ZVD 100 TABLETS /ZVD 300 TABLETS

(Zidovudine Tablets 100mg/300mg)

Composition:
I) Each Tablet contains:
Zidovudine IP 100mg

II) Each Tablet contains:
Zidovudine IP 300mg

Presentation:
10x10's

Pharmacology:
Zidovudine is a synthetic nucleoside analogue of the naturally occurring nucleoside, thymidine, in which the 3'-hydroxy (- OH) group is replaced by an azido (- N3) group. Within cells, zidovudine is converted to the active metabolite, zidovudine 5'-triphosphate (AztTP), by the sequential action of the cellular enzymes. Zidovudine 5'-triphosphate inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 5'- triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3'- OH group in the incorporated nucleoside analogue prevents the formation of the 5'to 3' phosphodiester linkage essential for DNA chain elongation and therefore, the viral DNA growth is terminated. The active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture
Pharmacokinetics:
The pharmacokinetics of zidovudine has been evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation study. After oral dosing (capsules), zidovudine was rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within 0.5 to 1.5 hours. Dose-independent kinetics was observed over the range of 2 mg/kg every 8 hours to 10 mg/kg every 4 hours. The mean zidovudine half-life was approximately 1 hour and ranged from 0.78 to 1.93 hours following oral dosing.
Zidovudine is rapidly metabolized to 3'-azido-3'-deoxy-5'-O-?-D-glucopyra-nuronosylthymidine (GZDV) which has an apparent elimination half-life of 1 hour (range 0.61 to 1.73 hours). Following oral administration, urinary recovery of zidovudine and GZDV accounted for 14% and 74% of the dose, respectively, and the total urinary recovery averaged 90% (range 63% to 95%), indicating a high degree of absorption. However, as a result of first-pass metabolism, the average oral capsule bioavailability of zidovudine is 65% (range 52% to 75%). A second metabolite, 3-amino- 3-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. AMT area-under-the-curve (AUC) was one fifth of the AUC of zidovudine and had a half-life of 2.7 ± 0.7 hours. In comparison, GZDV AUC was about three-fold greater than the AUC of zidovudine.
Additional pharmacokinetic data following intravenous dosing indicated dose-independent kinetics over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours (range 0.48 to 2.86 hours). Total body clearance averaged 1900 mL/min per 70 kg and the apparent volume of distribution was 1.6 L/kg. Renal clearance is estimated to be 400 mL/min per 70 kg, indicating glomerular filtration and active tubular secretion by the kidneys.
Zidovudine plasma protein binding is 34% to 38%, indicating that drug interactions involving binding site displacement are not anticipated.
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in 39 patients receiving chronic therapy with zidovudine. The median ratio measured in 50 paired samples drawn 1 to 8 hours after the last dose of zidovudine was 0.6.

Indications:
Zidovudine is an antiviral agent, which is highly active in vitro against retroviruses including the Human Immunodeficiency Virus (HIV).
Management of patients with advanced HIV disease, e.g. those with the Acquired Immune Deficiency Syndrome (AIDS) or AIDS-related complex (ARC).

Treatment of HIV infection when CDC count is < 500/mm3 or symptomatic. Also approved for use in HIV-infected pregnant women in 2nd and 3rd trimesters, along with IV ZDV during labor and delivery, and ZDV syrup to newborn for 6 weeks.

Contra-indications:
Zidovudine is contraindicated in patients with clinically significant hypersensitivity to any of the components.
Zidovudine should not be given to patients with abnormally low neutrophil counts (<0.75x109/L) or abnormally low heamoglobin levels (<7.5g/dL or 4.65 mmol/L).

Dosage and directions for use:
Adults:
Although broad ranges of dosage regiments have been employed, 500 or 600 mg/day in 2-5 divided doses has been commonly used worldwide. Alternatively, a daily dosage of 2000 mg in 2 dividend doses has been shown to be effective. The effectiveness of lower dosages in the treatment or prevention of HIV-associated neurological dysfunciton and malignancies is unknown.

Children:
In children >3months, the recommended starting dosage is 180 mg/m2 body surface area every 6 hrs (720mg/m2/day.) The maximum dosage should not exceed 200 mg every 6 hrs.

Warnings:
Before combination therapy with Zidovudine is initiated, consult the complete prescribing information for each drug. The safety profile of Zidovudine 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
Zidovudine 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.

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 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. Treatment with zidovudine should be suspended in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown aetiology.

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.

Side-effects and special precautions:
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.

Special Precautions:
PREGNANCY
Category C. 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
HIV infected women are advised not to breast feed 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
Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver. In patients with severely impaired renal function, dosage reduction is recommended. Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity.
Drug Interactions:
Acyclovir, alpha interferon, dipyridamole (increased in vitro antiretroviral activity); amphotericin B, dapsone, pentamidine, TMP/SMX, acyclovir, ganciclovir, pentamidine, sulfadiazine/pyrimethamine (increased bone marrow toxicity); methadone (decreased ZDV metabolism); phenytoin (increased or decreased phenytoin levels); Nephrotoxic drugs or cytotoxic drugs, such as flucytosine, vincristine, or interferon, may increase ZDV toxicity. Acetominophen, probenecid, cimetidine, indomethacin, lorazepam, or aspirin may inhibit excretion and contribute to toxicity.

Known symptoms of overdosage and particulars of its treatment:
Limited data are available on the consequences of ingestion of acute overdoses in both adults and children. No fatalities occurred and all patients recovered. The highest recorded blood level of zidovudine was 185µM (49.4µg/Ml). No specific symptoms have been identified following such overdosage.
Dosages as high as 1250mg Zidovudine orally every 4 hrs for 4 weeks have been administered to 2 patients with advanced HIV Disease. One experienced anaemia and neutropenia while the other had no untoward effects.

Treatment:
Patients should be observed closely for evidence of toxicity and given the necessary supportive therapy.
Haemoodialysis and peritoneal dialysis appear to have a limited effect on the elimination zidovudine but enhance the elimination after glucuronide metabolite.

Storage conditions and period.
Store in cool, dry & dark place, preferably below 25°C. Shelf life is 2 years.

Package: 10 tablets packed in blister strip, 10 such blisters packed in a carton.