Combivir Online, Description, Chemistry, Ingredients - Lamivudine and zidovudine

Combivir Online, Description, Chemistry, Ingredients - Lamivudine and zidovudine

WARNING ZIDOVUDINE, ONE OF THE TWO ACTIVE INGREDIENTS IN COMBIVIR, HAS BEEN ASSOCIATED WITH HEMATOLOGIC TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA, PARTICULARLY IN PATIENTS WITH ADVANCED HIV DISEASE (SEE WARNINGS). PROLONGED USE OF ZIDOVUDINE HAS BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY. 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, ZIDOVUDINE, AND OTHER ANTIRETROVIRALS (SEE WARNINGS). SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE DISCONTINUED LAMIVUDINE, WHICH IS ONE COMPONENT OF COMBIVIR. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE COMBIVIR AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

DESCRIPTION

COMBIVIR Tablets are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR^®, 3TC^®) and zidovudine (RETROVIR^®, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against human immunodeficiency virus (HIV). COMBIVIR Tablets are for oral administration. Each film-coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Lamivudine

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.

The chemical name of zidovudine is 3¢-azido-3¢-deoxythymidine. It has a molecular formula of C₁₀H₁₃N₅O₄ and a molecular weight of 267.24.  It has the following structural formula:

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

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 transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue. L-TP is a weak inhibitor of mammalian DNA polymerases a and b, and mitochondrial DNA polymerase-g.

Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5¢-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleoside analogue. ZDV-TP is a weak inhibitor of the mammalian DNA polymerase-a and mitochondrial DNA polymerase-g and has been reported to be incorporated into the DNA of cells in culture.

The relationship between in vitro susceptibility of HIV to lamivudine or zidovudine and the inhibition of HIV replication in humans has not been established.

In HIV-1–infected MT-4 cells, lamivudine in combination with zidovudine had synergistic antiretroviral activity. Synergistic activity of lamivudine and zidovudine was also shown in a variable-ratio study.

In vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). IC₅₀ and IC₉₀ values (50% and 90% inhibitory concentrations) for lamivudine were 0.0006 mcg/mL to 0.034 mcg/mL and 0.015 to 0.321 mcg/mL, respectively. Lamivudine had anti–HIV-1 activity in all acute virus-cell infections tested.

In vitro activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The IC₅₀ and IC₉₀ values for zidovudine were 0.003 to 0.013 mcg/mL and 0.03 to 0.13 mcg/mL, respectively. Zidovudine had anti–HIV-1 activity in all acute virus-cell infections tested. However, zidovudine activity was substantially less in chronically infected cell lines. In cell culture drug combination studies with zidovudine, interferon-alpha demonstrated additive activity and zalcitabine, didanosine, saquinavir, indinavir, ritonavir, nelfinavir, nevirapine, and delavirdine demonstrated synergistic activity.

Lamivudine Plus Zidovudine Administered As Separate Formulations: 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. HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple mutations, the most essential of which may be at codon 333 (Gly® Glu). The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.

Lamivudine: Lamivudine-resistant isolates of HIV-1 have been selected in vitro and have also been recovered from patients treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of the resistant isolates showed that the resistance was due to mutations in the HIV-1 reverse transcriptase gene at codon 184 from methionine to either isoleucine or valine.

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

Cross-Resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognized.

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

Lamivudine: See Lamivudine Plus Zidovudine (above).

Zidovudine: HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients treated for ³1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of genotypic resistant mutations with such combination therapies was different (Ala62®Val, Val75®Ile, Phe77®Leu, Phe116®Tyr, and Gln151®Met) from the pattern with zidovudine monotherapy, with the 151 mutation being most commonly associated with multidrug resistance. The mutation at codon 151 in combination with the mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine. Multiple-drug resistance has been observed in 2 of 39 (5%) patients receiving zidovudine and didanosine combination therapy for 2 years.