Nevirapine Methadone

Nevirapine induces and is metabolized by CYP3A4 therefore, coadministration of drugs that induce or are metabolized by this isoenzyme may result in interactions. Nevirapine may decrease the effectiveness of ethinyl estradiol-based contraceptives and can lower plasma concentrations of methadone. Nevirapine should not be administered with ketoconazole, rifampin, or rifabutin. 

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... 

CYP3A4 activity, significantly decreasing plasma concentrations and the pharmacologic effect of a number of agents, including alprazolam, amitriptyline, cyclosporine, indinavir, methadone, nevirapine, simvastatin, tacrolimus, and oral contraceptives (69-77). 

Nervirapine is an HIV drug that is a CYP3A4 inducer in a small sample, nevirapine caused a 50% reduction in methadone blood levels, resulting in complaints of methadone withdrawal symptoms in patients receiving methadone maintenance may need to increase methadone dose in patients who have nevirapine added to their drug regimen. 

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. 

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. 

Since nevirapine is metabolized by the cytochrome P-450 system and induces 3A4 and 2B6, other drugs that are also metabolized by these isoenzymes will have low plasma levels when given in combination. It also increases the clearance of methadone and results in methadone withdrawal. Nevirapine decreases the plasma concentrations of norethindrone, ethinyl estradiol and protease inhibitors (HIV). 

Nevirapine NNRTI 200 mg bid Rash, hepatitis, nausea, headache Dose-escalate from 200 mg qd over 14 days to decrease frequency of rash. Avoid concurrent use with ketoconazole, methadone, and... 

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)... 

When methadone is used in HIV infection (for pain or treatment of opioid dependence) nevirapine given simultaneously can reduce methadone blood concentrations, the effect being sufficient to cause methadone withdrawal symptoms (24,25). 

Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy 1999 19(4) 471-2. 

Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis 2001 33(9) 1595-7. 

Of 80 injecting drug users who took two NRTIs + nevirapine (NNRTI), 20 discontinued treatment and 20 had treatment failures (5). Adverse events led to withdrawal of therapy in 10 patients eight had a rash (in one case Stevens-Johnson syndrome) one had liver failure thought to be unrelated to the drugs and one had general intolerance. Two patients taking methadone had opioid withdrawal symptoms, presumably due to induction of methadone metabolism by nevirapine. 

Acetaminophen, aldrin, alfentanil, amiodarone, aminopyrine, amitriptyline, amprenavir, androstenedione,antipyrine, astemizole, benzphetamine, budesonide, carbamazepine, celecoxib, chlorpromazine, chlorzoxazone, cisapride, clarithromycin, clozapine, cocaine, codeine, cortisol, cyclophosphamide,cyclosporin, dapsone, delavirdine, dextromethorphan, digitoxin, diltiazem, diazepam, erythromycin, 17j3-estradiol, ethinylestradiol, etoposide, felbamate, fentanyl, flutamide, hydroxyarginine, ifosphamide, imipramine, indinavir, ketoconazole, lansoprazole, loratidine, losartan, lovastatin, (iS)"mephen3d in, methadone, mianserin, miconazole, mifepristone, nelfinavir, nevirapine, nicardipine, nifedipine, odansetron, omeprazole, orphenadrine, proguanil, propafenone, quinidine, quinine, rapamycin, retinoic acid, ritonavir, saquinavir, selegiline, serindole, sufentanil, sulfinpyrazone, tacrolimus, tamoxifen, tamsulosin, taxol, teniposide, terfenadine, tetrahydrocannabinol, theophylline, toremifene, triazolam, trimethadone, trimethoprim, troleandomycin, verapamil, warfarin, zatosetron, Zolpidem, zonisamide... 

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]. 

Because nevirapine induces CYP3A4, this drug may lower plasma concentrations of coadministered CYP3A4 substrates. Methadone withdrawal has been reported in patients receiving nevirapine, presumably as a consequence of enhanced methadone clearance. Plasma ethinyl estradiol and norethindrone concentrations decrease by 20% with nevirapine, and alternative methods of birth control are advised. Nevirapine also can reduce concentrations of some coadministered HIV protease inhibitors. 

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, 8 patients taking methadone 30 to 120 mg daily had methadone levels measured before and 14 days after starting an antiretroviral regimen including nevirapine 200 mg daily. The methadone AUC decreased by 52%, and the maximum level by 36%. Six patients complained of symptoms of methadone withdrawal, and required a mean increase in methadone dose of 16%. ... 

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... 

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