RETROVIR

1 INDICATIONS AND USAGE RETROVIR 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 RETROVIR, 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 RETROVIR 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: 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.

2 DOSAGE AND ADMINISTRATION • 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. ( 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. Equivalent intravenous dosing is approximately 1 mg per kg every 6 to 8 hours. ( 2.5 ) 2.1 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. 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 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. 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 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. 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. 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 [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 RETROVIR in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised [see Use in Specific Populations ( 8.7 )] .

4 CONTRAINDICATIONS RETROVIR 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 formulations. Hypersensitivity to zidovudine or any of the components (e.g., anaphylaxis, Stevens-Johnson syndrome). ( 4 )

5 WARNINGS AND PRECAUTIONS • 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. ( 5.4 ) • 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. ( 5.4 ) • Immune reconstitution syndrome ( 5.5 ) and lipoatrophy ( 5.6 ) have been reported in patients treated with combination antiretroviral therapy. 5.1 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 [see Dosage and Administration ( 2.4 )] . 5.2 Myopathy Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of RETROVIR. 5.3 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. 5.4 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 [see Clinical Pharmacology ( 12.3 )] , 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. 5.5 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. 5.6 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.

7 DRUG INTERACTIONS • 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 RETROVIR 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.

6 ADVERSE REACTIONS 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 ViiV Healthcare at 1-877-844-8872 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 RETROVIR 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 RETROVIR 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 RETROVIR 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 RETROVIR 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) RETROVIR 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% The adverse reactions reported during IV administration of RETROVIR injection are similar to those reported with oral administration; neutropenia and anemia were reported most frequently. Long-term IV administration beyond 2 to 4 weeks has not been studied in adults and may enhance hematologic adverse reactions. Local reaction, pain, and slight irritation during IV administration occur infrequently. Pediatrics The clinical adverse reactions reported among adult recipients of RETROVIR 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 RETROVIR 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 RETROVIR (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 RETROVIR Didanosine Neutropenia (ANC <400 cells/mm 3 ) 8% 3% Anemia (Hgb <7.0 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 RETROVIR 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 RETROVIR for the prevention of maternal-fetal HIV-1 transmission, RETROVIR 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 9.0 g per dL) and neutropenia (less than 1,000 cells per mm 3 ). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1.0 g per dL for neonates receiving RETROVIR 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 RETROVIR. Neutropenia in neonates was reported with similar frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to RETROVIR are unknown. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of RETROVIR. 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.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RETROVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established ( see Data) . In an animal reproduction study, administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data) . Data Human Data: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens. A randomized, double‑blind, placebo‑controlled trial was conducted in HIV‑1–infected pregnant women to determine the utility of RETROVIR for the prevention of maternal‑fetal HIV‑1‑transmission [see Clinical Studies ( 14.3 )] . Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug. Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology ( 12.3 )] . There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown. Animal Data: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on Gestation Day 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.