Prescription Drug Guide

Drug Catalog List

	Abacavir

WARNINGS

Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis). Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. Permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.
Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
Reintroduction of ZIAGEN or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours (SEE WARNINGS, PRECAUTIONS: Information for Patients).
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including ZIAGEN and other antiretrovirals (SEE WARNINGS

DESCRIPTION

ZIAGEN is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV. The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)- 9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C₁₄H₁₈N₆O)₂·H₂SO₄ and a molecular weight of 670.76 daltons. It has the following structural formula:

Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25°C. It has an octanol/water (pH 7.1 to 7.3) partition coefficient (log P) of approximately 1.20 at 25°C.

ZIAGEN Tablets are for oral administration. Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir and the inactive ingredients colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.

ZIAGEN Oral Solution is for oral administration. One milliliter (1 mL) of ZIAGEN Oral Solution contains abacavir sulfate equivalent to 20 mg of abacavir (20 mg/mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), and sorbitol solution.

In vivo, abacavir sulfate dissociates to its free base, abacavir. In this insert, all dosages for ZIAGEN are expressed in terms of abacavir.

MICROBIOLOGY

Mechanism of Action: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted intracellularly by cellular enzymes to the active metabolite, carbovir triphosphate, an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. Abacavir is a weak inhibitor of cellular DNA polymerases α, β, and γ

Antiviral Activity: The in vitro anti.HIV-1 activity of abacavir was evaluated against a T-cell tropic laboratory strain HIV-1_IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV-1_BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to inhibit viral replication by 50 3 percent (IC₅₀) ranged from 3.7 to 5.8 µM (1 µM = 0.28 mcg/mL) and 0.07 to 1.0 µM against HIV-1_IIIB and HIV-1_BaL, respectively, and was 0.26 ± 0.18 µM against 8 clinical isolates. The IC₅₀ values of abacavir against different HIV-1 clades (A-E) ranged from 0.0015 to 1.0 µM, and against HIV-2 isolates, from 0.024 to 0.49 µM. Abacavir had synergistic activity in vitro in combination with amprenavir, nevirapine, and zidovudine, and additive activity in combination with didanosine, lamivudine, stavudine, tenofovir, and zalcitabine. Ribavirin had no effect on the in vitro anti-HIV-1 activity of abacavir.

Resistance:HIV-1 isolates with reduced susceptibility to abacavir have been selected in vitro and were also obtained from patients treated with abacavir. Genetic analysis of isolates from patients failing an abacavir-containing regimen demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V in HIV-1 RT contributed to abacavir resistance. In a study of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386), in a background regimen of lamivudine 300 mg once daily and efavirenz 600 mg once daily (Study CNA30021), the incidence of virologic failure at 48 weeks was similar between the 2 groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the RT mutations that emerged during abacavir once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir once daily (56%, 10/18) and twice daily (40%, 8/20).

Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a >2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Cross-Resistance: Cross-resistance has been observed among nucleoside

Cross-Resistance: Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). Recombinant laboratory strains of HIV-1HXB2 containing multiple abacavir resistance-associated mutations, namely, K65R, L74V, M184V, and Y115F, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in vitro. The K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. An increasing number of thymidine analogue mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.