EPIVIR-HBV®
(lamivudine)
Tablets
EPIVIR-HBV®
(lamivudine)
Oral Solution
DESCRIPTION
EPIVIR-HBV is a brand name for lamivudine, a synthetic nucleoside analogue with activity against hepatitis B virus (HBV) and HIV. Lamivudine was initially developed for the treatment of HIV infection as EPIVIR. Please see the complete prescribing information for EPIVIR Tablets and Oral Solution for additional information. The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. It has the following structural formula:
Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
EPIVIR-HBV Tablets are for oral administration. Each tablet contains 100 mg of lamivudine and the inactive ingredients hypromellose, macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate 80, red iron oxide, sodium starch glycolate, titanium dioxide, and yellow iron oxide.
EPIVIR-HBV Oral Solution is for oral administration. One milliliter (1 mL) of EPIVIR-HBV Oral Solution contains 5 mg of lamivudine (5 mg/mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).
MICROBIOLOGY
Mechanism of Action
Lamivudine is a synthetic nucleoside analogue. Lamivudine is phosphorylated intracellularly to lamivudine triphosphate, L-TP. Incorporation of the monophosphate form into viral DNA by HBV polymerase results in DNA chain termination. L-TP also inhibits the RNA- and DNA-dependent DNA polymerase activities of HIV-1 reverse transcriptase (RT). L-TP is a weak inhibitor of mammalian alpha-, beta-, and gamma-DNA polymerases.
Antiviral Activity In Vitro
In vitro activity of lamivudine against HBV was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. IC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 μM (2.3 ng/mL) to 5.6 μM (1.3 mcg/mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used . See the EPIVIR package insert for information regarding activity of lamivudine against HIV.
Drug Resistance
HBV
Genotypic analysis of viral isolates obtained from patients who show renewed evidence of replication of HBV while receiving lamivudine suggests that a reduction in sensitivity of HBV to lamivudine is associated with mutations resulting in a methionine to valine or isoleucine substitution in the YMDD motif of the catalytic domain of HBV polymerase (position 552) and a leucine to methionine substitution at position 528. It is not known whether other HBV mutations may be associated with reduced lamivudine susceptibility in vitro.
In 4 controlled clinical trials in adults, YMDD-mutant HBV were detected in 81 of 335 patients receiving lamivudine 100 mg once daily for 52 weeks. The prevalence of YMDD mutations was less than 10% in each of these trials for patients studied at 24 weeks and increased to an average of 24% (range in 4 studies: 16% to 32%) at 52 weeks. In limited data from a long-term follow-up trial in patients who continued 100 mg/day lamivudine after one of these studies, YMDD mutations further increased from 16% at 1 year to 42% at 2 years. In small numbers of patients receiving lamivudine for longer periods, further increases in the appearance of YMDD mutations were observed.
In a controlled trial in pediatric patients, YMDD-mutant HBV were detected in 31 of 166 (19%) patients receiving lamivudine for 52 weeks. For a subgroup who remained on lamivudine therapy in a follow-up study, YMDD mutations increased from 24% at 12 months to 45% (53 of 118) at 18 months of lamivudine treatment.
Mutant viruses were associated with evidence of diminished treatment response at 52 weeks relative to lamivudine-treated patients without evidence of YMDD mutations in both adult and pediatric studies (see PRECAUTIONS). The long-term clinical significance of YMDD-mutant HBV is not known.
HIV
In studies of HIV-1-infected patients who received lamivudine monotherapy or combination therapy with lamivudine plus zidovudine for at least 12 weeks, HIV-1 isolates with reduced in vitro susceptibility to lamivudine were detected in most patients (see WARNINGS).
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