RETROVIR®
(zidovudine)
Tablets
RETROVIR®
(zidovudine)
Capsules
RETROVIR®
(zidovudine)
Syrup

RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH HEMATOLOGIC TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA PARTICULARLY IN PATIENTS WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS (HIV) DISEASE (SEE WARNINGS). 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 (SEE WARNINGS).

RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV.

RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.

RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.

RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH.

The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural formula:

Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg/mL in water at 25°C.The molecular formula is C₁₀H₁₃N₅O₄.

Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.

The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC₅₀ and EC₉₀ values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to 9 μM, respectively. HIV from therapy-naive subjects with no mutations associated with resistance gave median EC₅₀ values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 93 baseline samples from COLA40263) and 0.02 µM (0.01 to 0.03 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC₅₀ values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from 0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of mutations.In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most commonly associated with multi-drug resistance. The mutation at codon 151 in combination with mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.

Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients (Table 3).

See Table 4 and PRECAUTIONS: Drug Interactions.

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

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.Thesafety of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been assessed (see 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 asymptomatic HIV-infected patients.

RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients who have potentially life-threatening allergic reactions to any of the components of the formulations.

COMBIVIR^®and TRIZIVIR^® are combination product tablets that contain zidovudine as one of their components. RETROVIR should not be administered concomitantly with COMBIVIR or TRIZIVIR.

The incidence of adverse reactions appears to increase with disease progression; patients should be monitored carefully, especially as disease progression occurs.

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. In patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant adverse events observed. 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 in patients with advanced HIV disease who are treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION).

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

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).

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/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin.Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of RETROVIR 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., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function which may increase the risk of hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

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 system responds 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.

Redistribution/accumulation of body fat, including centralobesity, 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.

RETROVIR is not a cure for HIV infection, and patients may continue to acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients should be advised to seek medical care for any significant change in their health status.

The safety and efficacy of RETROVIR in women, intravenous drug users, and racial minorities is not significantly different than that observed in white males.

Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. They should be told that if toxicity develops, they may require transfusions or drug discontinuation. They should be told of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV disease. They should be cautioned about the use of other medications, including ganciclovir and interferon alfa, which may exacerbate the toxicity of RETROVIR (see PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse effects of RETROVIR include nausea and vomiting. Patients should also be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with RETROVIR.

RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told of the importance of taking RETROVIR exactly as prescribed. They should be told not to share medication and not to exceed the recommended dose. Patients should be told that the long-term effects of RETROVIR are unknown at this time.

Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV transmission to their infants should be advised that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to RETROVIR are unknown, including the possible risk of cancer.

HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.

Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

See CLINICAL PHARMACOLOGY section (Table 4) for information on zidovudine concentrations when coadministered with other drugs. For patients experiencing pronounced anemia or other severe zidovudine-associated events while receiving chronic administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) uled in Table 4, zidovudine dose reduction may be considered.

Zidovudinewas administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on day 279.

In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine employed in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Zidovudine was mutagenic in a 5178Y/TK^+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates.

Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated area under the curve [AUC] in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.

Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission (see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RETROVIR (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV Transmission).

RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age who had HIV-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, INDICATIONS AND USAGE: Description of Clinical Studies, and CLINICAL PHARMACOLOGY: Pharmacokinetics).

Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 uled 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.

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.

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, potentialcausal connection to RETROVIR, or a combination of these factors.

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those uled as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances.All patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine while elimination of its primary metabolite, GZDV, is enhanced.

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

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.

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

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.

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 with a dark blue band) 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.October 2006 RL-2324