Side Effects Overview
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 )]. 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 )]. To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 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) 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% 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 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) 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% AST (>5 x ULN) 1% 2% ULN = Upper limit of normal. 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 Adverse Reaction EPIVIR plus Zidovudine (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% 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 Zidovudine Didanosine Neutropenia (ANC <400 cells/mm 3 ) 8% 3% Anemia (Hgb<7 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% ULN = Upper limit of normal. ANC = Absolute neutrophil count. 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 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 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 ( 5.7 )]. 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.
Advertencias y Precauciones
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 ) • 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 ) • Immune reconstitution syndrome ( 5.6 ) and lipoatrophy ( 5.7 ) 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 )]. 5.3 Myopathy Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine. 5.4 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. 5.5 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 full prescribing information for interferon and ribavirin. 5.6 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. 5.7 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.
Farmacocinética
12.3 Pharmacokinetics Absorption and Bioavailability In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as zidovudine tablets or syrup compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are summarized in Table 7. Table 7. Zidovudine Pharmacokinetic Parameters in Adult Subjects Parameter Mean ± SD (except where noted) Oral bioavailability (%) 64 ± 10 (n = 5) Apparent volume of distribution (L/kg) 1.6 ± 0.6 (n = 8) Cerebrospinal fluid (CSF):plasma ratio a 0.6 [0.04 to 2.62] (n = 39) Systemic clearance (L/h/kg) 1.6 ± 0.6 (n = 6) Renal clearance (L/h/kg) 0.34 ± 0.05 (n = 9) Elimination half-life (h) b 0.5 to 3 (n = 19) a Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on chronic therapy with zidovudine. b Approximate range. Distribution The apparent volume of distribution of zidovudine is 1.6 ± 0.6 L per kg (Table 7) and binding to plasma protein is low (less than 38%). Metabolism and Elimination Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second metabolite, 3'-amino-3'-deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours. Effect of Food on Absorption Zidovudine may be administered with or without food. The zidovudine AUC was similar when a single dose of zidovudine was administered with food. Specific Populations Patients with Renal Impairment: Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single 200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min. Table 8. Zidovudine Pharmacokinetic Parameters in Subjects with Severe Renal Impairment a Parameter Control Subjects (Normal Renal Function) (n = 6) Subjects with Renal Impairment (n = 14) CrCl (mL/min) 120 ± 8 18 ± 2 Zidovudine AUC (ng•h/mL) 1,400 ± 200 3,100 ± 300 Zidovudine half-life (h) 1.0 ± 0.2 1.4 ± 0.1 a Data are expressed as mean ± standard deviation. Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in subjects with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis [see Dosage and Administration ( 2.5 )]. Patients with Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, zidovudine is eliminated primarily by hepatic metabolism and it appears that zidovudine clearance is decreased and plasma concentrations are increased in subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of zidovudine in patients with impaired hepatic function or liver cirrhosis [see Dosage and Administration ( 2.6 )]. Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric subjects (Table 9). Patients Aged 3 Months to 12 Years: Overall, zidovudine pharmacokinetics in pediatric patients older than 3 months are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg per m 2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult subjects, the major route of elimination was by metabolism to GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and Administration ( 2.2 )]. Patients Aged Less than 3 Months: Zidovudine pharmacokinetics have been evaluated in pediatric subjects from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates less than or equal to 14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric subjects older than 14 days. For dose recommendations for neonates [see Dosage and Administration ( 2.3 )]. Table 9. Zidovudine Pharmacokinetic Parameters in Pediatric Subjects a Parameter Birth to 14 Days Aged 14 Days to 3 Months Aged 3 Months to 12 Years Oral bioavailability (%) 89 ± 19 (n = 15) 61 ± 19 (n = 17) 65 ± 24 (n = 18) CSF:plasma ratio no data no data 0.68 [0.03 to 3.25] b (n = 38) CL (L/h/kg) 0.65 ± 0.29 (n = 18) 1.14 ± 0.24 (n = 16) 1.85 ± 0.47 (n = 20) Elimination half-life (h) 3.1 ± 1.2 (n = 21) 1.9 ± 0.7 (n = 18) 1.5 ± 0.7 (n = 21) a Data presented as mean ± standard deviation except where noted. b Median [range]. Pregnant Women: Zidovudine pharmacokinetics have been studied in a Phase I trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Use in Specific Populations ( 8.1 )]. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. Geriatric Patients: Zidovudine pharmacokinetics have not been studied in subjects over 65 years of age. Male and Female Patients: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine AUC when a single dose of zidovudine was administered as a 300-mg zidovudine tablet. Drug Interaction Studies: [See Drug Interactions ( 7 ).] Table 10. Effect of Coadministered Drugs on Zidovudine AUC a Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS. Coadministered Drug and Dose Zidovudine Oral Dose n Zidovudine Concentrations Concentration of Coadministered Drug AUC Variability Atovaquone 750 mg every 12 h with food 200 mg every 8 h 14 ↑ 31% Range: 23% to 78% b ↔ Clarithromycin 500 mg twice daily 100 mg every 4 h x 7 days 4 ↓ 12% Range: ↓34% to ↑14% b Not Reported Fluconazole 400 mg daily 200 mg every 8 h 12 ↑ 74% 95% CI: 54% to 98% Not Reported Lamivudine 300 mg every 12 h single 200 mg 12 ↑ 13% 90% CI: 2% to 27% ↔ Methadone 30 to 90 mg daily 200 mg every 4 h 9 ↑ 43% Range: 16% to 64% b ↔ Nelfinavir 750 mg every 8 h x 7 to 10 days single 200 mg 11 ↓ 35% Range: 28% to 41% b ↔ Probenecid 500 mg every 6 h x 2 days 2 mg/kg every 8 h x 3 days 3 ↑ 106% Range: 100% to 170% b Not Assessed Rifampin 600 mg daily x 14 days 200 mg every 8 h x 14 days 8 ↓ 47% 90% CI: 41% to 53% Not Assessed Ritonavir 300 mg every 6 h x 4 days 200 mg every 8 h x 4 days 9 ↓25% 95% CI: 15% to 34% ↔ Valproic acid 250 mg or 500 mg every 8 h x 4 days 100 mg every 8 h x 4 days 6 ↑ 80% Range: 64% to 130% b Not Assessed ↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. a This table is not all inclusive. b Estimated range of percent difference. Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine, while in one case a high level was documented. However, in a pharmacokinetic interaction trial in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions ( 5.5 )].