Zidovudine

Aurobindo Pharma Limited

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use zidovudine safely and effectively. See full prescribing information for zidovudine capsules, USP.Zidovudine Capsules, USPInitial U.S. Approval: 1987 RECENT MAJOR CHANGES(5.6)BOXED WARNINGWARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS See full prescribing information for complete boxed warning.      Hematologic toxicity including neutropenia and severe anemia have been associated with the use of zidovudine. (5.1) Symptomatic myopathy associated with prolonged use of zidovudine. (5.2) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including zidovudine. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3) INDICATIONS AND USAGE  Treatment of Human Immunodeficiency Virus (HIV-1) infection in combination with other antiretroviral agents. (1.1) Prevention of maternal-fetal HIV-1 transmission. (1.2) DOSAGE AND ADMINISTRATION Treatment of HIV-1 infection:Adults: 600 mg/day in divided doses with other antiretroviral agents.        Pediatric patients (aged 4 weeks to

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS
• 1 ZIDOVUDINE INDICATIONS AND USAGE
  • 1.1 Treatment of HIV-1
  • 1.2 Prevention of Maternal-Fetal HIV-1 Transmission
• 2 ZIDOVUDINE DOSAGE AND ADMINISTRATION
  • 2.1 Treatment of HIV-1 Infection
  • 2.2 Prevention of Maternal-Fetal HIV-1 Transmission
  • 2.3 Patients With Severe Anemia and/or Neutropenia
  • 2.4 Patients With Renal Impairment
  • 2.5 Patients With Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ZIDOVUDINE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hematologic Toxicity/Bone Marrow Suppression
  • 5.2 Myopathy
  • 5.3 Lactic Acidosis/Severe Hepatomegaly With Steatosis
  • 5.4 Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV Co-Infected Patients
  • 5.5 Use With Other Zidovudine-Containing Products
  • 5.6 Immune Reconstitution Syndrome
  • 5.7 Fat Redistribution
• 6 ZIDOVUDINE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Antiretroviral Agents
  • 7.2 Doxorubicin
  • 7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10 OVERDOSAGE
• 11 ZIDOVUDINE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Reproductive and Developmental Toxicology Studies
• 14 CLINICAL STUDIES
  • 14.1 Adults
  • 14.2 Pediatric Patients
  • 14.3 Prevention of Maternal-Fetal HIV-1 Transmission
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Advice for the Patient
• PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 100 mg (100 Capsule Bottle)
• PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 100 mg Blister Carton (10 x 10 Unit-dose)

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Treatment of HIV-1

1.2 Prevention of Maternal-Fetal HIV-1 Transmission

• antepartum therapy of HIV-1 infected mothers
• intrapartum therapy of HIV-1 infected mothers
• post-partum therapy of HIV-1 exposed neonate.

• In most cases, zidovudine capsules, USP for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
• Prevention of HIV-1 transmission in women who have received zidovudine capsules, USP for a prolonged period before pregnancy has not been evaluated.
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with zidovudine capsules, USP during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.

2 DOSAGE AND ADMINISTRATION

2.1 Treatment of HIV-1 Infection

2.2 Prevention of Maternal-Fetal HIV-1 Transmission

2.3 Patients With Severe Anemia and/or Neutropenia

2.4 Patients With Renal Impairment

2.5 Patients With Hepatic Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity/Bone Marrow Suppression

5.2 Myopathy

5.3 Lactic Acidosis/Severe Hepatomegaly With Steatosis

5.4 Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV Co-Infected Patients

5.5 Use With Other Zidovudine-Containing Products

Zidovudine should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR^® [lamivudine and zidovudine] tablets or TRIZIVIR^® [abacavir sulfate, lamivudine, and zidovudine] tablets).

5.6 Immune Reconstitution Syndrome

5.7 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6 ADVERSE REACTIONS

• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.1) ].
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3) ].
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.4) ].

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Antiretroviral Agents

7.2 Doxorubicin

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

²[see Dosage and Administration (2.1)]

Patients Aged Less Than 3 Months: in utero[see Dosage and Administration (2.2)]

Table 9. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*

Parameter	Birth to 14 Days	Aged 14 Days to 3 Months	Aged 3 Months to 12 Years
*Data presented as mean ± standard deviation except where noted. †Median [range].
Oral bioavailability (%)	89 ± 19 (n = 15)	61 ± 19 (n = 17)	65 ± 24 (n = 18)
CSF:plasma ratio	no data	no data	0.68 [0.03 to 3.25] † (n = 38)
CL (L/hr/kg)	0.65 ± 0.29 (n = 18)	1.14 ± 0.24 (n = 16)	1.85 ± 0.47 (n = 20)
Elimination half-life (hr)	3.1 ± 1.2 (n = 21)	1.9 ± 0.7 (n = 18)	1.5 ± 0.7 (n = 21)

Pregnancy: [see Use in Specific Populations (8.1)].



Nursing Mothers: [see Use In Specific Populations (8.3) ]

Geriatric Patients

Gender:

Drug Interactions:[See Drug Interactions (7)]

Table 10. Effect of Coadministered Drugs on Zidovudine AUC*

Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered Drug and Dose	Zidovudine Dose	n	Zidovudine Concentrations		Concentration of Coadministered Drug
			AUC	Variability
↑ = Increase; ↓= Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. * This table is not all inclusive. † Estimated range of percent difference.
Atovaquone  750 mg q 12 hr with food	200 mg q 8 hr	14	↑AUC 31%	Range 23% to 78%†	↔
Clarithromycin  500 mg twice daily	100 mg q 4 hr x 7 days	4	↓AUC 12%	Range ↓34% to ↑14%	Not Reported
Fluconazole  400 mg daily	200 mg q 8 hr	12	↑AUC 74%	95% CI: 54% to 98%	Not Reported
Lamivudine  300 mg q 12 hr	single 200 mg	12	↑AUC 13%	90% CI: 2% to 27%	↔
Methadone  30 to 90 mg daily	200 mg q 4 hr	9	↑AUC 43%	Range 16% to 64%†	↔
Nelfinavir  750 mg q 8 hr  x 7 to 10 days	single 200 mg	11	↓AUC 35%	Range 28% to 41%	↔
Probenecid  500 mg q 6 hr x 2 days	2 mg/kg q 8 hr x 3 days	3	↑AUC 106%	Range 100% to 170%†	Not Assessed
Rifampin 600 mg  daily x 14 days	200 mg q 8 hr x 14 days	8	↓AUC 47%	90% CI: 41% to 53%	Not Assessed
Ritonavir  300 mg q 6 hr x 4 days	200 mg q 8 hr x 4 days	9	↓AUC 25%	95% CI: 15% to 34%	↔
Valproic acid  250 mg or 500 mg q 8 hr x 4 days	100 mg q 8 hr x 4 days	6	↑AUC 80%	Range 64% to 130%†	Not Assessed

Phenytoin:

Ribavirin: In vitro[see Warnings and Precautions (5.4)].

12.4 Microbiology

Mechanism of Action:

Antiviral Activity:_50905050

Resistance:

Cross-Resistance:

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

^+/-in vitro

13.2 Reproductive and Developmental Toxicology Studies

in vitro

14 CLINICAL STUDIES

14.1 Adults

Combination Therapy:



Monotherapy:³

14.2 Pediatric Patients

³₁₀

Table 11. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Endpoint	EPIVIR plus Zidovudine (n = 236)	Didanosine (n = 235)
HIV disease progression or death (total)	15 (6.4%)	37 (15.7%)
Physical growth failure	7 (3%)	6 (2.6%)
Central nervous system deterioration	4 (1.7%)	12 (5.1%)
CDC Clinical Category C	2 (0.8%)	8 (3.4%)
Death	2 (0.8%)	11 (4.7%)

14.3 Prevention of Maternal-Fetal HIV-1 Transmission

³³

16 HOW SUPPLIED/STORAGE AND HANDLING

Zidovudine Capsules USP, 100 mg are white/white size ‘3’ hard gelatin capsules imprinted with ‘D’ on white cap and ‘01’ on white body with black edible ink.

                    Bottles of 100                                     NDC 65862-107-01
                    10 x 10 Unit-dose Capsules                NDC 65862-107-10

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION

17.1 Advice for the Patient

Neutropenia and Anemia:[see Boxed Warning, Warnings and Precautions (5.1)]

Myopathy[see Boxed Warning, Warnings and Precautions (5.2)]

Lactic Acidosis/Hepatomegaly[see Boxed Warning, Warnings and Precautions (5.3)]

HIV-1/HCV Co-Infection[see Warnings and Precautions (5.4)]

Use With Other Zidovudine-Containing Products: [see Warnings and Precautions (5.5)]

Redistribution/Accumulation of Body Fat:[see Warnings and Precautions (5.7)]

Common Adverse Reactions:[see Adverse Reactions (6)]

Drug Interactions: [see Drug Interactions (7)]

Pregnancy:in utero [see Use in Specific Populations (8.1)]

[see Use in Specific Populations (8.3)].

Information About HIV-1 Infection:

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. Zidovudine is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 100 mg (100 Capsule Bottle)

NDC 65862-107-01
Zidovudine Capsules, USP
100 mg
Rx only           100 Capsules
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 100 mg Blister Carton (10 x 10 Unit-dose)

NDC 65862-107-10
Zidovudine Capsules, USP
100 mg
Rx only           100 Capsules (10 x 10 Unit-dose)
AUROBINDO

Zidovudine Zidovudine CAPSULE Product Information Product Type Human prescription drug label Item Code (Source) NDC:65862-107 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Zidovudine ZIDOVUDINE 100 mg Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline STARCH, CORN SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE FERROSOFERRIC OXIDE SHELLAC titanium dioxide SODIUM LAURYL SULFATE GELATIN Product Characteristics Color Size Imprint Code Shape WHITE 16 mm D;01 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-107-01 100 in 1 BOTTLE 2 10 in 1 BLISTER PACK 3 NDC:65862-107-10 10 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078128 2006-03-27