Liverpool HIV Interactions

Potential Interaction

Efavirenz (EFV)

Methadone

Quality of Evidence: High

Summary:

Coadministration of efavirenz (600 mg daily) to 11 subjects stable on methadone maintenance (35-100 mg daily) decreased methadone Cmax (45%) and AUC (52%). The methadone dose was increased by~22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required. Methadone has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Description:

Efavirenz is contraindicated with concomitant use of drugs that may cause prolonged QTc interval and Torsade de Pointes, such as methadone. Coadministration of efavirenz (600 mg once daily) with methadone (35-100 mg once daily, stable maintenance doses)decreased methadone AUC and Cmax by 52% and 45%, respectively. In a study of HIV-infected IV drug users, co-administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The 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.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

Coadministration of efavirenz (600 mg, once daily for 14 days) with methadone (30-100 mg daily, stable maintenance dose) was studied in 11 volunteers. Methadone Cmax and AUC decreased by 45% and 52%, respectively. Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

There is case study of 3 HIV-infected patients who were stable under methadone maintenance treatment, but who started to complain of opioid abstinence 3-7 days after the introduction of efavirenz to their antiretroviral regimen. Increases in methadone dosage of 66-133% were required before a subjective state of compensation was regained. Pharmacokinetic analyses were performed in one patient and revealed a 70% decrease in plasma methadone concentrations; this was eventually compensated for by a 133% increase in methadone dose. Efavirenz concentrations were comparable to historical data.

Undefined duration of opiate withdrawal induced by efavirenz in drug users with HIV infection and undergoing chronic methadone treatment. Boffito M, Rossati A, Reynolds HE, et al. AIDS Res Hum Retroviruses, 2002, 18:341-342.

Administration of efavirenz (600 mg once daily) to 11 HIV+ individuals who were receiving methadone resulted in a significant reduction in methadone AUC 0–24 h (5309 vs 12341 ng/ml.h; alone vs with efavirenz). There was a marked decrease in methadone Cmax in presence of efavirenz (358 vs 689 ng/ml; alone vs with efavirenz). 9/11 patients described symptoms of methadone withdrawal and received a dose increase (mean 22% increase).

The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Clarke S, Mulcahy F, Tjia J, et al. Br J Clin Pharmacol 2001, 51:213–17.

View all available interactions with Efavirenz (EFV) by clicking here.