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%). (minor). Elvitegravir: CYP3A, UGT1A1/3.

2 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). Tipranavir: mixed induction/inhibition Etravirine11: 3A4 (weak) Elvitegravir: CYP2C9 (modest).

4 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 ). 6 7. (Viracept ) , ritonavir (Norvir ) , tenofovir/emtricitabine)15, 8.

5 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. 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.

6 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. 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 ).)

7 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. 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.

8 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. 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.

9 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. 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.

10 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 ). Lunesta concentrations and withdrawal possible eszopiclone concentrations. Monitor and reduce benzodiazepine dose 15. if necessary. Flurazepam Parent: liver possible flurazepam concentrations possible flurazepam Elvitegravir/cobicistat: Dalmane Metabolites (active): concentrations and withdrawal possible flurazepam desalkyl, hydroxyethyl Flurazepam is no longer concentrations. Monitor and contraindicated in the Norvir reduce benzodiazepine dose 7 15.