Drugs affecting the concentration of etravirin in plasma
Etravirine is metabolised isozymes CYP3A4, CYP2C9 and CYP2C19, and its metabolites undergo glucuronidation under the influence of the enzyme uridindifosfatglyukuronozil transferase. Drugs that induce isozymes CYP3A4, CYP2C9 or CYP2C19, can accelerate the clearance of etravirine, thereby reducing its concentration in plasma.
Simultaneous use of the drug Intelens® and drugs that inhibit isozymes CYP3A4, CYP2C9 or CYP2C19, etravirine may slow clearance and increase its concentration in plasma.
Medicines, the metabolism of which is affected by etravirine
Etravirine is a weak inducer of the isoenzyme CYP3A4. The simultaneous use of the preparation of Intelence® and preparations that are metabolized mainly by the isoenzyme CYP3A4, can lead to a decrease in the concentrations of such drugs in the plasma and, consequently, to weaken or shorten their therapeutic effects.
Besides, etravirine is a weak inhibitor of the isoenzymes CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein, but is not its substrate.
The simultaneous use of etravirine and preparations that are metabolized mainly by CYP2C9 or CYP2C19 isoenzymes or transported by P-glycoprotein can increase the concentration of such drugs in plasma and, therefore, enhance or prolong their therapeutic or side effects.
Drug interactions of etravirine with other antiretroviral drugs Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (eg, efavirenz, nevirapine, delavirdine, rilpivirine)
It is not recommended to use Intelence® at the same time as other non-nucleoside reverse transcriptase inhibitors.
Nucleoside reverse transcriptase inhibitors (NRTIs)
- Didanosine (400 mg once a day): the combination can be used without dose adjustment.
Didanosine is taken on an empty stomach, and therefore it must be taken 1 hour before or 2 hours after taking the drug Intelence® (which should be taken after meals).
- Tenofovir (300 mg once a day): the combination can be used without dose adjustment.
- Others (for example: abacavir, emtricitabine, lamivudine, stavudine and zidovudine) are eliminated mainly by the kidneys, and therefore it is considered that etravirine does not interact with these drugs. These combinations can be used without dose adjustment.
Protease inhibitors without concurrent administration of low-dose ritonavir
- Atazanavir (400 mg once a day): not recommended at the same time atazanavir without simultaneous administration of low-dose ritonavir and Intelence® (atazanavir concentration decreases by 47%, etravirin concentration increases by 58%).
- Ritonavir: a combination of the drug Intelens® with a full dose of ritonavir (600 mg twice daily) can cause a significant decrease in plasma etravirine.This can lead to a loss of the therapeutic effect of the drug Intelence®. Given this, it is not recommended to simultaneously use the full dose of ritonavir and Intelence®.
- Nelfinavir: simultaneous use can cause an increase in the concentration of nelfinavir in the plasma. It is not recommended simultaneous use of the drug Intelens® with nelfinavir.
- Indinavir: simultaneous use can cause a significant decrease in the concentration of indinavir in the blood plasma and a decrease in the therapeutic effect of indinavir. It is not recommended simultaneous use of the preparation of Intelence® with indinavir.
- Fosamprenavir: simultaneous use may cause an increase in the concentration of amprenavir in plasma.
- Others: It is not recommended to use the preparation of Intelence ® with other protease inhibitors without simultaneous reception of a low dose of ritonavir (including saquinavir).
Protease inhibitors with simultaneous administration of ritonavir
- Tipranavir / ritonavir (500/200 mg twice daily): it is not recommended to simultaneously use the combination of tipranavir / ritonavir and Intelence® (the concentration of tipranavir is increased by 24%, the concentration of etravirine is reduced by 82%).
- Fosamprenavir / ritonavir (700/100 mg twice daily): with the simultaneous use of the drug Intelens® and fosamprenavir / ritonavir combination, dosage adjustment of these drugs may be required.
- Atazanavir / ritonavir (300/100 mg once a day): Intelence® can be used concomitantly with the combination of atazanavir / ritonavir without dose adjustment.
- Darunavir / ritonavir (600/100 mg twice daily): Intelence® can be used concomitantly with the darunavir / ritonavir combination without dose adjustment.
- Lopinavir / ritonavir (soft gelatin capsules, tablets) (400/100 mg twice daily): Intelence® can be used concurrently with a combination of lopinavir / ritonavir without dose adjustment.
- Saquinavir / ritonavir (soft gelatin capsules) (1000/100 mg twice daily): Intellans® can be used concomitantly with a combination of saquinavir / ritonavir without dose adjustment.
Combination of two protease inhibitors with simultaneous administration of ritonavir
- Lopinavir / saquinavir / ritonavir (400/800 - 1000/100 mg twice daily): Intellans® can be used concomitantly with a combination of lopinavir / saquinavir / ritonavir without dose adjustment.
CCR5 receptor antagonists
- Maraviroc (300 mg 2 times a day): with the simultaneous use of the drug Intelens® and maraviroc, a significant decrease in the concentration of maraviroc in plasma may occur.
With the simultaneous administration of Intelence® with maraviroc in the absence of a potent CYP3A isoenzyme inhibitor (eg, protease inhibitors with simultaneous ritonavir administration), the recommended dose of maraviroc is 600 mg twice daily. No changes in the Intellence® dose are required.
- Maraviroc / darunavir / ritonavir (150/600/100 mg twice daily): In the case of using Intelens® and maraviroc together with a potent inhibitor of CYP3A isoenzymes (eg with a protease inhibitor with simultaneous ritonavir intake), to change the dose of maraviroc, refer to the appropriate instructions for medical use, given that Intelence® exhibits the properties of an inducer of CYP3A isoenzymes (similar to efavirenz). No changes in the Intellence® dose are required.
Inhibitors of fusion
- Enfuvirtide (90 mg 2 times a day): it is assumed that with the simultaneous use of Intelence® and enfuvirtide they will not interact with each other.
Integrase inhibitors
- Dolutegravir (50 mg once daily), dolutegravir / darunavir / ritonavir (50 mg once daily +
600/100 mg twice daily), dolutegravir / lopinavir / ritonavir (50 mg once daily + 400/100 mg twice daily): etravirine significantly reduces the concentration of dolutegravir in plasma. Based on a comparison of the data obtained with the data of pharmacokinetic studies of etravirine, it can be assumed that dolutegravir does not affect the pharmacokinetics of etravirine. The effect of etravirine on the concentration of dolutegravir in plasma is reduced with the simultaneous use of darunavir / ritonavir or lopinavir / ritonavir combinations, and is likely to decrease with atazanavir / ritonavir combination. Dolutegravir can be used concomitantly with the preparation of Intelence® only in case of simultaneous application of the combination atazanavir / ritonavir, darunavir / ritonavir or lopinavir / ritonavir.
- Elvitegravir / ritonavir (150/100 mg once a day): a combination of Intelence® and elvitegravir / ritonavir can be used without dose adjustment.
- Raltegravir (400 mg twice daily): the combination of Intelence® and raltegravir can be used without dose adjustment.
Drug Interactions Intelence® with other drugs
Antiarrhythmics
- Digoxin (0.5 mg once): a combination of digoxin and Intelence® preparation can be used without dose changes.It is recommended to monitor the concentration of digoxin in plasma.
- Amiodarone, bepridil, disopyramid, flecainide, lidocaine (intravenously), mexiletine, propafenone, quinidine: concentrations of these antiarrhythmic agents may decrease when they are used concomitantly with the preparation of Intelence®. With the simultaneous use of the drug Intelens ® and antiarrhythmic drugs should be careful and, if possible, monitor the concentrations of the latter in the plasma.
Anticoagulants
- Warfarin: the concentrations of warfarin may vary with its application at the same time as Intelence®. It is recommended to monitor the international normalized ratio while using warfarin and Intelence®.
Anticonvulsants (carbamazepine, phenobarbital, phenytoin): are inducers of isoenzymes of the CYP450 system. Intelence® can not be used concomitantly with these drugs, as this can cause a significant decrease in plasma etravirin concentrations, which in turn can lead to a loss of the therapeutic effect of Intelence®.
Antifungal means:
- Fluconazole (200 mg once daily in the morning): the incidence of side effects in patients taking fluconazole and the preparation of Intelence®, is comparable to that of patients receiving fluconazole and placebo. Simultaneous use of the preparation Intellens® and fluconazole can be carried out without changes in the doses.
- Voriconazole (200 mg twice a day): the simultaneous use of the drug Intelens® and voriconazole can be carried out without changing the dose.
- Itraconazole, ketoconazole, posaconazole: posaconazole is a potent inhibitor of CYP3A4 isoenzymes and can cause an increase in plasma etravirin concentrations. Itraconazole and ketoconazole also are the substrates of the isoenzyme CYP3A4. Simultaneous use of the preparation of Intelence® and itraconazole or ketoconazole may lead to an increase in the concentration of etravirin in the plasma. And concurrently, the concentrations of itraconazole or ketoconazole in plasma may decrease under the influence of etravirine. Simultaneous application of these agents and the preparation of Intelence® can be carried out without changes in the doses.
Antimalarials
Artemether / lumefantrine (80/480 mg, 6 doses according to the schedule: 0 h, 8 h, 24 h, 36 h, 48 h, 60 h): no dose adjustment is required while taking Intellens® and artemether / lumefantrine.Nevertheless, caution should be exercised while taking these medications at the same time, since it is not known whether a decrease in the exposure of artemether or its active metabolite dihydroartemisinin can lead to a decrease in antimalarial activity.
Anti-TB drugs:
- Rifampicin, rifapentin are strong inducers of CYP450 isoenzymes.
Intelence® should not be used in combination with rifampicin and rifapentin, as this can cause a significant decrease in plasma etravirin concentrations and, therefore, lead to a loss of its therapeutic effect.
- Rifabutin (300 mg once a day): if Intelence® is not used concomitantly with a protease inhibitor, an enhanced dose of ritonavir, then Intelence® and rifabutin can be used without dose adjustment. If you simultaneously use Intelens® with darunavir, lopinavir or saquinavir with simultaneous administration of ritonavir, caution should be exercised rifabutin in connection with the possible significant reduction in the concentration of etravirin in plasma. In such cases, the dose of rifabutin should be given in accordance with the instructions in the instructions for the medical use of protease inhibitors.
Antibacterials:
- Proceeding from the fact that azithromycin Eliminated with bile, no drug interactions between azithromycin and Intelence® are expected. Simultaneous use of azithromycin and Intelence® preparation can be carried out without correction of the doses of both drugs.
- Clarithromycin (500 mg twice daily): etravirine decreased the concentration of clarithromycin in plasma by 53%; At the same time, the concentration of the active metabolite, 14-hydroxyclarithromycin, increased by 46%. Since 14-hydroxyclarithromycin has a reduced activity against the complex Mycobacterium avium complex (MAS), the overall activity of clarithromycin and its metabolite against this pathogen can change. Therefore, for the treatment of infections caused by MAS, it is desirable to use a means alternative to clarithromycin, for example, azithromycin.
Benzodiazepines
Diazepam: the use of etravirine simultaneously with diazepam may increase the concentration of the latter in plasma.
Glucocorticosteroids
Dexamethasone for systemic use: dexamethasone induces the isoenzyme CYP3A4 and can reduce plasma etravirin concentrations. A consequence of this may be the loss of the therapeutic effect of Intelence®. Dexamethasone (for systemic use) should be used with caution or alternatives, especially with prolonged therapy.
Contraceptives based on estrogens (ethinyl estradiol, norethisterone): a combination of contraceptives based on estrogen and / or progesterone and Intelence® can be used without dose adjustment.
Antiviral drugs
- Boceprevir (800 mg 3 times a day): with the simultaneous use of the preparation of Intelence® and boceprevira, dose adjustment is not required. With the simultaneous use of the drug Intelence® and boceprevir, or another drug that can reduce the concentration of etravirin in plasma, caution should be exercised. It is recommended to carefully monitor the virologic response to the treatment of the hepatitis C virus and HIV.
Refer for information on the instructions for use of the drug.
- Ribavirin is eliminated by the kidneys, and therefore it most likely does not interact with the preparation of Intelence®.
- Telaprevir (750 mg every 8 hours): no simultaneous use of Intelence® and telaprevir is required.
Drugs containing St. John's wortHypericum perforatum): St. John's wort (Hypericum perforatum) is a strong inducer of cytochrome P450 isoenzymes. Intelence® should not be used concomitantly with preparations containing St. John's wort, as this can lead to a significant decrease in plasma etravirin concentrations and a loss of its therapeutic effect.
Inhibitors of reductase HMG-KoA (statins):
- Atorvastatin (40 mg once a day): with the simultaneous administration of Intelence® and atorvastatin, the dose of the latter must be adjusted to achieve the desired clinical effect (atorvastatin concentration decreases by 37%, the concentration of 2-hydroxyorthovastatin increases by 27%).
- Pravastatin, most likely, does not interact with Intelence®.
- Lovastatin, rosuvastatin and simvastatin are substrates of CYP3A4 and simultaneous use of these drugs with etravirine can cause a decrease in their concentrations in the plasma.
- Fluvastatin, rosuvastatin and, to a lesser extent, Pitavastatin is metabolized by the CYP2C9 isoenzyme and their simultaneous use with the preparation of Intelence® can lead to an increase in the plasma concentrations of statins. You may need to adjust their dose.
Blockers H2-receptors
Ranitidine (150 mg 2 times a day): can be used simultaneously without dose adjustment.
Immunosuppressive drugs:
Cyclosporine, sirolimus, tacrolimus: caution should be exercised when using Intelence® concurrently with systemic immunosuppressants, since etravirine can change their concentration in the plasma.
Narcotic analgesics:
Methadone (60-130 mg per day): during simultaneous use with the preparation of Intelence® and after that there was no need to correct the dose of methadone.
Inhibitors of phosphodiesterase type 5 (inhibitors PDE-5)
Sildenafil, vardenafil, tadalafil (50 mg per day): concomitant use of PDE5 and Intelence® inhibitors may require correction of the dose of PDE5 inhibitors in order to achieve the desired clinical effect (sildenafil and N-desmethyl-sildenafil concentrations decreased by 57% and 41%, respectively).
Clopidogrel
The conversion of clopidogrel to its active metabolite can be reduced by the combined use of clopidogrel with Intelence®. Alternative treatment options should be considered.
Proton Pump Inhibitors:
Omeprazole (40 mg once a day): can be used without dose adjustment.
Selective serotonin reuptake inhibitors:
Paroxetine (40 mg once a day): can be used without dose adjustment.