combivir

DESCRIPTION
COMBIVIR: COMBIVIR Tablets are combination tablets containing lamivudine andzidovudine combivir. Lamivudine (EPIVIR®, 3TC®) and zidovudine (RETROVIR®,azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activityagainst human immunodeficiency virus (HIV) combivir.

COMBIVIR Tablets are for oral administration combivir. Each film-coated tablet contains150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidalsilicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose,polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide combivir.

Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one combivir. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine combivir. Lamivudinehas also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine combivir. It has a molecularformula of C 8 H 11 N 3 O 3 S combivir.

Lamivudine is a white to off-white crystalline solid with a solubility of approximately70 mg/mL in water at 20°C combivir.

Zidovudine: The chemical name of zidovudine is 3'-azido-3'-deoxythymidine combivir. It has a molecular formula of C 10 H 13 N 5 O 4 and a molecular weight of 267.24 combivir.

Zidovudine is a white to beige, odorless, crystalline solid with a solubilityof 20.1 mg/mL in water at 25°C combivir.

MICROBIOLOGY
Mechanism of Action: Lamivudine: Lamivudine is a synthetic nucleoside analogue combivir. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphatemetabolite, lamivudine triphosphate (L-TP) combivir. The principal mode of action ofL-TP is inhibition of reverse transcriptase (RT) via DNA chain termination afterincorporation of the nucleoside analogue combivir. L-TP is a weak inhibitor of mammalianDNA polymerases (alpha) and (beta), and mitochondrial DNA polymerase-(gamma) combivir.

Zidovudine: Zidovudine is a synthetic nucleoside analogue combivir. Intracellularly,zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudinetriphosphate (ZDV-TP) combivir. The principal mode of action of ZDV-TP is inhibitionof RT via DNA chain termination after incorporation of the nucleoside analogue combivir. ZDV-TP is a weak inhibitor of the mammalian DNA polymerase-(alpha) and mitochondrialDNA polymerase-(gamma) and has been reported to be incorporated into the DNAof cells in culture combivir.

Antiviral Activity In Vitro: The relationship between in vitro susceptibilityof HIV to lamivudine or zidovudine and the inhibition of HIV replication inhumans has not been established combivir.

Lamivudine Plus Zidovudine: In HIV-1-infected MT-4 cells, lamivudine in combinationwith zidovudine had synergistic antiretroviral activity combivir. Synergistic activityof lamivudine and zidovudine was also shown in a variable-ratio study combivir.

Lamivudine: In vitro activity of lamivudine against HIV-1 was assessed in anumber of cell lines (including monocytes and fresh human peripheral blood lymphocytes) combivir. IC 50 and IC 90 values (50% and 90% inhibitory concentrations) for lamivudinewere 0.0006 mcg/mL to 0.034 mcg/mL and 0.015 to 0.321 mcg/mL, respectively combivir. Lamivudine had anti-HIV-1 activity in all acute virus-cell infections tested combivir.

Zidovudine: In vitro activity of zidovudine against HIV-1 was assessed in anumber of cell lines (including monocytes and fresh human peripheral blood lymphocytes) combivir. The IC 50 and IC 90 values for zidovudine were 0.003 to 0.013 mcg/mL and 0.03to 0.13 mcg/mL, respectively combivir. Zidovudine had anti-HIV-1 activity in all acutevirus-cell infections tested combivir. However, zidovudine activity was substantiallyless in chronically infected cell lines combivir. In cell culture drug combination studieswith zidovudine, interferon-alpha demonstrated additive activity and zalcitabine,didanosine, saquinavir, indinavir, ritonavir, nelfinavir, nevirapine, and delavirdinedemonstrated synergistic activity combivir.

Drug Resistance: Lamivudine Plus Zidovudine Administered As Separate Formulations:In patients receiving lamivudine monotherapy or combination therapy with lamivudineplus zidovudine, HIV-1 isolates from most patients became phenotypically andgenotypically resistant to lamivudine within 12 weeks combivir. In some patients harboringzidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudinewas restored by 12 weeks of treatment with lamivudine and zidovudine combivir. Combinationtherapy with lamivudine plus zidovudine delayed the emergence of mutations conferringresistance to zidovudine combivir.

HIV-1 strains resistant to both lamivudine and zidovudine have been isolatedfrom patients after prolonged lamivudine/zidovudine therapy combivir. Dual resistancerequired the presence of multiple mutations, the most essential of which maybe at codon 333 (Gly->Glu) combivir. The incidence of dual resistance and the durationof combination therapy required before dual resistance occurs are unknown combivir.

Lamivudine: Lamivudine-resistant isolates of HIV-1 have been selected in vitroand have also been recovered from patients treated with lamivudine or lamivudineplus zidovudine combivir. Genotypic analysis of the resistant isolates showed that theresistance was due to mutations in the HIV-1 reverse transcriptase gene at codon184 from methionine to either isoleucine or valine combivir.

Zidovudine: HIV isolates with reduced susceptibility to zidovudine have beenselected in vitro and were also recovered from patients treated with zidovudine combivir. Genotypic analyses of the isolates showed mutations which result in 5 aminoacid substitutions (Met41->Leu, Asp67->Asn, Lys70->Arg, Thr215->Tyror Phe, and Lys219->Gln) in the HIV-1 reverse transcriptase gene combivir. In general,higher levels of resistance were associated with greater number of mutations combivir.

Cross-Resistance: Cross-resistance among certain reverse transcriptase inhibitorshas been recognized combivir.

Lamivudine Plus Zidovudine: Cross-resistance between lamivudine and zidovudinehas not been reported combivir. In some patients treated with lamivudine alone or incombination with zidovudine, isolates have emerged with a mutation at codon184, which confers resistance to lamivudine combivir. In the presence of the 184 mutation,cross-resistance to didanosine and zalcitabine has been seen in some patients;the clinical significance is unknown combivir. In some patients treated with zidovudineplus didanosine or zalcitabine, isolates resistant to multiple drugs, includinglamivudine, have emerged (see under Zidovudine below) combivir.

Lamivudine: See Lamivudine Plus Zidovudine (above) combivir.

Zidovudine: HIV isolates with multidrug resistance to zidovudine, didanosine,zalcitabine, stavudine, and lamivudine were recovered from a small number ofpatients treated for >/=1 year with zidovudine plus didanosine or zidovudineplus zalcitabine combivir. The pattern of genotypic resistant mutations with such combinationtherapies was different (Ala62->Val, Val75->Ile, Phe77->Leu, Phe116->Tyr,and Gln151->Met) from the pattern with zidovudine monotherapy, with the 151mutation being most commonly associated with multidrug resistance combivir. The mutationat codon 151 in combination with the mutations at 62, 75, 77, and 116 resultsin a virus with reduced susceptibility to zidovudine, didanosine, zalcitabine,stavudine, and lamivudine combivir.

Multiple-drug resistance has been observed in 2 of 39 (5%) patients receivingzidovudine and didanosine combination therapy for 2 years combivir.

CLINICAL PHARMACOLOGY
Pharmacokinetics in Adults: COMBIVIR: One COMBIVIR Tablet was bioequivalentto one EPIVIR Tablet (150 mg) plus one RETROVIR Tablet (300 mg) following single-doseadministration to fasting healthy subjects (n = 24) combivir.

Lamivudine: The pharmacokinetic properties of lamivudine in fasting patientsare summarized in Table 1 combivir. Following oral administration, lamivudine is rapidlyabsorbed and extensively distributed combivir. Binding to plasma protein is low combivir. Approximately70% of an intravenous dose of lamivudine is recovered as unchanged drug in theurine combivir. Metabolism of lamivudine is a minor route of elimination combivir. In humans,the only known metabolite is the trans-sulfoxide metabolite (approximately 5%of an oral dose after 12 hours) combivir.

Zidovudine: The pharmacokinetic properties of zidovudine in fasting patientsare summarized in Table 1 combivir. Following oral administration, zidovudine is rapidlyabsorbed and extensively distributed combivir. Binding to plasma protein is low combivir. Zidovudineis eliminated primarily by hepatic metabolism combivir. The major metabolite of zidovudineis 3'-azido-3'-deoxy-5'- O -(beta)- D -glucopyranuronosylthymidine (GZDV) combivir. GZDVarea under the curve (AUC) is about 3-fold greater than the zidovudine AUC combivir. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dosefollowing oral administration, respectively combivir. A second metabolite, 3'-amino-3'-deoxythymidine(AMT), has been identified in plasma combivir. The AMT AUC was one fifth of the zidovudineAUC combivir.

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