(i) ROUTE OF ADMINISTRATION
Oral
DOSAGE AND ADMINISTRATION

A randomized, double-blind, dose-frequency study of zidovudine in 320 patients with AIDS or advanced ARC was conducted to assess the safety and tolerability of 600 mg zidovudine per day given as either 100 mg every 4 hours or as 300 mg every 12 hours for 48 weeks. No significant difference was detected between the two dose frequencies with regard to adverse experiences or hematologic abnormalities.
The recommended total oral daily dose of Health 2000 Zidovudine 100 mg capsule is 600 mg per day in divided doses in combination wth other antiretroviral agents and 500 mg (100 mg every 4 hours while awake) or 600 mg per day in divided doses for monotherapy. The effectiveness of this dose compared to higher dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown.

Paediatrics: The recommended dose in children 3 months to 12 years of age is 180 mg/m2 every 6 hours (720 mg/m2 per day), not to exceed 200 mg every 6 hours

MaternalFetal 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 per day until the start of labour. During labour and delivery, intravenous zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg/kg/h (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 intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.

Patient Monitoring
Haematologic 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 anaemia or granulocytopenia (See Warnings and Precautions). In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks.

Dose adjustment: Significant anaemia (hemoglobin 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 Warnings and Precautions). For less severe anaemia or neutropenia, a reduction in daily dose may be adequate. In patients who develop significant anaemia, dose modification does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may be appropriate depending on hematologic indices and patient tolerance.

In end-stage renal disease patients maintained on hemodialysis or peritoneal dialysis, recommended dosing is 100 mg every 6 to 8 hours.

There are insufficient data to recommend dosage adjustment of Zidovudine in patients with impaired hepatic function.

(ii) THERAPEUTIC / DIAGNOSTIC CLAIMS

Health 2000 Zidovudine 100 mg capsule is indicated for the treatment of HIV infection when antiretroviral therapy is warranted. Therapy with zidovudine has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease at initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients. Other randomized studies suggest that the duration of the clinical benefit of monotherapy with zidovudine is time-limited.
Zidovudine in combination with certain antiretroviral agents has been shown to be superior to monotherapy in one or more of the following: delaying death, delaying development of AIDS, increasing CD4 cell counts, and decreasing plasma HIV RNA. The complete prescribing information for each drug should be consulted before combination therapy which includes Health 2000 Zidovudine 100 mg capsule is initiated.

Maternal Fetal HIV Transmission: Health 2000 Zidovudine 100 mg capsule is also indicated for the prevention of maternalfetal HIV transmission as part of a regimen that includes oral Zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labour and administration of zidovudine to the newborn after birth. Using this regimen, the relative reduction in transmission risk was found to be 67.5%. The safety of zidovudine for the mother or foetus during the first trimester of pregnancy has not been assessed.

(iii) DESCRIPTION OF DOSAGE FORM

Zidovudine, a thymidine analogue, is an anti-retroviral drug active against human immunodeficiency virus (HIV). Cellular thymidine kinase converts zidovudine into zidovudine monophosphate and further to the diphosphate. Zidovudine diphosphate is converted 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 DNA polymerase at concentrations 100fold higher than those required to inhibit reverse transcriptase. In vitro, reverse transcriptase incorporates zidovudine triphos-phate into the growing chain of DNA, and the DNA chain is terminated.

(iv) CONTRAINDICATIONS

Patients who exhibit potentially life-threatening allergic reactions to any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Before combination therapy with Health 2000 Zidovudine 100 mg capsule is initiated, consult the complete prescribing information for each drug. The safety profile of Health 2000 Zidovudine 100 mg capsule 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.

BONE MARROW SUPPRESSION
Health 2000 Zidovudine 100 mg capsule should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuance of the drug.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with zidovudine. For patients with asymptomatic or early HIV disease, periodic blood counts are recommended.If anaemia or neutropenia develops, dosage adjustments may be necessary (See Dosage and Administration).

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

LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS
Rare occurrences of potentially fatal lactic acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported with the use of certain antiretroviral nucleoside analogues. Therapy with Health 2000 Zidovudine 100 mg capsule should be suspended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised when administering Health 2000 Zidovudine 100 mg capsule to any patient, particularly obese women, with hepatomegaly, hepatitis, or other known risk factor for liver disease. Treatment with zidovudine should be suspended in the setting of rapidly elevating aminotransferase levels, progressive hepato-megaly, or metabolic/lactic acidosis of unknown etiology.

OTHER SERIOUS ADVERSE REACTIONS
Reports of pancreatitis, sensitization reactions, 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.
Patients who exhibit potentially life-threatening allergic reactions to any of the components of the formulation.

Zidovudine may be associated with hematologic toxicity including granulocytopenia and severe anaemia particularly in patients with advanced HIV disease. Prolonged use of zidovudine has been associated with symptomatic myopathy similar to that produced by Human Immunodeficiency Virus. Rare occurrences of potentially fatal lactic acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported with the use of certain antiretroviral nucleoside analogues (See Warnings).

INTERACTION
Ganciclovir, interferon alpha: Use of zidovudine in combination with either ganciclovir or interferon alpha increases the risk of hematologic toxicities in some patients with advanced HIV disease. Hematologic parameters should be monitored frequently in all patients receiving either of these combinations.
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 by reducing renal excretion of zidovudine.
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine. In one study, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Methadone: No adjustments in methadonemaintenance requirements were reported in a study of nine HIVpositive patients receiving methadone maintenance.
Fluconazole: The co-administration of fluconazole with zidovudine has been reported to interfere with the oral clearance and metabolism of zidovudine.
Atovaquone: A decrease in zidovudine oral clearance was observed.
Valproic Acid: Data suggest that valproic acid increases the oral bioavailability of zidovudine through inhibition of firstpass hepatic metabolism. Patients should be monitored for a possible increase in zidovudinerelated adverse events.
Lamivudine: Co-administration of zidovudine with lamivudine resulted in an increase in the maximum concentration (Cmax) of zidovudine.
Other nucleoside analogues: Experimental nucleoside analogues affecting DNA replication such as ribavirin antagonize the in vitro antiviral activity of zidovudine against HIV.

PREGNANCY
Congenital abnormalities were found to occur 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 recognised on ultrasound before or immediately after initiation of study drugs.

NURSING MOTHERS
HIVinfected women are advised not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected. Zidovudine is excreted in human milk.

IMPAIRED RENAL AND HEPATIC FUNCTION
See Dosage and Administration.

(v) SIDE EFFECTS

MONOTHERAPY
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.
The anaemia reported in patients with advanced HIV disease receiving zidovudine appeared to be the result of impaired erythrocyte maturation. Thrombocytopenia has also been reported in patients with advanced disease. Mild drug-associated elevations in total bilirubin levels have been reported as an uncommon occurrence in patients treated for asymptomatic HIV infection.
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 were: fever, headache, nausea, vomiting, anorexia, myalgia, insomnia, dizziness, paraesthesia, dyspnoea and rash. Malaise, gastrointestinal pain, dyspepsia, and taste perversion were also reported.
Paediatrics
Anaemia and granulocytopenia among paediatric patients with advanced HIV disease receiving zidovudine occurred with similar incidence to that reported for adults with AIDS or advanced Aids-Related Complex. Macrocytosis was frequently observed.
Other adverse events were similar to that observed in adults.
Maternal-Foetal Transmission
The most commonly reported adverse experiences were anaemia and neutropenia. The long-term consequences of in vitro and infant exposure to zidovudine are unknown.

(vi) TOXIC EFFECTS

Mutagenicity, Carcinogenicity and Teratogenicity
Zidovudine induces significant toxic effects in humans exposed to therapeutic doses... Cytogenetic observations on H9-AZT cells showed an increase in chromosomal aberrations and nuclear fragmentation when compared with unexposed H9 cells... The toxicities explored here suggest that the mechanisms of AZT induced cytotoxicity in bone marrow of the patients chronically exposed to the drug in vivo may involve both chromosomal and mitochondrial DNA damage."
The AZT animals [Macaques given AZT during pregnancy] developed an asymptomatic macrocytic anemia, but hematologic parameters returned to normal when AZT was discontinued. Total leukocyte count decreased during pregnancy and was further affected by AZT administration. AZT-exposed infants were mildly anemic at birth. AZT caused deficits in growth, rooting and snouting reflexes, and the ability to fixate and follow near stimuli visually"
Although fetal exposures during pregnancy have long been a concern of teratology research and reproductive epidemiology, less is known about toxic exposures before pregnancy that might impair fertility or about the effects of exposures during pregnancy on subsequent infant and child health.