VIREAD® TABLETS
SCHEDULING STATUS:
S4
PROPRIETARY NAME
(and dosage form):
VIREAD® TABLETS
COMPOSITION:
Each tablet contains 300mg of tenofovir disoproxil fumarate, which is equivalent to 245mg of tenofovir disoproxil.
WARNING LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).
TENOFOVIR IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITISB VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF TENOFOVIR HAS NOT BEEN ESTABLISHED IN PATIENTS COINFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITISB HAVE BEEN REPORTED IN PATIENTS WHO ARE COINFECTED WITH HBV AND HIV AND HAVE DISCONTINUED TENOFOVIR.
HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE TENOFOVIR AND ARE COINFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITISB THERAPY MAY BE WARRANTED (SEE WARNINGS).
PHARMACOLOGICAL CLASSIFICATION:
A 20.2.8 Antimicrobial (Chemotherapeutic) Agents. Antiviral Agents
PHARMACOLOGICAL ACTION:
Mechanism of Action: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha, beta, and mitochondrial DNA polymerase Y.
Drug Resistance:
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2-4 fold reduction in susceptibility to tenofovir.
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir in combination with certain antiretroviral agents. In treatment-naïve patients treated with tenofovir + lamivudine + efavirenz, viral isolates from 8/47 (17%) patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-experienced patients, 14/304 (4.6%) of the tenofovir-treated patients with virologic failure through week 96 showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 reverse transcriptase gene resulting in the K65R amino acid substitution.
Cross-resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognised. The K65R mutation selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R mutation. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.
Pharmacodynamics: The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04microM to 8.5microM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in vitro against HIV1 clades A, B, C, D, E, F, G, and O (IC50 values ranged from 0.5microM to 2.2microM). The IC50 values of tenofovir against HIV-2 ranged from 1.6microM to 4.9microM.
Pharmacokinetics:
The pharmacokinetics of tenofovir disoproxil fumarate have been eva luated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption: Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients is approximately 25%. Following oral administration of a single dose of tenofovir 300mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 + 0.4hrs. Cmax and AUC values are 296 + 90ng/mL and 2287 + |
