Etravirine

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 Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of Etravirine with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of Etravirine (see Table 4 ) [see Clinical Pharmacology (12.3) ].

7.2 Potential for Etravirine 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 may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4 ) [see Clinical Pharmacology (12.3) ].

7.3 Significant Drug Interactions Table 4 shows significant drug interactions based on which, alterations in dose or regimen of Etravirine and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Etravirine are also included in Table 4 [see Clinical Pharmacology (12.3) ] . 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 Etravirine 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 should only be used with Etravirine when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. dolutegravir/lopinavir /ritonavir ↔ dolutegravir ↔ etravirine 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 with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of Etravirine. Co-administration of Etravirine and other NNRTIs is not recommended.

delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. Etravirine and delavirdine should not be co-administered. rilpivirine ↓ rilpivirine ↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Co-administration of Etravirine and rilpivirine is not recommended. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) ↓ atazanavir Co-administration of Etravirine and atazanavir without low-dose ritonavir is not recommended. atazanavir/ritonavir ↓ atazanavir ↔ etravirine Concomitant use of Etravirine with atazanavir/ritonavir decreased atazanavir C min but it is not considered clinically relevant.

The mean systemic exposure (AUC) of etravirine after co-administration of Etravirine 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 and darunavir/ritonavir (as part of the background regimen). Etravirine and atazanavir/ritonavir can be co-administered without dose adjustments. atazanavir/cobicistat ↓ atazanavir ↓ cobicistat Co-administration of Etravirine with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir.

darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when Etravirine 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 and darunavir/ritonavir can be co-administered without dose adjustments. darunavir/cobicistat ↓ cobicistat darunavir: effect unknown Co-administration of Etravirine with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

fosamprenavir (without ritonavir) ↑ amprenavir Concomitant use of Etravirine with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of Etravirine and fosamprenavir without low-dose ritonavir is not recommended. fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of Etravirine and fosamprenavir/ritonavir have not been established. Co-administration of Etravirine and fosamprenavir/ritonavir is not recommended.

indinavir (without ritonavir) ↓ indinavir Concomitant use of Etravirine with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of Etravirine and indinavir without low-dose ritonavir is not recommended. lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of Etravirine 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 and lopinavir/ritonavir can be co-administered without dose adjustments. nelfinavir (without ritonavir) ↑ nelfinavir Concomitant use of Etravirine with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co-administration of Etravirine and nelfinavir without low-dose ritonavir is not recommended.

ritonavir ↓ etravirine Concomitant use of Etravirine with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of Etravirine. Co-administration of Etravirine and ritonavir 600 mg twice daily is not recommended. saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when Etravirine 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, Etravirine and saquinavir/ritonavir can be co-administered without dose adjustments. tipranavir/ritonavir ↓ etravirine Concomitant use of Etravirine with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of Etravirine. Co-administration of Etravirine and tipranavir/ritonavir is not recommended.

CCR5 antagonists maraviroc ↔ etravirine ↓ maraviroc When Etravirine is 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 is needed. maraviroc/darunavir/ ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. ↔ etravirine ↑ maraviroc When Etravirine is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily.

No dose adjustment of Etravirine is needed. Other agents Antiarrhythmics : digoxin ↔ etravirine ↑ digoxin For patients who are initiating a combination of Etravirine and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating Etravirine, no dose adjustment of either Etravirine 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.

amiodarone bepridil disopyramide flecainide lidocaine (systemic) mexiletine propafenone quinidine ↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with Etravirine. Etravirine and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to Etravirine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Prospective pregnancy data from clinical trials and the APR are not sufficient to adequately assess the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Etravirine use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show 1 birth defect in 66 first trimester exposures to etravirine-containing regimens (see Data ) . The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, no adverse developmental effects were observed with orally administered etravirine at exposures equivalent to those at the maximum recommended human dose (MRHD) of 400 mg daily (see Data ) . Data Human Data Based on prospective reports to the APR of 116 live births following exposure to etravirine-containing regimens during pregnancy (including 66 exposed in the first trimester and 38 exposed in the second/third trimester), the number of birth defects in live births for etravirine was 1 out of 66 with first trimester exposure and 0 out of 38 with second/third trimester exposure.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to Etravirine is compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes. Etravirine (200 mg twice daily) in combination with other antiretroviral agents was evaluated in a clinical trial enrolling 15 pregnant subjects during the second and third trimesters of pregnancy and postpartum.

Thirteen subjects completed the trial through postpartum period (6–12 weeks after delivery). The pharmacokinetic data demonstrated that…