Efavirenz / Emtricitabine / Tenofovir Disoproxil Fumarate

Pronunciation: eh-FAV-ir-enz/EM-trye-SYE-ta-been/ten-OF-oh-vir DYE-soe-PROX-il FUE-ma-rate
Class: Antiretroviral combination

Trade Names

Atripla
- Tablets, oral efavirenz 600 mg, emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg

Pharmacology

Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase. Emtricitabine inhibits activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5′-triphosphate and by being incorporated into nascent viral DNA, resulting in chain termination. Tenofovir disoproxil fumarate is a prodrug of tenofovir, which inhibits the activity of HIV-1 reverse transcriptase by competing with deoxyadenosine 5′-triphosphate and by DNA chain termination after incorporation into DNA.

Slideshow: Flashback: FDA Drug Approvals 2013

Indications and Usage

Treatment of HIV-1 infection in adults when used alone or in combination with other antiretroviral agents.

Contraindications

Coadministration of bepridil, cisapride, ergot derivatives, midazolam, pimozide, St. John's wort, triazolam, or voriconazole; previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to efavirenz.

Dosage and Administration

Adults

PO 1 tablet once daily on an empty stomach.

General Advice

  • Dosing at bedtime may improve tolerability of CNS symptoms.
  • Should be taken on an empty stomach.

Storage/Stability

Store between 59° and 86°F. Keep container tightly closed.

Drug Interactions

Amprenavir, atazanavir, calcium channel blockers (eg, diltiazem, felodipine, nicardipine, nifedipine, verapamil), carbamazepine, etravirine, fosamprenavir, HMG-CoA reductase inhibitors (ie, atorvastatin, pravastatin, simvastatin), immunosuppressants (eg, cyclosporine, sirolimus, tacrolimus), itraconazole, ketoconazole, lopinavir, methadone, phenobarbital, phenytoin, posaconazole, rifabutin, sertraline

Plasma levels of these agents may be reduced, decreasing their efficacy. Monitor the clinical response. Adjust the dose of these agents as needed.

Atazanavir, lopinavir/ritonavir

Tenofovir plasma levels may be elevated, increasing the therapeutic effect and risk of adverse reactions. Closely monitor for tenofovir-associated adverse reactions. Coadministration with atazanavir is not recommended.

Bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), midazolam, pimozide, St. John's wort, triazolam, voriconazole

Coadministration of these agents with efavirenz/emtricitabine/tenofovir is contraindicated.

Clarithromycin

Clarithromycin plasma concentrations may decrease while clarithromycin hydroxy metabolite concentrations increase with coadministration. In uninfected volunteers, 46% developed a rash while receiving efavirenz/emtricitabine/tenofovir and clarithromycin. Clinical importance of this is unknown. Consider alternatives (eg, azithromycin) to clarithromycin.

Didanosine

Didanosine plasma concentrations may be elevated; use with caution and monitor for didanosine-associated adverse reactions.

Drugs primarily metabolized by CYP2C9, 2C19, or 3A4 isozymes

Plasma levels of these drugs may be elevated by efavirenz, necessitating dosage adjustments. Efavirenz may also decrease plasma levels of drugs metabolized by CYP3A4.

Drugs that induce CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin)

Efavirenz plasma levels may be reduced, decreasing its efficacy. Monitor patient response and adjust treatment as needed.

Drugs that reduce renal function or compete for active tubular secretion (eg, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir)

Emtricitabine and tenofovir serum levels may be elevated, increasing the risk of adverse reactions.

Food

Administration of efavirenz with a high-fat meal increased the mean AUC and C max of efavirenz compared with administration in the fasted state. Compared with fasted administration, dosing of tenofovir and emtricitabine in combination with a high-fat or light meal increased the mean AUC and C max of tenofovir, without affecting emtricitabine exposures. Administer efavirenz/emtricitabine/tenofovir on an empty stomach.

Ginkgo biloba

Efavirenz plasma concentrations may be reduced, decreasing the efficacy. Patients taking efavirenz should avoid Ginkgo biloba .

Hormonal contraceptives (eg, ethinyl estradiol)

Ethinyl estradiol plasma levels may be increased. However, until the interaction is fully characterized, a reliable method of barrier contraception should be used in addition to an oral contraceptive.

Indinavir

Efavirenz may increase the metabolism of indinavir. Increasing the indinavir dosage does not compensate for the increased indinavir metabolism.

Maraviroc

Efavirenz may decrease maraviroc plasma concentrations. Dosage adjustment of maraviroc may be required. Consult official package labeling. Coadministration is contraindicated in patients with severe renal impairment (CrCl 30 mL/min).

Nelfinavir

Nelfinavir concentrations may be increased. Monitor the clinical response and adjust the nelfinavir dose as needed.

Nevirapine

Efavirenz plasma concentrations may be reduced; however, the risk of adverse reactions may be increased. Coadministration is not recommended.

Progestins (eg, norethindrone)

The efficacy of norethindrone may be reduced. A higher dose of progestin may be needed. If the progestin is being used for contraception, a barrier method of contraception in addition to hormonal contraception should be used.

Ritonavir

Ritonavir and efavirenz plasma concentrations may be elevated, increasing their therapeutic effect and the risk of adverse reactions.

Saquinavir

Do not use saquinavir with efavirenz/emtricitabine/tenofovir as the sole protease inhibitor because of decreased AUC and C max of saquinavir.

Warfarin

Warfarin plasma levels may be increased or decreased. Monitor coagulation parameters and adjust the warfarin dose as needed.

Laboratory Test Interactions

Efavirenz therapy may produce a false-positive urine assay screening test for cannabinoid.

Adverse Reactions

The incidence stated for the following adverse reactions were reported with administration of emtricitabine plus tenofovir in combination with efavirenz. Adverse reactions occurring with administration of either efavirenz, emtricitabine, or tenofovir are listed in their respective monographs.

CNS

Abnormal dreams (10% or more); depression, fatigue (9%); dizziness (8%); headache (6%); anxiety, insomnia (5%).

Dermatologic

Rash (includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular) (7%).

EENT

Nasopharyngitis (5%).

GI

Diarrhea, nausea (9%); vomiting (2%).

Lab Tests

Increased cholesterol (22%); increased creatine kinase (9%); increased serum amylase (8%); increased fasting triglycerides (4%); decreased neutrophils, hematuria, increased AST (3%); hyperglycemia, increased ALT (2%); increased alkaline phosphatase (1%).

Respiratory

Sinusitis, upper respiratory tract infections (8%).

Precautions

Warnings

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with use of nucleoside analogs in combination with other antiretroviral agents. Not indicated for treatment of chronic hepatitis B virus (HBV) infection. Safety and efficacy have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued emtricitabine or tenofovir.


Monitor

Test all patients with HIV for the presence of chronic HBV before initiating antiretroviral therapy. Perform pregnancy testing in women of child bearing potential before initiating therapy. Calculate CrCl in all patients prior to initiating therapy and as clinically appropriate during therapy. Monitor liver enzymes before and during treatment in patients with underlying hepatic disease, including hepatitis B or C infection, marked transaminase elevations, and in patients treated with other medications associated with liver toxicity. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who discontinue therapy and are coinfected with HIV and HBV. Consider bone mineral density (BMD) monitoring for HIV-infected patients with a history of pathologic bone fracture or those at risk of osteopenia. Monitor for changes in serum creatinine and phosphorus in patients at risk for renal impairment.


Pregnancy

Category D . Efavirenz may cause fetal harm when administered during the first trimester. Women of childbearing potential should avoid pregnancy and use adequate contraception for 12 wk after the discontinuation of therapy.

Lactation

Undetermined. HIV-infected mothers should not breast-feed their infants.

Children

Safety and efficacy not established.

Elderly

Use with caution, usually starting at the low end of the dosage range because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Renal Function

Not for use in patients requiring dosage adjustment. Do not administer to patients with CrCl less than 50 mL/min. Avoid use in patients with current or recent use of nephrotoxic agents.

Hepatic Function

Use with caution in patients with preexisting hepatic impairment.

Bone mineral density

Antiretroviral regimens containing tenofovir have been associated with decreases in BMD. Cases of osteomalacia have also been reported in association with tenofovir.

CNS symptoms

CNS symptoms (eg, abnormal dreams, agitation, depersonalization, dizziness, euphoria, hallucinations, impaired concentration, insomnia, somnolence, stupor) have been reported. Symptoms generally started during the first 2 days and resolved within 2 to 4 wk.

Convulsions

Convulsions have been observed in patients receiving efavirenz therapy, particularly in the presence of a known history of seizures.

Fat redistribution

Redistribution and accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, may occur.

Hepatotoxicity

There have been a few postmarketing reports of hepatic failure in patients with no preexisting hepatic disease or other identifiable risk factors. In patients with persistent elevations of serum transaminases to more than 5 × ULN, weigh the benefits against the risks of liver toxicity.

HIV and HBV coinfection

Severe acute exacerbations of HBV have been reported in patients coinfected with HIV and HBV after the discontinuation of emtricitabine and tenofovir. In some patients treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure.

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy, including components of efavirenz/emtricitabine/tenofovir therapy. Initially, patients may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection), necessitating additional evaluation and treatment.

Psychiatric symptoms

Serious psychiatric symptoms have been reported with efavirenz therapy.

Related drugs

Related drugs that should not be coadministered with efavirenz/emtricitabine/tenofovir include efavirenz, emtricitabine, tenofovir, emtricitabine/tenofovir, and lamivudine.

Skin rash

New-onset skin rash, including blistering, erythema multiforme, moist desquamation, Stevens-Johnson syndrome, or ulceration, has been reported with efavirenz treatment.

Overdosage

Symptoms

Increased CNS symptoms, muscle contractions (efavirenz). No adverse reactions were reported with a single dose of emtricitabine 1,200 mg. No severe adverse reactions were reported with tenofovir 600 mg for 28 days.

Patient Information

  • Advise patient to read the patient information leaflet before using product the first time and with each refill.
  • Explain this product is not a cure for HIV and illnesses associated with HIV infection may continue to occur.
  • Advise patient that this product has not been shown to reduce the risk of HIV transmission to others through sexual contact or blood contamination.
  • Advise patient to take this medication on a regular dosing schedule and to avoid missing doses.
  • Advise patient to take this medication on an empty stomach.
  • Advise patient that drug may cause drowsiness, impaired concentration, or dizziness, and to avoid potentially hazardous tasks, such as driving or operating machinery, if they experience these symptoms.
  • Instruct patient to contact health care provider right away if they experience symptoms of lactic acidosis or hepatotoxicity, including cold feeling, especially in the arms or legs; dark urine; fast or irregular heartbeat; feeling very weak or tired; pale stools; stomach pain with nausea and vomiting; trouble breathing; unusual muscle pain; or yellowing of the skin or eyes.
  • Instruct patient to seek immediate medical evaluation if they experience serious psychiatric symptoms, including depression, suicide attempts, aggressive behavior, delusions, paranoia, or psychosis-like symptoms.
  • Advise patient to contact health care provider right away if rash occurs.
  • Advise women of childbearing potential to avoid becoming pregnant and to use an effective barrier contraceptive in conjunction with other methods of contraception, including oral or hormonal contraception, during therapy, and for 12 wk following discontinuation of therapy.
  • Inform patient that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, and that the cause and long-term effects of this condition are not known.

Copyright © 2009 Wolters Kluwer Health.

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