Atripla (Efavirenz / Emtricitabine / Tenofovir Disoproxil Fumarate) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

This section describes clinically relevant drug interactions with ATRIPLA. Drug interaction studies are described elsewhere in the labeling [ see Clinical Pharmacology ].

Efavirenz

Efavirenz has been shown in vivo to induce CYP3A. Other compounds that are substrates of CYP3A may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.

Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

Emtricitabine and Tenofovir Disoproxil Fumarate

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of ATRIPLA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir.

Coadministration of tenofovir DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions [for didanosine dosing adjustment recommendations, see Table 4 ]. Suppression of CD4⁺ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir with ATRIPLA should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions [ See Table 4 ].

Coadministration of atazanavir with ATRIPLA is not recommended since coadministration of atazanavir with either efavirenz or tenofovir DF has been shown to decrease plasma concentrations of atazanavir. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA [ See Table 4 ].

Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate

Other important drug interaction information for ATRIPLA is summarized in Table 1 and Table 4. The drug interactions described are based on studies conducted with efavirenz, emtricitabine or tenofovir DF as individual agents or are potential drug interactions; no drug interaction studies have been conducted using ATRIPLA [for pharmacokinetics data see Clinical Pharmacology , Tables 5—9]. The tables include potentially significant interactions, but are not all inclusive.

Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name	Effect	Clinical Comment
Antiretroviral agents
Protease inhibitor:   atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor:   fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.   Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:   indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:   lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:   ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:   saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI:   didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:   warfarin	↑ or — warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:   carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin   phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant:   sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals:   itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective:   clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:   rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:   rifampin	↓ efavirenz concentration	Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
Calcium channel blockers:   diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of the CYP3A4 enzyme. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:   atorvastatin   pravastatin   simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Narcotic analgesic:   methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
Oral contraceptive:   ethinyl estradiol	↑ ethinyl estradiol concentration	Clinical significance unknown. Because the potential interaction of efavirenz with oral contraceptives has not been fully characterized, a reliable method of barrier contraception should be used in addition to oral contraceptives.

Efavirenz Assay Interference

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics Cedia DAU Multi-Level THC assay was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. For more information, please consult the SUSTIVA prescribing information.

OVERDOSAGE

If overdose occurs, the patient should be monitored for evidence of toxicity, including monitoring of vital signs and observation of the patient's clinical status; standard supportive treatment should then be applied as necessary. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. Hemodialysis can remove both emtricitabine and tenofovir DF (refer to detailed information below), but is unlikely to significantly remove efavirenz from the blood.

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

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.

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). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8 patients orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.

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.

CONTRAINDICATIONS

Hypersensitivity

ATRIPLA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Contraindicated Drugs

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 (eg cardiac arrhythmias, prolonged sedation, or respiratory depression). Drugs that are contraindicated with ATRIPLA are listed in Table 1.

Table 1 Drugs That Are Contraindicated or Not Recommended for Use With ATRIPLA

Drug Class: Drug Name	Clinical Comment
Antifungal: voriconazole	Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. Because ATRIPLA is a fixed dose combination product, the dose of efavirenz cannot be altered. [See Clinical Pharmacology Tables 5 and 6 ]
Ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Benzodiazepines: midazolam, triazolam	Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Calcium channel blocker: bepridil	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
GI motility agent: cisapride	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Neuroleptic: pimozide	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
St. John's wort (Hypericum perforatum)	May lead to loss of virologic response and possible resistance to efavirenz or to the class of NNRTIs.