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Viramune (Nevirapine) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

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 studies 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 studies 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 (12.3), Table 5 for Magnitude of Interaction.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment
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↓ EfavirenzAppropriate doses for this combination are not established.
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↑NevirapineBecause 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.
Indinavir↓ IndinavirAppropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole↓ KetoconazoleNevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir↓LopinavirKALETRA 400/100 mg tablets can be used twice-daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients.

A dose increase of  KALETRA tablets to 600/150 mg (3 tablets)  twice daily may be considered when used  in combination with nevirapine 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 twice daily with food is recommended in combination with nevirapine.

In children 6 months to 12 years of age, 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; and up to a maximum dose of 533/133 mg for those > 45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected. 
Methadone↓ MethadoneMethadone 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 Cmin
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin↑RifabutinRifabutin 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  ↓ NevirapineNevirapine 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↓SaquinavirAppropriate doses for this combination are not established, but an increase in the dosage of saquinavir may be required.

Potential Drug Interactions: 
  
Drug Class Examples of Drugs  
AntiarrhythmicsAmiodarone, disopyramide, lidocainePlasma Concentrations May Be Decreased
AnticonvulsantsCarbamazepine, clonazepam, ethosuximidePlasma Concentrations May Be Decreased
AntifungalsItraconazolePlasma Concentrations May Be Decreased
Calcium channel blockersDiltiazem, nifedipine, verapamilPlasma Concentrations May Be Decreased
Cancer chemotherapyCyclophosphamidePlasma Concentrations May Be Decreased
Ergot alkaloidsErgotaminePlasma Concentrations May Be Decreased
ImmunosuppressantsCyclosporin, tacrolimus, sirolimusPlasma Concentrations May Be Decreased
Motility agentsCisapridePlasma Concentrations May Be Decreased
Opiate agonistsFentanylPlasma Concentrations May Be Decreased
AntithromboticsWarfarinPlasma Concentrations May Be Increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

OVERDOSAGE

There is no known antidote for VIRAMUNE overdosage. Cases of VIRAMUNE overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of VIRAMUNE.

CONTRAINDICATIONS

VIRAMUNE is contraindicated in patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [ see Warning and Precautions and Use in Specific Populations ].

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