Retrovir Side Effects

Generic name: zidovudine

Generic Name: Zidovudine

Please note - some side effects for Retrovir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Retrovir - for the consumer

Retrovir

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Retrovir:

Headache; loss of appetite; nausea; tiredness; vomiting.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chills; dark urine; drowsiness; fast breathing; fever; muscle pain or aches; red, swollen, or blistered skin; seizures; shortness of breath; sore throat; stomach pain; unusual tiredness or weakness; yellowing of the skin or eyes.

Retrovir Capsules

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Retrovir Capsules:

Headache; loss of appetite; nausea; tiredness; vomiting.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chills; dark urine; drowsiness; fast breathing; fever; muscle pain or aches; red, swollen, or blistered skin; seizures; shortness of breath; sore throat; stomach pain; unusual tiredness or weakness; yellowing of the skin or eyes.

Retrovir Syrup

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Retrovir Syrup:

Headache; loss of appetite; nausea; tiredness; vomiting.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chills; dark urine; drowsiness; fast breathing; fever; muscle pain or aches; red, swollen, or blistered skin; seizures; shortness of breath; sore throat; stomach pain; unusual tiredness or weakness; yellowing of the skin or eyes.

For the professional

Retrovir

Adults

The frequency and severity of adverse events associated with the use of Retrovir are greater in patients with more advanced infection at the time of initiation of therapy.

Table 6 summarizes events reported at a statistically significant greater incidence for patients receiving Retrovir in a monotherapy study:

*Reported in ≥5% of study population.

†Not statistically significant versus placebo.

In addition to the adverse events listed in Table 6, other adverse events observed in clinical studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.

Selected laboratory abnormalities observed during a clinical study of monotherapy with Retrovir are shown in Table 7.

ULN = Upper limit of normal.

Pediatrics

Selected clinical adverse events and physical findings with a ≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus Retrovir 160 mg/m2 3 times daily compared with didanosine in therapy-naive (≤56 days of antiRetroviral therapy) pediatric patients are listed in Table 8.

*Includes pain, discharge, erythema, or swelling of an ear.

Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiRetroviral therapy) pediatric patients are listed in Table 9.

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

Additional adverse events reported in open-label studies in pediatric patients receiving Retrovir 180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.

The clinical adverse events reported among adult recipients of Retrovir may also occur in pediatric patients.

Use for the Prevention of Maternal-Fetal Transmission of HIV

In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility of Retrovir for the prevention of maternal-fetal HIV transmission, Retrovir 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 experiences were anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/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/dL for neonates receiving Retrovir compared to 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 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 uteroand infant exposure to Retrovir are unknown.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during use of Retrovir in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to Retrovir, or a combination of these factors.

Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat.

Cardiomyopathy, syncope.

Gynecomastia.

Macular edema.

Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.

Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.

Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Cough, dyspnea, rhinitis, sinusitis.

Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.

Amblyopia, hearing loss, photophobia, taste perversion.

Urinary frequency, urinary hesitancy.

Retrovir Infusion

The adverse events reported during intravenous administration of Retrovir IV Infusion are similar to those reported with oral administration; neutropenia and anemia were reported most frequently. Long-term intravenous administration beyond 2 to 4 weeks has not been studied in adults and may enhance hematologic adverse events. Local reaction, pain, and slight irritation during intravenous administration occur infrequently.

Adults

The frequency and severity of adverse events associated with the use of Retrovir are greater in patients with more advanced infection at the time of initiation of therapy.

Table 5 summarizes events reported at a statistically significantly greater incidence for patients receiving Retrovir orally in a monotherapy study:

*Reported in ≥5% of study population.

†Not statistically significant versus placebo.

In addition to the adverse events listed in Table 5, other adverse events observed in clinical studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.

Selected laboratory abnormalities observed during a clinical study of monotherapy with oral Retrovir are shown in Table 6.

ULN = Upper limit of normal.

Pediatrics

Selected clinical adverse events and physical findings with a ≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus Retrovir 160 mg/m2 orally 3 times daily compared with didanosine in therapy-naive (≤56 days of antiRetroviral therapy) pediatric patients are listed in Table 7.

*Includes pain, discharge, erythema, or swelling of an ear.

Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiRetroviral therapy) pediatric patients are listed in Table 8.

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

Additional adverse events reported in open-label studies in pediatric patients receiving Retrovir 180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.

The clinical adverse events reported among adult recipients of Retrovir may also occur in pediatric patients.

Use for the Prevention of Maternal-Fetal Transmission of HIV

In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility of Retrovir for the prevention of maternal-fetal HIV transmission, Retrovir 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 experiences were anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/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/dL for neonates receiving Retrovir compared to 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 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 uteroand infant exposure to Retrovir are unknown.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during use of Retrovir in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to Retrovir, or a combination of these factors.

Back pain, chest pain, flu-like syndrome, generalized pain.

Cardiomyopathy, syncope.

Gynecomastia.

Macular edema.

Constipation, dysphagia, flatulence, oral mucosal pigmentation, mouth ulcer.

Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Aplastic anemia, hemolytic anemia, leukopenia,lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.

Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Cough, dyspnea, rhinitis, sinusitis.

Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.

Amblyopia, hearing loss, photophobia, taste perversion.

Urinary frequency, urinary hesitancy.

By body system

General side effects

The adverse effects of zidovudine are sometimes difficult to distinguish from the symptomatology observed during the clinical course of AIDS, as well as from the possible adverse effects of other drugs used in the treatment of HIV infection. Many of the side effects associated with nucleoside reverse transcriptase inhibitor therapy (myopathy, pancreatitis, liver failure, lactic acidosis, etc.) are attributable to their direct toxic effect on mitochondria which causes decreased mitochondrial energy-generating capacity.

Hematologic side effects

Hematologic side effects are the major dose-limiting adverse effects of zidovudine and occur in up to 45% of patients. Zidovudine-induced bone marrow suppression results in neutropenia, granulocytopenia, anemia, and less frequently, thrombocytopenia. Increased hemoglobin A2 percentage has been reported. Aplastic anemia, hemolytic anemia, leukopenia, pancytopenia with marrow hypoplasia, and pure red cell aplasia have been reported during postmarketing experience.

Bone marrow suppression, the most common reason for cessation of zidovudine therapy, appears to be dose-dependent and may be seen as early as 2 to 6 weeks after initiation of therapy. Recombinant GM-CSF (sargramostim), G-CSF (filgrastim), and erythropoietin (epoetin alfa) have been used to control the hematologic toxicity of zidovudine.

Zidovudine should be used with extreme caution in patients with bone marrow suppression indicated by a granulocyte count below 1000 cells/mm3 or hemoglobin less than 9.5 g/dL. Routine blood counts are recommended, and generally should occur more frequently in patients with advanced disease. If bone marrow toxicity occurs, an interruption or discontinuation of zidovudine therapy may be necessary.

Gastrointestinal side effects

Gastrointestinal side effects have included nausea, vomiting, anorexia, dyspepsia, flatulence, constipation, diarrhea, abdominal cramps, abdominal pain, stomatitis, and splenomegaly. Dysphagia, oral mucosa pigmentation, mouth ulcer, and pancreatitis have been reported during postmarketing experience.

Hepatic side effects

One patient with preexisting hepatitis B developed acute hepatic failure two weeks after starting zidovudine therapy.

Patients with a history of liver disease should be monitored for further deterioration in liver function.

Hepatic side effects have included increases in liver function tests (ALT and AST), severe or fatal hepatomegaly with steatosis and lactic acidosis, fulminate hepatitis, and hepatic failure. Hepatic decompensation has been reported in patients coinfected with HIV-1 and hepatitis C. Hepatitis and jaundice have been reported during postmarketing experience.

Musculoskeletal side effects

In one study, myalgias and elevated CK occurred in 8% of treated patients with a CD4 cell count less than 200/mm3, and in none of the patients with higher CD4 cell counts. Dosage reduction has not affected the course of myopathy, although drug discontinuation sometimes resulted in improvement of symptoms, generally within a month. Muscle biopsy has shown atrophic and sometimes necrotic fibers, ragged-red fibers, and large accumulations of mitochondrial and fibrillar sarcoplasmic inclusions.

Musculoskeletal side effects have included myopathy, myositis, muscle tenderness, arthralgia, myalgias, musculoskeletal pain, and weakness in the arms and legs, and are generally associated with an elevation in serum creatine kinase. Zidovudine-related myopathy may occur after several weeks of therapy and may be difficult to distinguish from that associated with the natural progression of HIV disease. Increased lactate dehydrogenase, muscle spasm, rhabdomyolysis, and tremor have been reported during postmarketing experience.

Nervous system side effects

Nervous system side effects have included headache (common), dizziness, insomnia, numbness, and neuropathy. Generalized seizures, status epilepticus, confusion, paresthesia, somnolence, vertigo, and Wernicke's syndrome have been rarely reported. Loss of mental acuity has been reported during postmarketing experience.

Other side effects

Other side effects have included asthenia, malaise, fatigue, chills, fever, and lymphadenopathy. Back pain, chest pain, flu-like syndrome, generalized pain, hearing loss, and taste perversion have been reported during postmarketing experience.

In one case of zidovudine-associated fever, no source of infection was found after an extensive evaluation, but an anti-zidovudine immunoglobulin was isolated, indicating a possible hypersensitivity reaction.

Psychiatric side effects

Psychiatric side effects have included sleep disturbances and isolated cases of depression, mania, anxiety, and grandiosity.

Dermatologic side effects

Bluish or brownish-black discoloration of nails may develop during the first month or two of zidovudine therapy and usually disappears within 2 months if the drug is discontinued. Discoloration may occur as longitudinal streaks or transverse bands.

Dermatologic side effects have included case reports of nailbed hyperpigmentation, particularly in black people. Rarely, nail hyperpigmentation has been accompanied by mucocutaneous pigmentation or hypertrichosis. Skin rashes and leukocytoclastic vasculitis with eosinophilia and fever have also been reported. Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, and urticaria have been reported during postmarketing experience.

Other side effects

Zidovudine therapy may be associated with lower levels of vitamins B2 and C, folate, and zinc despite adequate dietary intake. The use of multivitamins with zidovudine is recommended.

Cardiovascular side effects

Cardiovascular side effects have included rare cases of reversible congestive heart failure, syncope, and vasodilation. Cardiomyopathy and vasculitis have been reported during postmarketing experience.

Ocular side effects

Ocular side effects have included a case of macular edema in a patient with a history of anterior uveitis secondary to syphilis. Amblyopia and photophobia have been reported during postmarketing experience.

Hypersensitivity side effects

Hypersensitivity reactions have included allergic skin rash. Sensitization reactions including anaphylaxis and angioedema have been reported during postmarketing experience.

Metabolic side effects

Metabolic side effects have included hyperbilirubinemia, hyperlipidemia, and redistribution and/or accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement and cushingoid appearance.

Respiratory side effects

Respiratory side effects have included cough, wheezing/abnormal breath sounds, nasal discharge, and congestion in pediatric patients. Dyspnea, rhinitis, and sinusitis have been reported during postmarketing experience.

Genitourinary side effects

Genitourinary side effects have included urinary frequency and urinary hesitancy during postmarketing experience.

Endocrine side effects

Endocrine side effects have included gynecomastia during postmarketing experience.

Other side effects

Ear pain, discharge, erythema, and swelling have been reported in pediatric patients.

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