Interactions Between …

1 Interactions Between Sedatives/ hypnotics / anxiolytics and Antiretrovirals antiretroviral Pharmacokinetic Characteristics (summary): Protease Inhibitors (PIs) Non-Nucleoside Reverse Transcriptase Integrase Inhibitors Inhibitors (NNRTIs). atazanavir (Reyataz )1, darunavir efavirenz (Sustiva )10, etravirine dolutegravir (Tivicay ),14, elvitegravir/cobicistat (Prezista )2, fosamprenavir (Telzir )3, (Intelence )11, nevirapine (Viramune )12, (Stribild , single-tablet regimen with indinavir (Crixivan )4, lopinavir/ritonavir rilpivirine (Edurant )13 tenofovir/emtricitabine)15, raltegravir (Kaletra )5, nelfinavir (Viracept )6, ritonavir (Isentress )16. (Norvir )7, saquinavir (Invirase )8, tipranavir (Aptivus )9. Metabolism Mainly CYP3A4 Efavirenz, nevirapine: CYP3A4, 2B6 Dolutegravir: UGT1A1, CYP3A4 (10-15%).

2 (minor). Elvitegravir: CYP3A, UGT1A1/3. Etravirine: CYP3A4, CYP2C9, and CYP2C19. Cobicistat: CYP3A, 2D6 (minor). Rilpivirine: CYP3A4 (major), as well as Raltegravir: UGT1A1. CYP2C19, 1A2, 2C8/9/10 (minor). Hepatic Inhibitor Mainly CYP3A4 (darunavir, indinavir, Efavirenz: 2C9, 2C1910 (? Clinical Cobicistat: CYP3A, CYP2D6; also p- nelfinavir, amprenavir >> saquinavir) significance). glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Atazanavir: 3A4, UGT1A1 >>2C8 (weak) Etravirine11: CYP2C9 (weak), CYP2C19. (moderate), p-glycoprotein (weak) Dolutegravir inhibits the renal organic cation Caution when unboosted atazanavir is transporter, coadministered with drugs that are 2C8. Delavirdine (Rescriptor ):20 3A4 (potent). substrates with narrow therapeutic indices Raltegravir has no inhibitory or inductive ( , paclitaxel, repaglinide); clinically potential in significant Interactions with 2C8 substrates are not expected when atazanavir is boosted with ritonavir.

3 Nelfinavir: 2B6 in vitro. Ritonavir: CYP3A4 (potent)> >2D6 >2C9. >2C19 >2A6 >1A2>2E1. At low boosting doses, ritonavir has a negligible effect in CYP2D6 Ritonavir inhibits CYP2B6 in vitro,17 but induces 2B6 in Tipranavir: 2D619. Hepatic Inducer Nelfinavir: UGT, 2B6, 2C8, 2C9/1921 Efavirenz: 3A4 (potent), 2B622 and Dolutegravir does not induce CYP1A2, UGT1A123 CYP2B6, or CYP3A4 in Ritonavir: UGT, CYP1A2, CYP2C9/19, 2B6. Prepared by: Michelle Foisy, , Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, & Alice Tseng, , Toronto General Hospital August 2013 Page 1 o f 9. Interactions Between Sedatives/ hypnotics / anxiolytics and Antiretrovirals Protease Inhibitors (PIs) Non-Nucleoside Reverse Transcriptase Integrase Inhibitors Inhibitors (NNRTIs).

4 Tipranavir: mixed induction/inhibition Etravirine11: 3A4 (weak) Elvitegravir: CYP2C9 (modest). effects; often acts as inducer of CYP3A4. (potent) and UGT, even when boosted with Nevirapine12: 3A4, 2B6 (potent) Raltegravir has no inhibitory or inductive ritonavir9 potential in Rilpivirine: 2C19 (moderate), CYP1A2, 2B6. and 3A4 (weak).24 A clinically relevant effect on CYP enzyme activity is considered unlikely with the 25 mg Protease Inhibitors NNRTIs Integrase Inhibitor 27 10. sedative Route of atazanavir (Reyataz ) , darunavir efavirenz (Sustiva ) , etravirine dolutegravir (Tivicay ),14, 25, 26 2 3 11. Metabolism (Prezista ) , fosamprenavir (Telzir ) , (Intelence ) , nevirapine elvitegravir/cobicistat 4 12. indinavir (Crixivan ) , (Viramune ) , rilpivirine (Stribild , single-tablet 5 13 regimen with lopinavir/ritonavir (Kaletra ) , nelfinavir (Edurant ).)

5 6 7. (Viracept ) , ritonavir (Norvir ) , tenofovir/emtricitabine)15, 8. saquinavir (Invirase ) , tipranavir raltegravir (Isentress )16. 9. (Aptivus ). Alprazolam Parent: CYP3A Possible alprazolam concentrations. possible alprazolam Elvitegravir/cobicistat: (APZ) Metabolite: UGT (4 concentrations and withdrawal possible alprazolam Xanax &alpha hydroxy) Alprazolam is no longer concentrations. Monitor and contraindicated in the Norvir reduce benzodiazepine dose 7 15. product monograph. if necessary. Short-term study of 1mg alprazolam with 4 doses of ritonavir 200 mg resulted in 148% alprazoma AUC. and t from 13 to 30 hours. 28. Steady-state study of 1 mg alprazolam with 12 days of ritonavir resulted in a 12% alprazolam AUC. This likely 29.

6 Reflects early inhibitory and chronic induction effects of ritonavir. Based on this, therapy can likely be initiated using very low alprazolam doses, and monitoring for tolerability and efficacy. After 2-3 weeks, alprazolam dosage may need to be increased. Bromazepam Parent: Hydroxylation Possible bromazepam possible bromazepam Elvitegravir/cobicistat: Prepared by: Michelle Foisy, , Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, & Alice Tseng, , Toronto General Hospital August 2013 Page 2 o f 9. Interactions Between Sedatives/ hypnotics / anxiolytics and Antiretrovirals Protease Inhibitors NNRTIs Integrase Inhibitor 27 10. sedative Route of atazanavir (Reyataz ) , darunavir efavirenz (Sustiva ) , etravirine dolutegravir (Tivicay ),14, 25, 26 2 3 11.

7 Metabolism (Prezista ) , fosamprenavir (Telzir ) , (Intelence ) , nevirapine elvitegravir/cobicistat 4 12. indinavir (Crixivan ) , (Viramune ) , rilpivirine (Stribild , single-tablet 5 13 regimen with lopinavir/ritonavir (Kaletra ) , nelfinavir (Edurant ). 6 7. (Viracept ) , ritonavir (Norvir ) , tenofovir/emtricitabine)15, 8. saquinavir (Invirase ) , tipranavir raltegravir (Isentress )16. 9. (Aptivus ). Lectopam concentrations concentrations and withdrawal possible bromazepam concentrations. Monitor and reduce benzodiazepine dose 15. if necessary. Buspirone Parent: CYP3A4 possible buspirone concentrations possible buspirone Elvitegravir/cobicistat: Buspar Buspirone has concentrations and withdrawal possible buspirone immunomodulating Case report of patient with Parkinson- concentrations.

8 Monitor and properties. A significant like symptoms (ataxia, shuffling gait, reduce benzodiazepine dose in CD4/CD8 ratio, and cogwheel rigidity, resting tremor, and if necessary. 15. a in CD8+ T-cell sad affect) 6 weeks after counts was observed in ritonavir/indinavir (400mg/400mg HIV patients who were BID) were added to buspirone 40mg 30 31. not on antiretrovirals. am/30mg pm. Chloral hydrate Parent: AD no predicted effect no predicted effect No predicted effect (Novo, PMS) Metabolite: UGT. (trichloroethanol). Clonazepam Parent: CYP3A4 possible clonazepam concentrations possible clonazepam Elvitegravir/cobicistat: Rivotril concentrations and withdrawal potential for clonazepam 15. concentrations. Clorazepate Parent: Acid hydrolysis possible metabolite concentrations possible metabolite Possible metabolite Tranxene Metabolites (active): concentrations and withdrawal concentrations with nordiazepam, 2C19- Clorazepate is no longer elvitegravir/cobicstat.

9 Desmethyldiazepam contraindicated in the Norvir . 7. product monograph; use with caution. Diazepam Parent: CYP2C19>3A possible diazepam and nordiazepam possible diazepam and Elvitegravir/cobicistat: Valium Metabolites (active): concentrations nordiazepam concentrations and possible diazepam nordiazepam, N- withdrawal concentrations. Monitor and desmethyldiazepam, Diazepam is no longer reduce benzodiazepine dose 15. temazepam contraindicated in the Norvir if necessary. 7. product monograph; ; use with caution. 32. Estazolam Parent: CYP3A4 possible estazolam concentrations possible estazolam Elvitegravir/cobicistat: Prosom concentrations and withdrawal possible estazolam concentrations. Monitor and reduce benzodiazepine dose 15.

10 If necessary. 33. Eszopiclone Parent: CYP3A4, 2E1 possible eszopiclone concentrations possible eszopiclone Elvitegravir/cobicistat: Prepared by: Michelle Foisy, , Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, & Alice Tseng, , Toronto General Hospital August 2013 Page 3 o f 9. Interactions Between Sedatives/ hypnotics / anxiolytics and Antiretrovirals Protease Inhibitors NNRTIs Integrase Inhibitor 27 10. sedative Route of atazanavir (Reyataz ) , darunavir efavirenz (Sustiva ) , etravirine dolutegravir (Tivicay ),14, 25, 26 2 3 11. Metabolism (Prezista ) , fosamprenavir (Telzir ) , (Intelence ) , nevirapine elvitegravir/cobicistat 4 12. indinavir (Crixivan ) , (Viramune ) , rilpivirine (Stribild , single-tablet 5 13 regimen with lopinavir/ritonavir (Kaletra ) , nelfinavir (Edurant ).)