RETROVIR is the brand name for 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 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 . RETROVIR capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and titanium dioxide. Each mL of RETROVIR oral solution contains 10 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH. RETROVIR injection is a sterile solution for IV infusion only. Each mL contains 10 mg zidovudine in water for injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH to approximately 5.5. RETROVIR injection contains no preservatives. zidovudine structural formula

RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for: • Treatment of Human Immunodeficiency Virus (HIV-1) infection in combination with other antiretroviral agents. • Prevention of maternal-fetal HIV-1 transmission

Treatment of HIV-1 RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection

Prevention of Maternal-Fetal HIV-1 Transmission RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission . The indication is based on a dosing regimen that included 3 components: 1. antepartum therapy of HIV‑1–infected mothers 2. intrapartum therapy of HIV‑1–infected mothers 3. post-partum therapy of HIV‑1–exposed neonate Points to consider prior to initiating RETROVIR in pregnant women for the prevention of maternal-fetal HIV-1 transmission include: • In most cases, RETROVIR 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 RETROVIR 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 RETROVIR 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.

• RETROVIR capsules 100 mg (white, opaque cap and body) containing 100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on body. • RETROVIR oral solution (colorless to pale yellow, strawberry‑flavored) containing 10 mg zidovudine in each mL. • RETROVIR injection is a clear, nearly colorless, sterile aqueous solution with a pH of approximately 5.5. Each vial contains 200 mg of zidovudine in 20 mL solution (10 mg per mL). • Capsules: 100 mg • Oral Solution: 10 mg per mL • Injection: (10 mg per mL) 20-mL single-use vial

• Treatment of HIV-1 infection: Adults: Recommended oral dosage is 300 mg twice a day with other antiretroviral agents. For patients who are unable to take the oral formulations, the recommended intravenous dose is 1 mg per kg infused over 1 hour every 4 hours. Pediatric patients (aged 4 weeks to less than 18 years): Dosage should be calculated based on body weight not to exceed adult dose. • Prevention of maternal-fetal HIV-1 transmission: Specific dosage instructions for mother and infant. • Patients with severe anemia and/or neutropenia: Dosage interruption may be necessary. • 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. Equivalent intravenous dosing is approximately 1 mg per kg every 6 to 8 hours

Adults – Treatment of HIV-1 Infection Oral Dosing The recommended oral dose of RETROVIR is 300 mg twice daily in combination with other antiretroviral agents. Intravenous (IV) Dosing The recommended intravenous dose is 1 mg per kg infused at a constant rate over 1 hour every 4 hours. Patients should receive RETROVIR injection only until oral therapy can be administered. • RETROVIR injection must be diluted prior to administration. The calculated dose should be removed from the 20-mL vial and added to 5% Dextrose injection solution to achieve a concentration no greater than 4 mg per mL. • After dilution, the solution is physically and chemically stable for 24 hours at room temperature and 48 hours if refrigerated at 2°C to 8°C (36°F to 46°F). As an additional precaution, the diluted solution should be administered within 8 hours if stored at 25°C (77°F) or 24 hours if refrigerated at 2°C to 8°C to minimize potential administration of a microbially contaminated solution. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit and discarded if either is observed. • Rapid infusion or bolus injection should be avoided. RETROVIR injection should not be given intramuscularly

Pediatric Patients (Aged 4 Weeks to Less than 18 Years) Healthcare professionals should pay special attention to accurate calculation of the dose of RETROVIR, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors. Prescribers should calculate the appropriate dose of RETROVIR for each child based on body weight (kg) and should not exceed the recommended adult dose. Before prescribing RETROVIR capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow a RETROVIR capsule, the RETROVIR 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 . RETROVIR oral solution should be used to provide accurate dosage when capsules are not appropriate. Table 1. Recommended Pediatric Oral Dosage of RETROVIR 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 RETROVIR can be based on body surface area (BSA) for each child. The recommended oral dose of RETROVIR 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

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 . During labor and delivery, intravenous RETROVIR 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 RETROVIR intravenously. See Table 2 for dosing recommendations. Table 2. Recommended Neonatal Dosages of RETROVIR 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

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 . 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

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. The intravenous dosing regimen equivalent to the oral administration of 100 mg every 6 to 8 hours is approximately 1 mg per kg every 6 to 8 hours

Patients with Hepatic Impairment There are insufficient data to recommend dose adjustment of RETROVIR in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised .

• See boxed warning for information about the following: hematologic toxicity, myopathy, and lactic acidosis and severe hepatomegaly. ( 5.1 , 5.2 , 5.3 ) • Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. • Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue RETROVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. • Immune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy

Hematologic Toxicity/Bone Marrow Suppression RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm 3 or hemoglobin less than 9.5 g per dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other antiretrovirals. Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with RETROVIR. For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed

Myopathy Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of RETROVIR

Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including zidovudine. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations

Use with Interferon- and Ribavirin-Based Regimens in HIV-1/HCV Co-infected Patients In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected subjects , exacerbation of anemia due to ribavirin has been reported when zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not advised. Consideration should be given to replacing zidovudine in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia. Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin

Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RETROVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment

Lipoatrophy Treatment with zidovudine has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and other zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

• Avoid use with stavudine. • Avoid use with doxorubicin. • Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine

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 RETROVIR against HIV-1; concomitant use of such drugs should be avoided

Doxorubicin Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro

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.