Retrovir Information
Retrovir (Zidovudine) Description
Retrovir (Zidovudine) is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV. Retrovir (Zidovudine) IV Infusion is a sterile solution for intravenous infusion only. Each mL contains 10 mg zidovudine in Water for Injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH to approximately 5.5. Retrovir (Zidovudine) IV Infusion contains no preservatives.
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 CHNO.
Retrovir (Zidovudine) Clinical Pharmacology
The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg/kg every 4 hours were 1.06 and 0.12 mcg/mL, respectively.
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in 39 patients receiving chronic therapy with Retrovir (Zidovudine) . The median ratio measured in 50 paired samples drawn 1 to 8 hours after the last dose of Retrovir (Zidovudine) was 0.6.
The pharmacokinetics and tolerance of oral 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).
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See Table 4 and PRECAUTIONS: Drug Interactions.
Retrovir (Zidovudine) Indications And Usage
Retrovir (Zidovudine) IV Infusion in combination with other antiRetrovir (Zidovudine) al agents is indicated for the treatment of HIV infection.
Therapy with Retrovir (Zidovudine) has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease at the initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.
Retrovir (Zidovudine) in combination with other antiRetrovir (Zidovudine) al agents has been shown to be superior to monotherapy in one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA. The complete prescribing information for each drug should be consulted before combination therapy that includes Retrovir (Zidovudine) is initiated.
Retrovir (Zidovudine) Contraindications
Retrovir (Zidovudine) IV Infusion is contraindicated for patients who have potentially life-threatening allergic reactions to any of the components of the formulation.
Retrovir (Zidovudine) Warnings
COMBIVIR and TRIZIVIR are combination product tablets that contain zidovudine as one of their components. Retrovir (Zidovudine) 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 (Zidovudine) Precautions
Retrovir (Zidovudine) 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 (Zidovudine) in treating 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 (Zidovudine) 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 (Zidovudine) (see PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse effects of Retrovir (Zidovudine) 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 (Zidovudine) .
Pregnant women considering the use of Retrovir (Zidovudine) 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 neonatal exposure to Retrovir (Zidovudine) 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 (Zidovudine) has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
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.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of Retrovir (Zidovudine) against HIV; concomitant use of such drugs should be avoided.
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 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 (Zidovudine) 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 (Zidovudine) 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, (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV Transmission).
Retrovir (Zidovudine) Adverse Reactions
The adverse events reported during intravenous administration of Retrovir (Zidovudine) IV Infusion are similar to those reported with oral administration; neutropenia and anemia were reported most frequently. Long-term intravenous administration beyond 2 to 4 weeks has not been studied in adults and may enhance hematologic adverse events. Local reaction, pain, and slight irritation during intravenous administration occur infrequently.
The frequency and severity of adverse events associated with the use of Retrovir (Zidovudine) are greater in patients with more advanced infection at the time of initiation of therapy.
Table 5 summarizes events reported at a statistically significantly greater incidence for patients receiving Retrovir (Zidovudine) orally in a monotherapy study:
In addition to the adverse events listed in Table 5, 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 oral Retrovir (Zidovudine) are shown in Table 6.
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Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiRetrovir (Zidovudine) al therapy) pediatric patients are listed in Table 8.
Additional adverse events reported in open-label studies in pediatric patients receiving Retrovir (Zidovudine) 180 mg/m 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 (Zidovudine) may also occur in pediatric patients.
In addition to adverse events reported from clinical trials, the following events have been identified during use of Retrovir (Zidovudine) 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 (Zidovudine) , or a combination of these factors.
Retrovir (Zidovudine) 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.
Retrovir (Zidovudine) Dosage And Administration
The recommended intravenous dose is 1 mg/kg infused over 1 hour. This dose should be administered 5 to 6 times daily (5 to 6 mg/kg daily). The effectiveness of this dose compared to higher dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown. A small randomized study found a greater effect of higher doses of Retrovir (Zidovudine) on improvement of neurological symptoms in patients with pre-existing neurological disease.
Patients should receive Retrovir (Zidovudine) IV Infusion only until oral therapy can be administered. The intravenous dosing regimen equivalent to the oral administration of 100 mg every 4 hours is approximately 1 mg/kg intravenously every 4 hours.
The recommended dosing regimen for administration to pregnant women (>14 weeks of pregnancy) and their neonates is:
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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.
Retrovir (Zidovudine) IV Infusion must be diluted prior to administration. The calculated dose should be removed from the 20-mL vial and added to 5% Dextrose Injection solution to achieve a concentration no greater than 4 mg/mL. Admixture in biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) is not recommended.
After dilution, the solution is physically and chemically stable for 24 hours at room temperature and 48 hours if refrigerated at 2° to 8°C (36° to 46°F). Care should be taken during admixture to prevent inadvertent contamination. As an additional precaution, the diluted solution should be administered within 8 hours if stored at 25°C (77°F) or 24 hours if refrigerated at 2° to 8°C to minimize potential administration of a microbially contaminated solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Should either be observed, the solution should be discarded and fresh solution prepared.
Retrovir (Zidovudine) How Supplied
Retrovir (Zidovudine) IV Infusion, 10 mg zidovudine in each mL.
20-mL Single-Use Vial, Tray of 10 (NDC 0173-0107-93).
GlaxoSmithKlineResearch Triangle Park, NC 27709
©2006, GlaxoSmithKline. All rights reserved.
October 2006 RL-2308
Retrovir (Zidovudine) Principal Display Panel
Each mL contains 10 mg zidovudine.
20-mL Single-Use Vial
FOR INTRAVENOUS INFUSION ONLY. MUST BE DILUTED FOR ADMINISTRATION.
Dilute with 5% Dextrose Injection to a concentration no greater than 4mg/mL. Contains no preservative. The vehicle contains Water for Injection, qs. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. See prescribing information for dosage information. Store at 15 to 25C (59 to 77F) and protect from light.
GlaxoSmithKline, Research Triangle Park, NC 27709
Made in South Korea
10000000075404 Rev. 11/09
