Intelence (Etravirine) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE™ with drugs that induce or inhibit CYP3A4, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE™ (see Table 4). [ See also Clinical Pharmacology .]

Etravirine is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Therefore, co-administration of drugs that are substrates of CYP3A4, CYP2C9 and CYP2C19 with INTELENCE™ may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4). [See also Drug Interactions and Clinical Pharmacology .]

Table 4 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE™ and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE™ are also included in Table 4.

Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology]

Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz 1 nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE™ with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE™. INTELENCE™ and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE™ and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)—Unboosted (i.e., without co-administration of low-dose ritonavir)
atazanavir fosamprenavir nelfinavir indinavir (without ritonavir)	↓ atazanavir ↑ amprenavir ↑ nelfinavir ↓ indinavir	Concomitant use of INTELENCE™ with PIs without co-administration of low-dose ritonavir may cause a significant alteration in the plasma concentrations of the PI. INTELENCE™ should not be co-administered with PIs without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE™ with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE™. INTELENCE™ and ritonavir 600 mg b.i.d. should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)—Boosted (with co-administration of low-dose ritonavir)
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE™ with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE™. INTELENCE™ and tipranavir/ritonavir should not be co-administered.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE™ and fosamprenavir/ritonavir have not been established. INTELENCE™ and fosamprenavir/ritonavir should not be co-administered.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE™ with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin by about 38% and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE™ with atazanavir/ritonavir is anticipated to be about 100% higher than the mean systemic exposure of etravirine observed in the Phase 3 trials. INTELENCE™ and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced by about 37% when INTELENCE™ was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE™ and darunavir/ritonavir can be co-administered without dose adjustments.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced by about 35% after co-administration of INTELENCE™ with lopinavir/ritonavir (melt extrusion tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE™ and lopinavir/ritonavir can be co-administered without dose adjustments.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced by about 33% when INTELENCE™ was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE™ and saquinavir/ritonavir can be co-administered without any dose adjustments.
Other Agents
Antiarrhythmics: amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE™. INTELENCE™ and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE™. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE™.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE™ should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE™.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Fluconazole has been shown to increase etravirine exposure by about 86%; fluconazole concentrations are not affected by co-administration of INTELENCE™. The incidence of adverse events was similar in patients coadministering fluconazole and INTELENCE™ or placebo in the Phase 3 trials. Voriconazole has been shown to increase etravirine exposure by about 36%; voriconazole exposure is increased 14% by co-administration of INTELENCE™. The combination of INTELENCE™ with fluconazole or voriconazole can be used without dose adjustments.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE™ may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE™. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE™; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE™ should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE™.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25- O -desacetylrifabutin	If INTELENCE™ is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE™ is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE™ with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A4 and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE™. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE™ with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE™. INTELENCE™ and products containing St. John's wort should not be co-administered.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE™ and atorvastatin can be given without any dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE™ is expected. Lovastatin and simvastatin are CYP3A4 substrates and co-administration with INTELENCE™ may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE™ may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE™ and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics: methadone	↔ etravirine ↔ methadone	INTELENCE™ and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, vardenafil, tadalafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE™ and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.

In addition to the drugs included in Table 4, the interaction between INTELENCE™ and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [ see Clinical Pharmacology ]: didanosine, enfuvirtide, ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.

OVERDOSAGE

There is no specific antidote for overdose with INTELENCE™. Human experience of overdose with INTELENCE™ is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with INTELENCE™ consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

CONTRAINDICATIONS

None