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adverse reactions
6 ADVERSE REACTIONS The most commonly reported adverse reactions (incidence ≥15%) in adult HIV-1 clinical studies were headache, malaise, nausea, anorexia, and vomiting. ( 6.1 ) The most commonly reported adverse reactions (incidence ≥15%) in pediatric HIV-1 clinical studies were fever, cough, and digestive disorders. ( 6.1 ) The most commonly reported adverse reactions in neonates (incidence ≥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 Hetero Drugs Limited at 866-495-1995 and www.fda.gov/medwatch or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 )] . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 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 2 summarizes events reported at a statistically significant greater incidence for patients receiving zidovudine in a monotherapy study. Table 2. Percentage (%) of Patients With Adverse Reactionsa in Asymptomatic HIV-1 Infection (ACTG 019) a Reported in ≥5% of study population. b Not statistically significant versus placebo. Adverse Reaction Zidovudine 500 mg/day (n = 453) Placebo (n = 428) Body as a Whole Asthenia 9% b 6% Headache 63% 53% Malaise 53% 45% Gastrointestinal Anorexia 20% 11% Constipation 6% b 4% Nausea 51% 30% Vomiting 17% 10% In addition to the adverse reactions listed in Table 2, adverse reactions observed at an incidence of ≥5% in any treatment arm in clinical studies (NUCA3001, NUCA3002, NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these studies hyperbilirubinemia was reported at an incidence of ≤0.8%. Selected laboratory abnormalities observed during a clinical study of monotherapy with zidovudine are shown in Table 3. Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients 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% ALT (>5 x ULN) 1% 2% Pediatrics: The clinical adverse reactions reported among adult recipients of zidovudine may also occur in pediatric patients. Study ACTG300: Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus zidovudine 160 mg/m 2 3 times daily compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 4. a Includes pain, discharge, erythema, or swelling of an ear. Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in Pediatric Patients in Study ACTG300 Adverse Reaction EPIVIR plus idovudine (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 (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 5. Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in PediatricPatients in Study ACTG300 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<7.0 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 patients receiving zidovudine 180 mg/m 2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an incidence of <6% in these studies 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 Syrup at 2 mg/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 <9.0 g/dL) and neutropenia (<1,000 cells/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 1.0 g/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 In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zidovudine. 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. Endocrine: Gynecomastia. Eye: Macular edema. Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer. General: Sensitization reactions including anaphylaxis and angioedema, vasculitis. Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia. Hepatobiliary Tract and Pancreas: 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. Respiratory: Dyspnea, rhinitis, sinusitis. Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria. Special Senses: Amblyopia, hearing loss, photophobia, taste perversion. Urogenital: Urinary frequency, urinary hesitancy.