Prescription Drug Guide

Zidovudine

RETROVIR^Ò
(zidovudine)
Tablets

RETROVIR^Ò
(zidovudine)
Capsules

RETROVIR^Ò
(zidovudine)
Syrup

DESCRIPTION

RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV.

Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.

Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.

Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH.

The chemical name of zidovudine is 3’-azido-3’-deoxythymidine; it has the following structural formula:

Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg/mL in water at 25° C. The molecular formula is C₁₀H₁₃N₅O₄.

Mechanism of Action: 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 nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases a and g and has been reported to be incorporated into the DNA of cells in culture.

Antiviral Activity: 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 0.01 to 0.49 mM (1 mM = 0.27 mcg/mL) and 0.1 to 9 mM, 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. The IC₅₀ values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 mM, and against HIV-2 isolates from 0.00049 to 0.004 mM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in vitro.

Resistance: Genotypic analyses of the isolates selected in vitro and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of mutations. 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.

Cross-Resistance: In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ³1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most commonly associated with multi-drug resistance. The mutation at codon 151 in combination with mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.