Retrovir (Zidovudine) - Indications and Dosage

INDICATIONS AND USAGE

RETROVIR in combination with other antiretroviral agents is indicated for the treatment of HIV infection.

Maternal-Fetal HIV Transmission

RETROVIR is also indicated for the prevention of maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR beginning between 14 and 34 weeks of gestation, intravenous RETROVIR during labor, and administration of RETROVIR Syrup to the neonate after birth. The efficacy of this regimen for preventing HIV transmission in women who have received RETROVIR for a prolonged period before pregnancy has not been evaluated. The safety of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been assessed (see Description of Clinical Studies).

Description of Clinical Studies

Therapy with RETROVIR has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease and to delay disease progression in asymptomaticHIV-infected patients.

Combination Therapy in Adults

RETROVIR in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA. The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in study ACTG320. This study was a multi-center, randomized, double-blind, placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR^® 300 mg/day to RETROVIR plus EPIVIR plus indinavir 800 mg t.i.d. The incidence of AIDS-defining events or death was lower in the triple-drug−containing arm compared to the 2-drug−containing arm (6.1% versus 10.9%, respectively).

The complete prescribing information for each drug should be consulted before combination therapy that includes RETROVIR is initiated.

Monotherapy in Adults

In controlled studies of treatment-naive patients conducted between 1986 and 1989, monotherapy with RETROVIR, as compared to placebo, reduced the risk of HIV disease progression, as assessed using endpoints that included the occurrence of HIV-related illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts between 200 and 500 cells/mm³ (ACTG016 and ACTG019). A survival benefit for monotherapy with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies showed that the clinical benefit of monotherapy with RETROVIR was time limited.

Pediatric Patients

ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic, HIV-infected therapy-naive pediatric patients were enrolled in these 2 treatment arms. The median age was 2.7 years (range 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells/mm³, and the mean baseline plasma HIV-1 RNA was 5.0 log₁₀ copies/mL. The median duration that patients remained on study was approximately 10 months. Results are summarized in Table 5.

Table 5. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Endpoint	EPIVIR plus RETROVIR (n = 236)	Didanosine (n = 235)
HIV disease progression or death (total)	15 (6.4%)	37 (15.7%)
Physical growth failure	7 (3.0%)	6 (2.6%)
Central nervous system deterioration	4 (1.7%)	12 (5.1%)
CDC Clinical Category C	2 (0.8%)	8 (3.4%)
Death	2 (0.8%)	11 (4.7%)

Pregnant Women and Their Neonates

The utility of RETROVIR for the prevention of maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG076) conducted in HIV-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm³ (median in the treated group: 560 cells/mm³) who had little or no previous exposure to RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of RETROVIR during labor and delivery. Following birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically significant difference in the incidence of HIV infection in the neonates (based on viral culture from peripheral blood) between the group receiving RETROVIR and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV infection was 7.8% in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

DOSAGE AND ADMINISTRATION

Adults

The recommended oral dose of RETROVIR is 600 mg per day in divided doses in combination with other antiretroviral agents.

Pediatrics

The recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m² every 8 hours (480 mg/m²/day up to a maximum of 200 mg every 8 hours) in combination with other antiretroviral agents.

Maternal-Fetal HIV Transmission

The recommended dosing regimen for administration to pregnant women (>14 weeks of pregnancy) and their neonates is:

Maternal Dosing

100 mg orally 5 times per day until the start of labor (see INDICATIONS AND USAGE: Description of Clinical Studies). During labor and delivery, intravenous RETROVIR should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.

Neonatal Dosing

2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See PRECAUTIONS if hepatic disease or renal insufficiency is present.)

Monitoring of Patients

Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks.

Dose Adjustment

Anemia

Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of baseline) and/or significant neutropenia (granulocyte count of<750 cells/mm³ or reduction of >50% from baseline) may require a dose interruption until evidence of marrow recovery is observed (see WARNINGS). In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level and patient tolerance.

For patients experiencing pronounced anemia while receiving chronic coadministration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose reduction may be considered.

End-Stage Renal Disease

In patients maintained on hemodialysis or peritoneal dialysis, recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Hepatic Impairment

There are insufficient data to recommend dose adjustment of RETROVIR in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these patients. Frequent monitoring for hematologic toxicities is advised (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).

HOW SUPPLIED

RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg zidovudine, one side engraved“GX CW3” and “300” on the other side.

Bottle of 60 (NDC 0173-0501-00).

Store at 15° to 25°C (59° to 77°F).

RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on body.

Bottles of 100 (NDC 0173-0108-55).

Unit Dose Pack of 100 (NDC 0173-0108-56).

Store at 15° to 25°C (59° to 77°F) and protect from moisture.

RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg zidovudine in each teaspoonful (5 mL).

Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.

Store at 15° to 25°C (59° to 77°F).

GlaxoSmithKline

Research Triangle Park, NC 27709

©2006, GlaxoSmithKline. All rights reserved. November 2006RL-2325