Zidovudine

Bryant Ranch Prepack
Bryant Ranch Prepack

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use zidovudine safely and effectively. See full prescribing information for zidovudine tablets, USP. Zidovudine Tablets, USP Initial U.S. Approval: 1987RECENT MAJOR CHANGES(2.1)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 (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
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Information About Therapy With Zidovudine
• Zidovudine 300mg Tablet

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 tablets 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 tablets 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 tablets 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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

• 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) ].

^{® 2}

Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in Pediatric Patients in Study ACTG 300

Adverse Reaction	EPIVIR plus Zidovudine (n = 236)	Didanosine (n = 235)
*Includes pain, discharge, erythema, or swelling of an ear.
Body as a whole
Fever	25%	32%
Digestive
Hepatomegaly	11%	11%
Nausea & vomiting	8%	7%
Diarrhea	8%	6%
Stomatitis	6%	12%
Splenomegaly	5%	8%
Respiratory
Cough	15%	18%
Abnormal breath sounds/wheezing	7%	9%
Ear, Nose, and Throat
Signs or symptoms of ears*	7%	6%
Nasal discharge or congestion	8%	11%
Other
Skin rashes	12%	14%
Lymphadenopathy	9%	11%

Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in Study ACTG 300

Test (Abnormal Level)	EPIVIR plus Zidovudine	Didanosine
ULN = Upper limit of normal. ANC = Absolute neutrophil count.
Neutropenia (ANC<400 cells/mm3)	8%	3%
Anemia (Hgb<7 g/dL)	4%	2%
Thrombocytopenia (platelets<50,000/mm3)	1%	3%
ALT (>10 x ULN)	1%	3%
AST (>10 x ULN)	2%	4%
Lipase (>2.5 x ULN)	3%	3%
Total amylase (>2.5 x ULN)	3%	3%

²

Use for the Prevention of Maternal-Fetal Transmission of HIV-1:³in utero

6.2 Postmarketing Experience

Body as a Whole:[see Warnings and Precautions (5.7)]

Cardiovascular:,

Endocrine:

Eye:

Gastrointestinal:

General:

Hemic and Lymphatic:

Hepatobiliary Tract and Pancreas:

Musculoskeletal:

Nervous:

Respiratory:

Skin:

Special Senses:

Urogenital:

7 DRUG INTERACTIONS

7.1 Antiretroviral Agents

Stavudine:in vitro

Nucleoside Analogues Affecting DNA Replication:in vitro

7.2 Doxorubicin

in vitro

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C.

[see Clinical Studies (14.3)]

[see Clinical Studies (14.3)]

[see Nonclinical Toxicology (13.2)]

Antiretroviral Pregnancy Registry:

8.3 Nursing Mothers

[see Clinical Pharmacology (12.3)]

8.4 Pediatric Use

[see Dosage and Administration (2.1), Adverse Reactions (6.1) , Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)]

8.5 Geriatric Use

8.6 Renal Impairment

[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

[see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

OD

11 DESCRIPTION

₁₀₁₃₅₄

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

[see Clinical Pharmacology (12.4)]

12.3 Pharmacokinetics

Absorption and Bioavailability:

Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients

Parameter	Mean ± SD (except where noted)
*Median [range]. †Approximate range.
Oral bioavailability (%)	64 ± 10 (n = 5)
Apparent volume of distribution (L/kg)	1.6 ± 0.6 (n = 8)
Plasma protein binding (%)	<38
CSF:plasma ratio*	0.6 [0.04 to 2.62] (n = 39)
Systemic clearance (L/hr/kg)	1.6 ± 0.6 (n = 6)
Renal clearance (L/hr/kg)	0.34 ± 0.05 (n = 9)
Elimination half-life (hr)†	0.5 to 3 (n = 19)

Distribution:

Metabolism and Elimination:

Effect of Food on Absorption:

Special Populations: Renal Impairment:

Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment*

Parameter	Control Subjects (Normal Renal Function) (n = 6)	Patients With Renal Impairment (n = 14)
*Data are expressed as mean ± standard deviation.
CrCl (mL/min)	120 ± 8	18 ± 2
Zidovudine AUC (ng•hr/mL)	1,400 ± 200	3,100 ± 300
Zidovudine half-life (hr)	1 ± 0.2	1.4 ± 0.1

Hemodialysis and Peritoneal Dialysis:[see Dosage and Administration (2.4)]

Hepatic Impairment: [see Dosage and Administration (2.5)].

Pediatric Patients:

Patients 3 Months to 12 Years of Age: ²[see Dosage and Administration (2.1)]

Patients <3 Months of Age: in utero[see Dosage and Administration (2.2)]

Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*

Parameter	Birth to 14 Days of Age	14 Days to 3 Months of Age	3 Months to 12 Years of Age
*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 9. 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 10. 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

17 PATIENT COUNSELING INFORMATION

17.1 Information About Therapy With Zidovudine

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)]

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 Therapy With Zidovudine:








Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited

Zidovudine 300mg Tablet

Zidovudine Zidovudine TABLET, FILM COATED Product Information Product Type Human prescription drug label Item Code (Source) NDC:63629-4144(NDC:65862-024) Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Zidovudine ZIDOVUDINE 300 mg Inactive Ingredients Ingredient Name Strength Hypromellose 2910 (5 Mpa.s) MAGNESIUM STEARATE cellulose, microcrystalline polyethylene glycol 400 SODIUM STARCH GLYCOLATE TYPE A POTATO titanium dioxide HYPROMELLOSE 2910 (6 MPA.S) Product Characteristics Color Size Imprint Code Shape WHITE 10 mm D;11 ROUND Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63629-4144-1 10 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077267 2005-09-19