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

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® (hydroxy) concentrations. elvitegravir/cobicistat.15 Saquinavir: case report of prolonged sedation requiring flumazenil with Parenteral midazolam: combination. 34 Kinetic study showing potential for ↑ midazolam 5-fold ↑ PO MDZ AUC and 2.4-fold ↑ concentrations with IV MDZ AUC. 35 elvitegravir/cobicistat . Coadministration should be In a retrospective cohort study, 51 done in a setting that ensures patients were exposed to midazolam close clinical monitoring and and PIs while undergoing appropriate medical bronchoscopy. The relative risk of management in case of severe prolonged sedation was 6.21 respiratory depression and/or (9.80% in PI exposed vs. 1.58% in PI prolonged sedation. non-exposed). The length of Dosage reduction for hospitalization was 3 days longer in the midazolam should be PI exposed group. Coadministration of considered, especially if more these agents should be avoided and than a single dose of alternate sedatives used for midazolam is administered. 15 procedures. If the combination is used, intensive monitoring is required. 36 Nitrazepam Parent: nitro-reduction, possible ↑ nitrazepam concentrations possible ↓ nitrazepam Possible ↑ nitrazepam

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 4 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals

In vitro study showed ritonavir is a strong inhibitor of triazolam. 39 Short- term study of 0.125mg triazolam with 4 doses of ritonavir 200 mg resulted in ↑ triazolam  half-life from 3.7 to 50 hours. 40, 41 This likely reflects early inhibitory effects of ritonavir, but does not account for chronic induction. Valerian Root May inhibit CYP3A4. 42, A significant interaction is unlikely. A significant interaction is unlikely. A significant interaction is 43 Potential for additive CNS toxicity unlikely. when starting EFV. Zaleplon Aldehyde oxidase > Possible ↑ zaleplon concentrations. Possible ↓ zaleplon Possible ↑ zaleplon 44 Starnoc  CYP3A4 concentrations. concentrations with 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 5 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals

Key: CYP= Hepatic Cytochrome P450 isoenzyme; AD= Alcohol dehydrogenase; substrate= route of hepatic elimination of that specific drug (specified by a specific cytochrome P450 isoenzyme); inducer= leads to more rapid clearance of substrates of a specific hepatic isoenzyme (lowers levels of the respective drug and may lead to decreased efficacy); inhibitor= leads to decreased clearance of substrates of a specific hepatic isoenzyme (increases levels of a respective drug and may lead to toxicity). UGT= Uridine diphosphate glucuronyltransferase

Please note: This chart summarizes some of the major drug interactions identified to date, based on current available data; other drug interactions may exist. Please use caution whenever adding/modifying therapy. The information in this table is intended for use by experienced physicians and pharmacists. It is not intended to replace sound professional judgment in individual situations, and should be used in conjunction with other reliable sources of information. Due to the rapidly changing nature of information about HIV treatment and therapies, users are advised to recheck the information contained herein with the original source before applying it to patient care.

References: 1. Bristol-Myers Squibb Canada. Reyataz (atazanavir) Product Monograph. Montreal, QC May 11, 2012.

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 6 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals

2. Janssen Inc. Prezista (darunavir) Product Monograph. Toronto, Ontario September 21, 2011.

3. ViiV Healthcare ULC. Telzir (fosamprenavir) Prescribing Information. Montreal, QC January 24, 2011.

4. Merck Frosst Canada Ltd. Crixivan (indinavir) Product Monograph. Kirkland, QC April 17, 2012.

5. AbbVie Corporation. Kaletra (lopinavir/ritonavir) Prescribing Information. Saint Laurent, Canada November 1, 2012.

6. Pfizer Canada Inc. Viracept (nelfinavir) Product Monograph. Kirkland, QC March 4, 2011.

7. AbbVie Corporation. Norvir (ritonavir) Prescribing Information. Saint-Laurent, QC December 18, 2012.

8. Hoffmann-La Roche Ltd. Invirase (saquinavir) Product Monograph. Mississauga, ON May 11, 2012.

9. Boehringer Ingelheim. Aptivus (tipranavir) Product Monograph. Burlington, ON March 11, 2011.

10. Bristol-Myers Squibb Canada. Sustiva (efavirenz) Prescribing Information. Montreal, QC June 11, 2012.

11. Janssen Inc. Intelence (etravirine) Product Monograph. Toronto, ON November 9, 2011.

12. Boehringer Ingelheim (Canada) Ltd. Viramune and Viramune XR (nevirapine) Product Monograph. Burlington, ON May 30, 2011.

13. Janssen Inc. Edurant (rilpivirine) Product Monograph. Toronto, ON July 20, 2011.

14. ViiV Healthcare ULC. Tivicay (dolutegravir) Prescribing Information. Research Triangle Park, NC August, 2013.

15. Gilead Sciences Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Prescribing Information. Foster City, CA August, 2012.

16. Merck Frosst Canada Ltd. Isentress (raltegravir) Prescribing Information. Kirkland, QC February 10, 2012.

17. Hesse LM, von Moltke LL, Shader RI, et al. Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metabolism & Disposition 2001;29:100-02.

18. Kharasch ED, Mitchell D, Coles R, et al. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother 2008;52(5):1663-9.

19. Vourvahis M, Dumond J, Patterson K, et al. Effects of tipranavir/ritonavir on the activity of cytochrome p450 enzymes 1A2, 2C9 and 2D6 in healthy volunteers [abstract 52]. 8th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2007, Budapest, Hungary.

20. ViiV Healthcare ULC. Rescriptor (delavirdine) Product Monograph. Montreal, QC December 15, 2009.

21. Dixit V, Hariparsad N, Li F, et al. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Dispos 2007;35(10):1853-9.

22. Robertson SM, Maldarelli F, Natarajan V, et al. Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects. J Acquir Immune Defic Syndr 2008;49(5):513-9. 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 7 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals

23. Lee L, Soon GH, Shen P, et al. Effect of efavirenz and darunavir/ritonavir on bilirubin levels in healthy adult volunteers: role of induction of UGT1A1 and bile efflux transporters [abstract 27]. 11th International Workshop on Clinical Pharmacology of HIV Therapy, April 5-7, 2010, Sorrento, Italy.

24. Crauwels HM, Van Heeswijk R, Stevens T, et al. The effect of TMC278, a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) on CYP3A activity in vivo [abstract P_28]. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam.

25. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clinical Pharmacokinetics 1997;32(3):210-58.

26. [internet database] [database on the Internet]. Thomson Reuters (Healthcare) Inc. 2009 [cited June 10].

27. Bristol-Myers Squibb Canada. Reyataz (atazanavir) Product Monograph. Montreal, QC January, 2011.

28. Greenblatt D, Motlke L, Harmatz J, et al. Alprazolam-ritonavir interaction: Implications for product labeling. Clinical Pharmacology and Therapeutics 2000;67:335-41.

29. Frye R, Bertz R, Granneman GR, et al. Effect of ritonavir on the pharmacokinetics and pharmacodynamics of alprazolam [abstract A59]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 28-October 1, 1997, Toronto.

30. Eugen-Olsen J, Benfield T, Axen TE, et al. Effect of the serotonin receptor agonist, buspirone, on immune function in HIV-infected individuals: a six-month randomized, double-blind, placebo-controlled trial. HIV Clinical Trials 2000;1(1):20-6.

31. Clay PG, Adams MM. Pseudo-Parkinson disease secondary to ritonavir-buspirone interaction. Annals of Pharmacotherapy 2003;37:202-5.

32. Abbott Laboratories. ProSom (estazolam) Prescribing Information. North Chicago, IL. December, 2004.

33. Sepracor I. Lunesta (eszopiclone) Prescribing Information. Marborough, MA February, 2008.

34. Merry C, Mulcahy F, Barry M, et al. Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease [letter]. AIDS 1997;11(2):268-9.

35. Paklama VJ, Ahonen J, Neuvonen PJ, et al. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clinical Pharmacology and Therapeutics 1999;66:33-9.

36. Hsu AJ, Carson KA, Yung R, et al. Severe prolonged sedation associated with coadministration of protease inhibitors and intravenous midazolam during bronchoscopy. Pharmacother 2012;32(6):538-45.

37. Takeda Pharmaceuticals America I. Rozerem (ramelteon) Prescribing Information. Deerfield, IL October, 2008.

38. Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003;17(7):513-32.

39. von Moltke LL, Greenblatt DY, Grassi JM, et al. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. Journal of Clinical Pharmacology 1998;38:106-11.

40. Greenblatt DJ, von Moltke LL, Daily JP, et al. Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical 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 8 o f 9 Interactions Between Sedatives/Hypnotics/Anxiolytics and Antiretrovirals

dilemma of concurrent inhibition and induction. Journal of Clinical Psychopharmacology 1999;19:293-6.

41. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Differential impairment of triazolam and zolpidem clearance by ritonavir. Journal of the Acquired Immune Deficiency Syndrome 2000;24(2):129-36.

42. Budzinski JW, Foster BC, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 2000;7:273-82.

43. Lefebvre T, Foster BC, Drouin CE, et al. In vitro activity of commercial valerian root extracts against human cytochrome P450 3A4. J Pharm Pharm Sci 2004;7(2):265-73.

44. Servier Canada Inc. Starnoc Product Monograph. Laval, Quebec 2000.