Nevirapineinteractions

Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction trials conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between Nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction trials in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs. The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently. Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology, Table 5 for Magnitude of Interaction. Drug Name Effect on concentration of Nevirapine or Concomitant drug Clinical Comment Atazanavir/Ritonavir ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination. Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended Fluconazole ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events. Fosamprenavir ↓Amprenavir ↑Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir ↓Amprenavir ↑Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Nelfinavir ↓Nelfinavir M8 Metabolite ↓Nelfinavir C min The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. Rifabutin ↑Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. Saquinavir/Ritonavir The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. Potential Drug Interactions Drug Class Examples of Drugs Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased. Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased. Ergot alkaloids Ergotamine Plasma concentrations may be decreased. Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased. Motility agents Cisapride Plasma concentrations may be decreased. Opiate agonists Fentanyl Plasma concentrations may be decreased. Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. Co-administration of NEVIRAPINE can alter the concentrations of other drugs and other drugs may alter the concentration of nevirapine. The potential for drug interactions must be considered prior to and during therapy