ZIDOVUDINE

Zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3'-azido-3'-deoxythymidine; it has the following structural formula: Zidovudine USP is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C 10 H 13 N 5 O 4 . Zidovudine Oral Solution, USP is for oral administration. Each (mL) of zidovudine oral solution contains 10 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid anhydrous, strawberry cream flavor, glycerin, and sucrose. Meets USP Organic Impurities Procedure 2 Chemical Structure

Zidovudine oral solution is a nucleoside analogue reverse transcriptase inhibitor indicated for: 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) 1.1 Treatment of HIV-1 Zidovudine oral solution, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. 1.2 Prevention of Maternal-Fetal HIV-1 Transmission Zidovudine oral solution is indicated for the prevention of maternal-fetal HIV-1 transmission [see Dosage and Administration (2.3) ]. The indication is based on a dosing regimen that included 3 components: antepartum therapy of HIV-1-infected mothers intrapartum therapy of HIV-1-infected mothers post-partum therapy of HIV-1-exposed neonate Points to consider prior to initiating zidovudine oral solution in pregnant women for the prevention of maternal-fetal HIV-1 transmission include: In most cases, zidovudine oral solution 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 oral solution 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 oral solution 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.

Treatment of HIV-1 infection: Adults: Recommended oral dosage is 300 mg twice a day with other antiretroviral agents. ( 2.1 ) Pediatric patients (aged 4 weeks to less than 18 years): Dosage should be calculated based on body weight not to exceed adult dose. ( 2.2 ) Prevention of maternal-fetal HIV-1 transmission: Specific dosage instructions for mother and infant. ( 2.3 ) Patients with severe anemia and/or neutropenia: Dosage interruption may be necessary. ( 2.4 ) Renal impairment: Recommended oral dosage in hemodialysis or peritoneal dialysis or in patients with creatinine clearance (CrCl) less than 15 mL per minute is 100 mg every 6 to 8 hours. ( 2.5 ) 2.1 Adults - Treatment of HIV-1 Infection Oral Dosing The recommended oral dose of zidovudine oral solution is 300 mg twice daily in combination with other antiretroviral agents. 2.2 Pediatric Patients (Aged 4 Weeks to Less than 18 Years) Healthcare professionals should pay special attention to accurate calculation of the dose of zidovudine oral solution, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors. Prescribers should calculate the appropriate dose of zidovudine oral solution for each child based on body weight (kg) and should not exceed the recommended adult dose. Before prescribing zidovudine capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow a zidovudine capsule, the zidovudine oral solution formulation should be prescribed. The recommended oral dosage in pediatric patients aged 4 weeks to less than 18 years and weighing greater than or equal to 4 kg is provided in Table 1. Zidovudine oral solution should be used to provide accurate dosage when capsules are not appropriate. Table 1. Recommended Pediatric Oral Dosage of Zidovudine Oral Solution Body Weight (kg) Total Daily Dose Dosage Regimen and Dose Twice Daily Three Times Daily 4 to <9 24 mg/kg/day 12 mg/kg 8 mg/kg ≥9 to <30 18 mg/kg/day 9 mg/kg 6 mg/kg ≥30 600 mg/day 300 mg 200 mg Alternatively, dosing for zidovudine oral solution can be based on body surface area (BSA) for each child. The recommended oral dose of zidovudine oral solution is 480 mg per m 2 per day in divided doses (240 mg per m 2 twice daily or 160 mg per m 2 three times daily). In some cases the dose calculated by mg per kg will not be the same as that calculated by BSA. 2.3 Prevention of Maternal-Fetal HIV-1 Transmission The recommended dosage regimen for administration to pregnant women (greater than 14 weeks of pregnancy) and their neonates is: Maternal Dosing 100 mg orally 5 times per day until the start of labor [see Clinical Studies (14.3) ]. During labor and delivery, intravenous zidovudine should be administered at 2 mg per kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg per kg per hour (total body weight) until clamping of the umbilical cord. Neonatal Dosing Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered zidovudine intravenously. See Table 2 for dosing recommendations. Table 2. Recommended Neonatal Dosages of Zidovudine Route Total Daily Dose Dose and Dosage Regimen Oral 8 mg/kg/day 2 mg/kg every 6 hours Intravenous 6 mg/kg/day 1.5 mg/kg infused over 30 minutes, every 6 hours Use an appropriate-sized syringe with 0.1 mL graduation to ensure accurate dosing of the oral solution formulation in neonates. 2.4 Patients with Severe Anemia and/or Neutropenia Significant anemia (hemoglobin less than 7.5 g per dL or reduction greater than 25% of baseline) and/or significant neutropenia (granulocyte count less than 750 cells per mm 3 or reduction greater than 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed [see Warnings and Precautions (5.1) ] . In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoietin level and patient tolerance. 2.5 Patients with Renal Impairment In patients maintained on hemodialysis or peritoneal dialysis or with creatinine clearance (CrCl) by Cockcroft-Gault less than 15 mL per min, the recommended oral dosage is 100 mg every 6 to 8 hours [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ] . 2.6 Patients with Hepatic Impairment There are insufficient data to recommend dose adjustment of zidovudine oral solution in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised [see Use in Specific Populations (8.7) ] .

Zidovudine oral solution is contraindicated in patients who have had a potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulation. Hypersensitivity to zidovudine or any of the components (e.g., anaphylaxis, Stevens-Johnson syndrome). (4)

The following adverse reactions are discussed in greater detail in other sections of the labeling: 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) ]. Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult HIV-1 clinical trials were headache, malaise, nausea, anorexia, and vomiting. (6.1) Most commonly reported adverse reactions (incidence greater than or equal to 15%) in pediatric HIV-1 clinical trials were fever and cough. (6.1) Most commonly reported adverse reactions in neonates (incidence greater than or equal to 15%) in the prevention of maternal-fetal transmission of HIV-1 clinical trial were anemia and neutropenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The frequency and severity of adverse reactions associated with the use of zidovudine are greater in patients with more advanced infection at the time of initiation of therapy. Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for subjects receiving oral zidovudine in a monotherapy trial. Table 3. Percentage (%) of Subjects with Adverse Reactions (Greater than or Equal to 5% Frequency) in Asymptomatic HIV-1 Infection (ACTG 019) a Not statistically significant versus placebo. Adverse Reaction Zidovudine 500 mg/day (n = 453) Placebo (n = 428) Body as a whole Asthenia 9% a 6% Headache 63% 53% Malaise 53% 45% Gastrointestinal Anorexia 20% 11% Constipation 6% a 4% Nausea 51% 30% Vomiting 17% 10% In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002, NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%. Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral zidovudine are shown in Table 4. Table 4. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Subjects with Asymptomatic HIV-1 Infection (ACTG 019) ULN = Upper limit of normal. Test (Abnormal Level) Zidovudine 500 mg/day (n = 453) Placebo (n = 428) Anemia (Hgb <8 g/dL) 1% <1% Granulocytopenia (<750 cells/mm 3 ) 2% 2% Thrombocytopenia (platelets <50,000/mm 3 ) 0% <1% ALT (>5 x ULN) 3% 3% AST (>5 x ULN) 1% 2% Pediatrics The clinical adverse reactions reported among adult recipients of zidovudine may also occur in pediatric patients. Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with EPIVIR (lamivudine) oral suspension 4 mg per kg twice daily plus zidovudine 160 mg per m 2 3 times daily compared with didanosine in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5. Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG 300 a Includes pain, discharge, erythema, or swelling of an ear. Adverse Reaction EPIVIR plus Zidovudine (n = 236) Didanosine (n = 235) 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 a 7% 6% Nasal discharge or congestion 8% 11% Other Skin rashes 12% 14% Lymphadenopathy 9% 11% Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6. Table 6. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Subjects in Trial ACTG 300 ULN = Upper limit of normal. ANC = Absolute neutrophil count. Test (Abnormal Level) EPIVIR plus Zidovudine Didanosine Neutropenia (ANC <400 cells/mm 3 ) 8% 3% Anemia (Hgb <7 g/dL) 4% 2% Thrombocytopenia (platelets <50,000/mm 3 ) 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% Macrocytosis was reported in the majority of pediatric subjects receiving zidovudine 180 mg per m 2 every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss. Use for the Prevention of Maternal-Fetal Transmission of HIV-1 In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission, zidovudine oral solution at 2 mg per kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia (hemoglobin less than 9 g per dL) and neutropenia (less than 1,000 cells per mm 3 ). Anemia occurred in 22% of the neonates who received zidovudine and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1 g per dL for neonates receiving zidovudine compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with zidovudine. Neutropenia in neonates was reported with similar frequency in the group that received zidovudine (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to zidovudine are unknown. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of zidovudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat [see Warnings and Precautions (5.6) ] . Cardiovascular Cardiomyopathy , syncope. Eye Macular edema. Gastrointestinal Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer. General Sensitization reactions including anaphylaxis and angioedema, vasculitis. Hematologic Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia. Hepatobiliary Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis. Musculoskeletal Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor. Nervous Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo. Reproductive System and Breast Gynecomastia. Respiratory Dyspnea, rhinitis, sinusitis. Skin and Subcutaneous Tissue Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweating, urticaria. Special Senses Amblyopia, hearing loss, photophobia, taste perversion. Renal and Urinary Urinary frequency, urinary hesitancy.

Avoid use with stavudine. ( 7.1 ) Avoid use with doxorubicin. ( 7.2 ) Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.3 ) 7.1 Antiretroviral Agents Stavudine Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro . Nucleoside Analogues Affecting DNA Replication Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided. 7.2 Doxorubicin Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro . 7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.