Retrovir 100 mg

Coadministration of RETROVIR (AZT) (zidovudine) with other drugs metabolized by glucuronidation should be avoided because the toxicity of either drug may be potentiated.

Hematologic toxicities appear to be related to pre-treatment 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 Reactions). In patients who experience hematologic toxicity, reduction in haemoglobin 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.

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. RETROVIR (AZT) must not be given intra-muscularly.

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

• Maternal Dosing. 100 mg orally 5 times per day until the start of labour. During labour and delivery, intravenous RETROVIR (AZT) should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion at 1 mg/kg/h (total body weight) until clamping of the umbilical cord.

  
  

• Infant Dosing. 2 mg/kg of oral solution 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 RETROVIR (AZT) intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. See Warnings and Precautions if hepatic disease or renal insufficiency is present.

The recommended dose of RETROVIR (AZT) I.V. injection in children 3 months to 12 years of age is 120 mg/m² every 6 hours, infused over 1 hour (480 mg/m² per day). Do not exceed 160 mg for any individual dose.

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.

Significant anemia (haemoglobin of <7.5 g/dL or reduction of >25% of baseline) and/or significant granulocytopenia (granulocyte count of <750 cells/mm³ or reduction of >50% from baseline) may require a dose interruption until evidence of marrow recovery is observed (see Adverse Reactions). In patients who develop significant anemia, dose modification dose 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 intravenous infusion.

There are insufficient data to recommend dose adjustment of RETROVIR (AZT) in patients with impaired hepatic function.

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

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 intravenous RETROVIR (AZT) 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.

RETROVIR (AZT) injection is administered intravenously at a constant rate over 1 hour. Rapid infusion or bolus injection should be avoided. RETROVIR (AZT) injection should not be given intramuscularly.

The effectiveness of the intravenous 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 RETROVIR (AZT) on improvement of neurological symptoms in patients with pre-existing neurological disease.

oral mucosa pigmentation.

The following events have been reported in patients treated with RETROVIR (AZT) without regard to causality. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. A reduction in dose or suspension of RETROVIR (AZT) therapy may be warranted in the management of these conditions.

In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their infants conducted to determine the utility of RETROVIR (AZT) for the prevention of maternal-fetal HIV transmission, RETROVIR (AZT) 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 (hemoglobin <9.0 g/dL) and neutropenia (<1000 cells/mm³). Anemia occurred in 22% of the infants who received RETROVIR (AZT) and in 12% of the infants who received placebo. The mean difference in hemoglobin values was less than 1.0 g/dL for infants receiving RETROVIR (AZT) compared to infants receiving placebo. No infants with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with RETROVIR (AZT). Neutropenia was reported with similar frequency in the group that received RETROVIR (AZT) (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to RETROVIR (AZT) are unknown.

anorexia, hyperlactatemia, lactic acidosis (see Warnings and Precautions: Hepatic/Biliary/Pancreatic, Lactic Acidosis/Severe Hepatomegaly with Steatosis).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

gynecomastia, myopathy, hyperlactatemia.

redistribution/accumulation of body fat (see Warnings and Precautions: Endocrine and Metabolism, Fat Redistribution). Convulsions, cardiomyopathy (thrombocytopenia, pancytopenia).

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

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 RETROVIR (AZT) permanently discontinued because of neutropenia.

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

Number and Percentage of Patients with Clinical Adverse Experiences Occurring in >3% of Patients Considered Possibly or Probably Related to Study Drug

arthralgia, muscle spasm, tremor, twitch.

raised blood levels of liver enzymes and bilirubin.

Several serious adverse events have been reported with the use of RETROVIR (AZT) in clinical practice. Myopathy and myositis with pathological changes similar to that produced by HIV disease have been associated with prolonged use of RETROVIR (AZT). 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 RETROVIR (AZT). Changes in skin and nail pigmentation have been associated with the use of RETROVIR (AZT) (see Warnings and Precautions).

dysuria, polyuria, urinary frequency, urinary hesitancy.

Clinical adverse events which occurred in less than 5% of all adult patients treated with 1500 mg/day of RETROVIR (AZT) 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 RETROVIR (AZT), their possible relationship to the drug is unknown.

sweating, nail and skin discoloration.

Anemia (which may require transfusions), neutropenia, leucopenia, aplastic anemia, thrombocytopenia, pancytopenia (with marrow hypoplasia) and pure red cell aplasia.

Anemia, neutropenia, leucopenia and aplastic anemia occur more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm³. Dosage reduction or cessation of therapy may become necessary (see Dosage and Administration). The incidence of neutropenia was also increased in those patients whose neutrophil counts, hemoglobin levels and serum vitamin B₁₂ levels were low at the start of RETROVIR (AZT) therapy.

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

amblyopia, hearing loss, photophobia.

vasodilation.

RETROVIR (AZT) is also indicated for:

• the prevention of maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR (AZT) beginning between 14 and 34 weeks of gestation, intravenous RETROVIR (AZT) during labour, and administration of RETROVIR (AZT) 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 RETROVIR (AZT) for a prolonged period before pregnancy has not been evaluated. The safety of RETROVIR (AZT) for the mother or fetus during the first trimester of pregnancy has not been assessed.

The utility of RETROVIR (AZT) 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 RETROVIR (AZT) and CD4 cell counts of 200 to 1818 cells/mm³ (median in the treated group: 560 cells/mm³). Oral RETROVIR (AZT) was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by intravenous administration of RETROVIR (AZT) during labour and delivery. After birth, infants received oral RETROVIR (AZT) 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 RETROVIR (AZT) 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 RETROVIR (AZT) and 25.5% in the placebo group, a relative reduction in transmission risk of 67.5%.

RETROVIR (AZT) 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 RETROVIR (AZT) 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 RETROVIR (AZT). The long-term consequences of in utero and infant exposure to RETROVIR (AZT) are unknown.

Each gelatin capsule, with a white opaque cap and body, printed with “Wellcome” and a Unicorn logo on cap and “Y9C” 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. Bottles of 100.

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.

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.

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 Dosage and Administration). Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity.

Very rare occurrences of pure red cell aplasia have been reported with zidovudine use. Discontinuation of zidovudine has resulted in normalization of hematological parameters in patients with suspected zidovudine-induced pure red cell aplasia.

Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination whereas elimination of the glucuronide metabolite is increased. For patients with end-stage renal disease maintained on haemodialysis or peritoneal dialysis, the recommended dose is 100 mg every 6 to 8 h (see Action and Clinical Pharmacology, Pharmacokinetics).

RETROVIR (AZT) should be used with extreme caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm³ or hemoglobin <9.5 g/dL. In all of the placebo-controlled studies, but most frequently in patients with advanced symptomatic disease, anemia and granulocytopenia were the most significant adverse events observed (see Adverse Reactions). There have been reports of pancytopenia associated with the use of RETROVIR (AZT), which was reversible in most instances after discontinuation of the drug.

Rare occurrences of lactic acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis, (even in the absence of marked transaminase elevations) have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including RETROVIR (AZT) 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 RETROVIR (AZT) develops unexplained tachypnea, dyspnea, or fall in serum bicarbonate level. Under these circumstances, therapy with RETROVIR (AZT) should be suspended until the diagnosis of lactic acidosis has been excluded.

Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnea and tachypnea).

Caution should be exercised when administering RETROVIR (AZT) 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 RETROVIR (AZT). The significance of elevated aminotransferase levels (suggesting hepatic injury) in HIV-infected patients prior to starting RETROVIR (AZT) or while on RETROVIR (AZT) is unclear. Treatment with RETROVIR (AZT) should be suspended in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology.

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

Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage adjustments may be necessary, but as there is only limited data available precise recommendations cannot be made. If monitoring of plasma zidovudine levels is not feasible, physicians will need to monitor for signs of intolerance and adjust the dose and/or increase the interval between doses as appropriate.

To monitor maternal-fetal outcomes of pregnant women exposed to RETROVIR (AZT), an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department 1-800-387-7374.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant women to determine the utility of RETROVIR (AZT) (zidovudine) for the prevention of maternal-fetal HIV-transmission. Congenital abnormalities occurred with similar frequency between infants born to mothers who received RETROVIR (AZT) 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 RETROVIR (AZT) 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 (AZT) are unknown. The long-term effects of early or short-term use of RETROVIR (AZT) in pregnant women are also unknown.

There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Zidovudine pharmacokinetics have not been studied in patients over 65 years of age and no specific data are available. However, since special care is advised in this age group due to age-associated changes such as the decrease in renal function and alterations in haematological parameters, appropriate monitoring of patients before and during use of zidovudine is advised.

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

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB) which may necessitate further evaluation and treatment.

Several serious adverse events have been reported with use of RETROVIR (AZT) (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 RETROVIR (AZT).

Before combination therapy with RETROVIR (AZT) is initiated, consult the complete prescribing information for each drug. The safety profile of RETROVIR (AZT) plus other antiretroviral agents reflects the individual safety profiles of each component.

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

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.

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child Pugh >6) (see the complete prescribing information for interferon and ribavirin).

See Indications and Clinical Use; Adverse Reactions and Dosage and Administration. The pharmacokinetics of zidovudine in pediatric patients greater than 3 months of age is similar to that of zidovudine in adult patients.

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.

It is advisable to caution mothers against breastfeeding to avoid postnatal transmission of HIV to a child who may not yet be infected. Zidovudine is excreted in human milk at similar concentration to that found in serum.

Lactating mice administered zidovudine (200 mg/kg intraperitoneally) were found to have milk concentrations of zidovudine five times the corresponding serum zidovudine concentration. Milk concentrations of zidovudine declined at a slower rate than serum zidovudine concentrations.

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co-administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This is particularly important in patients with a known history of zidovudine induced anaemia.

Pharmacokinetic studies of RETROVIR (AZT) following intravenous 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-β-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 intravenous 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 (AZT) Capsules and Syrup are bioequivalent. In pediatric patients older than 3 months, the pharmacokinetics of zidovudine are similar to those in adult patients.

RETROVIR (AZT) (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 α-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 α-DNA polymerase may occur, but only to a very small extent and not in all test systems. Cellular γ-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.