Methadone Efavirenz

Drugs that may affect nelfinavir include anticonvulsants, azithromycin, azole antifungals, efavirenz, delavirdine, HMG-CoA reductase inhibitors, indinavir, interleukins, nevirapine, rifabutin, rifampin, ritonavir, saquinavir, St. John s wort. Drugs that may be affected by nelfinavir include amiodarone, antiarrhythmics (amiodarone, quinidine), azithromycin, benzodiazepines, efavirenz, ergot alkaloids, delavirdine, didanosine, fentanyl, indinavir, lamivudine methadone, nonsedating antihistamines, oral contraceptives, phenytoin, pimozide, quinidine, rifabutin, saquinavir, sildenafil, sirolimus, tacrolimus, zidovudine. 

Drugs that may be affected by nevirapine include rifamycins, clarithromycin, oral contraceptives, efavirenz, ketoconazole, methadone, protease inhibitors, warfarin, zidovudine. 

St. John s wort, rifamycins, and ritonavir. Drugs that may be affected by efavirenz include phenytoin, phenobarbital, carbamazepine, itraconazole, ketoconazole, methadone, ritonavir, amprenavir, benzodiazepines, clarithromycin, ethinyl estradiol, indinavir, nelfinavir, saquinavir, and warfarin. 

B6 Artemisinin, bupropion, cyclophosphamide, efavirenz, ifosfamide, ketamine, S-mephobarbital, S-mephenytoin (/V-demethylation to nirvanol), methadone, nevirapine, propofol, selegiline, sertraline, ticlopidine Phenobarbital, cyclophosphamide Ticlopidine, clopidogrel... 

Nevirapine is a moderate inducer of CYP3A metabolism, resulting in decreased levels of amprenavir, indinavir, lopinavir, saquinavir, efavirenz, and methadone (Table 49-4). Drugs that induce the CYP3A system, such as tipranavir, rifampin, rifabutin, and St. John s wort, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as fluconazole, ketoconazole, and clarithromycin, can increase nevirapine levels. 

Efavirenz inhibits the plasma levels of indinavir, saquinavir and amprenavir and increases the concentrations of ritonavir and nelfinavir. It also lowers the plasma levels of methadone, phenytoin, carbamazepine and phenobarbital. Drugs that stimulate the cytochrome P-450 system will increase its clearance and should not be coadministered. 

Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001 51(3) 213-7. 

METHADONE NNRTIs Methadone levels may be significantly 1 by efavirenz and nevirapine t CYP3A4- and 2B6-mediated metabolism of methadone Monitor closely for opioid withdrawal t dose as necessaiy. Likely to need dose titration of methadone (mean 22% but up to 186% t)... 

Following a report of withdrawal symptoms in three patients taking methadone maintenance therapy, serum methadone concentrations were measured before and after starting efavirenz in one patient (26). Serum methadone concentrations were as follows (R)-methadone (the active enantiomer) 168 ng/ml and 90 ng/ml before and after efavirenz. The corresponding (5)-methadone concentrations were 100 and 28 ng/ml. The dosage of methadone was increased from 100 to 180 mg/day before the patient s withdrawal symptoms resolved. 

Three patients taking methadone were given efavirenz-containing regimens and started to complain of opioid withdrawal symptoms 3-7 days later (27). In one case the plasma methadone concentration fell from about 170 ng/ml to about 50 ng/ml over 6 days. 

Since methadone is partly metabolized by CYP3A4, the interaction of efavirenz with methadone has been investigated prospectively in 11 patients taking stable methadone maintenance therapy (28). Efavirenz reduced the steady-state methadone AUC by 50%. However, patients generally only needed a 22% increase in their methadone dose to eliminate the symptoms of methadone withdrawal, and the full basis of the interaction is not understood. 

Marzolini C, TroUlet N, Telenti A, Baumann P, Decosterd LA, Eap CB. Efavirenz decreases methadone blood concentrations. AIDS 2000 14(9) 1291-2. 

Boffito M, Rossati A, Reynolds HE, Hoggard PG, Back DJ, Di Perri G. Undefined duration of opiate withdrawal induced by efavirenz in drug users with HIV infection and undergoing chronic methadone treatment. AIDS Res Hum Retroviruses 2002 18(5) 341-2. 

Clinically important, potentially hazardous interactions with alcohol, amprenavir, barbiturates, buprenorphine, chlorpheniramine, clarithromycin, CNS depressants, efavirenz, esomeprazole, eucalyptus, fluoroquinolones, imatinib, indinavir, ivermectin, macrolide antibiotics, MAO inhibitors, methadone, mianserin, nalbuphine, narcotics, nelfinavir, nilutamide, phenothiazines, ritonavir, SSRIs... 

Treatment with the NNRTIs efavirenz and nevirapine was noted to cause methadone withdrawal symptoms in patients with HIV [66, 52], Subsequently, both NNRTIs were shown to induce drug-metabolizing enzymes in cultured hepatocytes due to activation of CAR and weak activation of PXR [37]. 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Methadone plasma levels can be markedly reduced by efavirenz or nevirapine and withdrawal symptoms have been seen. In contrast, delavirdine slightly increased methadone levels in one study. 

In a pharmacokinetic study, 11 patients taking methadone 35 to 100 mg daily were given efavirenz with two nucleoside analogues. Nine of the patients developed methadone withdrawal symptoms and needed dose increases of 15 to 30 mg (mean 22%). A pharmacokinetic study of these patients found that 3 weeks after starting efavirenz their mean methadone AUCs were reduced by 57% and their maximum plasma levels by 48%. Similar results were found in another study in 5 HIV-positive patients taking methadone 4 patients experienced opioid withdrawal symptoms and a mean methadone dose increase of 52% was required. In another retrospective study, 6 out of 7 patients needed methadone dosage increases of 8% to 200% within 2 weeks to 8 months of starting an efavirenz-based... 

Efavirenz and nevirapine induce the metabolism of methadone (possibly by the cytochrome P450 isoenzyme CYP3A4, or CYP2B6 ), which results in reduced levels and effects. In contrast, delavirdine is an inhibitor... 

TashimaK, Bose T, Gormley J, Sousa H, Flanigan TP. The potential impact of efavirenz on methadone maintenance. Poster presented at 9th European Conference on Clinical Microbiology and Infectious Diseases, Berlin, March 23rd 1999 (Poster P0552). 

Nevirapine and efavirenz increase the R/S enantiomer concentration ratio, hence increasing the therapeutic effects of methadone, which are almost exclusively mediated by the R enantiomer, as has been shown in five patients taking nevirapine and nine taking efavirenz [97 ]. These interactions are thought to be mediated by induction of CYP2B. 

Esteban J, de la Cruz Pellin M, Gimeno C, Barril J, Gimenez J, Mora E, Garcia-Perez AG. Increase of R-/S-methadone enantiomer concentration ratio in serum of patients treated with either nevirapine or efavirenz. Drug Metab Lett 2008 2(4) 269-74. 

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