Retrovir Capsules, Retrovir Syrup, Retrovir Tablets (Glaxosmithkline)

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DESCRIPTION

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

Tablets:    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.

Capsules:    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.

Syrup:    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.

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 C ₁₀ H ₁₃ N ₅ O ₄ .

MICROBIOLOGY

Mechanism of Action:    Zidovudine is a synthetic nucleoside analogue of the naturally occurring nucleoside, thymidine, in which the 3'-hydroxy (-OH) group is replaced by an azido (-N ₃ ) group. Within cells, zidovudine is converted to the active metabolite, zidovudine 5'-triphosphate (AztTP), by the sequential action of the cellular enzymes. Zidovudine 5'-triphosphate inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 5'-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.

In Vitro HIV Susceptibility:    The in vitro anti-HIV activity of zidovudine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV. The IC ₅₀ and IC ₉₀ values (50% and 90% inhibitory concentrations) were 0.003 to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL). The IC ₅₀ and IC ₉₀ values of HIV isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell lines; however, activity was substantially less in chronically infected cell lines. In drug combination studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine, delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the inhibition of HIV replication in humans has not been established.

Drug Resistance:    HIV isolates with reduced sensitivity to zidovudine have been selected in vitro and were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates showed mutations that result in 5 amino acid substitutions (Met41->Leu, A67->Asn, Lys70->Arg, Thr215->Tyr or Phe, and Lys219->Gln) in the viral reverse transcriptase. In general, higher levels of resistance were associated with greater number of mutations with 215 mutation being the most significant.

Cross-Resistance:    The potential for cross-resistance between HIV reverse transcriptase inhibitors and protease inhibitors is low because of the different enzyme targets involved. Combination therapy with zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of zidovudine-resistant isolates. Combination therapy with RETROVIR plus EPIVIR® delayed the emergence of mutations conferring resistance to zidovudine. In some patients harboring zidovudine-resistant virus, combination therapy with RETROVIR plus EPIVIR restored phenotypic sensitivity to zidovudine by 12 weeks of treatment. HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients treated for >/=1 year with the combination of zidovudine and didanosine or zalcitabine. The pattern of resistant mutations in the combination therapy was different (Ala62->Val, Val75->lle, Phe77->116Tyr, and Gln->151Met) from monotherapy, with

CLINICAL PHARMACOLOGY

Pharmacokinetics:   Adults:    The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Binding to plasma protein is low. Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is 3'-azido-3'-deoxy-5'- O -(beta)- D -glucopyranuronosylthymidine (GZDV). GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second metabolite, 3'-amino-3'-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.

The extent of absorption (AUC) was equivalent when zidovudine was administered as RETROVIR Tablets or Syrup compared to RETROVIR Capsules.

Adults with Impaired Renal Function:    Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14) following a single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) >/=15 mL/min.

The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis (see DOSAGE AND ADMINISTRATION : Dose Adjustment ).

Adults with Impaired Hepatic Function:    Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma concentrations would be increased following administration of the recommended adult doses to patients with hepatic impairment (see DOSAGE AND ADMINISTRATION : Dose Adjustment ).

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

Patients from 3 Months to 12 Years of Age:    Overall, zidovudine pharmacokinetics in pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m ² every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV (see DOSAGE AND ADMINISTRATION : Pediatrics ).

Patients Younger Than 3 Months of Age:    Zidovudine pharmacokinetics have been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates </=14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for neonates, see DOSAGE AND ADMINISTRATION : Neonatal Dosing .

Pregnancy:    Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. Zidovudine pharmacokinetics were similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. However, in another patient population, a potential for interaction has been identified (see PRECAUTIONS ).

Nursing Mothers:    The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum (see PRECAUTIONS: Nursing Mothers ).

Geriatric Patients:    Zidovudine pharmacokinetics have not been studied in patients over 65 years of age.

Gender:    A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine exposure (AUC) when a single dose of zidovudine was administered as the 300-mg RETROVIR Tablet.

Effect of Food on Absorption:    RETROVIR may be administered with or without food. The extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was administered with food.

Drug Interactions:    See Table 4 and PRECAUTIONS : Drug Interactions .

Zidovudine Plus Lamivudine:    No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

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 asymptomatic HIV-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 RNA. The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in study ACTG320. This study was a multicenter, 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 two-drug-containing arm (6.1% versus 10.9%, respectively).

The complete prescribing information for each drug should be consulted before combination therapy that includesRETROVIR 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/mm ³ (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 multicenter, 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/mm ³ , and the mean baseline plasma HIV RNA was 5.0 log ₁₀ copies/mL. The median duration that patients remained on study was approximately 10 months. Results are summarized in Table 5.

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/mm ³ (median in the treated group: 560 cells/mm ³ ) 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.

CONTRAINDICATIONS

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

WARNINGS

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.

Bone Marrow Suppression:    RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm ³ 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:    Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of RETROVIR.

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).

PRECAUTIONS

General:    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 ).

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.

Information for Patients:    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-alpha, that 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.

Drug Interactions:    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) listed in Table 4, zidovudine dose reduction may be considered.

Antiretroviral Agents:    Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.

Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of RETROVIR against HIV; 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 (see CLINICAL PHARMACOLOGY for additional drug interactions).

Phenytoin:    Phenytoin plasma levels have been reported to be low in some patients receiving RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.

Overlapping Toxicities:    Coadministration of ganciclovir, interferon-alpha, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was 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:    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 per 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.

Antiretroviral Pregnancy Registry:    To monitor maternal-fetal outcomes of pregnant women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers:    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 ).

Pediatric Use:    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 ).

Geriatric Use:    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.

ADVERSE REACTIONS

Adults:    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:

In addition to the adverse events listed 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.

Pediatric:    Study ACTG300:    Selected clinical adverse events and physical findings with a >/=5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m ² 3 times daily compared with didanosine in therapy-naive (</=56 days of antiretroviral therapy) pediatric patients are listed in Table 8.

Selected laboratory abnormalities experienced by therapy-naive (</=56 days of antiretroviral therapy) pediatric patients are listed in Table 9.

Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR 180 mg/m ² every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss. The clinical adverse events reported among adult recipients of RETROVIR may also occur in pediatric patients.

Use for the Prevention of Maternal-Fetal Transmission of HIV:    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/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/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 utero and infant exposure to RETROVIR are unknown.

Observed During Clinical Practice:    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, potential causal connection to RETROVIR, or a combination of these factors.

Body as a Whole:    Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat (see PRECAUTIONS : Fat Redistribution ).

Cardiovascular:    Cardiomyopathy, syncope.

Endocrine:    Gynecomastia.

Eye:    Macular edema.

Gastrointestinal:    Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.

General:    Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Hemic and Lymphatic:    Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatobiliary Tract and Pancreas:    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 disease), rhabdomyolysis, tremor.

Nervous:    Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Respiratory:    Cough, dyspnea, rhinitis, sinusitis.

Skin:    Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.

Special Senses:    Amblyopia, hearing loss, photophobia, taste perversion.

Urogenital:    Urinary frequency, urinary hesitancy.

OVERDOSAGE

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 listed 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.

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/m ² every 8 hours (480 mg/m ² /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/mm ³ 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 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) and 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

©2003, Glaxosmithkline. All rights reserved.

April 2003/RL-1194

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