ETRAVIRINE Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
INTERACTIONS Co-administration of etravirine with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of etravirine. The potential drug-drug interactions must be considered prior to and during therapy. ( 7 , 12.3 )
7.1 Potential for Other Drugs to Affect Etravirine Tablets Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine tablets with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine tablets (see Table 4) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
7.2 Potential for Etravirine Tablets to Affect Other Drugs Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine tablets may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
7.3 Significant Drug Interactions Table 4 shows significant drug interactions based on which, alterations in dose or regimen of etravirine tablets and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with etravirine tablets are also included in Table 4 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
Table
4: Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment ↑ = increase; ↓ = decrease; ↔ = no change HIV-antiviral agents: integrase strand inhibitors dolutegravir The interaction between INTELENCE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ dolutegravir ↔ etravirine Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross - study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine. dolutegravir/darunavir/ritonavir ↓ dolutegravir ↔ etravirine The effect of etravirine on dolutegravir plasma concentrations was mitigated by co- administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. dolutegravir/lopinavir/ritonavir ↔ dolutegravir ↔ etravirine Dolutegravir should only be used with etravirine tablets when co- administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. HIV-antiviral agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz nevirapine ↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine tablets with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and other NNRTIs is not recommended. delavirdine rilpivirine ↓ etravirine ↓ rilpivirine ↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Etravirine tablets and delavirdine should not be co-administered. Combining two NNRTIs has not been shown to be beneficial. Co- administration of etravirine tablets and rilpivirine is not recommended. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) atazanavir/ritonavir atazanavir/cobicistat darunavir/ritonavir darunavir/cobicistat fosamprenavir (without ritonavir) fosamprenavir/ritonavir indinavir (without ritonavir) lopinavir/ritonavir ↓ atazanavir ↓ atazanavir ↔ etravirine ↓ atazanavir ↓ cobicistat ↓ etravirine ↓ cobicistat darunavir: effect unknown ↑ amprenavir ↑ amprenavir ↓ indinavir ↓ etravirine Co-administration of etravirine tablets and atazanavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of etravirine tablets with atazanavir/ritonavir in HIV-infected subjects was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen). Etravirine tablets and atazanavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets 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, etravirine tablets and darunavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. Concomitant use of etravirine tablets with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of etravirine tablets and fosamprenavir without low-dose ritonavir is not recommended. Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of etravirine tablets and fosamprenavir /ritonavir have not been established. Co- administration of etravirine tablets and fosamprenavir/ritonavir is not recommended. Concomitant use of etravirine tablets with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of etravirine tablets and indinavir without low- dose ritonavir is not recommended. The mean systemic exposure (AUC) of Etravirine was reduced after co-administration of etravirine tablets with lopinavir/ritonavir (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, etravirine tablets and lopinavir/ritonavir can be co-administered without dose adjustments. nelfinavir (without ritonavir) ritonavir saquinavir/ritonavir tipranavir/ritonavir ↑ nelfinavir ↓ etravirine ↓ etravirine ↓ etravirine Concomitant use of etravirine tablets with nelfinavir without low- dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co- administration of etravirine tablets and nelfinavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and ritonavir 600 mg twice daily is not recommended. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets were 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, etravirine tablets and saquinavir/ritonavir can be co-administered without dose adjustments. Concomitant use of etravirine tablets with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and tipranavir/ritonavir is not recommended. CCR5 antagonists maraviroc maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. ↔ etravirine ↓ maraviroc ↑ maraviroc When etravirine tablets are co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of etravirine tablets is needed. When etravirine tablets are co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of etravirine tablets is needed. Other agents Antiarrhythmics : digoxin amiodarone bepridil disopyramide flecainide lidocaine (systemic) mexiletine propafenone quinidine ↔ etravirine ↑ digoxin ↓ antiarrhythmics For patients who are initiating a combination of etravirine tablets and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating etravirine tablets, no dose adjustment of either etravirine tablets or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. Concentrations of these antiarrhythmics may be decreased when co- administered with etravirine tablets. Etravirine tablets and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. Anticoagulant : warfarin ↑ anticoagulants Warfarin concentrations may be increased when co-administered with etravirine tablets. The international normalized ratio (INR) should be monitored when warfarin is combined with etravirine tablets. Anticonvulsants : carbamazepine phenobarbital phenytoin ↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. Etravirine tablets should not with carbamazepine, phenobarbital, or phenytoin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Antifungals : fluconazole voriconazole ↑ etravirine ↔ fluconazole voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of etravirine tablets or fluconazole is needed. Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of etravirine tablets or voriconazole is needed. 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 etravirine tablets may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine tablets.
Dose
Adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co- administered drugs. Antiinfective : clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH- clarithromycin Clarithromycin exposure was decreased by etravirine tablets; 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. Antimalarial : artemether/lumefantrine ↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Caution is warranted when co-administering etravirine tablets and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for etravirine tablets. Antimycobacterials: rifampin rifapentine ↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. Etravirine tablets 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 etravirine tablets. Antimycobacterial: rifabutin ↓ etravirine ↓ rifabutin ↓ 25- O - desacetylrifabutin If etravirine tablets are NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If etravirine tablets are 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. Benzodiazepine: diazepam ↑ diazepam Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. Corticosteroid : dexamethasone (systemic) ↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine tablets. 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 etravirine tablets with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Etravirine tablets and products containing St. John's wort should not be co-administered. Hepatitis C virus (HCV) direct-acting antivirals : daclatasvir ↓ daclatasvir Co-administration of etravirine tablets with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily. elbasvir/grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration of etravirine tablets with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir. Co-administration is not recommended. simeprevir ↓ simeprevir Co-administration of etravirine tablets with simeprevir may decrease simeprevir concentrations. Co- administration is not recommended. HMG-CoA reductase inhibitors : atorvastatin ↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin The combination of etravirine tablets and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. pravastatin rosuvastatin ↔ etravirine ↔ pravastatin ↔ rosuvastatin No interaction between pravastatin, rosuvastatin and etravirine tablets are expected. Lovastatin simvastatin fluvastatin pitavastatin ↓ lovastatin ↓ simvastatin ↑ fluvastatin ↑ pitavastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with etravirine tablets 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 Etravirine tablets and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. Narcotic analgesics/treatment of opioid dependence: buprenorphine buprenorphine/naloxone methadone ↔ etravirine ↓ buprenorphine ↔ Norbuprenorphine ↔ methadone Etravirine tablets and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. Etravirine tablets 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 tadalafil vardenafil ↓ sildenafil ↓ N-desmethyl- sildenafil Etravirine tablets and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. Platelet aggregation inhibitors: clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co- administered with etravirine tablets. Alternatives to clopidogrel should be considered.
7.4 Drugs Without Clinically Significant Interactions with Etravirine Tablets In addition to the drugs included in Table 4, the interaction between etravirine tablets and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> : didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.
7.1 Potential for Other Drugs to Affect Etravirine Tablets Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine tablets with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine tablets (see Table 4) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
7.2 Potential for Etravirine Tablets to Affect Other Drugs Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine tablets may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.
7.3 Significant Drug Interactions Table 4 shows significant drug interactions based on which, alterations in dose or regimen of etravirine tablets and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with etravirine tablets are also included in Table 4 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
Table
4: Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment ↑ = increase; ↓ = decrease; ↔ = no change HIV-antiviral agents: integrase strand inhibitors dolutegravir The interaction between INTELENCE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ dolutegravir ↔ etravirine Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross - study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine. dolutegravir/darunavir/ritonavir ↓ dolutegravir ↔ etravirine The effect of etravirine on dolutegravir plasma concentrations was mitigated by co- administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. dolutegravir/lopinavir/ritonavir ↔ dolutegravir ↔ etravirine Dolutegravir should only be used with etravirine tablets when co- administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. HIV-antiviral agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz nevirapine ↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine tablets with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and other NNRTIs is not recommended. delavirdine rilpivirine ↓ etravirine ↓ rilpivirine ↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Etravirine tablets and delavirdine should not be co-administered. Combining two NNRTIs has not been shown to be beneficial. Co- administration of etravirine tablets and rilpivirine is not recommended. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) atazanavir/ritonavir atazanavir/cobicistat darunavir/ritonavir darunavir/cobicistat fosamprenavir (without ritonavir) fosamprenavir/ritonavir indinavir (without ritonavir) lopinavir/ritonavir ↓ atazanavir ↓ atazanavir ↔ etravirine ↓ atazanavir ↓ cobicistat ↓ etravirine ↓ cobicistat darunavir: effect unknown ↑ amprenavir ↑ amprenavir ↓ indinavir ↓ etravirine Co-administration of etravirine tablets and atazanavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of etravirine tablets with atazanavir/ritonavir in HIV-infected subjects was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen). Etravirine tablets and atazanavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets 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, etravirine tablets and darunavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. Concomitant use of etravirine tablets with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of etravirine tablets and fosamprenavir without low-dose ritonavir is not recommended. Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of etravirine tablets and fosamprenavir /ritonavir have not been established. Co- administration of etravirine tablets and fosamprenavir/ritonavir is not recommended. Concomitant use of etravirine tablets with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of etravirine tablets and indinavir without low- dose ritonavir is not recommended. The mean systemic exposure (AUC) of Etravirine was reduced after co-administration of etravirine tablets with lopinavir/ritonavir (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, etravirine tablets and lopinavir/ritonavir can be co-administered without dose adjustments. nelfinavir (without ritonavir) ritonavir saquinavir/ritonavir tipranavir/ritonavir ↑ nelfinavir ↓ etravirine ↓ etravirine ↓ etravirine Concomitant use of etravirine tablets with nelfinavir without low- dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co- administration of etravirine tablets and nelfinavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and ritonavir 600 mg twice daily is not recommended. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets were 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, etravirine tablets and saquinavir/ritonavir can be co-administered without dose adjustments. Concomitant use of etravirine tablets with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and tipranavir/ritonavir is not recommended. CCR5 antagonists maraviroc maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. ↔ etravirine ↓ maraviroc ↑ maraviroc When etravirine tablets are co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of etravirine tablets is needed. When etravirine tablets are co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of etravirine tablets is needed. Other agents Antiarrhythmics : digoxin amiodarone bepridil disopyramide flecainide lidocaine (systemic) mexiletine propafenone quinidine ↔ etravirine ↑ digoxin ↓ antiarrhythmics For patients who are initiating a combination of etravirine tablets and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating etravirine tablets, no dose adjustment of either etravirine tablets or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. Concentrations of these antiarrhythmics may be decreased when co- administered with etravirine tablets. Etravirine tablets and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. Anticoagulant : warfarin ↑ anticoagulants Warfarin concentrations may be increased when co-administered with etravirine tablets. The international normalized ratio (INR) should be monitored when warfarin is combined with etravirine tablets. Anticonvulsants : carbamazepine phenobarbital phenytoin ↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. Etravirine tablets should not with carbamazepine, phenobarbital, or phenytoin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Antifungals : fluconazole voriconazole ↑ etravirine ↔ fluconazole voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of etravirine tablets or fluconazole is needed. Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of etravirine tablets or voriconazole is needed. 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 etravirine tablets may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine tablets.
Dose
Adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co- administered drugs. Antiinfective : clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH- clarithromycin Clarithromycin exposure was decreased by etravirine tablets; 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. Antimalarial : artemether/lumefantrine ↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Caution is warranted when co-administering etravirine tablets and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for etravirine tablets. Antimycobacterials: rifampin rifapentine ↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. Etravirine tablets 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 etravirine tablets. Antimycobacterial: rifabutin ↓ etravirine ↓ rifabutin ↓ 25- O - desacetylrifabutin If etravirine tablets are NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If etravirine tablets are 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. Benzodiazepine: diazepam ↑ diazepam Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. Corticosteroid : dexamethasone (systemic) ↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine tablets. 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 etravirine tablets with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Etravirine tablets and products containing St. John's wort should not be co-administered. Hepatitis C virus (HCV) direct-acting antivirals : daclatasvir ↓ daclatasvir Co-administration of etravirine tablets with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily. elbasvir/grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration of etravirine tablets with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir. Co-administration is not recommended. simeprevir ↓ simeprevir Co-administration of etravirine tablets with simeprevir may decrease simeprevir concentrations. Co- administration is not recommended. HMG-CoA reductase inhibitors : atorvastatin ↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin The combination of etravirine tablets and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. pravastatin rosuvastatin ↔ etravirine ↔ pravastatin ↔ rosuvastatin No interaction between pravastatin, rosuvastatin and etravirine tablets are expected. Lovastatin simvastatin fluvastatin pitavastatin ↓ lovastatin ↓ simvastatin ↑ fluvastatin ↑ pitavastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with etravirine tablets 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 Etravirine tablets and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. Narcotic analgesics/treatment of opioid dependence: buprenorphine buprenorphine/naloxone methadone ↔ etravirine ↓ buprenorphine ↔ Norbuprenorphine ↔ methadone Etravirine tablets and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. Etravirine tablets 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 tadalafil vardenafil ↓ sildenafil ↓ N-desmethyl- sildenafil Etravirine tablets and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. Platelet aggregation inhibitors: clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co- administered with etravirine tablets. Alternatives to clopidogrel should be considered.
7.4 Drugs Without Clinically Significant Interactions with Etravirine Tablets In addition to the drugs included in Table 4, the interaction between etravirine tablets and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> : didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.
Contraindications
None. None. ( 4 )
Related Warnings
AND PRECAUTIONS Severe, potentially life threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, toxic epidermal necrolysis and erythema multiforme. Immediately discontinue treatment if severe hypersensitivity, severe rash or rash with systemic symptoms or liver transaminase elevations develops and monitor clinical status, including liver transaminases closely. ( 5.1 ) Monitor for immune reconstitution syndrome and fat redistribution. ( 5.3, 5.4 )
5.1 Severe Skin and Hypersensitivity Reactions Severe, potentially life-threatening and fatal skin reactions have been reported. In clinical trials, these include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure.
In Phase
3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving etravirine compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving etravirine discontinued from Phase 3 trials due to rash [see Adverse Reactions (6.1 )] . Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females [see Adverse Reactions (6.1) ] . Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving etravirine in combination with other HIV-1 antiretroviral agents in an observational study. Discontinue etravirine immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping etravirine treatment after the onset of severe rash may result in a life-threatening reaction.
5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of etravirine and other drugs may result in potentially significant drug interactions, some of which may lead to <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span>: Loss of therapeutic effect of concomitant drug or etravirine and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of etravirine or other concomitant drugs.
See Table
4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during etravirine therapy and review concomitant medications during etravirine therapy.
5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including etravirine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.4 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.1 Severe Skin and Hypersensitivity Reactions Severe, potentially life-threatening and fatal skin reactions have been reported. In clinical trials, these include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure.
In Phase
3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving etravirine compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving etravirine discontinued from Phase 3 trials due to rash [see Adverse Reactions (6.1 )] . Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females [see Adverse Reactions (6.1) ] . Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving etravirine in combination with other HIV-1 antiretroviral agents in an observational study. Discontinue etravirine immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping etravirine treatment after the onset of severe rash may result in a life-threatening reaction.
5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of etravirine and other drugs may result in potentially significant drug interactions, some of which may lead to <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span>: Loss of therapeutic effect of concomitant drug or etravirine and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of etravirine or other concomitant drugs.
See Table
4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during etravirine therapy and review concomitant medications during etravirine therapy.