Zidovudine

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS Zidovudine capsules 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) ] . Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2) ] . 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. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3) ] . WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS 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 )

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 zidovudine 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 Zidovudine 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 zidovudine, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of zidovudine, and/or blood transfusions, has occurred during treatment with zidovudine 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 zidovudine. 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 zidovudine. 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 zidovudine 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 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 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 zidovudine. 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.

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 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 Headache Malaise Gastrointestinal Anorexia Constipation Nausea Vomiting 9% a 63% 53% 20% 6% a 51% 17% 6% 53% 45% 11% 4% 30% 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) Granulocytopenia (<750 cells/mm 3 ) Thrombocytopenia (platelets <50,000/mm 3 ) ALT (>5 x ULN) AST (>5 x ULN) 1% 2% 0% 3% 1% <1% 2% <1% 3% 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 Digestive Hepatomegaly Nausea & vomiting Diarrhea Stomatitis Splenomegaly Respiratory Cough Abnormal breath sounds/wheezing Ear, Nose, and Throat Signs or symptoms of ears a Nasal discharge or congestion Other Skin rashes Lymphadenopathy 25% 11% 8% 8% 6% 5% 15% 7% 7% 8% 12% 9% 32% 11% 7% 6% 12% 8% 18% 9% 6% 11% 14% 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 ) Anemia (Hgb <7 g/dL) Thrombocytopenia (platelets <50,000/mm 3 ) ALT (>10 x ULN) AST (>10 x ULN) Lipase (>2.5 x ULN) Total amylase (>2.5 x ULN) 8% 4% 1% 1% 2% 3% 3% 3% 2% 3% 3% 4% 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.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 3. Percentage (%) of Subjects with Adverse Reactions (Greater than or Equal to 5% Frequency) in Asymptomatic HIV-1 Infection (ACTG 019) </caption><colgroup><col width="30.62%"/><col width="32.66%"/><col width="36.74%"/></colgroup><tfoot><tr><td colspan="3">^a Not statistically significant versus placebo.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">Adverse Reaction</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Zidovudine 500 mg/day</content> <content styleCode="bold">(n = 453)</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 428)</content> </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold"> Body as a whole</content> Asthenia Headache Malaise <content styleCode="bold"> Gastrointestinal</content> Anorexia Constipation Nausea Vomiting </td><td styleCode="Rrule" align="center" valign="middle"> 9%^a 63% 53% 20% 6%^a 51% 17% </td><td styleCode="Rrule" align="center" valign="middle"> 6% 53% 45% 11% 4% 30% 10% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 4. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Subjects with Asymptomatic HIV-1 Infection (ACTG 019) </caption><colgroup><col width="48.96%"/><col width="29.16%"/><col width="21.88%"/></colgroup><tfoot><tr><td colspan="3">ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">Test</content> <content styleCode="bold">(Abnormal Level)</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Zidovudine 500 mg/day</content> <content styleCode="bold">(n = 453)</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 428)</content> </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"> Anemia (Hgb &lt;8 g/dL) Granulocytopenia (&lt;750 cells/mm³) Thrombocytopenia (platelets &lt;50,000/mm³) ALT (&gt;5 x ULN) AST (&gt;5 x ULN) </td><td styleCode="Rrule" align="center" valign="middle">1% 2% 0% 3% 1% </td><td styleCode="Rrule" align="center" valign="middle">&lt;1% 2% &lt;1% 3% 2% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG 300 </caption><colgroup><col width="49.06%"/><col width="29.94%"/><col width="21%"/></colgroup><tfoot><tr><td colspan="3">^a Includes pain, discharge, erythema, or swelling of an ear.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">Adverse Reaction</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">EPIVIR plus Zidovudine</content> <content styleCode="bold">(n = 236)</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Didanosine</content> <content styleCode="bold">(n = 235)</content> </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> Body as a whole</content> Fever <content styleCode="bold"> Digestive</content> Hepatomegaly Nausea &amp; vomiting Diarrhea Stomatitis Splenomegaly <content styleCode="bold"> Respiratory</content> Cough Abnormal breath sounds/wheezing <content styleCode="bold"> Ear, Nose, and Throat</content> Signs or symptoms of ears^a Nasal discharge or congestion <content styleCode="bold"> Other</content> Skin rashes Lymphadenopathy </td><td styleCode="Rrule" align="center" valign="top"> 25% 11% 8% 8% 6% 5% 15% 7% 7% 8% 12% 9% </td><td styleCode="Rrule" align="center" valign="top"> 32% 11% 7% 6% 12% 8% 18% 9% 6% 11% 14% 11% </td></tr></tbody></table>