RETROVIR (Page 2 of 6)

4 CONTRAINDICATIONS

RETROVIR Tablets, Capsules, and Syrup are contraindicated in patients who have had potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations.

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity/Bone Marrow Suppression

RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/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 RETROVIR, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR 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 RETROVIR. 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 (2.3)].

5.2 Myopathy

Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of RETROVIR.

5.3 Lactic Acidosis/Severe Hepatomegaly With Steatosis

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. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering RETROVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with RETROVIR 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 patients [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 >6) (see the complete prescribing information for interferon and ribavirin).

5.5 Use With Other Zidovudine-Containing Products

RETROVIR should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR® [lamivudine and zidovudine] Tablets or TRIZIVIR® [abacavir sulfate, lamivudine, and zidovudine] Tablets).

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RETROVIR. 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.

5.7 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6 ADVERSE REACTIONS

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 RETROVIR 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 RETROVIR in a monotherapy study.

Table 2. Percentage (%) of Patients With Adverse Reactionsa in Asymptomatic HIV-1 Infection (ACTG 019)
Adverse Reaction

RETROVIR 500 mg/day

Placebo

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%
a Reported in ≥5% of study population.
b Not statistically significant versus placebo.

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 RETROVIR 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

RETROVIR 500 mg/day

Placebo

Anemia (Hgb<8 g/dL) 1% <1%
Granulocytopenia (<750 cells/mm3) 2% 2%
Thrombocytopenia (platelets<50,000/mm3) 0% <1%
ALT (>5 x ULN) 3% 3%
AST (>5 x ULN) 1% 2%

Pediatrics: The clinical adverse reactions reported among adult recipients of RETROVIR may also occur in pediatric patients.

Study ACTG 300: Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with EPIVIR® (lamivudine) Oral Suspension 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 4.

Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in Pediatric Patients in Study ACTG 300
a Includes pain, discharge, erythema, or swelling of an ear.
Adverse Reaction

EPIVIR plus RETROVIR

Didanosine

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 earsa 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 Pediatric Patients in Study ACTG 300

Test

EPIVIR plus RETROVIR Didanosine
Neutropenia (ANC<400 cells/mm3) 8% 3%
Anemia (Hgb<7.0 g/dL) 4% 2%
Thrombocytopenia (platelets<50,000/mm3) 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 patients receiving RETROVIR 180 mg/m2 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 RETROVIR for the prevention of maternal-fetal HIV-1 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 reactions 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 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.

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