拉米夫定在美国的说明书

　　PRODUCT INFORMATION

　　EPIVIR ® Tablets

　　(lamivudine tablets)

EPIVIR ® Oral Solution

　　(lamivudine oral solution)

　 WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH?STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE?OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING?LAMIVUDINE AND OTHER ANTIRETROVIRALS (SEE WARNINGS).EPIVIR TABLETS AND ORAL SOLUTION (USED TO TREAT HIV INFECTION)CONTAIN A HIGHER DOSE OF THE ACTIVE INGREDIENT (LAMIVUDINE) THAN?EPIVIR-HBV ® TABLETS AND ORAL SOLUTION (USED TO TREAT CHRONIC

　　HEPATITIS B). PATIENTS WITH HIV INFECTION SHOULD RECEIVE ONLY?DOSING FORMS APPROPRIATE FOR TREATMENT OF HIV (SEE WARNINGS AND?PRECAUTIONS).

　　DEs criptION: EPIVIR (also known as 3TC) is a brand name for lamivudine, a synthetic

　　nucleoside analogue with activity against human immunodeficiency virus-1 (HIV-1) and hepatitis B virus (HBV). 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 hasthe 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 Tablets are for oral administration. Each tablet contains 150 mg of lamivudine and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Opadry YS-1-7706-G White is the coloring agent in the tablet coating.

　　EPIVIR Oral Solution is for oral administration. One milliliter (1 mL) of EPIVIR Oral Solution contains 10 mg of lamivudine (10 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

　　EPIVIR ® Tablets (lamivudine tablets)

　　EPIVIR ®Oral Solution (lamivudine oral solution)

　　2

　　MICROBIOLOGY:

　　Mechanism of Action: Lamivudine is a synthetic nucleoside analogue.Intracellularly,

　　lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate(L-TP). The principal mode of action of L-TP is inhibition of reverse trans criptase (RT) via DNA chain termination after incorporation of the nucleoside analogue. L-TP is a weak inhibitor of mammalian DNA polymerases á and â , and mitochondrial DNA polymerase.

　　Antiviral Activity In Vitro: The relationship between in vitro susceptibility of HIV to lamivudine and the inhibition of HIV replication in humans has not been established. In vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. IC50 values (50% inhibitory concentrations) were in the range of 2 nM to 15 µM. Lamivudine had antiŒHIV-1 activity in all acute virus-cell infections tested. In HIV-1Œinfected MT-4 cells, lamivudine in combination with zidovudine had synergistic antiretroviral activity. Synergistic activity of?lamivudine/zidovudine was also shown in a variable-ratio study. Please see the EPIVIR-HBV package insert for information regarding activity of lamivudine in studies using in vitro model systems such as transfected cells for study of HBV replication.

　　Drug Resistance: Lamivudine-resistant isolates of HIV-1 have been selected in vitro. The resistant isolates showed reduced susceptibility to lamivudine and genotypic analysis showed that the resistance was due to specific substitution mutations in the HIV-1 reverse trans criptase at codon 184 from methionine to either isoleucine or valine. HIV-1 strains resistant to both lamivudine and zidovudine have been isolated.

　　Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine. Mutations in the HBV polymerase YMDD motif have been associated with reduced susceptibility of HBV to lamivudine in vitro. In studies of non-HIV-infected patients with chronic hepatitis B, HBV isolates with YMDD mutations were detected in some patients who received lamivudine daily for 6 months or more, and were associated with evidence of diminished treatment response; similar HBV mutants have been reported in HIV-infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus (see PRECAUTIONS).