 Recommended Dosage

The recommended dosage of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals. ONGLYZA tablets must not be split or cut.

2.2 Dosage in Patients with Renal Impairment

No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment (creatinine clearance [CrCl] >50 mL/min).

The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min) [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis.

Because the dosage of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula. [See Clinical Pharmacology (12.3).]

2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors

The dosage of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). [See Drug Interactions (7.1) and Clinical Pharmacology (12.3).]

2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. [See Warnings and Precautions (5.2).]
Azactam

Azactam

Dosage in Adult Patients

AZACTAM, an intravenous solution in GALAXY plastic containers (PL 2040), is intended for intravenous use only. Dosage should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.
Table 4: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency(hours) * Maximum recommended dose is 8 g per day. Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8
Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infections.

The duration of therapy depends on the severity of infection. Generally, AZACTAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Persistent infections may require treatment for several weeks. Doses smaller than those indicated should not be used.

Renal Impairment in Adult Patients

Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, the dosage of AZACTAM should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr). The serum creatinine should represent a steady state of renal function.

weight (kg) × (140−age) Males: Clcr = ——————————————— 72 × serum creatinine (mg/dL)

Females: 0.85 × above value

In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g, or 2 g should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours. For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

Dosage in the Elderly

Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary.

Dosage in Pediatric Patients

AZACTAM should be administered intravenously to pediatric patients with normal renal function. There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment. (See PRECAUTIONS: Pediatric Use.)
Table 5: Azactam Dosage Guidelines for Pediatric Patients* Type of Infection Dose Frequency(hours) * Maximum recommended dose is 120 mg/kg/day. Mild to moderate infections 30 mg/kg 8 Moderate to severe infections 30 mg/kg 6 or 8
CLINICAL STUDIES

A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

Directions for Use of AZACTAM (aztreonam injection) in GALAXY Plastic Container (PL 2040).

AZACTAM is to be administered as an intermittent intravenous infusion only.

Storage

Store in a freezer capable of maintaining a temperature of –20°C (–4°F).

Thawing of Plastic Containers

Thaw frozen container at room temperature, 25°C (77°F) or in a refrigerator, 2°C to 8°C (36°F-46°F). After thawing is complete, invert the container to assure a well-mixed solution. (DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION.)

Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired.

The container should be visually inspected. Thawed solutions should not be used unless clear; solutions will be colorless to yellow. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. If after visual inspection the solution remains discolored, cloudy, or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.

DO NOT ADD SUPPLEMENTARY MEDICATION.

The thawed solution in GALAXY plastic container (PL 2040) remains chemically stable for either 14 days under refrigeration (2°C-8°C/36°F-46°F) or for 48 hours at room temperature (25°C/77°F). DO NOT REFREEZE THAWED ANTIBIOTICS.

Preparation for Intravenous Administration

Use aseptic technique.
Suspend container(s) from eyelet support. Remove protector from outlet port at bottom of container. Attach administration set. Refer to complete directions accompanying set.
Additives or other medication should not be added to AZACTAM or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, it should be flushed before and after infusion of AZACTAM with an infusion solution compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040)* and any other drug(s) administered via this common line.

It is recommended that the intravenous administration apparatus be replaced at least once every 48 hours.

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

Intravenous Administration

Infusion of AZACTAM should be completed within a 20- to 60-minute period. The plastic container is a single-dose unit; discard any unused portion remaining in the container.

*The following infusion solutions are compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040):
Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ®-R Normosol ®-R and 5% Dextrose Normosol ®-M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose
CLINICAL STUDIES

A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

Directions for Use of AZACTAM (aztreonam injection) in GALAXY Plastic Container (PL 2040).

AZACTAM is to be administered as an intermittent intravenous infusion only.

Preparation for Intravenous Administration

Use aseptic technique.
Suspend container(s) from eyelet support. Remove protector from outlet port at bottom of container. Attach administration set. Refer to complete directions accompanying set.
Additives or other medication should not be added to AZACTAM or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, it should be flushed before and after infusion of AZACTAM with an infusion solution compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040)* and any other drug(s) administered via this common line.

It is recommended that the intravenous administration apparatus be replaced at least once every 48 hours.

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

Intravenous Administration

Infusion of AZACTAM should be completed within a 20- to 60-minute period. The plastic container is a single-dose unit; discard any unused portion remaining in the container.

*The following infusion solutions are compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040):
Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ®-R Normosol ®-R and 5% Dextrose Normosol ®-M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose
Azactam

Azactam

Dosage in Adult Patients

AZACTAM may be administered intravenously or by intramuscular injection. Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.
Table 4: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency(hours) * Maximum recommended dose is 8 g per day. Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8
Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infections.

The duration of therapy depends on the severity of infection. Generally, AZACTAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Persistent infections may require treatment for several weeks. Doses smaller than those indicated should not be used.

Renal Impairment in Adult Patients

Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, the dosage of AZACTAM should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr). The serum creatinine should represent a steady state of renal function.

                                             weight (kg) × (140−age)               Males: Clcr = ———————————————                                          72 × serum creatinine (mg/dL)

               Females: 0.85 × above value

In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g, or 2 g should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours. For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

Dosage in the Elderly

Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary.

Dosage in Pediatric Patients

AZACTAM should be administered intravenously to pediatric patients with normal renal function. There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment. (See PRECAUTIONS: Pediatric Use.)
Table 5: Azactam Dosage Guidelines for Pediatric Patients* Type of Infection Dose Frequency(hours) * Maximum recommended dose is 120 mg/kg/day. Mild to moderate infections 30 mg/kg 8 Moderate to severe infections 30 mg/kg 6 or 8
CLINICAL STUDIES

A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

Preparation of Parenteral Solutions

General

Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously. Constituted solutions are not for multiple-dose use; should the entire volume in the container not be used for a single dose, the unused solution must be discarded.

Depending upon the concentration of aztreonam and diluent used, constituted AZACTAM yields a colorless to light straw yellow solution which may develop a slight pink tint on standing (potency is not affected). Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Admixtures with Other Antibiotics

Intravenous infusion solutions of AZACTAM not exceeding 2% w/v prepared with Sodium Chloride Injection, USP 0.9% or Dextrose Injection, USP 5%, to which clindamycin phosphate, gentamicin sulfate, tobramycin sulfate, or cefazolin sodium have been added at concentrations usually used clinically, are stable for up to 48 hours at room temperature or 7 days under refrigeration. Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection, USP 0.9% are stable for 24 hours at room temperature and 48 hours under refrigeration; stability in Dextrose Injection, USP 5% is 2 hours at room temperature and 8 hours under refrigeration.

Aztreonam-cloxacillin sodium and aztreonam-vancomycin hydrochloride admixtures are stable in Dianeal 137 (Peritoneal Dialysis Solution) with 4.25% Dextrose for up to 24 hours at room temperature.

Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole.

Other admixtures are not recommended since compatibility data are not available.

Intravenous Solutions

For Bolus Injection: The contents of an AZACTAM 15 mL capacity vial should be constituted with 6 to 10 mL Sterile Water for Injection, USP.

For Infusion: If the contents of a 15 mL capacity vial are to be transferred to an appropriate infusion solution, each gram of aztreonam should be initially constituted with at least 3 mL Sterile Water for Injection, USP. Further dilution may be obtained with one of the following intravenous infusion solutions:
Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ®-R Normosol ®-R and 5% Dextrose Normosol ®-M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose
Intramuscular Solutions

The contents of an AZACTAM 15 mL capacity vial should be constituted with at least 3 mL of an appropriate diluent per gram aztreonam. The following diluents may be used:
Sterile Water for Injection, USP Sterile Bacteriostatic Water for Injection, USP (with benzyl alcohol or with methyl- and propylparabens) Sodium Chloride Injection, USP, 0.9% Bacteriostatic Sodium Chloride Injection, USP (with benzyl alcohol)
Stability of Intravenous and Intramuscular Solutions

AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature (59°F-86°F/15°C-30°C) or within 7 days if refrigerated (36°F-46°F/2°C-8°C).

AZACTAM solutions at concentrations exceeding 2% w/v, except those prepared with Sterile Water for Injection, USP or Sodium Chloride Injection, USP, should be used promptly after preparation; the 2 excepted solutions must be used within 48 hours if stored at controlled room temperature or within 7 days if refrigerated.

Intravenous Administration

Bolus Injection: A bolus injection may be used to initiate therapy. The dose should be slowly injected directly into a vein, or the tubing of a suitable administration set, over a period of 3 to 5 minutes (see next paragraph regarding flushing of tubing).

Infusion: With any intermittent infusion of aztreonam and another drug with which it is not pharmaceutically compatible, the common delivery tube should be flushed before and after delivery of aztreonam with any appropriate infusion solution compatible with both drug solutions; the drugs should not be delivered simultaneously. Any AZACTAM infusion should be completed within a 20- to 60-minute period. With use of a Y-type administration set, careful attention should be given to the calculated volume of aztreonam solution required so that the entire dose will be infused. A volume control administration set may be used to deliver an initial dilution of AZACTAM (see Preparation of Parenteral Solutions: Intravenous Solutions: For Infusion) into a compatible infusion solution during administration; in this case, the final dilution of aztreonam should provide a concentration not exceeding 2% w/v.

Intramuscular Administration

The dose should be given by deep injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aztreonam is well tolerated and should not be admixed with any local anesthetic agent.

Dosage in Adult Patients

AZACTAM may be administered intravenously or by intramuscular injection. Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.
Table 4: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency(hours) * Maximum recommended dose is 8 g per day. Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8
Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infections.

The duration of therapy depends on the severity of infection. Generally, AZACTAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Persistent infections may require treatment for several weeks. Doses smaller than those indicated should not be used.

Renal Impairment in Adult Patients

Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, the dosage of AZACTAM should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr). The serum creatinine should represent a steady state of renal function.

                                             weight (kg) × (140−age)               Males: Clcr = ———————————————                                          72 × serum creatinine (mg/dL)

               Females: 0.85 × above value

In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g, or 2 g should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours. For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

CLINICAL STUDIES

A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

Preparation of Parenteral Solutions

General

Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously. Constituted solutions are not for multiple-dose use; should the entire volume in the container not be used for a single dose, the unused solution must be discarded.

Depending upon the concentration of aztreonam and diluent used, constituted AZACTAM yields a colorless to light straw yellow solution which may develop a slight pink tint on standing (potency is not affected). Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Admixtures with Other Antibiotics

Intravenous infusion solutions of AZACTAM not exceeding 2% w/v prepared with Sodium Chloride Injection, USP 0.9% or Dextrose Injection, USP 5%, to which clindamycin phosphate, gentamicin sulfate, tobramycin sulfate, or cefazolin sodium have been added at concentrations usually used clinically, are stable for up to 48 hours at room temperature or 7 days under refrigeration. Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection, USP 0.9% are stable for 24 hours at room temperature and 48 hours under refrigeration; stability in Dextrose Injection, USP 5% is 2 hours at room temperature and 8 hours under refrigeration.

Aztreonam-cloxacillin sodium and aztreonam-vancomycin hydrochloride admixtures are stable in Dianeal 137 (Peritoneal Dialysis Solution) with 4.25% Dextrose for up to 24 hours at room temperature.

Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole.

Other admixtures are not recommended since compatibility data are not available.

Intravenous Solutions

For Bolus Injection: The contents of an AZACTAM 15 mL capacity vial should be constituted with 6 to 10 mL Sterile Water for Injection, USP.

For Infusion: If the contents of a 15 mL capacity vial are to be transferred to an appropriate infusion solution, each gram of aztreonam should be initially constituted with at least 3 mL Sterile Water for Injection, USP. Further dilution may be obtained with one of the following intravenous infusion solutions:
Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ®-R Normosol ®-R and 5% Dextrose Normosol ®-M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose
Intramuscular Solutions

The contents of an AZACTAM 15 mL capacity vial should be constituted with at least 3 mL of an appropriate diluent per gram aztreonam. The following diluents may be used:
Sterile Water for Injection, USP Sterile Bacteriostatic Water for Injection, USP (with benzyl alcohol or with methyl- and propylparabens) Sodium Chloride Injection, USP, 0.9% Bacteriostatic Sodium Chloride Injection, USP (with benzyl alcohol)
Stability of Intravenous and Intramuscular Solutions

AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature (59°F-86°F/15°C-30°C) or within 7 days if refrigerated (36°F-46°F/2°C-8°C).

AZACTAM solutions at concentrations exceeding 2% w/v, except those prepared with Sterile Water for Injection, USP or Sodium Chloride Injection, USP, should be used promptly after preparation; the 2 excepted solutions must be used within 48 hours if stored at controlled room temperature or within 7 days if refrigerated.

Intravenous Administration

Bolus Injection: A bolus injection may be used to initiate therapy. The dose should be slowly injected directly into a vein, or the tubing of a suitable administration set, over a period of 3 to 5 minutes (see next paragraph regarding flushing of tubing).

Infusion: With any intermittent infusion of aztreonam and another drug with which it is not pharmaceutically compatible, the common delivery tube should be flushed before and after delivery of aztreonam with any appropriate infusion solution compatible with both drug solutions; the drugs should not be delivered simultaneously. Any AZACTAM infusion should be completed within a 20- to 60-minute period. With use of a Y-type administration set, careful attention should be given to the calculated volume of aztreonam solution required so that the entire dose will be infused. A volume control administration set may be used to deliver an initial dilution of AZACTAM (see Preparation of Parenteral Solutions: Intravenous Solutions: For Infusion) into a compatible infusion solution during administration; in this case, the final dilution of aztreonam should provide a concentration not exceeding 2% w/v.

Intramuscular Administration

The dose should be given by deep injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aztreonam is well tolerated and should not be admixed with any local anesthetic agent.

General

Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously. Constituted solutions are not for multiple-dose use; should the entire volume in the container not be used for a single dose, the unused solution must be discarded.

Depending upon the concentration of aztreonam and diluent used, constituted AZACTAM yields a colorless to light straw yellow solution which may develop a slight pink tint on standing (potency is not affected). Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Admixtures with Other Antibiotics

Intravenous infusion solutions of AZACTAM not exceeding 2% w/v prepared with Sodium Chloride Injection, USP 0.9% or Dextrose Injection, USP 5%, to which clindamycin phosphate, gentamicin sulfate, tobramycin sulfate, or cefazolin sodium have been added at concentrations usually used clinically, are stable for up to 48 hours at room temperature or 7 days under refrigeration. Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection, USP 0.9% are stable for 24 hours at room temperature and 48 hours under refrigeration; stability in Dextrose Injection, USP 5% is 2 hours at room temperature and 8 hours under refrigeration.

Aztreonam-cloxacillin sodium and aztreonam-vancomycin hydrochloride admixtures are stable in Dianeal 137 (Peritoneal Dialysis Solution) with 4.25% Dextrose for up to 24 hours at room temperature.

Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole.

Other admixtures are not recommended since compatibility data are not available.

Intravenous Solutions

For Bolus Injection: The contents of an AZACTAM 15 mL capacity vial should be constituted with 6 to 10 mL Sterile Water for Injection, USP.

For Infusion: If the contents of a 15 mL capacity vial are to be transferred to an appropriate infusion solution, each gram of aztreonam should be initially constituted with at least 3 mL Sterile Water for Injection, USP. Further dilution may be obtained with one of the following intravenous infusion solutions:
Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ®-R Normosol ®-R and 5% Dextrose Normosol ®-M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose

For Bolus Injection: The contents of an AZACTAM 15 mL capacity vial should be constituted with 6 to 10 mL Sterile Water for Injection, USP.

For Infusion: If the contents of a 15 mL capacity vial are to be transferred to an appropriate infusion solution, each gram of aztreonam should be initially constituted with at least 3 mL Sterile Water for Injection, USP. Further dilution may be obtained with one of the following intravenous infusion solutions:
Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ®-R Normosol ®-R and 5% Dextrose Normosol ®-M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose
Intramuscular Solutions

The contents of an AZACTAM 15 mL capacity vial should be constituted with at least 3 mL of an appropriate diluent per gram aztreonam. The following diluents may be used:
Sterile Water for Injection, USP Sterile Bacteriostatic Water for Injection, USP (with benzyl alcohol or with methyl- and propylparabens) Sodium Chloride Injection, USP, 0.9% Bacteriostatic Sodium Chloride Injection, USP (with benzyl alcohol)
Stability of Intravenous and Intramuscular Solutions

AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature (59°F-86°F/15°C-30°C) or within 7 days if refrigerated (36°F-46°F/2°C-8°C).

AZACTAM solutions at concentrations exceeding 2% w/v, except those prepared with Sterile Water for Injection, USP or Sodium Chloride Injection, USP, should be used promptly after preparation; the 2 excepted solutions must be used within 48 hours if stored at controlled room temperature or within 7 days if refrigerated.

Intravenous Administration

Bolus Injection: A bolus injection may be used to initiate therapy. The dose should be slowly injected directly into a vein, or the tubing of a suitable administration set, over a period of 3 to 5 minutes (see next paragraph regarding flushing of tubing).

Infusion: With any intermittent infusion of aztreonam and another drug with which it is not pharmaceutically compatible, the common delivery tube should be flushed before and after delivery of aztreonam with any appropriate infusion solution compatible with both drug solutions; the drugs should not be delivered simultaneously. Any AZACTAM infusion should be completed within a 20- to 60-minute period. With use of a Y-type administration set, careful attention should be given to the calculated volume of aztreonam solution required so that the entire dose will be infused. A volume control administration set may be used to deliver an initial dilution of AZACTAM (see Preparation of Parenteral Solutions: Intravenous Solutions: For Infusion) into a compatible infusion solution during administration; in this case, the final dilution of aztreonam should provide a concentration not exceeding 2% w/v.

Bolus Injection: A bolus injection may be used to initiate therapy. The dose should be slowly injected directly into a vein, or the tubing of a suitable administration set, over a period of 3 to 5 minutes (see next paragraph regarding flushing of tubing).

Infusion: With any intermittent infusion of aztreonam and another drug with which it is not pharmaceutically compatible, the common delivery tube should be flushed before and after delivery of aztreonam with any appropriate infusion solution compatible with both drug solutions; the drugs should not be delivered simultaneously. Any AZACTAM infusion should be completed within a 20- to 60-minute period. With use of a Y-type administration set, careful attention should be given to the calculated volume of aztreonam solution required so that the entire dose will be infused. A volume control administration set may be used to deliver an initial dilution of AZACTAM (see Preparation of Parenteral Solutions: Intravenous Solutions: For Infusion) into a compatible infusion solution during administration; in this case, the final dilution of aztreonam should provide a concentration not exceeding 2% w/v.

Intramuscular Administration

The dose should be given by deep injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aztreonam is well tolerated and should not be admixed with any local anesthetic agent.
Everyday Clean Dandruff...

Everyday Clean Dandruff

2.1 Recommended Dosing

The recommended starting dose of FARXIGA is 5 mg once daily, taken in the morning, with or without food. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily.

In patients with volume depletion, correcting this condition prior to initiation of FARXIGA is recommended [see Warnings and Precautions (5.1), Use in Specific Populations (8.5, 8.6), and Patient Counseling Information (17)].

2.2 Patients with Renal Impairment

Assessment of renal function is recommended prior to initiation of FARXIGA therapy and periodically thereafter.

FARXIGA should not be initiated in patients with an eGFR less than 60 mL/min/1.73 m2.

No dose adjustment is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater).

FARXIGA should be discontinued when eGFR is persistently less than 60 mL/min/1.73 m2 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
Loperamide Hcl

Loperamide Hcl

2.1 Recommended Dosage for Melanoma
• The recommended dose of OPDIVO administered as a single agent is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. • The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses [see Clinical Studies (14.1)]. The recommended subsequent dose of OPDIVO, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Review the Full Prescribing Information for ipilimumab prior to initiation.
2.2 Recommended Dosage for NSCLC

The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

2.3 Dose Modifications

Guidelines for treatment modifications are provided in Table 1.

There are no recommended dose modifications for hypothyroidism or hyperthyroidism.

Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions.
Table 1: Recommended Dose Modifications for OPDIVO a  Resume treatment when adverse reaction returns to Grade 0 or 1.
Adverse Reaction

Severity

Dose Modification

Colitis

Grade 2 diarrhea or colitis

Withhold dosea

Grade 3 diarrhea or colitis

     Single-agent OPDIVO

Withhold dosea

     OPDIVO, in combination with ipilimumab

Permanently discontinue

Grade 4 diarrhea or colitis

Permanently discontinue

Pneumonitis

Grade 2 pneumonitis

Withhold dosea

Grade 3 or 4 pneumonitis

Permanently discontinue

Hepatitis

Aspartate aminotransferase (AST)/or alanine aminotransferase (ALT) more than 3 and up to 5 times the upper limit of normal or total bilirubin more than 1.5 and up to 3 times the upper limit of normal

Withhold dosea

AST or ALT more than 5 times the upper limit of normal or total bilirubin more than 3 times the upper limit of normal

Permanently discontinue

Hypophysitis

Grade 2 or 3 hypophysitis

Withhold dosea

Grade 4 hypophysitis

Permanently discontinue

Adrenal Insufficiency

Grade 2 adrenal insufficiency

Withhold dosea

Grade 3 or 4 adrenal insufficiency

Permanently discontinue

Nephritis and Renal Dysfunction

Serum creatinine more than 1.5 and up to 6 times the upper limit of normal

Withhold dosea

Serum creatinine more than 6 times the upper limit of normal

Permanently discontinue

Rash

Grade 3 rash

Withhold dosea

Grade 4 rash

Permanently discontinue

Encephalitis

New onset moderate or severe neurologic signs or symptoms

Withhold dosea

Immune-mediated encephalitis

Permanently discontinue

Other

Other Grade 3 adverse reaction

     First occurrence

Withhold dosea

     Recurrence of same Grade 3 adverse reactions

Permanently discontinue

Life-threatening or Grade 4 adverse reaction

Permanently discontinue

Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks

Permanently discontinue

Persistent Grade 2 or 3 adverse reactions lasting 12 weeks or longer

Permanently discontinue

When OPDIVO is administered in combination with ipilimumab, if OPDIVO is withheld, ipilimumab should also be withheld.

2.4 Preparation and Administration

Visually inspect drug product solution for particulate matter and discoloration prior to administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial.

Preparation
• Withdraw the required volume of OPDIVO and transfer into an intravenous container. • Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake. • Discard partially used vials or empty vials of OPDIVO.
Storage of Infusion

The product does not contain a preservative.

After preparation, store the OPDIVO infusion either:
• at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or • under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of infusion preparation.
Do not freeze.

Administration

Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).

Do not coadminister other drugs through the same intravenous line.

Flush the intravenous line at end of infusion.

When administered in combination with ipilimumab, infuse OPDIVO first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.
Zerit

Zerit

The interval between doses of ZERIT (stavudine) should be 12 hours. ZERIT may be taken with or without food.

2.1   Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:
• For patients weighing less than 60 kg: 30 mg every 12 hours. • For patients weighing at least 60 kg: 40 mg every 12 hours.
2.2   Recommended Pediatric Dosage
• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours. • For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours. • For pediatric patients weighing at least 30 kg: use the recommended adult dosage.
2.3   Dosage Adjustment

Renal Impairment

Adult Patients: ZERIT may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.
Table 1: Recommended Dosage Adjustment for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Recommended ZERIT Dose by Patient Weight at least 60 kg less than 60 kg * Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
greater than 50

40 mg every 12 hours

30 mg every 12 hours

26–50

20 mg every 12 hours

15 mg every 12 hours

10–25

20 mg every 24 hours

15 mg every 24 hours

Hemodialysis

20 mg every 24 hours*

15 mg every 24 hours*

Pediatric Patients: Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of ZERIT in this patient population.

2.4   Method of Preparation for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg stavudine per mL of solution, as follows:
1. Add 202 mL of purified water to the container. 2. Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL stavudine solution. The solution may appear slightly hazy. 3. Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.
2.1   Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:
• For patients weighing less than 60 kg: 30 mg every 12 hours. • For patients weighing at least 60 kg: 40 mg every 12 hours.
2.2   Recommended Pediatric Dosage
• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours. • For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours. • For pediatric patients weighing at least 30 kg: use the recommended adult dosage.
2.3   Dosage Adjustment

Renal Impairment

Adult Patients: ZERIT may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.
Table 1: Recommended Dosage Adjustment for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Recommended ZERIT Dose by Patient Weight at least 60 kg less than 60 kg * Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
greater than 50

40 mg every 12 hours

30 mg every 12 hours

26–50

20 mg every 12 hours

15 mg every 12 hours

10–25

20 mg every 24 hours

15 mg every 24 hours

Hemodialysis

20 mg every 24 hours*

15 mg every 24 hours*

Pediatric Patients: Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of ZERIT in this patient population.

Renal Impairment

Adult Patients: ZERIT may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.
Table 1: Recommended Dosage Adjustment for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Recommended ZERIT Dose by Patient Weight at least 60 kg less than 60 kg * Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
greater than 50

40 mg every 12 hours

30 mg every 12 hours

26–50

20 mg every 12 hours

15 mg every 12 hours

10–25

20 mg every 24 hours

15 mg every 24 hours

Hemodialysis

20 mg every 24 hours*

15 mg every 24 hours*

Pediatric Patients: Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of ZERIT in this patient population.

2.4   Method of Preparation for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg stavudine per mL of solution, as follows:
1. Add 202 mL of purified water to the container. 2. Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL stavudine solution. The solution may appear slightly hazy. 3. Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.
Pravachol

Pravachol

2.1 General Dosing Information

The patient should be placed on a standard cholesterol-lowering diet before receiving PRAVACHOL and should continue on this diet during treatment with PRAVACHOL [see NCEP Treatment Guidelines for details on dietary therapy].

2.2 Adult Patients

The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal impairment, a starting dose of 10 mg daily is recommended. PRAVACHOL can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

2.3 Pediatric Patients

Children (Ages 8 to 13 Years, Inclusive)

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

Adolescents (Ages 14 to 18 Years)

The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.

Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C [see Indications and Usage (1.2)].

2.4 Concomitant Lipid-Altering Therapy

PRAVACHOL may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given either 1 hour or more before or at least 4 hours following the resin. [See Clinical Pharmacology (12.3).]

2.5 Dosage in Patients Taking Cyclosporine

In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine, therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

2.6 Dosage in Patients Taking Clarithromycin

In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily [see Drug Interactions (7.2)].

2.1 General Dosing Information

The patient should be placed on a standard cholesterol-lowering diet before receiving PRAVACHOL and should continue on this diet during treatment with PRAVACHOL [see NCEP Treatment Guidelines for details on dietary therapy].

2.2 Adult Patients

The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal impairment, a starting dose of 10 mg daily is recommended. PRAVACHOL can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

2.3 Pediatric Patients

Children (Ages 8 to 13 Years, Inclusive)

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

Adolescents (Ages 14 to 18 Years)

The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.

Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C [see Indications and Usage (1.2)].

Children (Ages 8 to 13 Years, Inclusive)

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

Adolescents (Ages 14 to 18 Years)

The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.

Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C [see Indications and Usage (1.2)].

2.4 Concomitant Lipid-Altering Therapy

PRAVACHOL may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, PRAVACHOL should be given either 1 hour or more before or at least 4 hours following the resin. [See Clinical Pharmacology (12.3).]

2.5 Dosage in Patients Taking Cyclosporine

In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine, therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

2.6 Dosage in Patients Taking Clarithromycin

In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily [see Drug Interactions (7.2)].
Yervoy

Yervoy

2.1   Recommended Dosing

The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.

2.2   Recommended Dose Modifications
● Withhold scheduled dose of YERVOY for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or equivalent per day, resume YERVOY at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier. ● Permanently discontinue YERVOY for any of the following: ○ Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day. ○ Failure to complete full treatment course within 16 weeks from administration of first dose. ○ Severe or life-threatening adverse reactions, including any of the following: ■ Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation ■ Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal ■ Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations ■ Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis ■ Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis) ■ Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy
2.3   Preparation and Administration
● Do not shake product. ● Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.
Preparation of Solution
● Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion. ● Withdraw the required volume of YERVOY and transfer into an intravenous bag. ● Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion. ● Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). ● Discard partially used vials or empty vials of YERVOY.
Administration Instructions
● Do not mix YERVOY with, or administer as an infusion with, other medicinal products. ● Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose. ● Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.
Orencia

Orencia

2.1 Adult Rheumatoid Arthritis

For adult patients with RA, ORENCIA may be administered as an intravenous infusion or a subcutaneous injection.

ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

For pediatric juvenile idiopathic arthritis, a dose calculated based on each patient's body weight is used [see Dosage and Administration (2.2)].

Intravenous Dosing Regimen

ORENCIA intravenous should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.
Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients Body Weight of Patient Dose Number of Vialsa a Each vial provides 250 mg of abatacept for administration.
Less than 60 kg

500 mg

2

60 to 100 kg

750 mg

3

More than 100 kg

1000 mg

4

Subcutaneous Dosing Regimen

ORENCIA 125 mg should be administered by subcutaneous injection once weekly and may be initiated with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, ORENCIA should be initiated with a single intravenous infusion (as per body weight categories listed in Table 1), followed by the first 125 mg subcutaneous injection administered within a day of the intravenous infusion.

Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

2.2 Juvenile Idiopathic Arthritis

Intravenous Dosing Regimen

The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg intravenously calculated based on the patient’s body weight at each administration. Pediatric patients weighing 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded.

Subcutaneous Dosing Regimen

The safety and efficacy of subcutaneous ORENCIA injection have not been studied in patients under 18 years of age.

2.3 Preparation and Administration Instructions for Intravenous Infusion

Use aseptic technique.

ORENCIA is provided as a lyophilized powder in preservative-free, single-use vials. Each ORENCIA vial provides 250 mg of abatacept for administration. The ORENCIA powder in each vial must be reconstituted with 10 mL of Sterile Water for Injection, USP, using only the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. After reconstitution, the concentration of abatacept in the vial will be 25 mg/mL. If the ORENCIA powder is accidentally reconstituted using a siliconized syringe, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes.

If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb 1-800-ORENCIA.
1) Use 10 mL of Sterile Water for Injection, USP to reconstitute the ORENCIA powder. To reconstitute the ORENCIA powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. Rotate the vial with gentle swirling to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation. 2) Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may be present. After reconstitution, each milliliter will contain 25 mg (250 mg/10 mL). The solution should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. 3) The reconstituted ORENCIA solution must be further diluted to 100 mL as follows. From a 100 mL infusion bag or bottle, withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the reconstituted ORENCIA solution required for the patient’s dose. Slowly add the reconstituted ORENCIA solution into the infusion bag or bottle using the same silicone-free disposable syringe provided with each vial. Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle will depend upon the amount of drug added, but will be no more than 10 mg/mL. Any unused portions in the vials must be immediately discarded. 4) Prior to administration, the ORENCIA solution should be inspected visually for particulate matter and discoloration. Discard the solution if any particulate matter or discoloration is observed. 5) The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 μm to 1.2 μm). 6) The infusion of the fully diluted ORENCIA solution must be completed within 24 hours of reconstitution of the ORENCIA vials. The fully diluted ORENCIA solution may be stored at room temperature or refrigerated at 2°C to 8°C (36°F to 46°F) before use. Discard the fully diluted solution if not administered within 24 hours. 7) ORENCIA should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of ORENCIA with other agents.
2.4 General Considerations for Subcutaneous Administration

ORENCIA Injection, 125 mg/syringe is not intended for intravenous infusion.

ORENCIA Injection is intended for use under the guidance of a physician or healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject with ORENCIA if a physician/healthcare practitioner determines that it is appropriate. Patients should be instructed to follow the directions provided in the Instructions for Use for additional details on medication administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use ORENCIA prefilled syringes exhibiting particulate matter or discoloration. ORENCIA should be clear and colorless to pale yellow.

Patients using ORENCIA for subcutaneous administration should be instructed to inject the full amount in the syringe (1 mL), which provides 125 mg of ORENCIA, according to the directions provided in the Instructions for Use.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

2.1 Adult Rheumatoid Arthritis

For adult patients with RA, ORENCIA may be administered as an intravenous infusion or a subcutaneous injection.

ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

For pediatric juvenile idiopathic arthritis, a dose calculated based on each patient's body weight is used [see Dosage and Administration (2.2)].

Intravenous Dosing Regimen

ORENCIA intravenous should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.
Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients Body Weight of Patient Dose Number of Vialsa a Each vial provides 250 mg of abatacept for administration.
Less than 60 kg

500 mg

2

60 to 100 kg

750 mg

3

More than 100 kg

1000 mg

4

Subcutaneous Dosing Regimen

ORENCIA 125 mg should be administered by subcutaneous injection once weekly and may be initiated with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, ORENCIA should be initiated with a single intravenous infusion (as per body weight categories listed in Table 1), followed by the first 125 mg subcutaneous injection administered within a day of the intravenous infusion.

Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

2.2 Juvenile Idiopathic Arthritis

Intravenous Dosing Regimen

The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg intravenously calculated based on the patient’s body weight at each administration. Pediatric patients weighing 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded.

Subcutaneous Dosing Regimen

The safety and efficacy of subcutaneous ORENCIA injection have not been studied in patients under 18 years of age.

2.3 Preparation and Administration Instructions for Intravenous Infusion

Use aseptic technique.

ORENCIA is provided as a lyophilized powder in preservative-free, single-use vials. Each ORENCIA vial provides 250 mg of abatacept for administration. The ORENCIA powder in each vial must be reconstituted with 10 mL of Sterile Water for Injection, USP, using only the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. After reconstitution, the concentration of abatacept in the vial will be 25 mg/mL. If the ORENCIA powder is accidentally reconstituted using a siliconized syringe, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes.

If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb 1-800-ORENCIA.
1) Use 10 mL of Sterile Water for Injection, USP to reconstitute the ORENCIA powder. To reconstitute the ORENCIA powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. Rotate the vial with gentle swirling to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation. 2) Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may be present. After reconstitution, each milliliter will contain 25 mg (250 mg/10 mL). The solution should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. 3) The reconstituted ORENCIA solution must be further diluted to 100 mL as follows. From a 100 mL infusion bag or bottle, withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the reconstituted ORENCIA solution required for the patient’s dose. Slowly add the reconstituted ORENCIA solution into the infusion bag or bottle using the same silicone-free disposable syringe provided with each vial. Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle will depend upon the amount of drug added, but will be no more than 10 mg/mL. Any unused portions in the vials must be immediately discarded. 4) Prior to administration, the ORENCIA solution should be inspected visually for particulate matter and discoloration. Discard the solution if any particulate matter or discoloration is observed. 5) The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 μm to 1.2 μm). 6) The infusion of the fully diluted ORENCIA solution must be completed within 24 hours of reconstitution of the ORENCIA vials. The fully diluted ORENCIA solution may be stored at room temperature or refrigerated at 2°C to 8°C (36°F to 46°F) before use. Discard the fully diluted solution if not administered within 24 hours. 7) ORENCIA should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of ORENCIA with other agents.
2.4 General Considerations for Subcutaneous Administration

ORENCIA Injection, 125 mg/syringe is not intended for intravenous infusion.

ORENCIA Injection is intended for use under the guidance of a physician or healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject with ORENCIA if a physician/healthcare practitioner determines that it is appropriate. Patients should be instructed to follow the directions provided in the Instructions for Use for additional details on medication administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use ORENCIA prefilled syringes exhibiting particulate matter or discoloration. ORENCIA should be clear and colorless to pale yellow.

Patients using ORENCIA for subcutaneous administration should be instructed to inject the full amount in the syringe (1 mL), which provides 125 mg of ORENCIA, according to the directions provided in the Instructions for Use.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.
Lysodren

Lysodren

The recommended treatment schedule is to start the patient at 2 g to 6 g of LYSODREN per day in divided doses, either 3 or 4 times a day. Doses are usually increased incrementally to 9 g to 10 g per day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 g to 16 g per day, but has usually been 9 g to 10 g per day. The highest doses used in the studies to date were 18 g to 19 g per day.

Treatment should be instituted in the hospital until a stable dosage regimen is achieved.

Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred.

If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production.

A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of LYSODREN is the best approach.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1

To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing LYSODREN tablets. LYSODREN tablets should not be crushed. Personnel should avoid exposure to crushed and/or broken tablets. If contact with broken tablets occurs, wash immediately and thoroughly. More information is available in the references listed below.
Etopophos

Etopophos

The usual dose of VePesid for Injection in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5. Equivalent doses of ETOPOPHOS should be used.

In small cell lung cancer, the VePesid for Injection dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days. Equivalent doses of ETOPOPHOS should be used.

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

ETOPOPHOS SHOULD NOT BE GIVEN BY BOLUS INTRAVENOUS INJECTION. ETOPOPHOS solutions may be administered at infusion rates from 5 to 210 minutes. Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.

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

Administration Precautions

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

Preparation for Intravenous Administration

Prior to use, the content of each vial must be reconstituted with Sterile Water for Injection, USP; 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Bacteriostatic Water for Injection with Benzyl Alcohol; or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol to a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide (22.7 or 11.4 mg/mL etoposide phosphate, respectively). Use the quantity of diluent shown below to reconstitute the product.
Vial Strength Volume of Diluent Final Concentration 100 mg 5 mL 20 mg/mL 10 mL 10 mg/mL
Following reconstitution, ETOPOPHOS can be further diluted to concentrations as low as 0.1 mg/mL etoposide with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.

Solutions of ETOPOPHOS should be prepared in an aseptic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Stability

Unopened vials of ETOPOPHOS for Injection are stable until the date indicated on the package when stored under refrigeration 2° to 8°C (36°-46°F) in the original package. When reconstituted as directed, ETOPOPHOS solutions can be stored in glass or plastic containers under refrigeration 2° to 8°C (36°-46°F) for 7 days; at controlled room temperature 20° to 25°C (68°-77°F) for 24 hours following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP; or at controlled room temperature 20° to 25°C (68°-77°F) for 48 hours following reconstitution with Bacteriostatic Water for Injection with Benzyl Alcohol or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol. ETOPOPHOS solutions further diluted as directed can be stored under refrigeration 2° to 8°C (36°-46°F) or at controlled room temperature 20° to 25°C (68°-77°F) for 24 hours.
Butalbital

Butalbital

2.1 Recommended Dose

Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation

The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.

The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of the following characteristics:
● age ≥80 years ● body weight ≤60 kg ● serum creatinine ≥1.5 mg/dL
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
● In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days. ● In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.
Treatment of DVT and PE

The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.

Reduction in the Risk of Recurrence of DVT and PE

The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE [see Clinical Studies (14.3)].

2.2 Missed Dose

If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.

2.3 Temporary Interruption for Surgery and Other Interventions

ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.

2.4 Converting from or to ELIQUIS

Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started when the international normalized ratio (INR) is below 2.0.

Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue ELIQUIS and begin both a parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral): Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of ELIQUIS.

Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual time of the next dose of the anticoagulant other than warfarin.

2.5 Strong Dual Inhibitors of CYP3A4 and P-glycoprotein

For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) [see Clinical Pharmacology (12.3)].

In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)].

2.6 Administration Options

For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets may be crushed and suspended in 60 mL D5W and immediately delivered through a nasogastric tube (NGT) [see Clinical Pharmacology (12.3)]. Information regarding the administration of crushed and suspended ELIQUIS tablets swallowed by mouth is not available.

2.1 Recommended Dose

Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation

The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.

The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of the following characteristics:
● age ≥80 years ● body weight ≤60 kg ● serum creatinine ≥1.5 mg/dL
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
● In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days. ● In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.
Treatment of DVT and PE

The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.

Reduction in the Risk of Recurrence of DVT and PE

The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE [see Clinical Studies (14.3)].

2.2 Missed Dose

If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.

2.3 Temporary Interruption for Surgery and Other Interventions

ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.

2.4 Converting from or to ELIQUIS

Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started when the international normalized ratio (INR) is below 2.0.

Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue ELIQUIS and begin both a parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral): Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of ELIQUIS.

Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual time of the next dose of the anticoagulant other than warfarin.

2.5 Strong Dual Inhibitors of CYP3A4 and P-glycoprotein

For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) [see Clinical Pharmacology (12.3)].

In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)].
Nulojix

Nulojix

2.1 Dosage in Adult Kidney Transplant Recipients

NULOJIX should be administered in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. In clinical trials the median (25th-75th percentile) corticosteroid doses were tapered to approximately 15 mg (10-20 mg) per day by the first 6 weeks and remained at approximately 10 mg (5-10 mg) per day for the first 6 months post-transplant. Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience [see Warnings and Precautions (5.7) and Clinical Studies (14.1)].

Due to an increased risk of post-transplant lymphoproliferative disorder (PTLD) predominantly involving the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML), and serious CNS infections, administration of higher than the recommended doses or more frequent dosing of NULOJIX is not recommended [see Warnings and Precautions (5.1, 5.4, 5.5) and Adverse Reactions (6.1)].

NULOJIX is for intravenous infusion only. Patients do not require premedication prior to administration of NULOJIX.

Dosing instructions are provided in Table 1.
• The total infusion dose of NULOJIX should be based on the actual body weight of the patient at the time of transplantation, and should not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. • The prescribed dose of NULOJIX must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100. For example: – A patient weighs 64 kg. The dose is 10 mg per kg. – Calculated Dose: 64 kg × 10 mg per kg = 640 mg – The closest doses evenly divisible by 12.5 mg below and above 640 mg are 637.5 mg and 650 mg. – The nearest dose to 640 mg is 637.5 mg. – Therefore, the actual prescribed dose for the patient should be 637.5 mg. Table 1: Dosing*,† of NULOJIX for Kidney Transplant Recipients * [See Clinical Studies (14.1).]† The dose prescribed for the patient must be evenly divisible by 12.5 mg (see instructions above; e.g., evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100).
Dosing for Initial Phase

Dose

   Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose)

10 mg per kg

   End of Week 2 and Week 4 after transplantation

10 mg per kg

   End of Week 8 and Week 12 after transplantation

10 mg per kg

Dosing for Maintenance Phase

Dose

   End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter

5 mg per kg

2.2 Preparation and Administration Instructions

NULOJIX is for intravenous infusion only.

Caution: NULOJIX must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial.

If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb at 1-888-NULOJIX.

Preparation for Administration
1. Calculate the number of NULOJIX vials required to provide the total infusion dose. Each vial contains 250 mg of belatacept lyophilized powder. 2. Reconstitute the contents of each vial of NULOJIX with 10.5 mL of a suitable diluent using the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. Suitable diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in water (D5W). Note: If the NULOJIX powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. 3. To reconstitute the NULOJIX powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial. 4. To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. 5. The reconstituted solution contains a belatacept concentration of 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. 6. Calculate the total volume of the reconstituted 25 mg/mL NULOJIX solution required to provide the total infusion dose. Volume of 25 mg/mL NULOJIX solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL 7. Prior to intravenous infusion, the required volume of the reconstituted NULOJIX solution must be further diluted with a suitable infusion fluid (NS or D5W). NULOJIX reconstituted with: • SWFI should be further diluted with either NS or D5W • NS should be further diluted with NS • D5W should be further diluted with D5W 8. From the appropriate size infusion bag or bottle, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted NULOJIX solution required to provide the prescribed dose. With the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept solution from the vial, inject it into the infusion bag or bottle, and gently rotate the infusion bag or bottle to ensure mixing. The final belatacept concentration in the infusion bag or bottle should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution remaining in the vials must be discarded. 9. Prior to administration, the NULOJIX infusion should be inspected visually for particulate matter and discoloration. Discard the infusion if any particulate matter or discoloration is observed. 10. The entire NULOJIX infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm). • The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of reconstitution of the NULOJIX lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C [68°-77°F] and room light). • Infuse NULOJIX in a separate line from other concomitantly infused agents. NULOJIX should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents.
Preparation for Administration
1. Calculate the number of NULOJIX vials required to provide the total infusion dose. Each vial contains 250 mg of belatacept lyophilized powder. 2. Reconstitute the contents of each vial of NULOJIX with 10.5 mL of a suitable diluent using the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. Suitable diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in water (D5W). Note: If the NULOJIX powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. 3. To reconstitute the NULOJIX powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial. 4. To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. 5. The reconstituted solution contains a belatacept concentration of 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. 6. Calculate the total volume of the reconstituted 25 mg/mL NULOJIX solution required to provide the total infusion dose. Volume of 25 mg/mL NULOJIX solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL 7. Prior to intravenous infusion, the required volume of the reconstituted NULOJIX solution must be further diluted with a suitable infusion fluid (NS or D5W). NULOJIX reconstituted with: • SWFI should be further diluted with either NS or D5W • NS should be further diluted with NS • D5W should be further diluted with D5W 8. From the appropriate size infusion bag or bottle, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted NULOJIX solution required to provide the prescribed dose. With the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept solution from the vial, inject it into the infusion bag or bottle, and gently rotate the infusion bag or bottle to ensure mixing. The final belatacept concentration in the infusion bag or bottle should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution remaining in the vials must be discarded. 9. Prior to administration, the NULOJIX infusion should be inspected visually for particulate matter and discoloration. Discard the infusion if any particulate matter or discoloration is observed. 10. The entire NULOJIX infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm). • The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of reconstitution of the NULOJIX lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C [68°-77°F] and room light). • Infuse NULOJIX in a separate line from other concomitantly infused agents. NULOJIX should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents.
Bicnu

Bicnu

The recommended dose of BiCNU as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This may be given as a single dose or divided into daily injections such as 75 to 100 mg/m2 on 2 successive days. When BiCNU is used in combination with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted, the doses should be adjusted accordingly.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:
Nadir After Prior Dose Percentage of Prior Dose tobe Given Leukocytes/mm3 Platelets/mm3 >4000 >100,000 100% 3000–3999 75,000–99,999 100% 2000–2999 25,000–74,999 70% <2000 <25,000 50%
A repeat course of BiCNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3, leukocytes above 4,000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

Administration Precautions

As with other potentially toxic compounds, caution should be exercised in handling BiCNU and preparing the solution of BiCNU. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 Accidental contact of reconstituted BiCNU with the skin has caused transient hyperpigmentation of the affected areas. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing BiCNU. If BiCNU lyophilized material or solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. More information is available in the references listed below.

Reconstituted solution should only be administered by slow intravenous infusion. Administration of BiCNU over a period of less than 2 hours can lead to pain and burning at the site of injection.

Preparation of Intravenous Solutions

First, dissolve BiCNU with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Second, aseptically add 27 mL Sterile Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of BiCNU in 10% ethanol. Such solutions should be protected from light.

Reconstitution as recommended results in a clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Important Note

The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose vial.

Stability

The unopened vial of the dry drug must be stored in a refrigerator (2°-8°C, 36°-46°F). The diluent ampules may be stored at controlled room temperature (15°-30°C, 59°-86°F) or in a refrigerator (2°-8°C, 36°-46°F). The recommended storage of unopened BiCNU vials provides a stable product for up to 3 years. After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F). Reconstituted vials should be examined for crystal formation prior to use. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation.

Vials reconstituted as directed and further diluted to a concentration of 0.2 mg/mL in 5% Dextrose Injection, USP, should be stored at room temperature, protected from light and utilized within 8 hours.

Glass containers were used for the stability data provided in this section. Only use glass containers for BiCNU administration.

Important Note

BiCNU has a low melting point (30.5°-32.0°C or 86.9°-89.6°F). Exposure of the drug to this temperature or above will cause the drug to liquefy and appear as an oil film on the vials. This is a sign of decomposition and vials should be discarded. If there is a question of adequate refrigeration upon receipt of this product, immediately inspect the vial in each individual carton. Hold the vial to a bright light for inspection. The BiCNU will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the BiCNU is suitable for use and should be refrigerated immediately.
Reyataz

Reyataz

2.1 Overview
• REYATAZ capsules and oral powder must be taken with food. • Do not open the capsules. • The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H 2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.2, 2.3, 2.4, 2.5) and Drug Interactions (7)]. • REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)]. • REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.4) ]. • Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.
2.2 Dosage of REYATAZ in Adult Patients

Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.
Table 1: Recommended REYATAZ and Ritonavir Dosage in Adultsa,b a See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir.
REYATAZ Once Daily

Dosage

Ritonavir Once Daily

Dosage

Treatment-Naive Adult Patients
recommended regimen
300 mg

100 mg
unable to tolerate ritonavir
400 mg

N/A
in combination with efavirenz
400 mg

100 mg

Treatment-Experienced Adult Patients
recommended regimen
300 mg

100 mg
in combination with both H2RA and tenofovir
400 mg

100 mg

2.3 Dosage of REYATAZ Capsules in Pediatric Patients

The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).
Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)a,b Body weight REYATAZ Daily Dosage Ritonavir Daily Dosage
Treatment-Naive and Treatment-Experiencedc

Less than 15 kg

Capsules not recommended

N/A

15 kg to less than 20 kg

150 mg

100 mg

20 kg to less than 40 kg

200 mg

100 mg

At least 40 kg

300 mg

100 mg

Treatment-Naive, at least 13 years old and cannot tolerate ritonavirc

At least 40 kg

400 mg

N/A

a Administer REYATAZ capsules and ritonavir simultaneously with food.b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir.

2.4 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients

REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.
Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg)a,b Body Weight Daily Dosage of REYATAZ Oral Powder Daily Dosage of Ritonavir a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir.c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring.d Each packet contains 50 mg of REYATAZ.
5 kg to less than 15 kg

200 mg (4 packets)c,d

80 mgc

15 kg to less than 25 kg

250 mg (5 packets)d

80 mgc

Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use]
• Determine the number of packets (3, 4, 5 or 6 packets) that are needed. • Prior to mixing, tap the packet to settle the powder. • It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered. • Use a clean pair of scissors to cut each packet along the dotted line. • Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture. • Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time. • Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant. • Administer ritonavir immediately following REYATAZ powder administration. • Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation (may leave the mixture at room temperature during this one hour period). Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.
2.5 Dosage Adjustments in Pregnant Patients

Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults). [See Use in Specific Populations (8.1).]
Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa REYATAZ Once Daily Dosage Ritonavir Once Daily Dosage a See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with both tenofovir and H2RA.
Treatment-Naive and Treatment-Experienced

Recommended Regimen

300 mg

100 mg

Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovirb

In combination with either H2RA or tenofovir

400 mg

100 mg

2.6 Dosage in Patients with Renal Impairment

For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Use in Specific Populations (8.7).]

2.7 Dosage Adjustments in Patients with Hepatic Impairment

Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.
Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment
REYATAZ Once Daily Dosage

Mild hepatic impairment (Child-Pugh Class A)

400 mg

Moderate hepatic impairment (Child-Pugh Class B)

300 mg

Severe hepatic impairment (Child-Pugh Class C)

REYATAZ with or without ritonavir is not recommended

2.1 Overview
• REYATAZ capsules and oral powder must be taken with food. • Do not open the capsules. • The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H 2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.2, 2.3, 2.4, 2.5) and Drug Interactions (7)]. • REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)]. • REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.4) ]. • Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.
2.2 Dosage of REYATAZ in Adult Patients

Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.
Table 1: Recommended REYATAZ and Ritonavir Dosage in Adultsa,b a See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir.
REYATAZ Once Daily

Dosage

Ritonavir Once Daily

Dosage

Treatment-Naive Adult Patients
recommended regimen
300 mg

100 mg
unable to tolerate ritonavir
400 mg

N/A
in combination with efavirenz
400 mg

100 mg

Treatment-Experienced Adult Patients
recommended regimen
300 mg

100 mg
in combination with both H2RA and tenofovir
400 mg

100 mg

2.3 Dosage of REYATAZ Capsules in Pediatric Patients

The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).
Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)a,b Body weight REYATAZ Daily Dosage Ritonavir Daily Dosage
Treatment-Naive and Treatment-Experiencedc

Less than 15 kg

Capsules not recommended

N/A

15 kg to less than 20 kg

150 mg

100 mg

20 kg to less than 40 kg

200 mg

100 mg

At least 40 kg

300 mg

100 mg

Treatment-Naive, at least 13 years old and cannot tolerate ritonavirc

At least 40 kg

400 mg

N/A

a Administer REYATAZ capsules and ritonavir simultaneously with food.b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir.

2.4 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients

REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.
Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg)a,b Body Weight Daily Dosage of REYATAZ Oral Powder Daily Dosage of Ritonavir a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir.c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring.d Each packet contains 50 mg of REYATAZ.
5 kg to less than 15 kg

200 mg (4 packets)c,d

80 mgc

15 kg to less than 25 kg

250 mg (5 packets)d

80 mgc

Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use]
• Determine the number of packets (3, 4, 5 or 6 packets) that are needed. • Prior to mixing, tap the packet to settle the powder. • It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered. • Use a clean pair of scissors to cut each packet along the dotted line. • Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture. • Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time. • Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant. • Administer ritonavir immediately following REYATAZ powder administration. • Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation (may leave the mixture at room temperature during this one hour period). Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.
2.5 Dosage Adjustments in Pregnant Patients

Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults). [See Use in Specific Populations (8.1).]
Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa REYATAZ Once Daily Dosage Ritonavir Once Daily Dosage a See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with both tenofovir and H2RA.
Treatment-Naive and Treatment-Experienced

Recommended Regimen

300 mg

100 mg

Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovirb

In combination with either H2RA or tenofovir

400 mg

100 mg

2.6 Dosage in Patients with Renal Impairment

For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Use in Specific Populations (8.7).]

2.7 Dosage Adjustments in Patients with Hepatic Impairment

Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.
Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment
REYATAZ Once Daily Dosage

Mild hepatic impairment (Child-Pugh Class A)

400 mg

Moderate hepatic impairment (Child-Pugh Class B)

300 mg

Severe hepatic impairment (Child-Pugh Class C)

REYATAZ with or without ritonavir is not recommended
Kenalog-10

Kenalog-10

General

NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS).

IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 to 48 mg/m2bsa/day).

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

Cortisone, 25

Triamcinolone, 4

Hydrocortisone, 20

Paramethasone, 2

Prednisolone, 5

Betamethasone, 0.75

Prednisone, 5

Dexamethasone, 0.75

Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

Intra-Articular Administration

Dosage

The initial dose of Kenalog-10 Injection for intra-articular administration may vary from 2.5 mg to 5 mg for smaller joints and from 5 mg to 15 mg for larger joints, depending on the specific disease entity being treated. Single injections into several joints, up to a total of 20 mg or more, have been given.

Intralesional

For intralesional administration, the initial dose per injection site will vary depending on the specific disease entity and lesion being treated. The site of injection and volume of injection should be carefully considered due to the potential for cutaneous atrophy.

Multiple sites separated by one centimeter or more may be injected, keeping in mind that the greater the total volume employed the more corticosteroid becomes available for systemic absorption and systemic effects. Such injections may be repeated, if necessary, at weekly or less frequent intervals.

Localization of Doses

The lower dosages in the initial dosage range of triamcinolone acetonide may produce the desired effect when the corticosteroid is administered to provide a localized concentration. The site and volume of the injection should be carefully considered when triamcinolone acetonide is administered for this purpose.

Administration

STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, inject without delay to prevent settling in the syringe.

Injection Technique

For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid.

With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy.

In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of Kenalog-10 Injection is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness.

Intralesional

For treatment of dermal lesions, Kenalog-10 Injection should be injected directly into the lesion, ie, intradermally or subcutaneously. For accuracy of dosage measurement and ease of administration, it is preferable to employ a tuberculin syringe and a small-bore needle (23-25 gauge). Ethyl chloride spray may be used to alleviate the discomfort of the injection.
Kenalog-40

Kenalog-40

General

NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS).

The initial dose of Kenalog-40 Injection may vary from 2.5 mg to 100 mg per day depending on the specific disease entity being treated (see Dosage section below). However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Dosage

SYSTEMIC

The suggested initial dose is 60 mg, injected deeply into the gluteal muscle. Atrophy of subcutaneous fat may occur if the injection is not properly given. Dosage is usually adjusted within the range of 40 mg to 80 mg, depending upon patient response and duration of relief. However, some patients may be well controlled on doses as low as 20 mg or less.

Hay fever or pollen asthma: Patients with hay fever or pollen asthma who are not responding to pollen administration and other conventional therapy may obtain a remission of symptoms lasting throughout the pollen season after a single injection of 40 mg to 100 mg.

In the treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of triamcinolone for a week followed by 64 mg every other day for one month are recommended (see PRECAUTIONS: Neuro-Psychiatric).

In pediatric patients, the initial dose of triamcinolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 to 1.6 mg/kg/day in 3 or 4 divided doses (3.2 to 48 mg/m2bsa/day).

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

Cortisone, 25

Triamcinolone, 4

Hydrocortisone, 20

Paramethasone, 2

Prednisolone, 5

Betamethasone, 0.75

Prednisone, 5

Dexamethasone, 0.75

Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

LOCAL

Intra-articular administration: A single local injection of triamcinolone acetonide is frequently sufficient, but several injections may be needed for adequate relief of symptoms.

Initial dose: 2.5 mg to 5 mg for smaller joints and from 5 mg to 15 mg for larger joints, depending on the specific disease entity being treated. For adults, doses up to 10 mg for smaller areas and up to 40 mg for larger areas have usually been sufficient. Single injections into several joints, up to a total of 80 mg, have been given.

Administration

GENERAL

STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be shaken before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used. After withdrawal, Kenalog-40 Injection should be injected without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing infection.

SYSTEMIC

For systemic therapy, injection should be made deeply into the gluteal muscle (see WARNINGS). For adults, a minimum needle length of 1½ inches is recommended. In obese patients, a longer needle may be required. Use alternative sites for subsequent injections.

LOCAL

For treatment of joints, the usual intra-articular injection technique should be followed. If an excessive amount of synovial fluid is present in the joint, some, but not all, should be aspirated to aid in the relief of pain and to prevent undue dilution of the steroid.

With intra-articular administration, prior use of a local anesthetic may often be desirable. Care should be taken with this kind of injection, particularly in the deltoid region, to avoid injecting the suspension into the tissues surrounding the site, since this may lead to tissue atrophy.

In treating acute nonspecific tenosynovitis, care should be taken to ensure that the injection of the corticosteroid is made into the tendon sheath rather than the tendon substance. Epicondylitis may be treated by infiltrating the preparation into the area of greatest tenderness.
Baraclude

Baraclude

2.1   Timing of Administration

BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).

2.2   Recommended Dosage in Adults

Compensated Liver Disease

The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.

The recommended dose of BARACLUDE in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.

Decompensated Liver Disease

The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.

2.3   Recommended Dosage in Pediatric Patients

Table 1 describes the recommended dose of BARACLUDE for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg.
Table 1:   Dosing Schedule for Pediatric Patients Recommended Once-Daily Dose of Oral Solution (mL) Body Weight (kg) Treatment-NaïvePatientsa Lamivudine-ExperiencedPatientsb
10 to 11

3

6

greater than 11 to 14

4

8

greater than 14 to 17

5

10

greater than 17 to 20

6

12

greater than 20 to 23

7

14

greater than 23 to 26

8

16

greater than 26 to 30

9

18

greater than 30

10

20

a  Children with body weight greater than 30 kg should receive 10 mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily.b  Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily.

2.4   Renal Impairment

In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see Clinical Pharmacology (12.3)]. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred.
Table 2:   Recommended Dosage of BARACLUDE in Adult Patients with Renal Impairment Creatinine Clearance(mL/min) Usual Dose (0.5 mg) Lamivudine-Refractory or Decompensated Liver Disease (1 mg) a  For doses less than 0.5 mg, BARACLUDE Oral Solution is recommended.b  If administered on a hemodialysis day, administer BARACLUDE after the hemodialysis session.
50 or greater

0.5 mg once daily

1 mg once daily

30 to less than 50

0.25 mg once dailya OR0.5 mg every 48 hours

0.5 mg once dailyOR1 mg every 48 hours

10 to less than 30

0.15 mg once dailya OR0.5 mg every 72 hours

0.3 mg once dailya OR1 mg every 72 hours

Less than 10Hemodialysisb or CAPD

0.05 mg once dailya OR0.5 mg every 7 days

0.1 mg once dailya OR1 mg every 7 days

Although there are insufficient data to recommend a specific dose adjustment of BARACLUDE in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered.

2.5   Hepatic Impairment

No dosage adjustment is necessary for patients with hepatic impairment.

2.6   Duration of Therapy

The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

E.r. Squibb & Sons, L.l.c.

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