WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS Hematologic Toxicity RETROVIR® (zidovudine) capsules, syrup, and injection have been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease [see Warnings and Precautions (5.1)]. Myopathy Prolonged use of RETROVIR has been associated with symptomatic myopathy [see Warnings and Precautions (5.3)]. Lactic Acidosis and Severe Hepatomegaly Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including RETROVIR and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)]. WARNING: 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. (5.3) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including RETROVIR. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.4)
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: •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 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.
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 |
3 DOSAGE FORMS AND STRENGTHS •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 syrup (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 (3) Syrup: 10 mg per mL (3) Injection: (10 mg per mL) 20-mL single-use vial (3)
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, 5.3, 5.4) •The vial stoppers for RETROVIR injection contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals. (5.2) •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. (5.5) •Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue zidovudine as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.5) •RETROVIR should not be administered with other zidovudine-containing combination products. (5.6) •Immune reconstitution syndrome (5.7) and redistribution/accumulation of body fat (5.8) 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 mm3 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 Latex The vial stoppers for RETROVIR injection contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals. 5.3 Myopathy Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of RETROVIR. 5.4 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering RETROVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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). 5.5 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 zidovudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of zidovudine 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 complete prescribing information for interferon and ribavirin). 5.6 Use with Other Zidovudine-containing Products RETROVIR 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). 5.7 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. 5.8 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 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 (5.3)]. •Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.4)]. •Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.5)]. • 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) 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% a Not statistically significant versus placebo. 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) Test (Abnormal Level) RETROVIR 500 mg/day (n = 453) Placebo (n = 428) Anemia (Hgb<8 g/dL) 1% <1% Granulocytopenia (<750 cells/mm3) 2% 2% Thrombocytopenia (platelets<50,000/mm3) 0% <1% ALT (>5 x ULN) 3% 3% AST (>5 x ULN) 1% 2% ULN = Upper limit of normal. 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 m2 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 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 earsa 7% 6% Nasal discharge or congestion 8% 11% Other Skin rashes 12% 14% Lymphadenopathy 9% 11% a Includes pain, discharge, erythema, or swelling of an ear. 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 Test (Abnormal Level) EPIVIR plus RETROVIR Didanosine Neutropenia (ANC<400 cells/mm3) 8% 3% Anemia (Hgb<7.0 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% ULN = Upper limit of normal. ANC = Absolute neutrophil count. Macrocytosis was reported in the majority of pediatric subjects receiving RETROVIR 180 mg per m2 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 syrup 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 mm3). 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 postmarketing 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 (5.8)]. 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.
7 DRUG INTERACTIONS •Stavudine: Concomitant use with zidovudine should be avoided. (7.1) •Doxorubicin: Use with zidovudine should be avoided. (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.
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. In humans, treatment with RETROVIR 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 RETROVIR [see Clinical Studies (14.3)]. There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations. 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)]. 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. Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg per day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose [see Nonclinical Toxicology (13.2)]. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. 8.3 Nursing Mothers Zidovudine is excreted in human milk. After administration of a single dose of 200 mg zidovudine to 13 HIV‑1‑infected women, the mean concentration of zidovudine was similar in human milk and serum. The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RETROVIR. 8.4 Pediatric Use RETROVIR has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3)]. 8.5 Geriatric Use Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Unchanged zidovudine and its glucuronide metabolite (formed in the liver) are primarily eliminated from the body by renal excretion. In patients with severely impaired renal function (CrCl less than 15 mL per min), dosage reduction is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment RETROVIR is primarily eliminated by hepatic metabolism and zidovudine concentrations appear to be increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are insufficient data to recommend dose adjustment of RETROVIR in patients with impaired hepatic function or liver cirrhosis [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].