Intelence (Page 3 of 9)

6.2 Postmarketing Experience

The following events have been identified during postmarketing use of INTELENCE. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported [see Warnings and Precautions (5.1)].

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.1)].

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect INTELENCE

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

7.2 Potential for INTELENCE 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 INTELENCE 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 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 [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
*
The interaction between INTELENCE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir.
HIV-antiviral agents: integrase strand inhibitors
dolutegravir * ↓ 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 INTELENCE 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 INTELENCE with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE. Co-administration of INTELENCE and other NNRTIs is not recommended.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. INTELENCE and delavirdine should not be co-administered.
rilpivirine ↓ rilpivirine↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Co-administration of INTELENCE and rilpivirine is not recommended.
HIV-antiviral agents: protease inhibitors (PIs)
atazanavir *(without ritonavir) ↓ atazanavir Co-administration of INTELENCE and atazanavir without low-dose ritonavir is not recommended.
atazanavir/ritonavir * ↓ atazanavir↔ etravirine Concomitant use of INTELENCE with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE 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 INTELENCE and darunavir/ritonavir (as part of the background regimen). INTELENCE and atazanavir/ritonavir can be co-administered without dose adjustments.
atazanavir/cobicistat ↓ atazanavir↓ cobicistat Co-administration of INTELENCE 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 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.
darunavir/cobicistat ↓ cobicistatdarunavir: effect unknown Co-administration of INTELENCE 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 INTELENCE with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of INTELENCE 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 INTELENCE and fosamprenavir/ritonavir have not been established. Co-administration of INTELENCE and fosamprenavir/ritonavir is not recommended.
indinavir *(without ritonavir) ↓ indinavir Concomitant use of INTELENCE with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of INTELENCE 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 INTELENCE 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, INTELENCE and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir(without ritonavir) ↑ nelfinavir Concomitant use of INTELENCE with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co-administration of INTELENCE and nelfinavir without low-dose ritonavir is not recommended.
ritonavir * ↓ etravirine Concomitant use of INTELENCE with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE. Co-administration of INTELENCE and ritonavir 600 mg twice daily is not recommended.
saquinavir/ritonavir * ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced 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 dose adjustments.
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. Co-administration of INTELENCE and tipranavir/ritonavir is not recommended.
CCR5 antagonists
maraviroc * ↔ etravirine↓ maraviroc When INTELENCE 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 INTELENCE is needed.
maraviroc/darunavir/ritonavir * ↔ etravirine↑ maraviroc When INTELENCE 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 INTELENCE is needed.
Other agents
Antiarrhythmics: digoxin * ↔ etravirine↑ digoxin For patients who are initiating a combination of INTELENCE and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE, no dose adjustment of either INTELENCE 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.
amiodaronebepridildisopyramideflecainidelidocaine (systemic)mexiletinepropafenonequinidine ↓ 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.
Anticoagulant: 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:carbamazepinephenobarbitalphenytoin ↓ 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 * ↑ etravirine↔ fluconazole 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 INTELENCE or fluconazole is needed.
voriconazole * ↑ voriconazole 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 INTELENCE or voriconazole is needed.
Antifungals:itraconazoleketoconazoleposaconazole ↑ 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.
Antiinfective: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.
Antimalarial:artemether/lumefantrine * ↔ etravirine↓ artemether↓ dihydroartemisinin↓ lumefantrine Caution is warranted when co-administering INTELENCE 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 INTELENCE.
Antimycobacterials: rifampinrifapentine ↓ 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.
Antimycobacterial: 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 once daily 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.
Benzodiazepine: diazepam ↑ diazepam Concomitant use of INTELENCE 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 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.
Hepatitis C virus (HCV) direct-acting antivirals:
daclatasvir ↓ daclatasvir Co-administration of INTELENCE with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily.
elbasvir/grazoprevir ↓ elbasvir↓ grazoprevir Co-administration of INTELENCE 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 INTELENCE with simeprevir may decrease simeprevir concentrations. Co-administration is not recommended.
HMG-CoA reductase inhibitors:atorvastatin * ↔ etravirine↓ atorvastatin↑ 2-OH-atorvastatin The combination of INTELENCE and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.
pravastatinrosuvastatin ↔ etravirine↔ pravastatin↔ rosuvastatin No interaction between pravastatin, rosuvastatin and INTELENCE is expected.
lovastatinsimvastatin ↓ lovastatin↓ simvastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE may result in lower plasma concentrations of the HMG-CoA reductase inhibitor.
fluvastatinpitavastatin ↑ fluvastatin↑ pitavastatin Fluvastatin and pitavastatin are 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:cyclosporinesirolimustacrolimus ↓ immunosuppressant INTELENCE 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: buprenorphinebuprenorphine/naloxone *methadone * ↔ etravirine↓ buprenorphine↔ norbuprenorphine↔ methadone INTELENCE 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.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 *tadalafilvardenafil ↓ 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.
Platelet aggregation inhibitors: clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE. Alternatives to clopidogrel should be considered.

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