1 INDICATIONS AND USAGE RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for: • Treatment of Human Immunodeficiency Virus (HIV-1) infection in combination with other antiretroviral agents.

( 1.1 ) • Prevention of maternal-fetal HIV-1 transmission.

( 1.2 ) 1.1 Treatment of HIV-1 RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

1.2 Prevention of Maternal-Fetal HIV-1 Transmission RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see Dosage and Administration ( 2.3 )].

The indication is based on a dosing regimen that included 3 components: 1.

antepartum therapy of HIV‑1–infected mothers 2.

intrapartum therapy of HIV‑1–infected mothers 3.

post-partum therapy of HIV‑1–exposed neonate Points to consider prior to initiating RETROVIR in pregnant women for the prevention of maternal-fetal HIV-1 transmission include: • In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.

• Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged period before pregnancy has not been evaluated.

• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks’ gestation.

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.

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)].

• Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult HIV-1 clinical trials were headache, malaise, nausea, anorexia, and vomiting.

( 6.1 ) • Most commonly reported adverse reactions (incidence greater than or equal to 15%) in pediatric HIV-1 clinical trials were fever and cough.

( 6.1 ) • Most commonly reported adverse reactions in neonates (incidence greater than or equal to 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 ViiV Healthcare at 1-877-844-8872 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 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) a Not statistically significant versus placebo.

Adverse Reaction RETROVIR 500 mg/day (n = 453) Placebo (n = 428) Body as a whole Asthenia 9% a 6% Headache 63% 53% Malaise 53% 45% Gastrointestinal Anorexia 20% 11% Constipation 6% a 4% Nausea 51% 30% Vomiting 17% 10% 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) ULN = Upper limit of normal.

Test (Abnormal Level) RETROVIR 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% 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 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 a Includes pain, discharge, erythema, or swelling of an ear.

Adverse Reaction EPIVIR plus RETROVIR (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 (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 ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

Test (Abnormal Level) EPIVIR plus RETROVIR 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 subjects receiving RETROVIR 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 RETROVIR for the prevention of maternal-fetal HIV-1 transmission, RETROVIR oral solution 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 mm 3 ).

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.

6.2 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 [see Warnings and Precautions ( 5.

6)] .

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.