Retrovir (Zidovudine)

Retrovir (AZT)

Glaxo Wellcome

Zidovudine

Antiretroviral Agent

Action And Clinical Pharmacology: Zidovudine is a potent inhibitor of the in vitro replication of some retroviruses including human immunodeficiency virus, HIV. Zidovudine is a thymidine analogue in which the 3-hydroxy (-OH) group is replaced by an azido(-N3) group. Cellular thymidine kinase converts zidovudine into zidovudine monophosphate. The monophosphate is further converted into the diphosphate by cellular thymidylate kinase and to the triphosphate derivative by other cellular enzymes. Zidovudine triphosphate interferes with the HIV viral RNA dependent DNA polymerase (reverse transcriptase) and thus inhibits viral replication. Zidovudine triphosphate also inhibits cellular a-DNA polymerase, but at concentrations 100-fold higher than those required to inhibit reverse transcriptase. In vitro, zidovudine triphosphate has been shown to be incorporated into growing chains of DNA by viral reverse transcriptase. When incorporation by the viral enzyme occurs, the DNA chain is terminated. Studies in cell culture suggest that zidovudine incorporation by cellular a-DNA polymerase may occur, but only to a very small extent and not in all test systems. Cellular g-DNA polymerase shows some sensitivity to inhibition by the zidovudine triphosphate with 50% inhibitory concentration (IC50) values 400 to 900 times greater than that for HIV reverse transcriptase.

Pharmacokinetics: Pharmacokinetic studies of zidovudine following i.v. dosing in adults indicate dose-independent kinetics over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours. Zidovudine is rapidly metabolized in the liver to 3-azido-3-deoxy-5-O-b-D-glucopyranuronosylthymidine (GZDV, formerly called GAZT), and both are rapidly eliminated by the kidney. A second metabolite, 3-amino-3-deoxythymidine (AMT) has been identified in the plasma following single dose i.v. administration of zidovudine. After oral dosing in adults, zidovudine is rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within 0.5 to 1.5 hours, with an average oral bioavailability of 65%. Retrovir capsules and syrup are bioequivalent. In pediatric patients older than 3 months, the pharmacokinetics of zidovudine are similar to those in adult patients.

Indications And Clinical Uses: Monotherapy: Adults: Zidovudine is indicated for the initial treatment of HIV-infected adults with CD4 cell counts of approximately 500 cells/mmor less. Therapy with zidovudine has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease at the time of initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.

Zidovudine should be considered as initial therapy for adult HIV-infected patients who have not received previous antiretroviral treatment. However, randomized studies have shown that for some patients with advanced disease on prolonged therapy with zidovudine, modifying the antiviral regimen may be more effective in delaying disease progression than remaining on monotherapy with zidovudine.

Children: Zidovudine is also indicated for HIV-infected children over 3 months of age who have HIV-related symptoms or who are asymptomatic with abnormal laboratory values indicating significant HIV-related immunosuppression.

Maternal-Fetal HIV Transmission: Zidovudine is also indicated for the prevention of maternal-fetal HIV transmission as part of a regimen that includes oral zidovudine beginning between 14 and 34 weeks of gestation, i.v. zidovudine during labor, and administration of zidovudine syrup to the newborn after birth. However, transmission to infants may still occur in some cases despite the use of this regimen. The efficacy of this regimen for preventing HIV transmission in women who have received zidovudine for a prolonged period before pregnancy has not been evaluated. The safety of zidovudine for the mother or fetus during the first trimester of pregnancy has not been assessed.

The utility of zidovudine for the prevention of maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-infected pregnant women who had little or no previous exposure to zidovudine and CD4 cell counts of 200 to 1 818 cells/mm(median in the treated group: 560 cells/mm. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by i.v. administration of zidovudine during labor and delivery. After birth, infants received oral zidovudine syrup for 6 weeks. The study showed a statistically significant difference in the incidence of HIV infection in the infants (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 infants evaluated in the study, the estimated risk of HIV infection was 8.3% in the group receiving zidovudine and 25.5% in the placebo group, a relative reduction in transmission risk of 67.5%.

Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups. The mean difference in hemoglobin values was less than 1.0 g/dL for infants receiving zidovudine compared to infants receiving placebo. Infants did not require transfusion and hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with zidovudine. The long-term consequences of in utero and infant exposure to zidovudine are unknown.

Combination Therapy with zidovudine and zalcitabine: Zidovudine in combination with zalcitabine is indicated for the treatment of selected patients with advanced HIV disease (CD4 cell count 300 cells/mm. In patients without prior exposure to zidovudine, this indication is based on greater increases in CD4 cell counts that were maintained longer for patients treated with combination therapy as compared to monotherapy with zidovudine. In patients with no prior exposure to zidovudine, there have been no studies showing clinical benefit from combination therapy compared to zidovudine alone.

Contra-Indications: Patients who have potentially life-threatening allergic reactions to any of the components of the formulations.

Manufacturers’ Warnings In Clinical States: Bone Marrow Suppression: Zidovudine should be used with extreme caution in patients who have bone marrow compromise evidenced by granulocyte.

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

Lactic Acidosis/Severe Hepatomegaly with Steatosis: Rare occurrences of lactic acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported with the use of antiretroviral nucleoside analogues, including zidovudine and zalcitabine, and are potentially fatal; it is not known whether these events are causally related to the use of these drugs. Lactic acidosis should be considered whenever a patient receiving therapy with zidovudine develops unexplained tachypnea, dyspnea, or fall in serum bicarbonate level. Under these circumstances, therapy with zidovudine should be suspended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised when administering zidovudine to any patient, particularly obese women, with hepatomegaly, hepatitis, or other known risk factors for liver disease. These patients should be followed closely while on therapy with zidovudine. The significance of elevated aminotransferase levels (suggesting hepatic injury) in HIV-infected patients prior to starting zidovudine or while on zidovudine is unclear. Treatment with zidovudine should be suspended in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology.

Other Serious Adverse Reactions: Several serious adverse events have been reported with use of zidovudine in clinical practice. Reports of pancreatitis, sensitization reactions (including anaphylaxis in one patient), vasculitis, and seizures have been rare. These adverse events, except for sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation have been associated with the use of zidovudine.

Coadministration of zidovudine with other drugs metabolized by glucuronidation should be avoided because the toxicity of either drug may be potentiated (see Precautions, Drug Interactions).

The full safety and efficacy profile of zidovudine has not been defined, particularly in regard to prolonged use and especially in HIV-infected individuals who have less advanced disease. The incidence of adverse reactions appears to increase with disease progression, and patients should be monitored carefully, especially as disease progression occurs.

Combination Therapy with zidovudine and zalcitabine: At present, there are no results from controlled studies evaluating the effect of combined use of zidovudine and zalcitabine on the clinical progression of HIV infections such as survival or the incidence of opportunistic infections.

In patients who have shown clinical or immunologic deterioration, consideration should be given to the use of alternative antiretroviral therapy.

The major clinical toxicities of zalcitabine are peripheral neuropathy and much less frequently pancreatitis. Toxicities associated with zidovudine monotherapy are likely to occur in patients treated with combined zidovudine and zalcitabine therapy. It is recommended that physicians refer to the product monograph for zalcitabine before prescribing combination therapy with zidovudine and zalcitabine.

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, dosage reduction is recommended (see Pharmacology and Dosage). Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity.

Infancy: A positive test for HIV-antibody in children under 15 months of age may represent passively acquired maternal antibodies, rather than an active antibody response to infection in the infant. Thus, the presence of HIV-antibody in a child less than 15 months of age must be interpreted with caution, especially in the asymptomatic infant. Auxiliary diagnostic tests may be required to confirm infection in such children.

Children: See Indications, Adverse Effects and Dosage. The pharmacokinetics of zidovudine in pediatric patients greater than 3 months of age is similar to that of zidovudine in adult patients.

Pregnancy: A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-transmission. Congenital abnormalities occurred with similar frequency between infants born to mothers who received zidovudine and infants 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.

Pregnant women considering the use of 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 infant exposure to zidovudine are unknown. The long-term effects of early or short-term use of zidovudine in pregnant women are also unknown.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine, an Antiretroviral Pregnancy Registry has been established. Physicans are encouraged to register patients by calling 1-800-668-6051.

Lactation: It is not known whether zidovudine is excreted in human milk or whether zidovudine reduces the potential for transmission of HIV in breast milk. Lactating mice administered zidovudine (200 mg/kg intraperitoneally) were found to have milk concentrations of zidovudine 5 times the corresponding serum zidovudine concentration. Milk concentrations of zidovudine declined at a slower rate than serum zidovudine concentrations.

It is advisable to caution mothers against breast-feeding to avoid postnatal transmission of HIV to a child who may not yet be infected.

Drug Interactions: Ganciclovir: Use of zidovudine in combination with ganciclovir increases the risk of hematologic toxicities in some patients with advanced HIV disease. Should the use of this combination become necessary in the treatment of patients with HIV disease, dose reduction or interruption of one or both agents may be necessary to minimize hematologic toxicity. Hematologic parameters, including hemoglobin, hematocrit, and white blood cell count with differential, should be monitored frequently in all patients receiving this combination.

Interferon-alpha: Hematologic toxicities have also been seen when zidovudine is used concomitantly with interferon-alpha. As with the concomitant use of zidovudine and ganciclovir, dose reduction or interruption of one or both agents may be necessary, and hematologic parameters should be monitored frequently.

Bone Marrow Suppressive Agents/Cytotoxic Agents: Coadministration of zidovudine with drugs that are cytotoxic or which interfere with RBC/WBC number or function (e.g., dapsone, flucytosine, vincristine, vinblastine, or adriamycin) may increase the risk of hematologic toxicity.

Probenecid: Limited data suggest that probenecid may increase zidovudine levels by inhibiting glucuronidation and/or reducing renal excretion of zidovudine. Some patients who have used zidovudine concomitantly with probenecid have developed flu-like symptoms consisting of myalgia, malaise, and/or fever and maculopapular rash.

Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine, 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.

Methadone: In a pharmacokinetic study of 9 HIV-positive patients receiving methadone-maintenance (30 to 90 mg daily) concurrent with 200 mg of zidovudine every 4 hours, no changes were observed in the pharmacokinetics of methadone upon initiation of therapy with zidovudine and after 14 days of treatment with zidovudine. No adjustments in methadone-maintenance requirements were reported. However, plasma levels of zidovudine were elevated in some patients while remaining unchanged in others. The exact mechanism and clinical significance of these data are unknown.

Fluconazole: Preliminary data suggest that fluconazole interferes with the oral clearance and metabolism of zidovudine. In a pharmacokinetic interaction study in which 12 HIV-positive men received zidovudine alone and in combination with fluconazole, increases in the mean peak serum concentration (79%), AUC (70%) and half-life (38%) were observed at steady state. The clinical significance of this interaction is unknown.

Other Nucleoside Analogues: Some experimental nucleoside analogues which are being evaluated in HIV-infected patients may affect RBC/WBC number or function and may increase the potential for hematologic toxicity of zidovudine. Some experimental nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV and thus, concomitant use of such drugs should be avoided.

Other Agents: Some drugs such as trimethoprim-sulfamethoxazole, pyrimethamine, and acyclovir may be necessary for the management or prevention of opportunistic infections. In the placebo-controlled trial in patients with advanced HIV disease, increased toxicity was not detected with limited exposure to these drugs. However, there is one published report of neurotoxicity (profound lethargy) associated with concomitant use of zidovudine and acyclovir. Preliminary data from a drug interaction study (n=10) suggest that coadministration of 200 mg zidovudine and 600 mg rifampin decreases the area under the plasma concentration curve by an average of 48%±34%. However, the effect of once daily dosing of rifampin on multiple daily doses of zidovudine is unknown.

Adverse Reactions: Adults: The frequency and severity of adverse events associated with the use of zidovudine in adults are greater in patients with more advanced infection at the time of initiation of therapy.

Anemia and Granulocytopenia: In all of the placebo-controlled studies, but most frequently in patients with advanced symptomatic HIV disease, anemia and granulocytopenia were the most significant adverse events observed.

Significant anemia most commonly occurred after 4 to 6 weeks of therapy and in many cases required dose adjustment, discontinuation of zidovudine and/or blood transfusions. Frequent blood counts are strongly recommended in patients with advanced HIV disease taking zidovudine. For asymptomatic HIV-infected individuals and patients with early HIV disease, most of whom have better marrow reserve, blood counts may be obtained less frequently, depending upon the patient’s overall status. If anemia or granulocytopenia develops, dosage adjustments may be necessary (see Dosage).

Other Adverse Events (Advanced HIV Disease): The anemia reported in patients with advanced HIV disease receiving zidovudine appeared to be the result of impaired erythrocyte maturation as evidenced by macrocytosis while on drug. Although mean platelet counts in patients receiving zidovudine were significantly increased compared to mean baseline values, thrombocytopenia did occur in some of these patients with advanced disease. Twelve percent of patients receiving zidovudine compared to 5% of patients receiving placebo had >50% decreases from baseline platelet count. Mild drug-associated elevations in total bilirubin levels have been reported as an uncommon occurrence in patients treated for asymptomatic HIV infection. The HIV-infected adults participating in these clinical trials often had baseline symptoms and signs of HIV disease and/or experienced adverse events at some time during the study. It was often difficult to distinguish adverse events possibly associated with administration of zidovudine from underlying signs of HIV disease or intercurrent illnesses.

Table II summarizes clinical adverse events or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with 1 500 mg/day of zidovudine in the original placebo-controlled study. Of the items listed in the table, only severe headache, nausea, insomnia and myalgia were reported at a significantly greater rate in patients receiving zidovudine.

Clinical adverse events which occurred in less than 5% of all adult patients treated with 1 500 mg/day of zidovudine in the advanced HIV study are listed below. Since many of these adverse events were seen in placebo-treated patients as well as patients treated with zidovudine, their possible relationship to the drug is unknown.

Body as a Whole: body odor, chills, edema of the lip, flu syndrome, hyperalgesia, back pain, chest pain, lymphadenopathy.

Cardiovascular: vasodilation.

Gastrointestinal: constipation, dysphagia, edema of the tongue, eructation, flatulence, bleeding gums, rectal hemorrhage, mouth ulcer.

Musculoskeletal: arthralgia, muscle spasm, tremor, twitch.

Nervous: anxiety, confusion, depression, emotional lability, nervousness, syncope, loss of mental acuity, vertigo.

Respiratory: cough, epistaxis, pharyngitis, rhinitis, sinusitis, hoarseness.

Skin: acne, pruritus, urticaria.

Special Senses: amblyopia, hearing loss, photophobia.

Urogenital: dysuria, polyuria, urinary frequency, urinary hesitancy.

Other Adverse Events (Early Symptomatic/Asymptomatic HIV Disease): All events of a severe or life-threatening nature were monitored for adults in the placebo controlled studies in early HIV disease and asymptomatic HIV infection. Data concerning the occurrence of additional signs or symptoms were also collected. No distinction was made between events possibly associated with the administration of the study medication and those due to the underlying disease. Tables III and IV summarize all those events reported significantly more frequently by patients receiving zidovudine in these studies.

Several serious adverse events have been reported with the use of zidovudine in clinical practice. Myopathy and myositis with pathological changes similar to that produced by HIV disease have been associated with prolonged use of zidovudine. Reports of hepatomegaly with steatosis, hepatitis, pancreatitis, lactic acidosis, sensitization reactions (including anaphylaxis in one patient), hyperbilirubinemia, vasculitis, and seizures have been rare. These adverse events, except for sensitization, have also been associated with HIV disease. A single case of macular edema has been reported with the use of zidovudine. Changes in skin and nail pigmentation have been associated with the use of zidovudine (see Warnings).

Combination Therapy with Zidovudine and Zalcitabine: Only limited safety data are available on the combined use of zidovudine with zalcitabine. The major toxicities of zalcitabine are peripheral neuropathy and, less frequently, pancreatitis.

Children: Anemia and Granulocytopenia: The incidences of anemia and granulocytopenia among children with advanced HIV disease receiving zidovudine occurred with similar incidence to that reported for adults with AIDS or advanced ARC (see above). Table VI summarizes the occurrence of anemia.

Management of neutropenia and anemia included, in some cases, dose modification and/or blood product transfusions. In the open-label studies, 17% had their dose modified (generally a reduction in dose by 30%) due to anemia, and 25% had their dose modified (temporary discontinuation or reduction by 30%) for neutropenia. Four children had zidovudine permanently discontinued because of neutropenia.

Macrocytosis was observed among the majority of children enrolled in the studies.

Other Adverse Events (Children): The clinical adverse events reported among adult recipients of zidovudine may also occur in children.

In the open-label studies involving 124 children, 16 different clinical adverse events were reported by 24 children. No event was reported by more than 5.6% of the study populations. Due to the open-label design of the studies, it was difficult to determine possible events related to the use of zidovudine versus disease-related events. Therefore, all clinical events reported as associated with therapy with zidovudine or of unknown relationship to therapy with zidovudine are presented

Prevention of Maternal-Fetal Transmission of HIV: In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their infants conducted to determine the utility of zidovudine for the prevention of maternal-fetal HIV transmission, zidovudine syrup at 2 mg/kg was administered every 6 hours for 6 weeks to infants beginning within 12 hours after birth. The most commonly reported adverse experiences were anemia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Cases of acute overdose in both children and adults have been reported with doses up to 50 g. None were fatal.

The only consistent finding in these cases of overdose was spontaneous or induced nausea and vomiting. Hematological changes were transient and not severe. Some patients experienced nonspecific CNS symptoms such as headache, dizziness, drowsiness, lethargy, and confusion. One report of a grand mal seizure possibly attributable to zidovudine occurred in a 35-year-old male 3 hours after ingesting 36 g of zidovudine. No other cause could be identified. 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: Capsules and Syrup: Adults: Asymptomatic HIV Infection: The recommended dose for adults is 100 mg (one 100 mg capsule or 10 mL of syrup) administered orally every 4 hours while awake for a total daily dose of 500 mg.

Symptomatic HIV Disease: The recommended dose for adults is 100 mg (one 100 mg capsule or 10 mL of syrup) administered orally every 4 hours around the clock for a total daily dose of 600 mg.

The effectiveness of the oral dose compared to higher dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown. A small randomized study has found a greater effect of higher doses of zidovudine on improvement of neurological symptoms in patients with pre-existing neurological disease.

Children: The recommended oral dose in children 3 months to 12 years of age is 180 mg/mevery 6 hours (720 mg/mday). This dose is equivalent to 1 200 mg/day in adults. Do not exceed 200 mg for any individual dose.

I.V. Infusion: Adults: The recommended dose is 1 to 2 mg/kg administered as a 1 hour infusion every 4 hours around the clock (6 times daily). Patients should receive i.v. zidovudine only until oral therapy can be administered.

The i.v. dosing regimen equivalent to the oral administration of 100 mg every 4 hours is approximately 1 mg/kg i.v. every 4 hours.

Zidovudine injection is administered i.v. at a constant rate over 1 hour. Rapid infusion or bolus injection should be avoided. Zidovudine injection should not be given i.m.

The effectiveness of the i.v. dose compared to higher dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown. A small randomized study has found a greater effect of higher doses of zidovudine on improvement of neurological symptoms in patients with pre-existing neurological disease.

Children: The recommended dose of zidovudine i.v. injection in children 3 months to 12 years of age is 120 mg/mevery 6 hours, infused over 1 hour (480 mg/mday). Do not exceed 160 mg for any individual dose.

Prevention of Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to pregnant women (>14 weeks of pregnancy) and their newborn infants is:

Maternal Dosing: 100 mg orally 5 times/day until the start of labor. During labor and delivery, i.v. zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous i.v. infusion at 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.

Infant Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing through 6 weeks of age. Infants unable to receive oral dosing may be administered zidovudine i.v. at 1.5 mg/kg, infused over 30 minutes, every 6 hours. See Precautions if hepatic disease or renal insufficiency is present.

Combination Therapy With Zidovudine and Zalcitabine: For the treatment of adult patients with advanced HIV infection (CD4 cell count 300 cells/mm, the daily recommended combination regimen is 200 mg of zidovudine administered concomitantly with one 0.75 mg tablet of zalcitabine every 8 hours (600 mg zidovudine total daily dose and 2.25 mg zalcitabine total daily dose).

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 granulocytopenia (see Adverse Effects). In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and granulocytopenia usually occurs after 6 to 8 weeks.

Patients treated with zidovudine should be under close clinical observation to manage potential opportunistic infections associated with HIV disease. Prompt recognition of infection or toxicities and appropriate management is required.

Dose Adjustment: Significant anemia (hemoglobin of 25% of baseline) and/or significant granulocytopenia (granulocyte count of 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed (see Adverse Effects). In patients who develop significant anemia, dose modification does not necessarily eliminate the need for transfusion.

For less severe anemia or granulocytopenia, a reduction in daily dose may be adequate. If marrow recovery occurs following dose modification, gradual increases in dose may be appropriate depending on hematologic indices and patient tolerance.

In end-stage disease patients maintained on hemodialysis or peritoneal dialysis, recommended dosing is 100 mg every 6 to 8 hours for oral administration and 1 mg/kg every 6 to 8 hours for i.v. infusion (see Pharmacology, Pharmacokinetics).

There are insufficient data to recommend dose adjustment of zidovudine in patients with impaired hepatic function.

Combination Therapy with Zidovudine and Zalcitabine: For recipients of combination therapy with zidovudine and zalcitabine, dose adjustments for either drug should be based on the known toxicity profile of the individual drugs. For toxicities more likely to be associated with zalcitabine (i.e., peripheral neuropathy, severe oral ulcers), zalcitabine should be interrupted or the dose reduced.

For patients experiencing toxicities more likely to be associated with zidovudine (i.e., anemia, granulocytopenia), zidovudine should be interrupted or the dose reduced first.

For any interruption of zalcitabine and especially if zalcitabine is permanently discontinued, the zidovudine dosage should be adjusted from 200 mg every 8 hours to 100 mg every 4 hours.

For severe toxicities or toxicities in which the causative drug is unclear, or those persisting after dose interruption or reduction of one drug, the other drug should also be interrupted or the dose reduced.

Method of Preparation of Retrovir (AZT) Injection: Retrovir (AZT) injection must be diluted prior to administration. The calculated dose should be removed from the 20 mL vial and added to a recommended diluent to achieve a concentration no greater than 4 mg/mL. Retrovir (AZT) injection does not contain preservatives. Unused portion of the vial should be discarded.

Recommended Diluents: 5% Dextrose Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection and 0.45% Sodium Chloride Injection, Lactated Ringer’s Injection, 5% Dextrose and Lactated Ringer’s Injection.

The diluted solution should be administered within 8 hours if stored at 25°C 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.

Incompatibility: Admixture in biologic or colloidal fluids (e.g., blood products, protein solutions) is not recommended.

Availability And Storage: Capsules: Each gelatin capsule, with a white opaque cap and body with dark blue band, printed with ‘Wellcome’ and Unicorn logo on cap and ‘C’ and ‘100’ on body, contains: zidovudine 100 mg. Nonmedicinal ingredients: cornstarch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Capsule shell: gelatin and imprinted with edible black ink. The blue band around the capsule contains gelatin and indigotine. Bottles of 100. Store at room temperature between 15 and 25°C. Protect from light and moisture.

I.V. Injection: Each mL of solution contains: zidovudine 10 mg in water for injection. Hydrochloric acid or sodium hydroxide may have been added to adjust pH to approximately 5.5. Preservative-free. Single use amber vials of 20 mL, boxes of 10. Store at room temperature between 15 and 25°C. Protect from light. Do not freeze.

Syrup: Each 5 mL of colorless to pale yellow, strawberry-flavored syrup contains: zidovudine 50 mg. Nonmedicinal ingredients: candied sugar flavor, citric acid, glycerin, strawberry flavor and sucrose. Sodium benzoate (0.2%) is added as a preservative and sodium hydroxide may have been added to adjust pH. Bottles of 240 mL. Store at 15 to 25°C. Protect from light. (Shown in Product Recognition Section)

Retrovir (AZT) Glaxo Wellcome Zidovudine Antiretroviral Agent

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