Drug Description

RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV-1.

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.

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.

[For information about RETROVIR IV Infusion, consult the RETROVIR IV Infusion full prescribing information].

HIV/AIDS-Related Uses

INDICATIONS AND USAGE

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.

Prevention of Maternal-Fetal HIV-1 Transmission
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission. 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.

Dosing Information

Mode of Delivery

Oral (tablets, capsules, and syrup).

Intravenous infusion.

Dosage Form

RETROVIR Capsules containing zidovudine 100 mg.

RETROVIR Syrup containing zidovudine 50 mg per 5 mL.

RETROVIR Tablets (film-coated) containing zidovudine 300 mg. 

RETROVIR IV Infusion, 10 mg zidovudine in each mL.

DOSAGE AND ADMINISTRATION

Treatment of HIV-1 Infection
Adults: The recommended oral dose of RETROVIR is 600 mg/day in divided doses in combination with other antiretroviral agents.

Pediatric Patients (4 Weeks to <18 Years of Age): Healthcare professionals should pay special attention to accurate calculation of the dose of RETROVIR, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.

Prescribers should calculate the appropriate dose of RETROVIR for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing RETROVIR Capsules or Tablets, children should be assessed for the ability to swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR Capsule or Tablet, the RETROVIR Syrup formulation should be prescribed.

The recommended dosage in pediatric patients 4 weeks of age and older and weighing  ≥4 kg is provided below. RETROVIR Syrup should be used to provide accurate dosage when whole tablets or capsules are not appropriate.

Recommended Pediatric Dosage of RETROVIR

Body Weight (kg): Dosage Regimen and Dose; (Total Daily Dose)

• 4 to <9 kg: 12 mg/kg bid or 8 mg/kg tid; (Total Daily Dose = 24 mg/kg/day)
• ≥9 to <30 kg: 9 mg/kg bid or 6 mg/kg tid; (Total Daily Dose = 18 mg/kg/day)
• ≥30 kg: 300 mg bid or 200 mg tid; (Total Daily Dose = 600 mg/day)

Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each child. The recommended oral dose of RETROVIR is 480 mg/m²/day in divided doses (240 mg/m² twice daily or 160 mg/m² three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.

Prevention of Maternal-Fetal HIV-1 Transmission
The recommended dosage 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. 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.

[For information about RETROVIR IV Infusion, consult the RETROVIR IV Infusion full prescribing information].

Patients With Severe Anemia and/or Neutropenia
Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or significant neutropenia (granulocyte count <750 cells/mm³ or reduction >50% from baseline) may require a dose interruption until evidence of marrow recovery is observed. 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.

Patients With Renal Impairment
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis, the recommended dosage is 100 mg every 6 to 8 hours.

Patients With Hepatic Impairment
There are insufficient data to recommend dose adjustment of RETROVIR in patients with mild to moderate impaired hepatic function or liver cirrhosis.

Storage

Store RETROVIR Tablets at 15° to 25°C (59° to 77°F).

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

Store RETROVIR Syrup at 15° to 25°C (59° to 77°F).

Store RETROVIR IV Infusion vials at 15° to 25°C (59° to 77°F) and protect from light.

Pharmacology

Mechanism of Action
Zidovudine is an antiviral agent.

Pharmacokinetics
Absorption and Bioavailability: In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as RETROVIR Tablets or Syrup compared with RETROVIR Capsules. The pharmacokinetic properties of zidovudine in fasting adult patients are summarized below.

Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients

Parameter: Mean ± SD (except where noted)
• Oral bioavailability (%):64 ± 10 (n = 5)
• Apparent volume of distribution (L/kg): 1.6 ± 0.6 (n = 8)
• Plasma protein binding (%): <38
• CSF:plasma ratio^a: 0.6 [0.04 to 2.62] (n = 39)
• Systemic clearance (L/hr/kg): 1.6 ± 0.6 (n = 6)
• Renal clearance (L/hr/kg): 0.34 ± 0.05 (n = 9)
• Elimination half-life (hr)^b: 0.5 to 3 (n = 19)

^a Median [range].
^b Approximate range.

Distribution: The apparent volume of distribution of zidovudine, following oral administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (see above).

Metabolism and Elimination: Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV 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.

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

Special Populations: Renal Impairment: 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 (see below). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.

Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment^a

• Control Subjects (Normal Renal Function) (n = 6) – CrCl (mL/min): 120 ± 8; Zidovudine AUC (ng•hr/mL): 1,400 ± 200; Zidovudine half-life (hr): 1.0 ± 0.2.

• Patients With Renal Impairment (n = 14) – CrCl (mL/min): 18 ± 2; Zidovudine AUC (ng•hr/mL): 3,100 ± 300; Zidovudine half-life (hr): 1.4 ± 0.1.

^aData are expressed as mean ± standard deviation.

Hemodialysis and Peritoneal Dialysis: 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.

Hepatic Impairment: 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.

Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric patients (See below).

Patients 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/m² 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.

Patients <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.

Zidovudine Pharmacokinetic Parameters in Pediatric Patients^a

• Birth to 14 Days of Age – Oral bioavailability (%):89 ± 19 (n = 15); CSF:plasma ratio: no data; CL (L/hr/kg): 0.65 ± 0.29 (n = 18); Elimination half-life (hr): 3.1 ± 1.2 (n = 21).

• 14 Days to 3 Months of Age – Oral bioavailability (%): 61 ± 19 (n = 17); CSF:plasma ratio: no data; CL (L/hr/kg): 1.14 ± 0.24 (n = 16); Elimination half-life (hr): 1.9 ± 0.7 (n = 18).

• 3 Months to 12 Years of Age – Oral bioavailability (%): 65 ± 24 (n = 18); CSF:plasma ratio: 0.68 [0.03 to 3.25]^b (n = 38); CL (L/hr/kg): 1.85 ± 0.47 (n = 20); Elimination half-life (hr): 1.5 ± 0.7 (n = 21).

^a Data presented as mean ± standard deviation except where noted.
^b Median [range].

Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those 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.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum.

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 AUC when a single dose of zidovudine was administered as the 300-mg RETROVIR Tablet.

Drug Interactions: [See Drug and Food Interactions]. For additional information, consult the RETROVIR full prescribing information.

Microbiology
Mechanism of Action: 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 reverse transcriptase (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.

Antiviral Activity: 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-1 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 = 92 baseline samples from COL40263) and 0.0017 μM (0.006 to 0.0340 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 abacavir, didanosine, and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Resistance: 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 amino acid substitutions. 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 substitutions conferring resistance to zidovudine.

Cross-Resistance: In a study of 167 HIV-1-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 amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions 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.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category C.
In humans, treatment with RETROVIR during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with RETROVIR. There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1-transmission. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.

Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one fifth the lethal dose.

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
Zidovudine is excreted in human milk.
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RETROVIR.

Pediatric Use
RETROVIR has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV-1.

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.

Renal Impairment
In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is recommended.

Hepatic Impairment
Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). 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.

[For information about RETROVIR IV Infusion, consult the RETROVIR IV Infusion full prescribing information].

Adverse Events/Toxicity

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS

• RETROVIR (zidovudine) Tablets, Capsules, and Syrup have been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease.
   
• 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. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

WARNINGS AND PRECAUTIONS

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.

Myopathy
Myopathy and myositis with pathological changes, similar to that produced by HIV-1 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).

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 , 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).

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).

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.

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.

Clinical Trials Experience
The most commonly reported adverse reactions (incidence ≥15%) in adult HIV-1 clinical studies were headache, malaise, nausea, anorexia, and vomiting.

The most commonly reported adverse reactions (incidence ≥15%) in pediatric HIV-1 clinical studies were fever, cough, and digestive disorders.

The most commonly reported adverse reactions in neonates (incidence ≥15%) in the prevention of maternal-fetal transmission of HIV-1 clinical trial were anemia and neutropenia.

[For information about RETROVIR IV Infusion, consult the RETROVIR IV Infusion full prescribing information].

Drug and Food Interactions

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

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 , 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).

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).

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

Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of RETROVIR against HIV-1; 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.

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

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. [1] [2]

References

[1] FDA Retrovir Tablets, Capsules, and Syrup Prescribing Information, May 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020518s019lbl.pdf. Accessed 10/11/2011.

[2] FDA Retrovir IV Infusion Prescribing Information, July 2006. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019951s023lbl.pdf. Accessed 10/11/2011.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Zidovudina.

Chemistry

CAS Name

Thymidine, 3'-azido-3'-deoxy- [1]

CAS Number

30516-87-1 [2]

Molecular Formula

C10-H13-N5-O4 [3]

Molecular Weight

267.24 [4]

Physical Description

White to beige, odorless, crystalline solid. [5]

Solubility

20.1 mg/mL in water at 25°C. [6]

References

[1] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/11/2011.

[2] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/11/2011.

[3] FDA Retrovir Tablets, Capsules, and Syrup Prescribing Information, May 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020518s019lbl.pdf. Accessed 10/11/2011.

[4] FDA Retrovir Tablets, Capsules, and Syrup Prescribing Information, May 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020518s019lbl.pdf. Accessed 10/11/2011.

[5] FDA Retrovir Tablets, Capsules, and Syrup Prescribing Information, May 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020518s019lbl.pdf. Accessed 10/11/2011.

[6] FDA Retrovir Tablets, Capsules, and Syrup Prescribing Information, May 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020518s019lbl.pdf. Accessed 10/11/2011.

Further Reading

Retrovir Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Retrovir IV Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Arvold ND, Ngo-Giang-Huong N, McIntosh K, Suraseranivong V, Warachit B, Piyaworawong S, Changchit T, Lallemant M, Jourdain G; Perinatal HIV Prevention Trial (PHPT-1), Thailand. Maternal HIV-1 DNA load and mother-to-child transmission. AIDS Patient Care STDS. 2007 Sep;21(9):638-43.
Cressey TR, Leenasirimakul P, Jourdain G, Tawon Y, Sukrakanchana PO, Lallemant M. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1-infected patients weighing less than 60 kg on highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2006 Jul;42(3):387-9.
Dao H, Mofenson LM, Ekpini R, Gilks CF, Barnhart M, Bolu O, Shaffer N. International recommendations on antiretroviral drugs for treatment of HIV-infected women and prevention of mother-to-child HIV transmission in resource-limited settings: 2006 update. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S42-55. Review.
Jamieson DJ, Clark J, Kourtis AP, Taylor AW, Lampe MA, Fowler MG, Mofenson LM. Recommendations for human immunodeficiency virus screening, prophylaxis, and treatment for pregnant women in the United States. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S26-32.

Manufacturer Information

Retrovir

GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
Phone: 888-825-5249

Zidovudine

GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
Phone: 888-825-5249

Zidovudine

PharmaForce, Inc.
960 Crupper Avenue Columbus, Ohio 43229
Phone: 614-436-2222
Fax: 614-436-2610