Side Effects of Retrovir (zidovudine)

Retrovir IV Infusion (zidovudine [ZDV] - formerly called azidothymidine [AZT]) is a type of antiviral medication called a pyrimidine nucleoside analogue used to treat human immunodeficiency virus (HIV) and to prevent HIV transmission from an infected mother to her fetus.

Common side effects of Retrovir include

• chills,
• rash,
• confusion,
• dizziness,
• severe headache,
• diarrhea,
• weakness,
• pain,
• insomnia,
• nausea, and
• weight loss.

Serious side effects of Retrovir include

• a decrease in blood cells,
• muscle pain,
• enlarged liver (hepatomegaly),
• metabolic disturbance (lactic acidosis), and
• liver toxicity, including neutropenia and severe anemia, particularly in patients with advanced human immunodeficiency virus (HIV) disease.

Drug interactions of Retrovir include fluconazole, probenecid, and trimethoprim, which reduce the elimination of Retrovir and therefore increase the blood concentration of Retrovir which can lead to increased side effects from Retrovir.

Retrovir is used to prevent transmission of the HIV virus from mother to fetus. Although it is unknown if Retrovir passes into breast milk, HIV infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant.

WARNING

Retrovir (zidovudine) has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced human immunodeficiency virus (HIV) disease.

Prolonged use of Retrovir has been associated with symptomatic myopathy.

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.

The most severe side effects of ziovudine are

• a decrease in blood cells,
• muscle pain (myopathy),
• enlarged liver,
• (hepatomegaly),
• and metabolic disturbance (lactic acidosis).

Other side effects are

• chills,
• rash,
• confusion,
• dizziness,
• severe headache,
• diarrhea,
• weakness,
• pain,
• insomnia,
• diarrhea,
• nausea, and
• weight loss.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hematologic toxicity, including neutropenia and anemia.
• Symptomatic myopathy.
• Lactic acidosis and severe hepatomegaly with steatosis.
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C.

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)

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)

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

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

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

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.

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.

Doxorubicin

Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.

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.