ATRIPLA™

In this article, we will discuss about ATRIPLA™ (Overview). So, let’s get started.

ATRIPLA™ is a fixed dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF).

ATRIPLA™ Tablets are for oral administration. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: croscarmellose sodium hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Mechanism of Action

Efavirenz: Efavirenz is a non-nucleoside reverse transcriptase inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5′-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5′-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir disoproxil fumarate: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF 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 RT 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 α, β and mitochondrial DNA polymerase γ.

Antiviral Activity

Efavirenz tivity, emtricitabine, and tenofovir disoproxil fumarate: In combination studies evaluating the antiviral activity in cell culture of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together,
additive to synergistic antiviral effects were observed.

Efavirenz: The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (EC90-95) ranged from 1.7-25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, nitonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated
additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against most non-clade B isolates (subtypes A, AE, AG, C,D,F,G, J, and N). but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV-2.

Emtricitabine: The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 μM (0.0003–0.158 μg/mL). In drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007-0.075 μM) and showed strain specific activity against HIV-2 (ECse values ranged from 0.007-1.5 μM).

Tenofovir disoproxil fumarate: The antiviral activity in cell culture 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 EC50 values for tenofovir were in the range of 0.04-8.5 μM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5-2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 4.9 μM).

Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

ATRIPLA™ is a three-drug fixed dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of ATRIPLA™ in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Warnings and Precautions

• Rash: Discontinue if severe rash develops.
• Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease.
• Risk of adverse reactions or loss of virologic response due to drug interactions: Consult full prescribing information prior to and during
treatment for important potential drug interactions. Consider alteratives to ATRIPLA™ in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes.
• Serious psychiatric symptoms: Immediate medical evaluation is
recommended.
• Nervous system symptoms (NSS): NSS are frequent, usually begin 1-2 days after initiating therapy, and resolve in 2-4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset
of psychiatric symptoms.
• New onset or worsening renal impairment Can include acute renal
failure and Fanconi syndrome. Prior to initiation and during use of ATRIPLA™, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Avoid administering ATRIPLA™ with concurrent or recent use of nephrotoxic drugs.
• Embryo fetal toxicity: Fetal harm may occur when administered to a pregnant woman during the first trimester. Avoid pregnancy while receiving ATRIPLA™ and for 12 weeks after discontinuation.
• Decreases in bone mineral density (BMD): Consider assessment of
BMD in patients with a history of pathological fracture or other risk factors for osteoporosis or bone loss.
• Convulsions: Use caution in patients with a history of seizures.
• Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
• Immune reconstitution syndrome: May necessitate further evaluation and treatment.
• Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.

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