Sustiva (Efavirenz) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Drug-Drug Interactions

Efavirenz has been shown in vivo to induce CYP3A. Other compounds that are substrates of CYP3A may have decreased plasma concentrations when coadministered with SUSTIVA. In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 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. Drug interactions with SUSTIVA are summarized in Tables 2 and 7 [for pharmacokinetics data see Clinical Pharmacology (12.3, Tables 8 and 9) ]. The tables include potentially significant interactions, but are not all inclusive.

Table 7: Established^a and Other Potentially Significant^b 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
a  See Clinical Pharmacology (12.3, Tables 8 and 9) for magnitude of established interactions.
b  This table is not all-inclusive.
Antiretroviral agents
Protease inhibitor:  Fosamprenavir  calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of the combinations 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 SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:  Atazanavir	↓ atazanavira	When coadministered with SUSTIVA in treatment-naive patients, the recommended dose of atazanavir is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg (all once daily). Dosing recommendations for SUSTIVA and atazanavir in treatment-experienced patients have not been established.
Protease inhibitor:  Indinavir	↓ indinavira	The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor:  Lopinavir/ritonavir	↓ lopinavira	Lopinavir/ritonavir tablets should not be administered once-daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor:  Ritonavir	↑ ritonavira ↑ efavirenza	When ritonavir 500 mg q12h was coadministered with SUSTIVA 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 SUSTIVA is used in combination with ritonavir.
Protease inhibitor:  Saquinavir	↓ saquinavira	Should not be used as sole protease inhibitor in combination with SUSTIVA.
Other agents
Anticoagulant:  Warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants:  Carbamazepine	↓ carbamazepinea ↓ efavirenza	There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
Phenytoin  Phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant:  Sertraline	↓ sertralinea	Increases in sertraline dosage should be guided by clinical response.
Antifungals:  Voriconazole	↓ voriconazolea ↑ efavirenza	SUSTIVA and voriconazole must not be coadministered at standard doses. 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 SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3, Tables 8 and 9) .]
Itraconazole	↓ itraconazolea ↓ hydroxyitraconazolea	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Ketoconazole	↓ ketoconazole	Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective:  Clarithromycin	↓ clarithromycina ↑ 14-OH metabolitea	Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterial:  Rifabutin	↓ rifabutina	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin	↓ efavirenza	Clinical significance of reduced efavirenz concentrations is unknown. Dosing recommendations for concomitant use of SUSTIVA and rifampin have not been established.
Calcium channel blockers:  Diltiazem	↓ diltiazema ↓ desacetyl diltiazema ↓ N-monodesmethyl diltiazema	Diltiazem dose adjustments should be guided by clinical response (refer to the complete prescribing information for diltiazem). No dose adjustment of efavirenz 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 CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the complete prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:   Atorvastatin   Pravastatin   Simvastatin	↓ atorvastatina ↓ pravastatina ↓ simvastatina	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the complete prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Narcotic analgesic:  Methadone	↓ methadonea	Coadministration in HIV-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 estradiola	Plasma concentrations increased by SUSTIVA; clinical significance unknown. 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.

Other Drugs

Based on the results of drug interaction studies [see Clinical Pharmacology (12.3, Tables 8 and 9) ], no dosage adjustment is recommended when SUSTIVA (efavirenz) is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir disoproxil fumarate, and zidovudine.

Specific drug interaction studies have not been performed with SUSTIVA and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.

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 SUSTIVA 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.

Of the three assays analyzed (Microgenics CEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic Reagents, Inc], and AxSYM Cannabinoid Assay), only the Microgenics CEDIA DAU Multi-Level THC assay showed false-positive results. The other two assays provided true-negative results. The effects of SUSTIVA on cannabinoid screening tests other than these three are unknown. The manufacturers of cannabinoid assays should be contacted for additional information regarding the use of their assays with patients receiving efavirenz.

OVERDOSAGE

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

Treatment of overdose with SUSTIVA should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with SUSTIVA. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

CONTRAINDICATIONS

Hypersensitivity

SUSTIVA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this 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 SUSTIVA are listed in Table 2.

Table 2: Drugs That Are Contraindicated or Not Recommended for Use With SUSTIVA

Drug Class: Drug Name	Clinical Comment
Antimigraine: 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 non-nucleoside reverse transcriptase inhibitors (NNRTI).