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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 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 (12.3), Table 5 for Magnitude of Interaction.
* The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of
Nevirapine or Concomitant Drug
Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*

↓ Atazanavir
↑ Nevirapine

Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.

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. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.

Indinavir*

↓ Indinavir

The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.

Lopinavir/Ritonavir*

↓Lopinavir

Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.

Nelfinavir*

↓Nelfinavir M8 Metabolite
↓Nelfinavir Cmin

The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.

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.

HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*

↓ Efavirenz

The appropriate doses of these combinations with respect to safety and efficacy have not been established.

Delavirdine
Etravirine
Rilpivirine

  Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.

Hepatitis C Antiviral Agents
Boceprevir

Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.

Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.

Telaprevir

Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.

Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.

Other Agents
Analgesics:  
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.

Antiarrhythmics:    
Amiodarone, disopyramide, lidocaine

Plasma concentrations may be decreased.

Appropriate doses for this combination have not been established.

Antibiotics:    
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.

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.

Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide


Plasma concentrations of nevirapine and the anticonvulsant may be decreased.


Use with caution and monitor virologic response and levels of anticonvulsants.

Antifungals:    
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.

Ketoconazole*

↓ Ketoconazole

Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.

Itraconazole

↓ Itraconazole

Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.

Antithrombotics:
Warfarin


Plasma concentrations may be increased.


Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium channel blockers:
Diltiazem, nifedipine, verapamil


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Cancer chemotherapy:
Cyclophosphamide


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Ergot alkaloids:
Ergotamine


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Immunosuppressants:
Cyclosporine, tacrolimus, sirolimus


Plasma concentrations may be decreased.


Appropriate doses for these combinations have not been established.

Motility agents:
Cisapride


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Opiate agonists:
Fentanyl


Plasma concentrations may be decreased.


Appropriate doses for this combination have not been established.

Oral contraceptives:    
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.

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

Hepatic Impairment

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

Post-Exposure Prophylaxis

VIRAMUNE is contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [see Warnings and Precautions ].

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