(Tenofovir Disoproxil Fumarate, Emtricitabine & Efavirenz Tablets)

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Each tablet contains:
Tenofovir Disoproxil Fumarate 300 mg
Emtricitabine 200mg
Efavirenz 600mg

is a fixed-dose combination of antiviral drugs tenofovir disoproxil fumarate, emtricitabine and efavirenz. Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog 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 and beta, and mitochondrial DNA polymerase gamma. Emtricitabine works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA.

Emtricitabine is a synthetic nucleoside analogue of cytidine. It is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which is responsible for the inhibition of HIV-1 reverse transcriptase. It competes with the natural substrate deoxycytidine 5'-triphosphate and incorporates into nascent viral DNA, resulting in early chain termination. Therefore emtricitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate deoxycytidine 5'-triphosphate and by its incorporation into viral DNA. By inhibiting HIV-1 reverse transcriptase, emtricitabine can help to lower the amount of HIV, or "viral load", in a patient's body and can indirectly increase the number of immune system cells (called T cells or CD4+ T-cells). Both of these changes are associated with healthier immune systems and decreased likelihood of serious illness. Efavirenz is a non-nucleoside reverse transcriptase (RT) 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 σ are not inhibited by efavirenz.

Emtricitabine: Following oral administration of emtricitabine tablets, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 6. Following oral administration of Tenofovir Disoproxil Fumarate:, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Tenofovir Disoproxil Fumarate:, the terminal elimination half-life of tenofovir is approximately 17 hours.

Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady- state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•hr.

Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled efavirenz, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.

TENMAC-EF, a combination of 2 nucleoside analog HIV-1 reverse transcriptase inhibitors and 1 non-nucleoside HIV-1 reverse transcriptase inhibitor, is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

Adults and pediatric patients 12 years of age and older with body weight at least 40 kg: One tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms. Renal Impairment: Because TENMAC-EF is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL/min).
Rifampin Coadministration: When TENMAC-EF is administered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.

Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of TENMAC-EF.
For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression).

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. Assess creatinine clearance (CrCl) before initiating treatment with TENMAC-EF. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering TENMAC-EF with concurrent or recent use of nephrotoxic drugs. 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. 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. Immune reconstitution syndrome: May necessitate further evaluation and treatment. Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. Coadministration with other products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate or with drugs containing lamivudine. efavirenz should not be coadministered with TENMAC-EF unless required for dose- adjustment when coadministered with rifampin. Do not administer in combination with adefovir dipivoxil.

Pregnancy: Fetal harm can occur when administered to a pregnant woman during the first trimester. Women should be apprised of the potential harm to the fetus. Women should avoid pregnancy while receiving TENMAC-EF and for 12 weeks after discontinuation. Nursing mothers: Women infected with HIV should be instructed not to breastfeed. Hepatic impairment: TENMAC-EF is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. Pediatrics: The incidence of rash was higher than in adults.

Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir DF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

Efavirenz: Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions must be considered before and during therapy. Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. Atazanavir: Coadministration of TENMAC-EF and atazanavir or atazanavir/ritonavir is not recommended. Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity.

Tenofovir Disoproxil Fumarate

Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one trial, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology trial single doses of emtricitabine 1200 mg were administered to 11 subjects..Hemodialysis treatment
removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of
emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min).

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

HDPE Bottle pack of 30 tablets and packed in a unit carton along with package insert.

24 months from the date of manufacturing

Keep in a dry place at a temperature below 30°C.

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