Zetavudin

Uses

Lamivudine and zidovudine tablets, a combination of 2 nucleoside analogue reverse transcriptase inhibitors, are used for combination with other antiretroviral agents for the treatment of HIV-1 infection

Zetavudin is also used to associated treatment for these conditions: Hepatitis B Chronic Infection, Human Immunodeficiency Virus (HIV) InfectionsHIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Perinatal HIV transmission

How Zetavudin works

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.

Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ.

Dosage

Zetavudin dosage

Recommended Dosage for Adults and Adolescents: The recommended dosage of lamivudine and zidovudine tablets in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily.

Recommended Dosage for Pediatric Patients: The recommended dosage of lamivudine and zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily on an empty stomach. Before prescribing lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed

Not Recommended Due to Lack of Dosage Adjustment Because lamivudine and zidovudine tablets are a fixed-dose formulation and cannot be dose adjusted, lamivudine and zidovudine tablets are not recommended for:

• Pediatric patients weighing less than 30 kg
• Patients with creatinine clearance less than 50 mL per minute
• Patients with hepatic impairment
• Patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of lamivudine and zidovudine tablets are available for these populations.

May be taken with or without food.

Side Effects

Side effects of this medicine-

• More common: Chills, fever, pale skin; sore throat; unusual tiredness or weakness, headache
• Less common: Abdominal pain, burning, tingling, numbness, or pain in the hands, arms, feet, or legs, muscle tenderness and weakness, nausea, skin rash, vomiting, yellow eyes or skin. Coughing, decreased appetite, diarrhea, dizziness and trouble in sleeping may occurs

Toxicity

The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD₅₀ is 3084 mg/kg (orally in mice).

Precaution

Patients with HIV and Hepatitis B virus Coinfection: Safety and efficacy of Lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. Emergence of hepatitis B virus variants associated with resistance to Lamivudine has also been reported in HIV-infected patients who have received Lamivuuine-containing antiretroviral regimens in the presence of concurrent infection with Hepatitis B virus. Post-treatment exacerbations of hepatitis have also been reported.

Patients with Impaired Renal Function: Reduction of the dosages of Lamivudine and Zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance <50 ml/min should not receive this combination tablet.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breastenlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy.

Interaction

Cross-resistance may develop when given with emtricitabine. Exacerbation of anaemia with concomitant use of zidovudine with ribavirin. Increased adverse effects to zidovudine with nephrotoxic or myelosuppressive drugs (e.g. systemic pentamide, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin). Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Antagonistic effect when zidovudine is used concomitantly with stavudine or doxorubicin.

Volume of Distribution

Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg

Elimination Route

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.

Half Life

5 to 7 hours (healthy or HBV-infected patients)

Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)

Clearance

• Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
• Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
• Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]

• 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age]
• 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age]
• 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine.

Elimination Route

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.

As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.

Pregnancy & Breastfeeding use

Pregnancy Category C. There arc no adequate and well controlled studies of this drug in pregnant women. This drug should be used during pregnancy only if the potential benefits outweigh the risks. The Centers for Disease Control and Prevention recommend that HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breast feed if they are receiving efavirenz.

Contraindication

This is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the product. Reduction of doses of Lamivudine is recommended for patients with low body weight (less than 50 kg or 110 lb); therefore, patients with low body weight should not receive Lamivudine & Zidovudine.

Special Warning

It is recommended that doses of Lamivudine should be adjusted in accordance with renal function. Dosage adjustment of Lamivudine in accordance with creatinine clearance is as follows:

• CrCl 50 ml/min: 100 mg once daily
• CrCl 30-49 ml/min: 100 mg first dose, then 50 mg once daily
• CrCl 15-29 ml/min: 100 mg first dose, then 25 mg once daily
• CrCl 5-14 ml/min: 35 mg first dose, then 15 mg once daily
• CrCl <5 ml/min: 35 mg first dose, then 10 mg once daily

Use in children: Safety and efficacy of lamivudine for the treatment of chronic hepatitis B in children have not been established.

Renal Impairment:

• ESRD maintained on haemodialysis or peritoneal dialysis: 100 mg 6-8 hrly.
• CrCl <10-15 mL/min: 100 mg 6-8 hrly.

Hepatic Impairment: Dose reduction may be needed.

Acute Overdose

Symptoms: Vomiting, CNS effects (e.g. fatigue, dizziness, drowsiness, lethargy, confusion), haematologic effects (e.g. anaemia, decreased Hb). Bone marrow hypoplasia, mild ataxia, tonic-clonic seizure and increased serum concentration of AST and ALT may also occur. Management: Supportive and symptomatic treatment. Induce emesis and admin activated charcoal to prevent further absorption of unrecovered drug.

Storage Condition

Stored at a cool and dry place, protected from light and moisture. Keep the medicine out of the reach of children.

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