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 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, 2C19 10 (? Clinical Cobicistat: CYP3A, CYP2D6; also p- nelfinavir, amprenavir >> saquinavir) significance). glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Atazanavir : 3A4, UGT1A1 >>2C8 (weak) Etravirine 11 : CYP2C9 (weak), CYP2C19 (moderate), p-glycoprotein (weak) Dolutegravir inhibits the renal organic cation Caution when unboosted atazanavir is transporter, OCT2. 14 coadministered with drugs that are 2C8 20 Delavirdine (Rescriptor®): 3A4 (potent) substrates with narrow therapeutic indices Raltegravir has no inhibitory or inductive (e.g., paclitaxel, repaglinide); clinically 16 potential in vitro. significant interactions with 2C8 substrates are not expected when atazanavir is boosted with ritonavir. Nelfinavir : 2B6 in vitro. Ritonavir : CYP3A4 (potent)> >2D6 >2C9 >2C19 >2A6 >1A2>2E1. At low boosting doses, ritonavir has a negligible effect in CYP2D6 inhibition. 5 Ritonavir inhibits CYP2B6 in vitro, 17 but induces 2B6 in vivo. 18 Tipranavir : 2D6 19 Hepatic Inducer Nelfinavir: UGT, 2B6, 2C8, 2C9/19 21 Efavirenz: 3A4 (potent), 2B6 22 and Dolutegravir does not induce CYP1A2, UGT1A1 23 CYP2B6, or CYP3A4 in vitro. 14 Ritonavir: UGT, CYP1A2, CYP2C9/19, 2B6 Prepared by: Michelle Foisy, Pharm.D., Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, Pharm.D. & Alice Tseng, Pharm.D., Toronto General Hospital August 2013 www.hivclinic.ca 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 Etravirine 11 : 3A4 (weak) Elvitegravir: CYP2C9 (modest) effects; often acts as inducer of CYP3A4 (potent) and UGT, even when boosted with Nevirapine 12 : 3A4, 2B6 (potent) Raltegravir has no inhibitory or inductive ritonavir 9 potential in vitro. 16 Rilpivirine: 2C19 (moderate), CYP1A2, 2B6 and 3A4 (weak). 24 A clinically relevant effect on CYP enzyme activity is considered unlikely with the 25 mg dose. 13 Protease Inhibitors NNRTIs Integrase Inhibitor Sedative Route of atazanavir (Reyataz®) 27 , darunavir efavirenz (Sustiva®) 10 , etravirine dolutegravir (Tivicay®), 14 , Metabolism 25, 26 (Prezista®) 2, fosamprenavir (Telzir®) 3, (Intelence )11 , nevirapine elvitegravir/cobicistat indinavir (Crixivan®) 4, (Viramune®) 12 , rilpivirine (Stribild®, single-tablet lopinavir/ritonavir (Kaletra )5, nelfinavir (Edurant®) 13 regimen with 6 7 tenofovir/emtricitabine) 15 , (Viracept®) , ritonavir (Norvir®) , 16 saquinavir (Invirase®) 8, tipranavir raltegravir (Isentress®) (Aptivus )9 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 product monograph. 7 if necessary. 15 Short-term study of 1mg alprazolam with 4 doses of ritonavir 200 mg resulted in 148% ↑ alprazoma AUC and ↑ t ½ from 13 to 30 hours. 28 Steady-state study of 1 mg alprazolam with 12 days of ritonavir resulted in a 12% ↓ alprazolam AUC. 29 This likely 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, Pharm.D., Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, Pharm.D. & Alice Tseng, Pharm.D., Toronto General Hospital August 2013 www.hivclinic.ca Page 2 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals Protease Inhibitors NNRTIs Integrase Inhibitor Sedative Route of atazanavir (Reyataz®) 27 , darunavir efavirenz (Sustiva®) 10 , etravirine dolutegravir (Tivicay®), 14 , Metabolism 25, 26 (Prezista®) 2, fosamprenavir (Telzir®) 3, (Intelence )11 , nevirapine elvitegravir/cobicistat indinavir (Crixivan®) 4, (Viramune®) 12 , rilpivirine (Stribild®, single-tablet lopinavir/ritonavir (Kaletra )5, nelfinavir (Edurant®) 13 regimen with 6 7 tenofovir/emtricitabine) 15 , (Viracept®) , ritonavir (Norvir®) , 16 saquinavir (Invirase®) 8, tipranavir raltegravir (Isentress®) (Aptivus )9 Lectopam® concentrations concentrations and withdrawal possible ↑ bromazepam concentrations. Monitor and reduce benzodiazepine dose if necessary. 15 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 not on antiretrovirals. 30 am/30mg pm. 31 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 concentrations. 15 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® product monograph; 7 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 temazepam contraindicated in the Norvir® if necessary. 15 product monograph; 7; use with caution. Estazolam Parent: CYP3A4 32 possible ↑ estazolam concentrations possible ↓ estazolam Elvitegravir/cobicistat: Prosom® concentrations and withdrawal possible ↑ estazolam concentrations. Monitor and reduce benzodiazepine dose if necessary. 15 Eszopiclone Parent: CYP3A4, 2E1 33 possible ↑ eszopiclone concentrations possible ↓ eszopiclone Elvitegravir/cobicistat: Prepared by: Michelle Foisy, Pharm.D., Northern Alberta Program, Edmonton, Alberta. Updated by Michelle Foisy, Pharm.D. & Alice Tseng, Pharm.D., Toronto General Hospital August 2013 www.hivclinic.ca Page 3 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals Protease Inhibitors NNRTIs Integrase Inhibitor Sedative Route of atazanavir (Reyataz®) 27 , darunavir efavirenz (Sustiva®) 10 , etravirine dolutegravir (Tivicay®), 14 , Metabolism 25, 26 (Prezista®) 2, fosamprenavir (Telzir®) 3, (Intelence )11 , nevirapine elvitegravir/cobicistat indinavir (Crixivan®) 4, (Viramune®) 12 , rilpivirine (Stribild®, single-tablet lopinavir/ritonavir (Kaletra )5, nelfinavir (Edurant®) 13 regimen with 6 7 tenofovir/emtricitabine) 15 , (Viracept®) , ritonavir (Norvir®) , 16 saquinavir (Invirase®) 8, tipranavir raltegravir (Isentress®) (Aptivus )9 Lunesta® concentrations and withdrawal possible ↑ eszopiclone concentrations. Monitor and reduce benzodiazepine dose if necessary. 15 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 product monograph; 7 use with caution. if necessary. 15 Lorazepam Parent: UGT Nelfinavir, ritonavir and tipranavir Tipranavir may ↓ lorazepam No predicted effect. Ativan® may ↓ lorazepam concentrations via concentrations (via UGT UGT induction. induction); no predicted effect with the NNRTIs. Midazolam Parent: CYP3A Contraindicated in product possible ↓ midazolam Oral midazolam is (MDZ) Metabolite: UGT monographs. Possible ↑↑ midazolam concentrations and efficacy contraindicated with Versed®