Hepatitis C Drug Therapy

Handbook of

Hepatitis C Drug Therapy

Editors Alice Tseng, Pharm.D., FCSHP, AAHIVP Immunodeficiency Clinic, University Health Network Leslie Dan Faculty of Pharmacy, University of Toronto Toronto, ON Pierre Giguère, B.Sc.Pharm., M.Sc. Immunodeficiency Clinic, The Ottawa Hospital The Ottawa Hospital Research Institute Ottawa, ON Sanjeev Sockalingam, MD, FRCPC Program in Medical Psychiatry, University Health Network Departments of Psychiatry and Medicine, University of Toronto Toronto, ON

Handbook of


Editors Alice Tseng, Pharm.D., FCSHP, AAHIVP Immunodeficiency Clinic, University Health Network Leslie Dan Faculty of Pharmacy, University of Toronto Toronto, ON Pierre Giguère, B.Sc.Pharm., M.Sc. Immunodeficiency Clinic, The Ottawa Hospital The Ottawa Hospital Research Institute Ottawa, ON Sanjeev Sockalingam, MD, FRCPC Program in Medical Psychiatry, University Health Network Departments of Psychiatry and Medicine, University of Toronto Toronto, ON

Acknowledgements

Handbook of


Contributors We would like to gratefully acknowledge the contributions of the following co-authors:

• Dominic Martel, M.Sc.Phm., Montreal (boceprevir chart)

• Marie-Hélène Irvine, Pharm.D., Toronto (telaprevir chart)

Sponsorship The production of this handbook is supported through an unrestricted educational grant from Merck Frosst Canada.

Distribution The 2013 Handbook on Hepatitis C Therapy is available in print and e-book versions. The information in this book is also available at: www.hcvdruginfo.ca, and is updated on a regular basis.

Disclaimer Editors Alice Tseng, Pharm.D., FCSHP, AAHIVP Immunodeficiency Clinic, University Health Network Leslie Dan Faculty of Pharmacy, University of Toronto Toronto, ON Pierre Giguère, B.Sc.Pharm., M.Sc. Immunodeficiency Clinic, The Ottawa Hospital The Ottawa Hospital Research Institute Ottawa, ON Sanjeev Sockalingam, MD, FRCPC Program in Medical Psychiatry, University Health Network Departments of Psychiatry and Medicine, University of Toronto Toronto, ON

The information in this Handbook is intended for use by and with experienced physicians and pharmacists. The information 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 hepatitis C treatment and therapies, users are advised to recheck the information contained herein with the original source before applying it to patient care. Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner knowledgeable about hepatitis-related illness and the treatments in question. Neither University Health Network, the Ottawa Hospital, nor the authors and contributors are responsible for deletions or inaccuracies in information or for claims of injury resulting from any such deletions or inaccuracies. Mention of specific drugs, drug doses or drug combinations within this book does not constitute endorsement by the authors, University Health Network, or the Ottawa Hospital.

Copyright 2013, Alice Tseng, Pharm.D. All rights reserved. All material in this handbook is copyrighted by the author and may be reprinted only with written permission of the author. Requests to reprint or reproduce material may be sent by fax or e-mail to Alice Tseng, Pharm.D., Toronto General Hospital, 416-340-4890, [email protected]. Additional information and updates may be found at: www.hcvdruginfo.ca

i

ACKNOWLEDGEMENTS

INTRODUCTION With the advent of directly acting antivirals (DAAs) in 2011, the field of hepatitis C therapy has been revolutionized. Factors such as efficacy, toxicity, drug interactions, medication adherence, and cost need to be carefully considered when designing a particular treatment regimen for an individual patient. This Handbook includes sections on pharmacologic and pharmacokinetic properties of directly acting antivirals as well as several drug interaction tables with commonly prescribed classes of medications. As principles of hepatitis therapy evolve, and as new agents continue to emerge, combination regimens will become increasingly complex. It is the responsibility of each practitioner to stay abreast of new developments. The information in this Handbook is not meant to be absolute nor universal, and should always be utilized in conjunction with the informed clinical judgement of the practitioner. Information in the pharmacologic and drug interactions sections is based on currently available data, including product monographs, published articles, conference abstracts and posted guidelines (as noted in the Reference section). However, given the rapid pace of developments in this therapeutic area, it is acknowledged that these tables are not all-inclusive. Not all possible drug combinations have been studied for potential interaction, and new drug combinations are continually being developed. Therefore, please use caution whenever adding or modifying therapy, and consult a health care professional when possible. Readers may also refer to the website: www.hcvdruginfo.ca, for additional information and regular updates.

INTRODUCTION

ii

Table of Contents for HEPATITIS C Handbook 2013 Acknowledgements��i INTRODUCTION��ii I. PHARMACOLOGIC PROPERTIES OF DIRECTLY ACTING ANTIVIRALS FOR HEPATITIS C

Boceprevir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Telaprevir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

II. DRUG INTERACTION TABLES

DAA Interactions Hepatitis C Directly Acting Antivirals . . . . . . . . . . . . . . . . . 33

Interactions with Other Drug Classes Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65 71 75 79

III. ADDITIONAL INFORMATION

Antiretroviral Treatment Options for Patients on DAAs . . 83

iV. GLOSSARY�� 87

boceprevir

1 2 boceprevir

TM

Other Names Manufacturer

Resistance - phenotypic

Resistance – genotypic


Activity

Activity

Mechanism of action

Pharmacology/

Mechanism of action Manufacturer

Pharmacology/

TM

A greater than 15-fold reduction in boceprevir anti-HCV activity was The fold decrease in boceprevir anti-HCV activity conferred by double conferred by the substitutions: resistance-associated substitutions was approximately equal to the T54C, R155G/I/T and A156S/T/V. product of that for the individual substitutions. The fold decrease in boceprevir anti-HCV activity conferred by double resistance-associated substitutions wasthe approximately equalSPRINT-2 to the In the pooled resistance analysis from Phase 3 Studies product of that for the and RESPOND-2, resistance associated polymorphisms were individual substitutions. detected in viruses from 6.7 % of subjects at baseline; 5.4 % had

Victrelis Merck Canada Inc. Combination formulation: TM Equal mixture diastereoisomers; the pharmacologically active boceprevir/ribavirin/peginterferon alfa-2b Victrelis Triple of: two SCH 534128 (S-isomer) and SCH 534129 (R-isomer). Merck Canada Mechanism of Inc. Action: Boceprevir is an inhibitor of the HCV NS3/4A protease. Boceprevir Equal mixture of two diastereoisomers; the pharmacologically active covalently, yet reversibly, binds to the NS3/4A protease active site SCH 534128 (S-isomer) and SCH 534129 (R-isomer). serine (Ser139) through a (alpha)-ketoamide functional group to inhibit Mechanism of Action: viral replication in HCV-infected host cells. Boceprevir is an inhibitor of the HCV NS3/4A protease. Boceprevir covalently, yet IC90 reversibly, to the NS3/4A protease active The IC50 and valuesbinds for BOC were approximately 200 nMsite and serine (Ser139) through group to inhibit 400 nM, respectively, in a (alpha)-ketoamide 72-hour cell culturefunctional assay. Loss of replicon viral HCV-infected host cells. to time of treatment. RNAreplication appears toinbe first-order with respect Treatment at IC90 for 72 hours resulted in a 1-log drop in replicon The IC50 and IC90 values for BOC were approximately 200 nM and RNA. Prolonged exposure resulted in a 2-log decrease in RNA levels 400 nM, respectively, in a 72-hour cell culture assay. Loss of replicon by Day 15. RNA appears to be first-order with respect to time of treatment. Treatment at IC90 for 72 hours resulted in a 1-log drop in replicon Boceprevir cell culture anti-HCV activity was approximately 2-fold RNA. Prolonged exposure resulted in a 2-log decrease in RNA levels lower for an HCV replicon derived from a single genotype 1a isolate, by Day 15. relative to the 1b isolate-derived replicon. Boceprevir had approximately 2-fold reduced activity against a genotype 2a isolate Boceprevir cell culture anti-HCV activity was approximately 2-fold relative to genotype 1a and 1b replicon isolates. In a biochemical lower for an HCV replicon derived from a single genotype 1a isolate, assay, boceprevir had approximately 3- and 2- fold reduced activity relative to the 1b isolate-derived replicon. Boceprevir had against NS3/4A proteases derived from single isolates representative approximately 2-fold reduced activity against a genotype 2a isolate of HCV genotypes 2 and 3a, respectively, relative to a genotype 1brelative to genotype 1a and 1b replicon isolates. In a biochemical derived NS3/4A protease. The presence of 50 % human serum assay, boceprevir had approximately 3- and 2- fold reduced activity reduced the cell culture anti-HCV activity of BOC by approximately 3against NS3/4A proteases derived from single isolates representative fold. of HCV genotypes 2 and 3a, respectively, relative to a genotype 1bEvaluation of varying combinations of boceprevir and interferon alfa-2b derived NS3/4A protease. The presence of 50 % human serum that produced 90 % suppression of replicon RNA showed additivity of reduced the cell culture anti-HCV activity of BOC by approximately 3effect; no evidence of synergy or antagonism was detected. fold. Evaluation combinations of HCV boceprevir and interferon The activityofofvarying boceprevir against the NS3/4A protease or alfa-2b that produced 90 % suppression of (2-to replicon showed additivity of genotype 1b replicon was reduced 10- RNA fold) by the following effect; of synergy antagonism wasdomain: detected. amino no acidevidence substitutions in the or NS3/4A protease V36A/I/M, Q41R, F43C/S, T54A/S, V55A/I, R155K/M/Q, V158I, The activity of boceprevir against the HCV NS3/4A protease or V170A/T and M175L. genotype 1b replicon was reduced (2-to 10- fold) by the following amino acid substitutions in the NS3/4A protease domain: A greater than 15-fold reduction in boceprevir anti-HCV activity was V36A/I/M, Q41R, F43C/S, T54A/S, V55A/I, R155K/M/Q, V158I, conferred by the substitutions: V170A/T and M175L. T54C, R155G/I/T and A156S/T/V.

Victrelis Selected Properties of Boceprevir Combination formulation: TM Victrelis Triple : boceprevir/ribavirin/peginterferon alfa-2b

Other Names

Selected Properties of Boceprevir

boceprevir

3 4 boceprevir

Effect of Food Oral Bioavailability

Oral Bioavailability

Cross-resistance

Cross-resistance

exposure Unknown to other NS3/4A PIs. Cross-resistance is not expected between boceprevir and interferons, or boceprevir and ribavirin. Boceprevir must be taken with food. Food enhanced the exposure of Unknown boceprevir by up to 60 % at the 800 mg TID dose when administered

the Phase 3 clinical trials have been demonstrated to reduce the antiThe to boceprevir treatment(PIs) failure on the HCVimpact activityofofprior otherexposure HCV NS3/4A ProteaseorInhibitors efficacy of other HCV NS3/4A PIs has not been studied. The efficacy of boceprevir been established for patients with a history The impact ofhas priornot exposure to boceprevir or treatment failure onof the exposure otherHCV NS3/4A PIs.PIs Cross-resistance is not expected efficacy oftoother NS3/4A has not been studied. The efficacy between boceprevir interferons, or boceprevir of boceprevir has notand been established for patientsand withribavirin. a history of

subjects whotreatment-emergent were previously exposed to amino boceprevir, or who Many of the NS3/4A acid substitutions previously treatment withsubjects a boceprevir-containing regimen. detected infailed boceprevir-treated who did not achieve SVR in the Phase 3 clinical trials have been demonstrated to reduce the antiMany of the treatment-emergent NS3/4A amino acid substitutions HCV activity of other HCV NS3/4A Protease Inhibitors (PIs) SVR in detected in boceprevir-treated subjects who did not achieve

substitutions detected after 2.5 years of follow-up were T54S and No data are available regarding the efficacy of boceprevir among R155K. subjects who were previously exposed to boceprevir, or who previously treatment with athe boceprevir-containing regimen. No data arefailed available regarding efficacy of boceprevir among

T54S (37 %), One or (26 more A156S %)boceprevir-treatment-emergent and V170A (32 %) in subjects substitutions with genotyperemained 1b viruses. detectable with a population-based sequencing assay in 25% of subjects afterboceprevir-treatment-emergent 2.5 years of follow-up. The most common NS3/4A One or more substitutions remained substitutions detected after 2.5 years of follow-up wereinT54S detectable with a population-based sequencing assay 25% and of R155K. subjects after 2.5 years of follow-up. The most common NS3/4A

were detected in 53 % of non-SVR patients. Interferon responsiveness The RAVs most with frequently detected post-baseline (> 25 % of subjects) was associated detection of fewer RAVs. in non-SVR subjects were amino acid substitutions V36M (61%) and R155K (68 most %) infrequently subjects with genotype 1a viruses(>and (42 %), The RAVs detected post-baseline 25 T54A % of subjects) T54S (37 %), in non-SVR subjects were amino acid substitutions V36M (61%) and A156S V170A with (32 %) in subjects with genotype 1b(42 viruses. R155K (26 (68 %) %) and in subjects genotype 1a viruses and T54A %),

period, the efficacy of boceprevir appeared to be reduced for those In a pooled analysis of T54S, patients whoor are previously untreated and who had V36M, T54A, V55A R155K at baseline. patients who have failed previous therapy who received four weeks of PegIFNα2b/RBV followed by boceprevir 800 mg TID in combination In a pooled analysis of patients who are previously untreated and with PegIFNα2b/RBV in two Phase 3 studies, post-baseline patients who have failed previous therapy who received fourRAVs weeks of were detected in 53 % of non-SVR patients. PegIFNα2b/RBV followed by boceprevir 800 Interferon mg TID in responsiveness combination was associated with detection of fewer RAVs. with PegIFNα2b/RBV in two Phase 3 studies, post-baseline RAVs

association with treatment response in patients who received the Baseline resistance polymorphisms were detected in 7 % combination of BOCassociated with PegIFNα2b/RBV. of subjects by a population based sequencing method.associated Overall, thepolymorphisms presence of these Baseline resistance werepolymorphisms detected in 7 % alone did not SVR rates. However, among subjects with a of subjects byimpact a population based relatively poor response to PegINFα2b/RBV 4-week lead-in sequencing method. Overall, the presence ofduring these the polymorphisms period, thenot efficacy boceprevir appearedamong to be reduced those alone did impactofSVR rates. However, subjectsfor with a who had V36M, T54A, T54S, V55A or R155K at baseline. relatively poor response to PegINFα2b/RBV during the 4-week lead-in

In the pooled resistance analysis from the Phase 3 Studies SPRINT-2 and RESPOND-2, resistance associated polymorphisms were detected in viruses from 6.7 % of subjects at baseline; 5.4 % had genotype 1a virus and 1.3 % had genotype 1b viruses. Overall, the Academic copyright. Prepared by Dominicpresence Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please of baseline RAVs alone did not appear to have a notable note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever association with treatment response in patients who received thethe genotype 1a virus and 1.3 % had genotype 1b viruses. Overall, beginning, stopping or modifying drug therapy. combination of BOC with PegIFNα2b/RBV. Updated July 2012 Page 1 of 7 presencewww.hivclinic.ca of baseline RAVs alone did not appear to have a notable

Resistance - phenotypic

The fold decrease in boceprevir anti-HCV activity conferred by double resistance-associated substitutions was approximately equal to the product of that for the individual substitutions.

T54C, R155G/I/T and A156S/T/V.

boceprevir

5 6 boceprevir

75 %

Protein Binding

Not studied Boceprevir is metabolized primarily by aldo-ketoreductase (AKR). Not studied Boceprevir is partly metabolized by CYP3A4/5. In vitro, boceprevir has been shownistometabolized be also a substrate Boceprevir primarilyof byp-glycoprotein. aldo-ketoreductase (AKR). Boceprevir is eliminated primarly by the liver. Boceprevir is partly metabolized by CYP3A4/5. In vitro, boceprevir has been shown to be also a substrate of p-glycoprotein. Following a single 800 mg oral dose of 14C-boceprevir, 79 % and 9 %

CSF (% oftrough serum) Minimum concentration (for wildtype virus) Metabolism CSF (% of serum) Excretion

Metabolism

No gender, race or age-related PK differences have been observed.

2 hours In the plasma the diastereoisomer ratio is about 2:1 in favour of the active diastereoisomer, SCH 534128. The plasma concentrations of 3 hours boceprevir described below consist of both diastereoisomers. In the plasma the diastereoisomer ratio is about 2:1 in favour of the In general, PK results were between healthyconcentrations and HCV subjects. active diastereoisomer, SCHsimilar 534128. The plasma of boceprevir described below consist of both diastereoisomers. AUC, Cmax and Cmin increased in a less-than dose-proportional manner andPK individual exposures substantially at 800 mg In general, results were similaroverlapped between healthy and HCV subjects. and 1,200 mg, suggesting diminished absorption at higher doses. AUC, Cmax and Cmin increased in a less-than dose-proportional PPK individual prediction from sparse data in HCV patientsat 800 mg manner and individual exposures overlapped substantially (boceprevir 800suggesting mg TID): diminished absorption at higher doses. and 1,200 mg, Cmax: 1013 ng/mL Cmin: 213 ng/mL PPK individual prediction from sparse data in HCV patients AUC: 4403 ng.hr/mL (boceprevir 800 mg TID): Cmax: 1013 ng/mL Population PK estimates HCV patients (boceprevir 800 mg TID): Cmin: 213 ng/mL Cmax: 1084ng.hr/mL ng/mL AUC: 4403 Cmin: 218 ng/mL AUC: 4642 PK ng.hr/mL Population estimates HCV patients (boceprevir 800 mg TID): Cmax: 1084 ng/mL Healthy subjects Cmin: 218 ng/mL(non-compartmental analysis)(boceprevir 800 mg TID): AUC: 4642 ng.hr/mL Cmax: 1723 ng/mL Cmin: 88subjects ng/mL (non-compartmental analysis)(boceprevir 800 mg Healthy AUC: TID): 5408 ng.hr/mL Cmax: 1723 ng/mL No gender, race or age-related PK differences have been observed. Cmin: 88 ng/mL AUC: 5408 ng.hr/mL (for wildtype virus)

Minimum trough concentration

Drug concentrations

Serum T ½

Tmaxconcentrations Drug

note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, or modifying drug therapy. Serum T stopping ½ 3 hours Updated July 2012 www.hivclinic.ca Page 2 of 7

717 L Academic copyright. Prepared by Dominic2Martel, Tmax hoursM.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please

Boceprevir must be taken with food. Food enhanced the exposure of boceprevir by up to 60 % at the 800 mg TID dose when administered with a meal, relative to the fasting state. Bioavailability is similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or after a meal.

Effect of Food

Vd

Unknown


The impact of prior exposure to boceprevir or treatment failure on the efficacy of other HCV NS3/4A PIs has not been studied. The efficacy of boceprevir has not been established for patients with a history of exposure to other NS3/4A PIs. Cross-resistance is not expected between boceprevir and interferons, or boceprevir and ribavirin.

boceprevir

7 8 boceprevir

It is important that the dose of boceprevir (800 mg) be taken orally TID (every 7-9 hours) with food (a meal or light snack).

Boceprevir should not be used as monotherapy but only in combination with PegIFNα/RBV.

Following a single 800 mg oral dose of 14C-boceprevir, 79 % and 9 % of the dose was excreted in feces and urine, respectively, with approximately 8 % and 3 % of the dosed eliminated as boceprevir in feces and urine.

Boceprevir is eliminated primarly by the liver.

4 PegIFNα/RBV followed by 44 weeks of boceprevir 800 mg D)weeks Patients with compensated cirrhosis (four 200 mg capsules) TID (every 7-9 hours) in combination with PegIFNα/RBV 4 weeks PegIFNα/RBV followed by 44 weeks boceprevir 800 mg (four 200 capsules) orally TID (every 7-9 D) Patients with compensated cirrhosis

Treatment is based on whether patients are previously B) Patientsduration with prior null response untreated or had previous treatment failures and their HCV-RNA levels at TW 8, TW 12 TW 24 these subjects should receive 4 weeks of If considered for and treatment, PegIFNα/RBV followed by 44 weeks of boceprevir 800mg (four 200 B) Patients withTID prior null 7-9 response capsules) orally (every hours) in combination with PegIFNα/RBV If considered for treatment, these subjects should receive 4 weeks of PegIFNα/RBV followed by 44 weeks of boceprevir 800mg (four with 200 a C) Patients without cirrhosis who are previously untreated capsules) orally TID (every 7-9 hours) in combination with poor interferon response PegIFNα/RBV (less than a 1.0-log10 decline in HCV-RNA at TW 4 with PegIFNα/RBV alone) C) Patients without cirrhosis who are previously untreated with a poor interferon response 4 weeks PegIFNα/RBV followed by 44 weeks of boceprevir 800 mg (less thanmg a 1.0-log10 in HCV-RNA at in TW 4 with (four 200 capsules)decline TID (every 7-9 hours) combination with PegIFNα/RBV PegIFNα/RBV alone)

A) Patients without who are untreated 1) Initiate therapy withcirrhosis PegIFNα/RBV for previously 4 weeks (TWs 1-4). or who are previous partial therapy: responders or relapsers PegIFNα/RBV 2) Add boceprevir 800 mg to (four 200 mg capsules) orally TID (every 79 hours) to PegIFNα/RBV regimen at TW 5. 1) Initiate therapy with PegIFNα/RBV for 4 weeks (TWs 1-4). Treatment duration is based on whether patients are previously 2) Add boceprevir 800 mg treatment (four 200 mg capsules) orally TID (every 7untreated or had previous failures and their HCV-RNA levels 9 hours) to PegIFNα/RBV regimen at TW 5. at TW 8, TW 12 and TW 24

strategies. null response). A) Patients without cirrhosis who are previously untreated or who Consult most up-to-date information for treatment duration and are previous partial strategies. responders or relapsers to PegIFNα/RBV therapy:

note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. Consult most up-to-date information for treatment duration and Updated July 2012 www.hivclinic.ca Page 3 of 7

Response-Guided Therapy is recommended for most patients, but longer dosing is recommended in target groups (e.g. cirrhosis, prior response). Academic copyright. Prepared by Dominicnull Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please

Dosing – Adult

Excretion

Boceprevir is metabolized primarily by aldo-ketoreductase (AKR).

Metabolism Boceprevir is partly metabolized by CYP3A4/5. In vitro, boceprevir has been shown to be also a substrate of p-glycoprotein.

Not studied

CSF (% of serum)

boceprevir

9 10 boceprevir

No data available No clinically significant differences in PK parameters were found and no dosage adjustment is recommended in patients with mild, moderate or severe hepatic impairment.

Special instructions for pediatric patients Adjust in Liver Dysfunction

Adjust in Renal Failure/Dialysis

ESRD subjects and matched subjects with normal renal function were administered a single 800 mg dose of boceprevir/ ESRD subjects were dosed prior to dialysis (Day 1) and 4 hours prior to dialysis (Day 4). The difference in exposure compared with healthy subjects was not clinically relevant, and dialysis did not alter PK parameters

No dosage adjustment is in patients with any degree of renal impairment.

PegIFNα2b/RBV is contraindicated in the hepatically impaired population. Thus, the use of boceprevir with PegIFNα2b/RBV is also contraindicated in this population.

Estimates of steady-state maximum AUC and Cmax parameters of patients infected with HCV in the Phase 3 studies were 9,715 ng·h/mL and 2,377 ng/mL, respectively.

Cmax: Mild vs healthy: 115 % (90%CI: 71-188) Moderate vs healthy: 128 % (90%CI: 79-208) Severe vs healthy: 162 % (90%CI: 99-263)

AUC (tf): Mild vs healthy: 107 % (90%CI: 75-152) Moderate vs healthy: 132 % (90%CI: 93-187) Severe vs healthy: 145 % (90%CI: 102-205)

Academic copyright. Prepared by Dominic Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. Updated July 2012 www.hivclinic.ca Page 4 of 7

The PK of a single 400 mg dose of boceprevir under fasted conditions was studied in non HCV-infected males and females with mild (ChildPugh score 5-6), moderate (Child-Pugh score 7-9), severe (ChildPugh score 10-12) impairment and matched subjects with normal hepatic function. Mean CL/F values in subjects with moderate and severe hepatic impairment were decreased but remained in the range of healthy subjects. Fasted dosing, a less than therapeutic dose and non-final formulation, limits the generalizability of the conclusions.

No data available

Dosing - Pediatric

4 weeks PegIFNα/RBV followed by 44 weeks boceprevir 800 mg (four 200 capsules) orally TID (every 7-9 hours) in combination with PegIFNα/RBV.

D) Patients with compensated cirrhosis

4 weeks PegIFNα/RBV followed by 44 weeks of boceprevir 800 mg (four 200 mg capsules) TID (every 7-9 hours) in combination with PegIFNα/RBV

(less than a 1.0-log10 decline in HCV-RNA at TW 4 with PegIFNα/RBV alone)

boceprevir

11 12 boceprevir

Because boceprevir is used in combination with PegIFNα/RBV, it is No studies in pregnant women are available. therefore contraindicated in pregnant women and men whose female partners are pregnant. Pregnancy risk category B (all trimesters).

Drug interactions interactions Drug

Effects of of boceprevir boceprevir on on Pharmacokinetics Pharmacokinetics of of Other Other Drugs Drugs Effects Boceprevir is is a a strong strong inhibitor inhibitor of of CYP3A4/5. CYP3A4/5. Drugs Drugs metabolized metabolized Boceprevir primarily by by CYP3A4/5 CYP3A4/5 may may have have increased increased exposure, exposure, which which could could primarily increase or or prolong prolong their their therapeutic therapeutic and and adverse adverse effects. effects. increase

Effect of of Other Other Drugs Drugs on on boceprevir boceprevir Pharmacokinetics Pharmacokinetics Effect Boceprevir is is partly partly metabolized metabolized by by CYP3A4/5. CYP3A4/5. Co-administration Co-administration with with Boceprevir drugs that that induce induce or or inhibit inhibit CYP3A4/5 CYP3A4/5 could could increase increase or or decrease decrease drugs exposure to to boceprevir. boceprevir. exposure

Account the the potential potential for for adverse adverse reactions reactions from from the the drug drug in in nursing nursing Account infants vs vs the the benefit benefit of of therapy therapy for for the the mother. mother. Available Available infants pharmacodynamic/toxicological data data in in animals animals have have shown shown excretion excretion pharmacodynamic/toxicological of boceprevir boceprevir and/or and/or metabolites metabolites in in milk. milk. Consequently Consequently a a risk risk to to of nursing newborns/infants newborns/infants cannot cannot be be excluded. excluded. nursing

Academic copyright. Prepared by Dominic Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. It is is unknown unknown whether boceprevir boceprevir is is excreted excreted into into human human breast milk. Updated July 2012 www.hivclinic.ca Page 5 of 7milk. It whether breast

No studies in pregnant women are available. No effects on fetal development have been observed in rats and rabbits with boceprevir exposures 11.8- and 2.0-fold higher, Pregnancy risk category B (all trimesters). respectively, than those in humans at the recommended dose of 800 TID. Boceprevir has been shown in animals to distribute across the No effects on fetal development have been observed in rats and Academic copyright. Prepared by Dominicrabbits Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, with boceprevir exposures 11.8and 2.0-fold higher,ON. Please note: This chart summarizes selected properties based on current available data. Please consult a health professional respectively, than those in humans at the recommended dosewhenever of 800 beginning, stopping or modifying drug therapy. TID. Boceprevir has been shown in animals to distribute across Updated July 2012 www.hivclinic.ca Page 5 of 7the placenta to to fetal fetal blood blood and and tissues. tissues. placenta

Pregnancy & Lactation

Pregnancy & Lactation

Toxicity

Toxicity

Adjust in Renal Failure/Dialysis

population. Thus, the use of boceprevir with PegIFNα2b/RBV is also impairment. contraindicated in this population. ESRD subjects and matched subjects with normal renal function were No dosage adjustment is in patients with any degree of renal administered a single 800 mg dose of boceprevir/ impairment. ESRD subjects were dosed prior to dialysis (Day 1) and 4 hours prior to dialysis (Day 4). The difference in exposure compared with healthy ESRD subjects and matched subjects with normal renal function were subjects was not clinically relevant, and dialysis did not alter PK administered a single 800 mg dose of boceprevir/ parameters ESRD subjects were dosed prior to dialysis (Day 1) and 4 hours prior to dialysis (Day The difference in exposure compared with healthy Many of the side4). effects may be related to PegIFNα2b/RBV subjects was not clinically relevant, and dialysis did not alter PK parameters Most common: Anemia (49% when used with PegIFNα2b/RBV) Many of the side effects may be related to PegIFNα2b/RBV Fatigue, anemia, nausea, headache, and dysgeusia (> 35% when used with PegIFNα2b/RBV) Most common: Anemia (49% when used with PegIFNα2b/RBV) Abdominal pain, constipation, diarrhea, dry mouth, vomiting, GERD Fatigue, anemia, nausea, headache, and dysgeusia Fever, chills, weight loss, decrease appetite, myalgia/arthralgia, (> 35% when used with PegIFNα2b/RBV) dizziness Anxiety, depression, insomnia, irritability, mood alteration Abdominal pain, constipation, diarrhea, dry mouth, vomiting, GERD Cough, dyspnea Fever, chills, weight loss, decrease appetite, myalgia/arthralgia, Dry skin, pruritus, rash dizziness Neutropenia, Thrombocytopenia Anxiety, depression, insomnia, irritability, mood alteration Blurred vision Cough, dyspnea Dry skin, boceprevir pruritus, rash Because is used in combination with PegIFNα/RBV, it is Neutropenia, Thrombocytopenia therefore contraindicated in pregnant women and men whose female Blurred vision partners are pregnant.

boceprevir

13 14 boceprevir

Capsulespregnancy (Hard-gelatin): Monthly test in female patients and in female partners of 200 mg (yellowish-brown) DIN 02370816 male patients

Decreases in the neutrophil countspatients may require reduction orof Monthly pregnancy test in female and indose female partners discontinuation male patients of PegIFNα/RBV.

If serum hemoglobin is < 100counts g/L, a may decrease in dose dose reduction or interruption Decreases in the neutrophil require or of RBV may be warranted. discontinuation of PegIFNα/RBV.

Deliverable Dose 80 mcg/0.5 mL A carton containing two boxes of 84 BOC capsules each for a total of

DIN: 02371448; 02371456; 02371464; 02371472

Boceprevir 200 mg capsules plus Ribavirin 200 mg capsules plus peginterferon alfa-2b powder for solution in REDIPEN® single dose delivery system

note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. Combination formulations: Updated July 2012 www.hivclinic.ca Page 6 of 7

Dosage (Hard-gelatin): Academic Forms copyright. Prepared by DominicCapsules Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart summarizes selected properties based on current availableDIN data.02370816 Please consult a health professional whenever 200 mg (yellowish-brown) beginning, stopping or modifying drug therapy. Peelable aclar/PVC/aluminium blisters containing 12 capsules. 7 Updated July 2012 Prepared by Dominicblisters www.hivclinic.ca Page 6 of 7Please Academic copyright. Martel, M.Sc.Phm. Reviewed A. Tseng, Pharm.D., AAHIVP, Toronto, ON. per folding cartonby and 2 folding cartons per outer carton

Dosage Forms

Routine Labs

Baseline assessment Routine Labs

Baseline assessment

Drug interactions

Boceprevir is partly metabolized by CYP3A4/5. Co-administration with drugs that induce or inhibit CYP3A4/5 could increase or decrease Effect of Other Drugs on boceprevir Pharmacokinetics exposure to boceprevir. Boceprevir is partly metabolized by CYP3A4/5. Co-administration with drugs that or inhibit CYP3A4/5 could increase or Drugs decrease Effects of induce boceprevir on Pharmacokinetics of Other exposure Boceprevirtoisboceprevir. a strong inhibitor of CYP3A4/5. Drugs metabolized primarily by CYP3A4/5 may have increased exposure, which could Effects ontherapeutic Pharmacokinetics of Other Drugs increaseoforboceprevir prolong their and adverse effects. Boceprevir is a strong inhibitor of CYP3A4/5. Drugs metabolized primarily by CYP3A4/5 may have increased exposure, which could See separate drug interaction chart. increase or prolong their therapeutic and adverse effects. Contraindicated Drugs: alfuzosin, amiodarone, propafenone, See separate drug interaction chart. quinidine, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, Contraindicated Drugs: amiodarone, cisapride, St. Johnʼs Wort,alfuzosin, lovastatin, simvastatin,propafenone, sildenafil or tadalafil quinidine, carbamazepine, phenobarbital, rifampin, when used for the treatment of pulmonaryphenytoin, arterial hypertension, dihydroergotamine, ergonovine, ergotamine, methylergonovine, pimozide, drospirenone, astemizole, terfenadine, midazolam (orally cisapride, St. Johnʼs Wort, lovastatin, simvastatin, sildenafil or tadalafil administered), and triazolam (orally administered). when used for the treatment of pulmonary arterial hypertension, CBC (with drospirenone, WBC differential count) terfenadine, midazolam (orally pimozide, astemizole, Pregnancy testand in female patients and in female partners of male administered), triazolam (orally administered). patients CBC (with WBC differential count) HCV-RNA levels monitored Treatment Weeks Pregnancy test inshould femalebe patients and at in female partners of (TWs) male 8, 12, and 24, at the End of patients Treatment (EOT), during treatment follow-up, and for other time points HCV-RNA should monitored at Treatment Weeks (TWs) 8, as clinicallylevels indicated. In be previously untreated subjects without 12, and 24, at the End of cirrhosis, monitoring of HCV-RNA levels at TW 4 is recommended to Treatment (EOT), during treatment follow-up, and for other time points determine interferon responsiveness. as clinically indicated. In previously untreated subjects without cirrhosis, of HCV-RNA TW 4 is recommended CBC (withmonitoring WBC differential count) levels shouldatbe obtained at TWs 4, 8 to and determine interferon responsiveness. 12 and should be closely monitored at other time points as considered clinically appropriate. CBC (with WBC differential count) should be obtained at TWs 4, 8 and 12 and should be closely monitored at other time points considered If serum hemoglobin is < 100 g/L, a decrease in dose or as interruption of clinically RBV mayappropriate. be warranted.

boceprevir

15 16 boceprevir



References TM Victrelis . Product Monograph. Merck Canada Inc, Kirkland, Quebec, Canada, June 13, 2012.

Can also be stored at room temperature (15°C – 30°C ) for up to 3 References TM months. Canada Inc, Kirkland, Quebec, Canada, June 13, 2012. Victrelis . Product Monograph. Merck Store in the original container.

Storage

Storage

delivery system Boceprevir 200 mg capsules plus Ribavirin 200 mg02371456; capsules plus DIN: 02371448; 02371464; 02371472 peginterferon alfa-2b powder for solution in REDIPEN® single dose delivery system Deliverable Dose 80 mcg/0.5 mL A carton containing two boxes of 84 BOC capsules each for a total of DIN: 02371448; 02371456; 02371464; 02371472 168 BOC capsules, two boxes of 28 RBV capsules each for a total of 56 RBV capsules, plus two PegIFNα2b REDIPEN® single dose Deliverable Dose80 80mcg/REDIPEN®, mcg/0.5 mL delivery systems, with two 30-gauge needles A carton containing two swabs boxes and of 84two BOC (0.3 x 8 mm), 4 alcohol pencapsules holders.each for a total of 168 BOC capsules, twomcg/0.5 boxes ofmL 28 RBV capsules each for a total of Deliverable Dose 100 56 RBV capsules, PegIFNα2b REDIPEN® singlefor dose A carton containingplus twotwo boxes of 84 BOC capsules each a total of delivery 80two mcg/REDIPEN®, withcapsules two 30-gauge needles 168 BOCsystems, capsules, boxes of 28 RBV each for a total of (0.3 x 8 mm), 4 alcohol swabs and two pen holders. single dose 56 RBV capsules, plus two PegIFNα2b REDIPEN® Deliverable Dose100 100mcg/REDIPEN®, mcg/0.5 mL delivery systems, with two 30-gauge needles A carton containing two swabs boxes and of 84two BOC (0.3 x 8 mm), 4 alcohol pencapsules holders.each for a total of 168 BOC capsules, two boxes of 28 RBV capsules each for a total of Deliverable Dose 120 mcg/0.5 mL 56 RBV capsules, PegIFNα2b REDIPEN® singlefor dose A carton containingplus twotwo boxes of 84 BOC capsules each a total of delivery 100 mcg/REDIPEN®, two 30-gauge 168 BOCsystems, capsules, two boxes of 35 RBVwith capsules each forneedles a total of (0.3 x 8 mm), 4 alcohol swabs and two pen holders. single dose 70 RBV capsules, plus two PegIFNα2b REDIPEN® Deliverable Dose120 120mcg/REDIPEN®, mcg/0.5 mL delivery systems, with two 30-gauge needles A carton containing two swabs boxes and of 84two BOC (0.3 x 8 mm), 4 alcohol pencapsules holders.each for a total of 168 BOC capsules, twomcg/0.5 boxes ofmL 35 RBV capsules each for a total of Deliverable Dose 150 70 capsules, plustwo twoboxes PegIFNα2b REDIPEN® single 1. ARBV carton containing of 84 BOC capsules eachdose for a total delivery systems, 120 mcg/REDIPEN®, with capsules two 30-gauge of 168 BOC capsules, two boxes of 42 RBV each needles for a total (0.3 8 mm), 4 alcohol swabs and two penREDIPEN® holders. single dose of 84x RBV capsules, plus two PegIFNα2b Deliverable Dose150 150mcg/REDIPEN®, mcg/0.5 mL delivery systems, with two 30-gauge 1. A carton boxesswabs of 84 BOC capsules each for a total needles (0.3containing x 8 mm), two 4 alcohol and two pen holders. of 168 BOC capsules, two boxes of 42 RBV capsules each 2. A carton containing two boxes of 84 BOC capsules each for for aa total total of PegIFNα2b REDIPEN® singlefor dose of 84 168RBV BOCcapsules, capsules,plus twotwo boxes of 49 RBV capsules each a total delivery systems, 150plus mcg/REDIPEN®, with two 30-gauge of 98 RBV capsules, two PegIFNα2b REDIPEN® single dose needles (0.3 x 8 mm), 4 alcohol swabs and holders. delivery systems, 150 mcg/REDIPEN®, withtwo twopen 30-gauge 2. A carton boxesswabs of 84 BOC capsules each for a total needles (0.3containing x 8 mm), two 4 alcohol and two pen holders. of 168 BOC capsules, two boxes of 49 RBV capsules each for a total o o Boceprevir capsules should refrigeratedREDIPEN® at 2 C – 8 single C. of 98 RBV capsules, plus twobePegIFNα2b dose delivery systems, 150 mcg/REDIPEN®, with two 30-gauge Can also(0.3 be stored at room temperature (15°C 30°Cholders. ) for up to 3 needles x 8 mm), 4 alcohol swabs and two–pen months. o o Boceprevir should be refrigerated at 2 C – 8 C. Store in thecapsules original container.

telaprevir

17 18 telaprevir

Resistance – phenotypic



Activity

Activity

Pharmacology/ Mechanism of Action

Manufacturer Other names Pharmacology/ Mechanism of Manufacturer Action

Other names

show that the population of wild-type virus increased and the population of telaprevir-resistant variants became undetectable over time after the end of telaprevir treatment.

(V36M, T54A and R155K 25-fold increase in telaprevir IC50). All telaprevir-resistant variants Predominant telaprevir-resistant variants at baseline were rare studied remained fully sensitive to interferon-alfa and(pre-treatment) ribavirin. (V36M, T54A and R155K 25-fold increaseR155K/T, in telaprevir telaprevir-resistant Variants V36A/M, T54A/S, andIC50). A156SAll conferred lower levelsvariants of in vitro studied remained fully sensitive to interferon-alfa and ribavirin. resistance to telaprevir (3- to 25-fold increase in telaprevir IC50), and the A156V/T

Telaprevir inhibits genotype 2 HCV NS3 serine with similar potency The approved indication for telaprevir is for HCVprotease genotype 1 infection only. to genotype 1a or 1b HCV proteases while its activity against genotype 3 and 4 HCV proteases is reduced. In Vitro Studies

The slow binding mechanism for the interaction of telaprevir with the HCVNS3•4A Telaprevir inhibitsingenotype 2 HCV NS3 serine protease with similar potency protease occurs 2 steps, with formation of a weaker complex followed by to genotype 1a or 1b HCV proteases while its activity against genotype 3 and 4 HCV rearrangement to the tightly bound form (covalent complex). proteases is reduced.

Telaprevir is a direct-acting antiviral (DAA)ofagainst thewith hepatitis C virus. This The slow binding mechanism for the agent interaction telaprevir the HCVNS3•4A agent is aoccurs specific theformation HCV NS3·4A protease which is essential protease in inhibitor 2 steps, of with of a weaker complex followed byfor viral replication. rearrangement to the tightly bound form (covalent complex).

TVR, Incivek® Selected Properties of Telaprevir Vertex Pharmaceuticals Incorporated TVR, Incivek® Telaprevir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. This agent a specific inhibitor of the HCV NS3·4A protease which is essential for viral VertexisPharmaceuticals Incorporated replication.

Selected Properties of Telaprevir

telaprevir

19 20 telaprevir

There is some overlap between telaprevirBoceprevir and boceprevir primary resistanceTelaprevir associated V36A/M variants: V36M T54A/S T54A R155K/T R155K Telaprevir Boceprevir A156T/V A156T V36A/M V36M

In clinical studies in healthy subjects in which a single 750-mg dose of telaprevir Drug concentrations in adult health subjectsthe andmean in subjects chronic hepatitis was administered after a regular breakfast, half-lifewith (t1/2) ranged from C are displayed below: 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.

Serum T ½ Drug Concentrations

Healthy CHC treatmentCHC treatmentDrug concentrations in adult health subjects andpatients in subjects with chronic hepatitis Volunteers naïve experienced C are displayed below: (n=39) (n=641) patients (n=191) 3040 (662) 3260 (946) 3990 (1120) Cmax (ng/mL) Healthy CHC treatmentCHC treatment1960 (548) 2690 (827) 3340 (1170) Cmin (ng/mL) Volunteers naïve patients experienced 24,400 30,100 AUC8h (ng*h/mL) 19,900 (n=39) (4710) (n=641)(7180) patients(8720) (n=191)

In clinical studies in healthy subjects in which a single 750-mg dose of telaprevir In clinical studies in healthy subjects in which single 750-mg of telaprevir was administered after a regular breakfast, thea median time of dose maximum was administered after a regular breakfast, the mean half-life (t1/2) ranged from concentration (tmax) ranged from 4.0 to 5.0 hours. 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.

Tmax Serum T ½

Drug Concentrations

In clinical studies volume in healthy subjects in which a single Typical apparent of distribution is estimated to 750-mg be 252 Ldose withof antelaprevir interwas administered after a regular breakfast, the median time of maximum individual variability of 72%. concentration (tmax) ranged from 4.0 to 5.0 hours.

T54A/S T54A Orally available, most likely absorbed in the small intestine, with no evidence for R155K/T in the colon. R155K absorption A156T/V A156T Exposure to telaprevir is higher during co-administration of peginterferon alfa and Orally available, most likely absorbed in the small intestine, with no evidence for ribavirin than after administration of telapreviralone. absorption in the colon. The systemic exposureis(AUC) telaprevir was decreased about 73% alfa when Exposure to telaprevir highertoduring co-administration of by peginterferon and telaprevir was administered under fasting conditions compared to when telaprevir ribavirin than after administration of telapreviralone. was administered following a standard fat meal (533 kcal, 21 g fat). The telaprevir exposure was decreased by about 39% with a low-fat meal (249 kcal, 3.6 g fat), The systemic exposure (AUC) to telaprevir was decreased by about 73% when while exposure was increased by about 20% with a high-fat meal (928 kcal, 56 g telaprevir was administered under fasting conditions compared to when telaprevir fat), compared to telaprevir administration with a standard fat meal. Therefore, was administered following a standard fat meal (533 kcal, 21 g fat). The telaprevir telaprevir should always be taken with food (not low fat; ~ 20g fat content). exposure was decreased by about 39% with a low-fat meal (249 kcal, 3.6 g fat), while exposure was increased by about 20% with a high-fat meal (928 kcal, 56 g Telaprevir is approximately to 76% bound human plasma proteins. fat), compared to telaprevir 59% administration with atostandard fat meal. Therefore, Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding telaprevir should always be taken with food (not low fat; ~ 20g fat content). is concentration dependent, decreasing with increasing concentrations of telaprevir. Telaprevir is approximately 59% to 76% bound to human plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding Typical apparentdependent, volume of distribution estimated to be 252 L with anof interis concentration decreasingiswith increasing concentrations individual variability of 72%. telaprevir.

Tmax Vd

Vd

Protein Binding

Protein Binding

Effect of Food

Oral Bioavailability Effect of Food


CrossResistance

Cross- copyright. Prepared There is some overlap betweenCandidate, telaprevir and boceprevir Academic by Marie-Hélène Irvine, Pharm.D. University of Toronto. primary Reviewedresistanceby A. Tseng, Resistance associated Pharm.D., AAHIVP, Toronto, ON. Pleasevariants: note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. Updated January 2012 www.hivclinic.ca Page 1 of 7

Resistance – phenotypic

genotype 1a. Among subjects treated with telaprevir, on-treatment virologic failure was more frequent in subjects with genotype 1a than with genotype 1b and more frequent in prior null responders than in other populations (treatment naïve, prior relapsers, prior partial responders). Follow-up analyses of telaprevir-treated subjects who did not achieve an SVR show that the population of wild-type virus increased and the population of telaprevir-resistant variants became undetectable over time after the end of telaprevir treatment.

telaprevir

21 22 telaprevir

CHC treatmentnaïve patients (n=641) 3260 (946) 2690 (827) 24,400 (7180)

CHC treatmentexperienced patients (n=191) 3990 (1120) 3340 (1170) 30,100 (8720)

and reduction. CYP3A4 is the major CYP isoform responsible for telaprevir metabolism. However, non-CYP mediated metabolism likely plays a role after multiple dosing of telaprevir. Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. CYP3A4 is the major CYP isoform responsible for telaprevir 82% of dose recovered in feces metabolism. However, non-CYP mediated metabolism likely plays a role after 9% of dose recovered in expired air multiple dosing of telaprevir. 1% of dose recovered in urine (within 96 hours following administration of a single radiolabeled dose of telaprevir 82%mg) of dose recovered in feces 750 9% of dose recovered in expired Apparent total clearance (Cl/F) isair estimated to be 32.4 L/h with an inter-individual 1% of dose recovered in urine variability of 27.2%. (within 96 hours following administration of a single radiolabeled dose of telaprevir Telaprevir 750 mg) must not be administered as monotherapy and must only be prescribed with both peginterferon andisribavirin Apparent total clearancealfa (Cl/F) estimated to be 32.4 L/h with an inter-individual variability of 27.2%.

In an HCV subtype 1b replicon assay, the telaprevir IC50 value against wild-type HCV was 0.354 µM, similar to a subtype 1a infectious virus assay IC50 of 0.28 µM.

Cmax (ng/mL) Cmin (ng/mL) AUC8h (ng*h/mL)

Healthy Volunteers (n=39) 3040 (662) 1960 (548) 19,900 (4710)

Drug concentrations in adult health subjects and in subjects with chronic hepatitis C are displayed below:

Dosing – Adult

Dosing – Adult

Excretion

Excretion

Metabolism

CSF (% of serum)

Treatment Duration Treatment-Naïve and Prior Relapse Patients The recommended duration of treatment with telaprevir is 12 weeks in combination HCV-RNA Triple Therapy Dual Therapy Total Treatment with peginterferon alfa and ribavirin: Duration (telaprevir, (peginterferon peginterferon alfa and ribavirin) Treatment-Naïve and Prior Relapse Patients alfa and ribavirin) HCV-RNA Triple Therapy Dual Therapy Total Treatment Undetectable at First 12 weeks Additional 12 24 weeks Duration (telaprevir, (peginterferon Weeks 4 and 12 weeks peginterferon alfa and ribavirin) Detectable (1000 First 12 weeks Additional 36 48 weeks alfa and ribavirin) IU/mL or less) at weeks Undetectable at First 12 weeks Additional 12 24 weeks Weeks 4 and/or Weeks 4 and 12 weeks 12 Detectable (1000 First 12 weeks Additional 36 48 weeks Prior Partial and Null Responder Patients

Treatment Duration If taken with efavirenz (not currently approved for use inisHIV The recommended duration of treatment with telaprevir 12 patients) weeks in combination 1125 mg orally 3 times a day every 7-9 hours with food (not low fat) with peginterferon alfa and ribavirin:

The recommended dose ofcurrently telaprevirapproved is 750 mgfor(two tablets) taken orally 3 If taken with efavirenz (not use375-mg in HIV patients) times a day (7-9 hours apart) with food (not low fat). The total daily 1125 mg orally 3 times a day every 7-9 hours with food (not low fat)dose is 6 tablets (2250 mg).

The recommended of telapreviras is monotherapy 750 mg (two 375-mg tablets) taken orally 3 Telaprevir must not dose be administered and must only be prescribed timesboth a day (7-9 hours apart) with food (not low fat). The total daily dose is 6 with peginterferon alfa and ribavirin tablets (2250 mg).

Academic serum)copyright. Prepared by Marie-Hélène Irvine, Pharm.D. Candidate, University of Toronto. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. Metabolism Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, Updated January 2012 www.hivclinic.ca Page 2 of 7

CSF (% of

Minimum target trough concentrations (for wildtype virus)

Drug Concentrations

telaprevir

23 24 telaprevir

Triple Therapy (telaprevir, peginterferon alfa and ribavirin) First 12 weeks

Dual Therapy (peginterferon alfa and ribavirin) Total Treatment Duration

Action Discontinue telaprevir and peginterferon alfa and ribavirin Discontinue peginterferon alfa and ribavirin

Dose modification of telaprevir is not required when administered to subjects with mild hepatic impairment (Child-Pugh A, score 5- 6).

Adjust in Liver Dysfunction

•

•

Steady-state exposure to telaprevir was reduced by 15% in HCV-negative subjects with mild hepatic impairment (Child-Pugh Class A) compared to healthy subjects. Steady-state exposure to telaprevir was reduced by 46% in HCV-negative subjects with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. No pharmacokinetic or safety data are available regarding the use of telaprevir in HCV-infected patients with moderate or severe hepatic

Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥ 7) or decompensated liver disease.

The use of telaprevir in pediatric patients is not recommended. No clinical data are available regarding the use of telaprevir in children and adolescents younger than 18 years of age.

Dosing – Pediatric

Missed Doses If a dose is missed within 4 hours of the scheduled time, it should be taken as soon as possible with food. If more than 4 hours has passed since the dose should have been taken, this dose should be skipped, and the usual dosing schedule resumed.

HCV-RNA Week 4 or Week 12: Greater than 1000 IU/mL Week 24: Detectable

Academic copyright. Prepared by Marie-Hélène Irvine, Pharm.D. Candidate, University of Toronto. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart summarizes selected properties based on current available data. Please consult a health professional whenever beginning, stopping or modifying drug therapy. Updated January 2012 www.hivclinic.ca Page 3 of 7

Treatment Failures Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment emergent resistance substitutions. Discontinuation of therapy is recommended in all patients with (1) HCV-RNA levels of greater than or equal to 1000 IU/mL at Treatment Week 4 or 12; or (2) confirmed detectable HCV-RNA levels at Treatment Week 24.

Undetectable at Additional 12 24 weeks Weeks 4 and 12 weeks Detectable (1000 First 12 weeks Additional 36 48 weeks IU/mL or less) at weeks Weeks 4 and/or 12 Prior Partial and Null Responder Patients Triple Therapy Dual Therapy Total Treatment Duration (telaprevir, (peginterferon peginterferon alfa and ribavirin) alfa and ribavirin) All Patients First 12 weeks Additional 36 48 weeks weeks

HCV-RNA

telaprevir

25 26 telaprevir

severe renal impairment (CrClfor < 30 mL/min), mean telaprevir Cmax No dose adjustment is necessary telaprevir in the HCV-infected patients withand mild, AUC were increased 10% and 21%, respectively, compared to healthy moderate or severe renal by impairment. • subjects. After administration of a single dose of 750 mg to HCV-negative subjects with • The safety and efficacy of(CrCl telaprevir combination therapy has not Cmax been and severe renal impairment < 30 mL/min), the mean telaprevir established in HCV-infected with a CrCl ≤ 50compared mL/min to healthy AUC were increased by 10%subjects and 21%, respectively, • Telaprevir subjects. has not been studied in patients with end-stage renal disease or on • (ESRD) The safety andhemodialysis efficacy of telaprevir combination therapy has not been • It is not known whether telaprevir is dialyzable by≤peritoneal or hemodialysis. established in HCV-infected subjects with a CrCl 50 mL/min •Common: Telaprevir has not been studied in patients with end-stage renal disease or on hemodialysis The (ESRD) most frequent adverse effects when used in combination with peginterferon •alfa Itand is not known whether telaprevir is dialyzable by peritoneal or hemodialysis. ribavirin include:

Toxicity

Potential for QT Prolongation:

>10-20%: Common: fatigue, pruritus, nausea, headache, influenza-like illness, rash, anemia, insomnia, diarrhea,adverse vomiting, pyrexia, hemorrhoids, and proctalgia The most frequent effects when used in combination with peginterferon alfa and ribavirin include: Serious: >10-20%: fatigue, pruritus, nausea, headache, influenza-like illness, rash, anemia, The most frequent adverse events were anemia and rash insomnia, diarrhea,serious vomiting, pyrexia, hemorrhoids, and proctalgia • Rash: Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS), were Serious: Academic copyright. Prepared Marie-Hélène Pharm.D. Candidate, University of Toronto. Reviewed Thebymost frequentIrvine, serious adverse events were anemia and rash by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart summarizes selected properties based on current available data. Please • Rash: Serious skin reactions, including Drug Rash with Eosinophilia and consult a health professional whenever beginning, stopping or modifying drug therapy. Systemic Symptoms (DRESS) and Stevens-Johnson SyndromePage (SJS), Updated January 2012 www.hivclinic.ca 4 of 7were reported in less than 1% of Candidate, subjects University who received telaprevir combination Academic copyright. Prepared by Marie-Hélène Irvine, Pharm.D. of Toronto. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: This chart to summarizes selected properties based on current available data. Please treatment compared none who received peginterferon alfa and ribavirin consult a health professional whenever stoppingskin or modifying drugall therapy. alone.beginning, These serious reactions required hospitalization and all patients Updated January 2012 www.hivclinic.ca Page 4 of 7 recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips). Telaprevir must not be restarted if discontinued due to rash (discontinuation of telaprevir combination treatment is not required for mild and moderate rash). • Anemia: In placebo-controlled Phase 2 and 3 clinical trials, the overall incidence and severity of anemia increased with telaprevir combination treatment compared to peginterferon alfa and ribavirin alone. Hemoglobin values of 2C9 • sildenafil substrate; weak (Viagra®, inhibitor of Revatio®); CYP1A2, 2C9, (CYP3A4>>2C9 2C19, 2D6, 2E1, substrate; weak 3A4 - unlikely to inhibitor of cause significant CYP1A2, 2C9, interactions) 2D6, 2E1, • 2C19, tadalafil 3A4 - unlikely to (Cialis, cause significant Adcirca®); interactions) CYP3A4 • tadalafil substrate • (Cialis, vardenafil Adcirca®); (Levitra); CYP3A4 substrate of substrate CYP3A4>3A5, • vardenafil 2C (Levitra); Rifampin substrate of CYP3A4>3A5, 2C Rifampin

boceprevir concentrations may be significantly reduced, possibly leading to 1 decreased virologic response. Coadministration is contraindicated, as boceprevir concentrations may be

exposure when co-administered with pegylated interferon alfa-2b. No BOC In healthy subjects, is there werewith no clinically dosage adjustment needed co4 relevant changes in either BOC or PEG2b administration. exposure co-administered with ↑ in PDE-5when inhibitor concentrations are pegylated interferon alfa-2b. No BOC in expected, and may result in an increase dosage is needed with coadverseadjustment effects, 4 including hypotension, administration. syncope, visual disturbances, and priapism. ↑ in PDE-5 inhibitor concentrations are expected, and may result in anarterial increase in For treatment of pulmonary 1 adverse effects, including hypotension, hypertension (PAH): syncope, visualordisturbances, • Sildenafil tadalafil useand for priapism. PAH is contraindicated with boceprevir. For treatment of pulmonary arterial 1 hypertension For treatment (PAH): of erectile dysfunction: •Use Sildenafil or and tadalafil use for PAH is with caution increased contraindicated boceprevir. monitoring for PDE-5 with inhibitor-associated toxicities. Do not exceed the following 1 For treatment of erectile dysfunction: doses: Use with caution increased • sildenafil: 25 and mg every 48 hours monitoring for10 PDE-5 inhibitor-associated • tadalafil: mg every 72 hours toxicities. Do not the24 following • vardenafil: 2.5exceed mg every hours (NB: 1 doses: this dose not approved in Canada; • sildenafil: mg every is 48not hours therefore, 25 combination • tadalafil: 10 mg every 72 hours recommended) • vardenafil: 2.5 mg every 24 hours (NB: this dose not approved in Canada; therefore, combination is not recommended) Coadministration is contraindicated, as

Boceprevir Alternative methods of non-hormonal (Victrelis®, BOC, SCH 503034) contraception are recommended. CoMerck of BOC withAAHIVP. drospirenone Academic copyright: administration Alice Tseng, Pharm.D., FCSHP, www.hivclinic.ca October 25, 2012 (Yaz®, Yasmin®, Angeliq®) 1 of non-hormonal Alternative methods is contraindicated. contraception are recommended. Coadministration of BOC with drospirenone (Yaz®, Yasmin®, Angeliq®) Pegylated In healthy subjects,1 there were no clinically is contraindicated. interferon alfa-2b relevant changes in either BOC or PEG2b

Oral contraceptives

NSAIDS

midazolam, triazolam). Dose adjustment of the benzodiazepine 1 should be considered.

rifampin 600 mg daily at steady-state and single dose telaprevir 750 mg led to 86% ↓ Cmax and 92% ↓ AUC of telaprevir. In healthy subjects, of Coadministration of coadministration rifampin and telaprevir is rifampin 600 mg13daily at steady-state and

↑ in PDE-5 inhibitor concentrations are expected, and may result in anarterial increase in For treatment of pulmonary 6 adverse effects. hypertension (PAH): • Sildenafil use for PAH is (contraindicated with telaprevir. For treatment of pulmonary arterial • Co-administration of tadalafil and 6 hypertension (PAH): telaprevir for PAH treatment is not • Sildenafil use for PAH is recommended. (contraindicated with telaprevir. •For Co-administration of tadalafil and treatment of erectile dysfunction: for and PAHincreased treatment is not Use telaprevir with caution recommended. monitoring for PDE-5 inhibitor-associated toxicities. Do not exceed the following 6 For treatment of erectile dysfunction: doses: Use with caution increased • sildenafil: 25 and mg every 48 hours monitoring for10 PDE-5 inhibitor-associated • tadalafil: mg every 72 hours toxicities. Do not exceed the following • vardenafil: contraindicated 6 doses: • sildenafil: 25 mg every 48 hours • tadalafil: 10 mg every 72 hours •In healthy vardenafil: contraindicated subjects, coadministration of

↑ in PDE-5 inhibitor concentrations are expected, and may result in an increase in adverse effects.

In healthy women receiving Modicon (0.5 mg norethindrone (NE) and 0.035 mg ethinyl estradiol (EE) for at least 3 months, the effect of steady-state telaprevir 750 mg q8h Telaprevir on the steady-state pharmacokinetics of EE (Incivek®, TVR, VX-950) and NE was assessed. In the presence of Pharmaceuticals telaprevir,Vertex EE Cmax ↓ 26%, Cmin ↓ 37% and AUC ↓ 28%. NE and telaprevir Telaprevir exposures were not significantly affected. (Incivek®, TVR, VX-950) LH and FSH concentrations at day 7 also ↑, Vertex Pharmaceuticals Toronto General Hospital, ON corresponding with the ↓ Toronto, EE concentrations. and AUC ↓ 28%. NE and telaprevir 10 of 16 Alternative methods ofpage contraception exposures significantly affected. should be were usednot when estrogen-based LH and FSH concentrations at day 7 also contraceptives are coadministered with↑, 38 corresponding with the ↓ EE concentrations. telaprevir. Alternative methods of contraception should be used when estrogen-based contraceptives are coadministered with 38 telaprevir.

Co-administration of telaprevir and parenteral midazolam should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged 6 sedation.

Interactions with Directly Acting Antivirals (DAAs)

55 56 Interactions with Directly Acting Antivirals (DAAs)

Coadministration is contraindicated, as boceprevir concentrations may be significantly reduced, possibly leading to 1 decreased virologic response.

this dose not approved in Canada; therefore, combination is not recommended)

Warfarin

1

Combination has not been studied. Potential for altered warfarin concentrations in the presence of boceprevir. Monitor INR when coadministering warfarin and

In healthy volunteers, the kinetics of singledose tacrolimus 0.5 mg was assessed alone and in the presence of single dose BOC 800 mg and steady-state BOC 800 mg TID. In the presence of BOC, tacrolimus AUC Boceprevir ↑ 17-fold and Cmax ↑ 9.9(Victrelis®, BOC, SCHwere 503034) fold; BOC pharmacokinetics not Merck affected by tacrolimus. Coadministration of BOC and tacrolimus would likely require significant dose Boceprevir reduction of tacrolimus BOC, SCH 503034) and/or(Victrelis®, prolongation of the dosing interval, Academic copyright: with Alice close Tseng, monitoring Pharm.D.,Merck FCSHP, AAHIVP. of tacrolimus www.hivclinic.ca October 25, 2012 BOC and tacrolimus would likely require concentrations and frequent assessments significant dose reduction of tacrolimus of renal function and tacrolimus-related 27 and/or prolongation of the dosing interval, side effects. with close monitoring of tacrolimus concentrations frequent assessments In five genotypeand 1 liver transplant patients of renal function and tacrolimus-related with HCV recurrence, boceprevir 800 mg 27 side effects. three times a day was initiated after a 4week lead-in phase. Concomitant In five genotype 1 liver transplant patients immunosuppressant therapy (IT) included with HCV recurrence, boceprevir 800 mg cyclosporine (3), tacrolimus (2) and three times (1). a day was initiated after period a 4everolimus The mean follow-up week HCV lead-in phase.was Concomitant since therapy 14.8±3.1 weeks. immunosuppressant therapy (IT)decreased included Estimated oral clearances of IT cyclosporine tacrolimus (2)reduced and on average by(3), 50%, requiring everolimus (1). The mean follow-up dosing regimens. Anaemia occurredperiod in all since HCV therapy was weeks. patients, with a mean fall14.8±3.1 in haemoglobin Estimated oral clearances of week IT decreased levels between baseline and 12 of on average by 50%, requiring reduced 3.12±2.27g/dL. All patients required dosing regimens. Anaemia occurred in all administration of β-erythropoietin, three patients,ribavirin with a mean in haemoglobin needed dose fall reduction and one a levels transfusion. between baseline and week 12 of blood A virological response 3.12±2.27g/dL. was observed inAll allpatients patientsrequired (mean HCV administration of β-erythropoietin, three vira load decrease at week 12: 6.64±0.35 28 dose reduction and one a needed ribavirin log(10)IU/mL). blood transfusion. A virological response was observed in all patients (mean HCV vira load decrease at week 12: 6.64±0.35 28 log(10)IU/mL).

Tacrolimus

substrate • vardenafil (Levitra); substrate of CYP3A4>3A5, 2C Rifampin

sildenafil: 25 mg every 48 hours tadalafil: 10 mg every 72 hours vardenafil: contraindicated

In healthy subjects, coadministration of rifampin 600 mg daily at steady-state and single dose telaprevir 750 mg led to 86% ↓ Cmax and 92% ↓ AUC of telaprevir. Coadministration of rifampin and telaprevir is 13 contraindicated. In healthy subjects, the pharmacokinetics of single dose tacrolimus was assessed alone (2 mg) and at a dose of 0.5 mg in the presence of steady-state telaprevir 750 mg q8h. When coadministered with telaprevir, Telaprevir tacrolimus exposure ↑ 70-fold and the TVR,from VX-950) elimination(Incivek®, t1/2 increased 40.7 to 196 Vertex kinetics Pharmaceuticals hours; telaprevir were similar to historical data, suggesting no major effect of 29 Telaprevir tacrolimus on telaprevir. (Incivek®, TVR, VX-950) Pharmaceuticals General HCV-1a Hospital, Toronto, ONpost-liver In aToronto case Vertex series, infected, page 11major of 16 effect of historical data, suggesting nopegylated transplant patients received 29 tacrolimus2a/b, on telaprevir. interferon ribavirin, and telaprevir. All subjects were on stable tacrolimus dosing In a case series,antiviral HCV-1atherapy. infected,Tacrolimus post-liver prior to starting transplant received pegylated doses werepatients pre-emptively reduced to 50% of interferon 2a/b,doses ribavirin, telaprevir. All pre-treatment and and given once weekly. subjectsTAC werelevels on stable dosing Trough weretacrolimus checked q2d for the prior2toweeks, starting antiviral therapy. Tacrolimus first then weekly until telaprevir doses were reduced to 50% of therapy was pre-emptively complete. Baseline TAC pre-treatment doses and once dosing was resumed aftergiven 5 days of weekly. Trough TAC levels were checked of q2d for the stopping telaprevir. No episodes acute first 2 weeks, then weekly untilnoted; telaprevir rejection or TAC toxicity were 4 therapy was TAC patients had complete. early rapid Baseline virologic response, dosing washad resumed after 5 days of 2 patients complete early virologic stopping telaprevir. No episodes of acute response, 1 patient was a non-responder. rejection TAC toxicity noted; 4(n=6 The mainor adverse effect were was anemia patients had early rapiddehydration, virologic response, required transfusions); renal 39 2 patients had complete early virologic insufficiency and infections also reported. response, 1 patient was a non-responder. The main adverse was anemia (n=6 In a series of 9 livereffect transplant HCV patients requiredwith transfusions); dehydration, renal treated telaprevir, pegylated interferon, 39 insufficiency and infections reported. and ribavirin in parallel with also tacrolimus (n=4), cyclosporine (n=4), or sirolimus (n=1), In a series of 9 liver transplant HCV patients immunosuppressant dose-reductions were treated with telaprevir, pegylated interferon, required in all patients (cyclosporine 2.5-fold, and ribavirin in parallel with 22-fold, tacrolimus (n=4), sirolimus 7-fold, tacrolimus cyclosporine (n=4), (n=1), respectively) during or thesirolimus course of the 12 immunosuppressant dose-reductions week triple therapy. Tacrolimus and were required in all patients (cyclosporine 2.5-fold, sirolimus were administered once weekly sirolimus 7-fold, tacrolimus 22-fold, while the average cyclosporine dose was respectively) course of the 12 4 48.5 mg dailyduring duringthe triple therapy. Four week triple therapy. Tacrolimus patients were HCV RNA negativeand by week 4 sirolimus were were administered once weeklyby and 8 patients HCV RNA negative 31 while the week 12. average cyclosporine dose was 48.5 mgthe daily during triple therapy. at Four 4 In vitro, effect of 14C-telaprevir patientsconcentrations were HCV RNAonnegative by week 4 various the proteinand 8 patients were HCV negative binding of313H-warfarin wasRNA evaluated in by week 12. human plasma. Protein-binding of 14C-

• • •



Merck CanadaRPG, Inc. Victrelis (boceprevir) Product Kirkland, QC June 13, 2012. Van Heeswijk Boogaerts G, De Paepe E,Monograph. et al. The effect of different types of food on the

Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, June 13, 2011, 2012. Van Heeswijk RPG, Boogaerts G, DePharmacology Paepe E, et al. effect of differentQC types of food on the International Workshop on Clinical ofThe Hepatitis Therapy, June 22-23, bioavailabilityMA. of the investigational HCV protease inhibitor telaprevir [abstract PK_19]. 6th Cambridge, Van HeeswijkWorkshop RPG, Boogaerts G,Pharmacology De Paepe E, et The effect of different types2011, of food on the International on Clinical of al. Hepatitis Therapy, June 22-23, bioavailability of the investigational HCV protease inhibitor telaprevir [abstract PK_19]. Cambridge, MA. Ghosal A, Yuan Y, Tong W, et al. Characterization of human liver enzymes involved in 6th the International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, biotransformation of boceprevir, a hepatitis C virus protease inhibitor. Drug Metab Dispos Ghosal A, Yuan Cambridge, MA.Y, Tong W, et al. Characterization of human liver enzymes involved in the

1.2.

3.

3.

2.

References: bioavailability of the investigational HCV protease inhibitor telaprevir [abstract PK_19]. 6th

1. 2.

References:

dose of zolpidem 5 mg alone and in Monitor INR when coadministering warfarin Monitor INR6 whenacoadministering warfarin combination single 750 mg telaprevir and telaprevir. with 6 and telaprevir. and multiple telaprevir of 750 Zolpidem In dose healthy subjects who receiveddoses a single Zolpidem In received a single mghealthy q8h,subjects zolpidem exposures dose ofpozolpidem 5 mgwho alone and in were dose of zolpidem 5 mg750 alone and in combination with a single mgtelaprevir, telaprevir unchanged after single dose while combination with single 750 mg telaprevir dose and multiple telaprevir doses of ↓ 750 zolpidem Cmax ↓a42% and AUC 47% after andzolpidem multiple telaprevir doses of 750 mgdose po q8h, exposures were The steady-state dosing of telaprevir. mean mg po q8h, zolpidem exposures were unchanged after single dose telaprevir, while t1/2 of zolpidem decreased from 4.32 hours unchanged after42% single dose while zolpidem andmultiple AUC telaprevir, ↓ 47% after to 3.37 Cmax hours↓following doses of 22 zolpidem and AUC 47% after steady-state dosing↓of42% telaprevir. The↓ mean telaprevir.Cmax steady-state of telaprevir. t1/2 of zolpidemdosing decreased from 4.32 The hoursmean zolpidem decreased to t1/2 3.37of hours following multiple from doses4.32 of hours 22 telaprevir. to 3.37 hours following multiple doses of 22 telaprevir. 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 Please note: This chart summarizes some of the major drug interactions identified to date, based on current replace sound professional judgment may in individualPlease situations, and should be used in conjunctiontherapy. with other available data; other drugsummarizes interactions use caution whenever adding/modifying Thereliable Please note: This chart someexist. of the major drugof interactions identified date, based current sources of information. Due to the for rapidly changing nature information about HIVtotreatment andon therapies, information in this table is intended use by experienced physicians and pharmacists. It is not intended to available data; other interactions may exist. Pleaseherein use caution adding/modifying therapy. The users aresound advised to drug recheck the information contained thewhenever original source beforewith applying it to patient replace professional judgment in use individual situations, andwith should be used in conjunction other reliable information in this table is intended for by experienced physicians and pharmacists. It is not intended to care. sourcessound of information. Duejudgment to the rapidly changingsituations, nature of information HIV in treatment and therapies, replace professional in individual and shouldabout be used conjunction with other reliable users are advised to recheck the information contained herein with the original source before applying it to patient sources of information. Due to the rapidly changing nature of information about HIV treatment and therapies, care. usersReferences: are advised to recheck the information contained herein with the original source before applying it to patient care.1. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.

week triple therapy. Tacrolimus and sirolimus were administered once weekly while the average cyclosporine dose was 48.5 mg daily during triple therapy. Four 4 patients were HCV RNA negative by week 4 and 8 patients were HCV RNA negative by 31 week 12. Warfarin Combination has not been studied. In vitro, the effect of 14C-telaprevir at Potential for altered warfarin concentrations various concentrations on the proteinin the presence of boceprevir. Monitor INR binding of 3H-warfarin was evaluated in when coadministering warfarin and human plasma. Protein-binding of 14C1 boceprevir. telaprevir in human plasma was 59.1-75.6% over the concentration range of 0.1 to 20 uM. The free fraction of 14C-telaprevir ↑ ~30% in the presence of warfarin at low 14C-telaprevir concentrations, but this was not observed at high 14C-telaprevir doses. Boceprevir Protein binding ofTelaprevir 3H-warfarin in human (Victrelis®, BOC, SCH 503034) (Incivek®, VX-950) plasma was 98% andTVR, was unchanged by the Merck Pharmaceuticals presence Vertex of telaprevir over the concentration range of 0.1 to 20Telaprevir uM. Boceprevir Boceprevir Telaprevir At low 14C-telaprevir concentrations, (Victrelis®,BOC, BOC,SCH SCH503034) 503034) (Incivek®, TVR, VX-950) (Victrelis®, (Incivek®, TVR, VX-950) warfarin and other ligands with high affinity Merck Vertex Pharmaceuticals Merck Vertex Pharmaceuticals binding to albumin or alpha1-acid glycoprotein may displace 14C-telaprevir AtAt lowlow 14C-telaprevir concentrations, 14C-telaprevir concentrations, Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. Toronto General Hospital, Toronto, ON from protein binding sites and ↑ affinity the free warfarin and other ligands high www.hivclinic.ca October 25, 2012 page 12 of 16 affinity 40 with warfarin and other ligands with high fraction of telaprevir. binding to albumin or alpha1-acid binding to albumin or alpha1-acid glycoprotein may displace 14C-telaprevir glycoprotein may displace 14C-telaprevir Monitor INR whensites coadministering from protein binding and ↑ the freewarfarin 6 40 sites and ↑ the free from protein binding and telaprevir. 40 fraction of telaprevir. fraction of telaprevir. Zolpidem In healthy subjects who received a single



Van Heeswijk RPG, Boogaerts G, De Paepe E, et al. The effect of different types of food on the bioavailability of the investigational HCV protease inhibitor telaprevir [abstract PK_19]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. Ghosal A, Yuan Y, Tong W, et al. Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor. Drug Metab Dispos 2011;39(3):510-21. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. Jumes P, Feng H-P, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and digoxin in healthy adult volunteers [abstract PK_05]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. Adiwijaya B, Chandorkar G, Van Heeswijk RPG, et al. Effect of mild and moderate hepatic

Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. Poland B, Kastrissios H, Gupta S, et al. Population pharmacokinetic analysis finds no clinically Adiwijaya Chandorkar G, Van Heeswijk RPG, et al. Effect of mild and moderate hepaticPK_6]. important B, effects of demographic and health covariates on boceprevir exposure [abstract impairment on telaprevir pharmacokinetics [abstract PK_1]. 6th International Workshop 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, on 2011, Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. Cambridge, MA.

Poland B, EGJ, Kastrissios H, Gupta pharmacokinetic no clinically Hulskotte Feng H-P, XuanS,F,etetal. al.Population Pharmacokinetic interactionanalysis betweenfinds the HCV protease important effects of demographic and health covariates oninhibitors boceprevir exposurelopinavir, [abstractand PK_6]. inhibitor boceprevir and ritonavir-boosted HIV-1 protease atazanavir, 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, JuneInfections, 22-23, 2011, darunavir [abstract 771LB] 19th Conference on Retroviruses and Opportunistic March Cambridge, MA. WA. 5-8, 2012, Seattle, Hulskotte Feng Agency. H-P, Xuan F, et al. Pharmacokinetic interaction between the HCV protease European EGJ, Medicines Questions and answers on drug interactions between Victrelis inhibitor boceprevir and ritonavir-boosted HIV-1 protease atazanavir, lopinavir, and (boceprevir) and ritonavir-boosted HIV protease inhibitors.inhibitors 2012 February 16. Report No.: darunavir [abstract 771LB] 19th Conference on Retroviruses and Opportunistic Infections, March EMA/CHMP/117973/2012. 5-8, 2012, Seattle, WA. Van Heeswijk RPG, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between European Medicines Agency. Questions answers on drug interactions Victrelis ARV agents and the investigational HCV and protease inhibitor TVR in healthy between volunteers [abstract (boceprevir) and ritonavir-boosted HIV protease inhibitors.Infections, 2012 February 16. Report No.: Boston, 119]. 18th Conference on Retroviruses and Opportunistic Feb 27-Mar 2, 2011, EMA/CHMP/117973/2012. USA. Van Heeswijk RPG, Vandevoorde A, al. Boogaerts G, et al. Pharmacokinetic between Henshaw J, Adiwijaya B, Adda N, et The pharmacokinetics of telaprevirinteractions and selected ART ARV agents and the investigational protease inhibitor TVR7th in healthy volunteers [abstract medications in HCV/HIV co-infectedHCV patients [abstract PK_08]. International Workshop on 119]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA. 2, 2011, Boston, USA. Garg V, Chandorkar G, Yang Y, et al. The effect of CYP3A inhibitors and inducers on the Henshaw J, Adiwijaya B, Adda [abstract N, et al. The pharmacokinetics of telaprevir pharmacokinetics of telaprevir PK_13]. 6th International Workshopand on selected Clinical ART medications in HCV/HIV co-infected [abstract 7th International Workshop on Pharmacology of Hepatitis Therapy, patients June 22-23, 2011,PK_08]. Cambridge, MA. Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA. Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between boceprevir and Garg V, Chandorkar Yang Y, et al. The effectJ of CYP3A inhibitors and 2012;Oct inducers on etravirine in HIV/HCVG,seronegative volunteers. Acq Immune Def Syndr 15 the [Epub pharmacokinetics ahead of print]. of telaprevir [abstract PK_13]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. Kakuda TN, Leopold L, Nijs S, et al. Pharmacokinetic interaction between etravirine or rilpivirine Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between and and telaprevir: a randomised, two-way crossover trial [abstract O_18]. 13th boceprevir International etravirine HIV/HCV seronegative volunteers. J Acq April Immune Def2012, SyndrBarcelona, 2012;Oct 15 [Epub Workshopinon Clinical Pharmacology of HIV Therapy, 16-18, Spain. ahead of print]. de Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor boceprevir on Kakuda TN, Leopold L,ofNijs etintegrase al. Pharmacokinetic interaction between etravirine rilpivirine the pharmacokinetics the S, HIV Inhibitor raltegravir [abstract 772LB]. 19thor Conference and telaprevir: aand randomised, two-way crossover trial [abstract O_18]. 13th on Retroviruses Opportunistic Infections March 5-8, 2012, Seattle, WA. International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain. Moreno A, Quereda C, Montes M, et al. Safe coadministration of raltegravir-based HAART in de Kanter C, patients Blonk M,with Colbers A, et al. The influence of the HCVwith protease inhibitor boceprevirJon HIV-infected HCV-cirrhosis receiving triple therapy telaprevir or boceprevir.

2.

3.

4.

5.

6. 7.

6. 8. 7.

8. 9.

9. 10.

11. 12.

17. 16.

16. 15.

15. 14.

14. 13.

13. 12.

11. 10.

telaprevir pharmacokinetics 6th International Workshop on Academic impairment copyright: Aliceon Tseng, Pharm.D., FCSHP, AAHIVP. [abstract PK_1]. Toronto General Hospital, Toronto, ON www.hivclinic.ca 25, 2012 page 13 of 16 Clinical Pharmacology of HepatitisOctober Therapy, June 22-23, 2011, Cambridge, MA.

Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.

1.



Moreno A, Quereda C, Montes M, et al. Safe coadministration of raltegravir-based HAART in HIV-infected patients with HCV-cirrhosis receiving triple therapy with telaprevir or boceprevir. J Acq Immune Def Syndr 2012;61(3):e47-9. Van Heeswijk RPG, Garg V, Boogaerts G, et al. The pharmacokinetic interaction between telaprevir and raltegravir in healthy volunteers [abstract A1-1738a]. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2011, Chicago, IL. Kempf DJ, Klein C, Chen HJ, et al. Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH 503034 by co-dosing with ritonavir. Antivir Chem Chemother 2007;18(3):163-7.

17.

18.

19.

29. 30.

GargPJ, V, Van Heeswijk RPG, M, LeeetJE, al.of Effect of telaprevir oninterferon/ribavirin the pharmacokinetics of Kwo Ghabril M, Lacerda al. et Use telaprevir plus peg for null cyclosporine and tacrolimus. Hepatology 2011;54(1):20-7.

Garg V, Luo X, McNair L, et al. Low-dose ritonavir and the pharmacokinetics of the investigational HCV protease inhibitor telaprevir in healthy volunteers [abstract 629]. 18th Conference on Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. Feb 27-Mar 2, 2011, TorontoBoston, General Hospital, Retroviruses and Opportunistic Infections, USA. Toronto, ON www.hivclinic.ca October 25,ritonavir 2012 of 16 20. Garg V, Luo X, McNair L, et al. Low-dose and the pharmacokinetics ofpage the14 investigational HCVHeeswijk proteaseR, inhibitor in healthy [abstract 629].interaction 18th Conference 21. Van Gysentelaprevir V, Googaerts G, et volunteers al. The pharmacokinetic betweenontenofovir Retroviruses and Opportunistic Infections, Feb 2, 2011, Boston, USA. disoproxil fumarate and the investigational HCV27-Mar protease inhibitor telaprevir [abstract A-966]. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 25-28, 2008, 21. Van HeeswijkDC. R, Gysen V, Googaerts G, et al. The pharmacokinetic interaction between tenofovir Washington, disoproxil fumarate and the investigational HCV protease inhibitor telaprevir [abstract A-966]. 48thX, Interscience Conference on Antimicrobial Agents Chemotherapy, October 25-28, of 2008, 22. Luo Van Heeswijk RPG, Alves K, et al. The effect ofand telaprevir on the pharmacokinetics Washington,and DC. alprazolam zolpidem in healthy volunteers [abstract PK_11]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. 22. Luo X, Van Heeswijk RPG, Alves K, et al. The effect of telaprevir on the pharmacokinetics of alprazolam zolpidem in healthy [abstract PK_11]. C 6th International 23. Lee JE, Vanand Heeswijk RPG, Alves K,volunteers et al. Effect of the hepatitis virus protease Workshop inhibitor on Clinical Pharmacology of Hepatitis of Therapy, Juneand 22-23, 2011, Cambridge, MA. telaprevir on the pharmacokinetics amlodipine atorvastatin. Antimicrob Agents Chemother 2011;55(10):4569-74. 23. Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on theFeng pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents 24. Hulskotte EGJ, H-P, Bruce RD, et al. Pharmacokinetic interaction between HCVChemother protease 2011;55(10):4569-74. inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy [abstract PK_09]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 24. Hulskotte EGJ, Feng H-P, Bruce RD, et al. Pharmacokinetic interaction between HCV protease June 27-28, 2012, Cambridge, MA. inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy [abstract PK_09]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 25. Luo X, Trevejo J, Van Heeswijk RPG, et al. Effect of telaprevir on the pharmacokinetics of June 27-28, 2012, Cambridge, buprenorphine in volunteers on MA. stable buprenorphine/naloxone maintenance therapy. Antimicrob Agents Chemother 2012;56(7):3641-7. 25. Luo X, Trevejo J, Van Heeswijk RPG, et al. Effect of telaprevir on the pharmacokinetics of buprenorphine in volunteers on stable buprenorphine/naloxone maintenance Antimicrob 26. Foisy MM, Yakiwchuk EMK, Chiu I, et al. Adrenal suppression and Cushing’s therapy. syndrome Agents Chemother 2012;56(7):3641-7. secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9(6):389-96. 26. Foisy MM, Yakiwchuk EMK, Chiu I, et al. Adrenal suppression and Cushing’s syndrome secondaryEGJ, to anGupta interaction between ritonavir and fluticasone: a review of thethe literature. HIV Med 27. Hulskotte S, Xuan F, et al. Pharmacokinetic interaction between HCV protease 2008;9(6):389-96. inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012;May 11 [Epub ahead of print]. 27. Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor and cyclosporine and tacrolimus in healthy volunteers. 2012;May 28. Coilly A, boceprevir Furlan V, Roche B, et al. Practical management of boceprevir andHepatology immunosuppressive 11 [Epubinahead of print]. recipients with hepatitis C virus recurrence. Antimicrob Agents therapy liver transplant Chemother 2012;56(11):5728-34. 28. Coilly A, Furlan V, Roche B, et al. Practical management of boceprevir and immunosuppressive therapy liver transplant recipients hepatitis virus recurrence. Antimicrob Agents 29. Garg V, in Van Heeswijk RPG, Lee JE,with et al. Effect ofCtelaprevir on the pharmacokinetics of Chemother 2012;56(11):5728-34. cyclosporine and tacrolimus. Hepatology 2011;54(1):20-7.

de Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase Inhibitor raltegravir [abstract 772LB]. 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, WA.

16.

20.

Kakuda TN, Leopold L, Nijs S, et al. Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir: a randomised, two-way crossover trial [abstract O_18]. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain.

15.

etravirine in HIV/HCV seronegative volunteers. J Acq Immune Def Syndr 2012;Oct 15 [Epub ahead of print].



Garg V, Van Heeswijk RPG, Lee JE, et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011;54(1):20-7. Kwo PJ, Ghabril M, Lacerda M, et al. Use of telaprevir plus peg interferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C [abstract 202]. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22nd, 2012, Barcelona. Werner CR, Egetemeyr DP, Lauer UM, et al. Short report: Telaprevir-based triple therapy in liver transplanted HCV patients: A 12 week pilot study providing safety and efficacy. Liver Transplantation 2012;Sep 1 [Epub ahead of print]. Garg V, Chandorkar G, Farmer HF, et al. Effect of telaprevir on the pharmacokinetics of midazolam and digoxin. J Clin Pharmacol 2012;Jan 26 [Epub ahead of print]. Hulskotte EGJ, Gupta S, Xuan F, et al. Coadministration of the HCV protease inhibitor boceprevir has no clinically meaningful effect on the pharmacokinetics of the selective serotonin reuptake inhibitor escitalopram in healthy volunteers [abstract]. HEP DART, December 4-8, 2011, Koloa, Hawaii. Van Heeswijk RPG, Boogaerts G, De Paepe E, et al. The pharmacokinetic interaction between

29. 30.

31.

32. 33.

34.

40.

40. 39.

39. 38.

37. 38.

36.

37.

36. 35.

34. 35.

Chakilam A, Chavan A, Smith G, et al. Telaprevir binding to isolated human plasma proteins and protein binding displacement interactions between telaprevir and ritonavir or warfarin [abstract PK_20]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA.

Van Heeswijk RPG, Vandevoorde P, et al. The pharmacokinetic interaction between Garg V, Van Heeswijk RPG, Yang A, Y, Verboven et al. The pharmacokinetic interaction between an oral methadone and the investigational HCV protease inhibitor telaprevir PK_18]. 6th contraceptive containing ethinyl estradiol and norethindrone and the [abstract HCV protease inhibitor International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, telaprevir. J Clin Pharmacol 2011;Oct 30. Cambridge, MA. Mantry PS, Hassett MS, Weinstein J, et al. Triple therapy using telaprevir in the treatment of Garg V, Van Heeswijk after RPG,liver Yang Y, et al. The pharmacokinetic interaction between an oral 90]. hepatitic C recurrence transplantation: an early single center experience [abstract contraceptive containing4-8, ethinyl estradiol norethindrone and the HCV protease inhibitor HEP DART, December 2011, Koloa, and Hawaii. telaprevir. J Clin Pharmacol 2011;Oct 30. Chakilam A, Chavan A, Smith G, et al. Telaprevir binding to isolated human plasma proteins and Mantry binding PS, Hassett MS, Weinstein J, et al.between Triple therapy using treatment of protein displacement interactions telaprevir andtelaprevir ritonavir in or the warfarin [abstract hepatitic 6th C recurrence after liver transplantation: an early single experience 90]. PK_20]. International Workshop on Clinical Pharmacology of center Hepatitis Therapy,[abstract June 22-23, HEP DART, December 2011, Cambridge, MA. 4-8, 2011, Koloa, Hawaii.

Van Heeswijk Boogaerts G,et Deal.Paepe E, et al. Theevaluation pharmacokinetic interactionbetween betweenthe Hulskotte EGJ,RPG, Gupta S, Xuan F, Pharmacokinetic of the interaction escitalopram the investigational HCV inhibitor telaprevir [abstract 12]. 5thand HCV proteaseand inhibitor boceprevir and theprotease HMG-CoA reductase inhibitors atorvastatin International[abstract]. WorkshopHEP on Clinical Pharmacology Hepatitis Therapy, pravastatin DART, December 4-8, of 2011, Koloa, Hawaii. June 23-24, 2010, Boston, MA. U.S. Food and Drug Administration. HIV/AIDS Update - Important info about interactions between Hulskotte Gupta S, Xuan F, et al. Pharmacokinetic of the interaction between the certain HIVEGJ, drugs and cholesterol-lowering statin drugs. evaluation March 1, 2012. HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin [abstract]. HEP DART, A, December 2011, Koloa, Hawaii. Van Heeswijk RPG, Vandevoorde Verboven4-8, P, et al. The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir [abstract PK_18]. 6th U.S. Food and Drug Administration. HIV/AIDS Update - Important info about International Workshop on Clinical Pharmacology of Hepatitis Therapy, June interactions 22-23, 2011,between certain HIV drugs Cambridge, MA. and cholesterol-lowering statin drugs. March 1, 2012.

Hawaii. MA. Boston,

Academicescitalopram copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. General Hospital,12]. Toronto, and the investigational HCV protease inhibitorToronto telaprevir [abstract 5th ON www.hivclinic.ca October 25, [abstract]. 2012 of Hepatitis page2011, 15 of 16 inhibitor escitalopram inon healthy volunteers HEP DART, December 4-8, Koloa, International Workshop Clinical Pharmacology Therapy, June 23-24, 2010,

Coilly A, Furlan V, Roche B, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother 2012;56(11):5728-34.

28.

11 [Epub ahead of print].

Interactions with Other Drug Classes - anticonvulsants

65 66 Interactions with Other Drug Classes - anticonvulsants

Substrate and strong inhibitor of 3 Potential forand ↓ DAA CYP3A4 p-glycoprotein. concentration and/or ↑ 4 anticonvulsant concentration.

Substrate and strong inhibitor of Telaprevir 3 CYP3A4 and TVR, p-glycoprotein. (Incivek®, VX-950) Vertex Pharmaceuticals

Potential for ↓ DAA concentrations and/or ↑/↓ anticonvulsant concentrations. Use combination with caution. Potential for ↓ DAA Clinical or laboratory concentrations and/ormonitoring ↑/↓ of phenobarbital concentrations anticonvulsant concentrations. and dose titration are Use combination with caution.

Potential for ↓ DAA concentrations and/or ↑/↓ anticonvulsant concentrations. Phenobarbital contraindicated Potential for ↓ is DAA 5 with boceprevir.and/or ↑/↓ concentrations anticonvulsant concentrations. Phenobarbital is contraindicated

Use combination with caution. Potential for ↓ DAA Clinical or laboratory monitoring concentration and/or ↑ 4 of carbamazepine anticonvulsant concentration. concentrations and dose titration are recommended to achieve the Carbamazepine is Use combination with caution. 3 5 desired or clinical response. contraindicated with boceprevir. Clinical laboratory monitoring of carbamazepine Consider an alternate agent with concentrations and dose titration non-inducing metabolic are recommended to achieve the 3 properties. desired clinical response. No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to agent clinicalwith Consider an alternate response. non-inducing metabolic No interaction expected based on known pharmacologic properties. characteristics. and titrate according to clinical No interaction Monitor expected based ondose known pharmacologic response. characteristics. Monitor and titrate dose according to clinical No interaction expectedresponse. based on known pharmacologic characteristics. and titrate according to clinical No interaction Monitor expected based ondose known pharmacologic response. characteristics. Monitor and titrate dose according to clinical NB: No data exist for levetiracetam for treating psychiatric disorders response. in the context of HCV. No interaction expected based on known pharmacologic No interaction Monitor expected based ondose known pharmacologic characteristics. and titrate according to clinical characteristics. Monitor and titrate dose according to clinical response. response and serum levels.psychiatric disorders NB: No data exist for levetiracetam for treating Potential for ↓ DAA concentrations decreased efficacy. Avoid in the contextand of HCV. combination if possible, and consider alternate anticonvulsant No interaction expected based onan known pharmacologic 7 with non-inducing properties. characteristics. Monitor and metabolic titrate dose according to clinical response and serum levels. Potential for ↓ DAA concentrations and decreased efficacy. Avoid combination if possible, and consider an alternate anticonvulsant 7 with non-inducing metabolic properties.

Substrate Boceprevir of CYP3A4, CYP3A5 1 and aldoketoreductases. (Victrelis®, BOC, SCH 503034) Strong, reversible Merck inhibitor of CYP3A4 and p-glycoprotein in 2 vitro. Substrate of CYP3A4, CYP3A5 1 Potential for ↓ DAA and aldoketoreductases. concentration and/orinhibitor ↓ Strong, reversible of 4 anticonvulsant CYP3A4 and concentration. p-glycoprotein in 2 vitro. Carbamazepine is Potential for ↓ DAA 5 contraindicated with boceprevir. concentration and/or ↓ 4 anticonvulsant concentration.

Academic copyright: Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON, Alice Tseng, Pharm.D., FCSHP, AAHIVP and 5 with boceprevir. Clinical or laboratory monitoring Sanjeev Sockalingam, MD, FRCPC, University Health Network, Toronto, ON. www.hivclinic.ca August 28, 2012 page 1 of 3 of phenobarbital concentrations

Potent inducer of CYP3A4, 1A2, 2C9/19, UGT

(parent - 2C9/19)

Oxcarbazepine (parent - UGT) Lithium (renal) Inhibitor of CYPC19 Potent inducer of CYP3A4. Oxcarbazepine Relative- to carbamazepine, (parent UGT) oxcarbazepine inducing effect is 6 54% lower Inhibitor of CYPC19 Phenobarbital Potent inducer of CYP3A4. (parent - to 2C9/19) Relative carbamazepine, oxcarbazepine inducing effect is 6 Potent inducer of CYP3A4, 1A2, 54% lower 2C9/19, UGT Phenobarbital

Levetiracetam Lithium (24% enzymatic hydrolysis, 66% (renal) renal)

Lamotrigine (UGT) Gabapentin (Renal) Levetiracetam (24% enzymatic hydrolysis, 66% Lamotrigine renal) (UGT)

Gabapentin (Renal)

Inducer of CYP3A, 2C9, 2C19, UGT and possibly 1A2

Inducer of CYP3A, 2C9, Carbamazepine 2C19, UGT and possibly (Parent: CYP3A>> 2C8, 1A2 1A2)

Carbamazepine (Parent: CYP3A>> 2C8, 1A2)

Anticonvulsant (route of metabolism)

Anticonvulsant Boceprevir Telaprevir (route of metabolism) (Victrelis®, BOC, SCH 503034) (Incivek®, TVR, VX-950) Merck Acting Antivirals (DAAs) Vertex Pharmaceuticals Actual/Potential Drug Interactions Between Directly and Anticonvulsants

Actual/Potential Drug Interactions Between Directly Acting Antivirals (DAAs) and Anticonvulsants

Interactions with Other Drug Classes - anticonvulsants

67 68 Interactions with Other Drug Classes - anticonvulsants

Phenytoin is contraindicated with Potential for5 ↓ DAA boceprevir. concentrations and/or ↑/↓ anticonvulsant concentrations.

Potent inducer of CYP3A4, Phenytoin 2C9/19, UGT (parent - 70% CYP2C9, minor 2C19)

concentrations and/or ↑/↓ Consider an alternate agent with anticonvulsant concentrations. non-inducing metabolic properties. Use combination with caution. Potential ↓ DAA monitoring Clinical orfor laboratory concentrations and/or ↑/↓ of phenobarbital concentrations anticonvulsant concentrations. and dose titration are

Potential for ↓ DAA concentrations and/or ↑/↓ anticonvulsant concentrations.

Phenytoin is contraindicated with 5 boceprevir.

Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012. Novartis Pharmaceuticals Canada Inc. Tegretol (Carbamazepine) Product Monograph. Dorval, Andreasen AH, Brosen K, Damkier P. A comparative pharmacokinetic study in healthy volunteers Que. 2011. of the effect of carbamazepine and oxcarbazepine on CYP3A4. Epilepsia 2007 Mar;48(3):490-6. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.

3. 5. 4. 6. 5.

Academic copyright: Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON, Alice Tseng, Pharm.D., FCSHP, AAHIVP and

4.

Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Novartis Pharmaceuticals Canada Inc. Tegretol (Carbamazepine) Product Monograph. Dorval, Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. Que. 2011.

3. 2.

References: 2. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, 1. Ghosal A, Yuan Y, Tong W, et al. Characterization of human liver enzymes involved in the excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and biotransformation of boceprevir, a hepatitis C virus protease inhibitor. Drug Metab Dispos Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. 2011;39(3):510-21.

Potent inducer of CYP3A4, 2C9/19, UGT

recommended to achieve the 3 Use combination with caution. desired clinical response. Clinical or laboratory monitoring of phenobarbital concentrations Consider an alternate agent with and dose titration are non-inducing metabolic recommended to achieve the properties. 3 desired clinical response. Pregabalin No interaction expected based on known pharmacologic (renal) characteristics. Monitor and titrate dose according to clinical Consider an alternate agent with response. non-inducing Topiramate Potential for ↓ DAA concentrations. Monitor metabolic and titrate dose properties. (renal) according to clinical response. Pregabalin No data interaction expected based on known pharmacologic NB: No exist for topiramate for treating psychiatric disorders in (renal) characteristics. Monitor and titrate dose according to clinical Induces 3A4 (mild), inhibits 2C19 the context of HCV. response. Valproic acid, divalproex No interaction expected based on known pharmacologic Topiramate Potential for ↓ DAA concentrations. Monitor and titrate dose (Parent – 50% UGT, > 2D6) Cmax of escitalopram 3 1 Level of Antidepressant Known or Potential Comments adjusted. with boceprevir. Evidence (route of metabolism) Interactions with DAAs Level 1 Escitalopram (CYP2C19, 3A4 Boceprevir: May escitalopram 21% ↓ ↓ escitalopram AUC, 19% ↓ AUC Telaprevir: need to 35% 2 >> 2D6) dose may need to be Cmax of escitalopram titrate escitalopram dose with telaprevir. 3 1 adjusted. to clinical with boceprevir. according 4 response. Telaprevir: need to 35% ↓ escitalopram AUC Level 2 Citalopram Monitor andMay titrate dose Potential for ↑ 2 titrate escitalopram with telaprevir. (CYP2C19, 3A4 >> 2D6) according to clinicaldose antidepressant according response.4to clinical concentrations. response. Paroxetine (2D6) No interaction expected Monitor and titrate dose Level 2 Citalopram Monitor and Potential ↑ based on for known according to titrate clinicaldose (CYP2C19, 3A4 >> 2D6) according to clinical antidepressant pharmacologic response. response. concentrations. characteristics. Paroxetine (2D6) No interaction expected Monitor and titrate dosefor NB: Evidence in RCT based on known according tomood clinical depressed pharmacologic response. of major component characteristics. depression only NB: Evidence in RCT Level 3 Nortriptyline (2D6) No interaction expected Monitor and titrate dosefor depressed based on known according tomood clinical component pharmacologic response. of major depression only characteristics. Level Nortriptyline (2D6) No Monitor Level 3 4 Bupropion (2B6) No interaction interaction expected expected Monitor and and titrate titrate dose dose based according Fluoxetine (2D6) based on on known known according to to clinical clinical pharmacologic response. pharmacologic response. characteristics. characteristics. Level 4 Bupropion (2B6) interaction Monitor titratemonitor dose Sertraline (CYP2B6 > 2C9/19, No Use withand caution; Potential for ↑ expected sertraline, Fluoxetine (2D6) on known according clinical 3A4, 2D6, UGT1A1 - possible) based and titrate to dose according mirtazapine, venlafaxine pharmacologic response. Mirtazapine (CYP2D6, 1A2, to clinical response. concentrations (clinical characteristics. 3A4) significance unknown). Sertraline (CYP2B6 > 2C9/19, Potential for ↑ sertraline, Use with caution; monitor Venlafaxine 3A4, 2D6, >UGT1A1 - possible) mirtazapine, venlafaxine and titrate dose according (CYP2D6 CYP3A4) Mirtazapine (CYP2D6, 1A2, to clinical response. concentrations Desvenlafaxine (UGT>>3A4) Use with caution; monitor Potential for ↑ (clinical 3A4) significance unknown). and titrate antidepressant desvenlafaxine Venlafaxine dose according to clinical concentrations (clinical (CYP2D6 > CYP3A4) response. Monitor for significance unknown). Desvenlafaxine (UGT>>3A4) Use withtocaution; monitor Potential for ↑ for ↓ efficacy HCV therapy. Also, potential and titrate antidepressant desvenlafaxine of DAAs concentrations dose according to clinical concentrations (clinical (clinical significance response. Monitor for significance unknown). unknown). efficacy HCV therapy. Also, potential for ↓ Tricyclic antidepressants Potential increase in TCA Use withtocaution with concentrations resulting of DAAs i.e. desipramine concentrations DAAs, lower TCA doses 3, 4 (clinical significance (CYP2D6>>UGT), imipramine in dizziness, hypotension are recommended. unknown). (CYP2D6, 1A2, 2C19, 3A > and syncope. Tricyclic antidepressants Potential increase in TCA Use cautioniswith UGT), trazodone (CYP2D6> NB: with Trazodone i.e. desipramine concentrations resulting DAAs, lower dosesfor CYP3A) primarily usedTCA clinically 3, 4 (CYP2D6>>UGT), imipramine in dizziness, hypotension are recommended. treating insomnia in HCV. (CYP2D6, 1A2, 2C19, 3A > and syncope. Inconclusive Modafinil (3A4; may induce Use with caution; monitor Potential for ↑ modafinil NB: titrate Trazodone is UGT), evidence as 3A4) trazodone (CYP2D6> and antidepressant concentrations and/or ↓ primarily used clinically for CYP3A) Academic copyright: Sanjeev Sockalingam, MD, FRCPC, Alice Tseng, Pharm.D., FCSHP, AAHIVP,treating University Health Network, insomnia in HCV. Toronto, ON, and Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON. Inconclusive Modafinil (3A4; may induce Use with caution; monitor Potential for ↑ modafinil www.hivclinic.ca September 26, 2012 page 1 of 2 evidence as 3A4) and titrate antidepressant concentrations and/or ↓

Antidepressant Treatment of Depression in Hepatitis C: Level of Evidence* and Drug Interactions with Directly Acting Antivirals (DAAs)

Interactions with Other Drug Classes - antidepressants

73 74 Interactions with Other Drug Classes - antidepressants

in dizziness, hypotension and syncope.

are recommended.

Criteria ≥ 2 RCTs or meta-analysis Criteria 1 RCT ≥ 2 RCTs or meta-analysis Prospective open label study (n ≥ 10) 1 RCT Anecdotal or expert opinion Prospective open label study (n ≥ 10) Anecdotal or expert opinion

Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011.

4.

Academic copyright: Sanjeev Sockalingam, MD, FRCPC, Alice Tseng, Pharm.D., FCSHP, AAHIVP, University Health Network, Toronto, ON, and Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON. Academic copyright: Sanjeev Sockalingam, MD, FRCPC, Alice 26, Tseng, www.hivclinic.ca September 2012Pharm.D., FCSHP, AAHIVP, University Health page 2Network, of 2 Toronto, ON, and Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON.

Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012. Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011.

3. 4.

References: 1. Hulskotte EGJ, Gupta S, Xuan F, et al. Coadministration of the HCV protease inhibitor boceprevir References: has no clinically meaningful effect on the pharmacokinetics of the selective serotonin reuptake 1. Hulskotte EGJ, Gupta S, Xuan F, et al. Coadministration of the HCV protease inhibitor boceprevir inhibitor escitalopram in helathy volunteers. Global Antiviral Journal 2011;7, Suppl 1:108-09 has no clinically meaningful effect on the pharmacokinetics of the selective serotonin reuptake (abstract). inhibitor escitalopram in helathy volunteers. Global Antiviral Journal 2011;7, Suppl 1:108-09 (abstract). 2. Van Heeswijk RPG, Boogaerts G, De Paepe E, et al. The pharmacokinetic interaction between escitalopram and the investigational HCV protease inhibitor telaprevir [abstract 12]. 5th 2. Van Heeswijk RPG, Boogaerts G, De Paepe E, et al. The pharmacokinetic interaction between International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 23-24, 2010, escitalopram and the investigational HCV protease inhibitor telaprevir [abstract 12]. 5th Boston, MA. International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 23-24, 2010, Boston, MA. 3. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.

Level of Evidence Level 1 Level of Evidence Level 2 Level 1 Level 3 Level 2 Level 4 Level 3 Level 4

Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, RCT = Randomized controlled trial, UGT = Uridine 5'-diphosphoglucuronosyltransferases

Nefazodone: potential for ↑ nefazodone and/or Nefazodone (3A4) Nefazodone: potential for DAA concentrations; also ↑ nefazodone and/or risk of hepatotoxicity. DAA= concentrations; also trial, UGT = Uridine 5'-diphosphoLegend: CYP = cytochrome P450, P-gp = p-glycoprotein, RCT Randomized controlled risk of hepatotoxicity. glucuronosyltransferases

Nefazodone (3A4)

NB: Trazodone is primarily used clinically for treating insomnia in HCV. Level of Antidepressant Known orforPotential Comments Inconclusive Modafinil (3A4; may induce Use with caution; monitor Potential ↑ modafinil Evidenceas (route of metabolism) Interactions with DAAs evidence 3A4) and titrate antidepressant concentrations and/or ↓ Level of Antidepressant Known or Potential Comments monotherapy DAA concentrations. dose according to clinical Evidence metabolism) with DAAs Academic copyright: (route Sanjeev of Sockalingam, MD, FRCPC, AliceInteractions Tseng, Pharm.D., FCSHP, AAHIVP,response. University Health Network, Monitor for Toronto, ON, and Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, ON. monotherapy DAAOttawa, concentrations. dose according to clinical efficacy to HCV therapy. www.hivclinic.ca September 26, 2012 1 of 2 for response. page Monitor efficacy to HCV therapy. Amantadine (minimal No interaction expected Monitor and titrate dose metabolism) based on known according to clinical Amantadine (minimal No interaction expected Monitor and titrate dose pharmacologic response. metabolism) based on known according to clinical characteristics. pharmacologic response. St. John's Wort (hypericum St. John’s Wort is Potential for ↓ DAA characteristics. perforatum); induces CYP3A4 contraindicated with concentrations. St. St. John’s Wort Potential for ↓ DAA andJohn's P-gp. Wort (hypericum boceprevir and is telaprevir. perforatum); induces CYP3A4 contraindicated with concentrations. Avoid Duloxetine (1A2, 2D6) Duloxetine: risk of Duloxetine is and P-gp. boceprevir and telaprevir. (exceptional hepatotoxicity. contraindicated in liver Avoid Duloxetine: risk of Duloxetine circumstances Duloxetine (1A2, 2D6) disease. is (exceptional hepatotoxicity. contraindicated in liver only) circumstances disease. only)

(CYP2D6>>UGT), imipramine (CYP2D6, 1A2, 2C19, 3A > UGT), trazodone (CYP2D6> CYP3A)

Interactions with Other Drug Classes - antipsychotics

75 76 Interactions with Other Drug Classes - antipsychotics

www.hivclinic.ca

Drug (route of metabolism)

August 28, 2012

page 1 of 2

Known or Potential Comments Interactions with DAAs Actual/Potential Drug2D6) Interactions Between Acting Antivirals and Antipsychotics Aripiprazole (CYP3A4, Use (DAAs) combination with caution, Potential for Directly ↑ aripiprazole and monitor for aripiprazoleconcentrations 1 Drug (route of metabolism) Known or Potential Comments related toxicity (sedation, sinus Interactions with DAAs tachycardia, nausea/vomiting, or Aripiprazole (CYP3A4, 2D6) Use combination with caution, Potential for ↑ aripiprazole dystonic reactions). and monitor for aripiprazoleconcentrations related toxicity (sedation, Consider starting with a sinus tachycardia, nausea/vomiting, decreased aripiprazole dose oror dystonic select anreactions). alternate agent. Asenapine (UGT, CYP1A2>> No interaction expected based Monitor and titrate dose Consider with a CYP3A4, 2D6) on known pharmacologic accordingstarting to clinical response. decreased aripiprazole dose or characteristics. select an alternate agent. Weak inhibitor of CYP2D6. Asenapine does (UGT,not CYP1A2>> No interaction expected based Monitor and titrate dose cause CYP3A4, 2D6) according to clinical response. induction of CYP1A2 or CYP3A4 on known pharmacologic characteristics. Clozapine (CYP1A2> 3A4, P-gp) Potential Clozapine has a narrow for ↑ clozapine Weak inhibitor of CYP2D6. therapeutic index. Use concentrations Asenapine does not cause combination with caution, and induction of CYP1A2 or CYP3A4 monitor for clozapine-related Clozapine (CYP1A2> 3A4, P-gp) Potential for ↑ clozapine Clozapine hasmarrow a narrow toxicity (bone therapeutic index. Use concentrations suppression, generalized combination with sedation, caution, and seizures, severe monitor forand clozapine-related confusion delirium). toxicity (bone marrow suppression, generalized Consider starting with a seizures, sedation, decreasedsevere clozapine dose or confusion and delirium). select an alternate agent. Clozapine therapeutic drug 2, 3 Consider with a monitoringstarting is recommended. decreased clozapine or Olanzapine Use combination withdose caution, Potential for ↑ olanzapine 4 select an alternate agent. (CYP1A2, UGT, PGP>2D6) and monitor for possible concentrations. Clozapine therapeutic drug olanzapine-related toxicity. 2, 3 monitoring recommended. Monitor andistitrate dose Olanzapine Use combination with caution, Potential for ↑ olanzapine according to clinical response. 4 (CYP1A2, UGT, PGP>2D6) and monitor possible concentrations. Paliperidone DAAs inhibit for both CYP3A4 and Potential for ↑ paliperidone 4 olanzapine-related (CYP3A4, PGP>2D6) PGP, and clinically toxicity. significant concentrations. Monitor andalthough titrate dose Minor CYP dependant interaction, unlikely, according clinical pathway(41%). cannot be to ruled out. response. Use 4 Paliperidone DAAs inhibit with both caution, CYP3A4and and Potential for ↑ paliperidone Substrate and inhibitor of PGP combination 4 (CYP3A4, PGP>2D6) PGP, and concentrations. monitor forclinically possiblesignificant Minor CYP dependant interaction, although toxicity unlikely,4 . paliperidone-related pathway(41%). cannot be ruled out. Use Quetiapine Use combination with caution, Potential for ↑ quetiapine 4 4 Substrate and inhibitor combination withquetiapinecaution, and (CYP3A4>2D6, PGP) of PGP and monitor for concentrations. monitortoxicity for possible related (excessive 4 . paliperidone-related sedation). Consider toxicity starting with Use combination with caution, Quetiapine Potential for ↑ quetiapine a decreased quetiapine dose or 4 5 and monitor for quetiapine(CYP3A4>2D6, PGP) concentrations. select an alternate agent . relatedits toxicity Risperidone Unlike active(excessive metabolite Potential for ↑ risperidone 4 sedation). Consider starting (CYP2D6, PGP>3A4) paliperidone, risperidone is with concentrations. a decreased quetiapine or primarily metabolized bydose 5 select an alternate CYP2D6. However,agent the . Risperidone Unlike its active metabolite Potential for ↑ risperidone 4 (CYP2D6, PGP>3A4) risperidone is and concentrations. Academic copyright: Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON, Alicepaliperidone, Tseng, Pharm.D., FCSHP, AAHIVP Sanjeev Sockalingam, MD, FRCPC, University Health Network, Toronto, ON. primarily metabolized by

1

Actual/Potential Drug Interactions Between Directly Acting Antivirals (DAAs) and Antipsychotics

Interactions with Other Drug Classes - antipsychotics

77 78 Interactions with Other Drug Classes - antipsychotics

Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004;24(1):62-9.

6.

Academic copyright: Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON, Alice Tseng, Pharm.D., FCSHP, AAHIVP and

5.

English Significant Psychotropic Drug-Drug HarriganBA, EP,Dortch Miceli M, JJ,Ereshefsky Anziano R,L, etet al.al. A Clinically randomized evaluation of the effects of six Interactions the Primary Care Setting. Curr and Psychiatry Rep Jun 17. antipsychoticinagents on QTc, in the absence presence of 2012 metabolic inhibition. J Clin Psychopharmacol 2004;24(1):62-9. AstraZeneca Canada Inc. Seroquel (quetiapine) Product Monograph. Mississauga, ON 2012.

4. 6.

References: 2. Eiermann B, Engel G, Johansson I, et al. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. British journal of clinical pharmacology. [Research Support, Non-U.S. 1. Boulton DW,Nov;44(5):439-46. DeVane CL, Liston HL, et al. In vitro P-glycoprotein affinity for atypical and Gov't] 1997 conventional antipsychotics. Life Sci 2002 May 31;71(2):163-9. 3. Spina E, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review. 2. Eiermann Engel G, Toxicol Johansson I, et al. The involvement of CYP1A2 and CYP3A4 in the Basic Clin B, Pharmacol 2007;100:4-22. metabolism of clozapine. British journal of clinical pharmacology. [Research Support, Non-U.S. Gov't] 4. English1997 BA, Nov;44(5):439-46. Dortch M, Ereshefsky L, et al. Clinically Significant Psychotropic Drug-Drug Interactions in the Primary Care Setting. Curr Psychiatry Rep 2012 Jun 17. 3. Spina E, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol 2007;100:4-22. 5. AstraZeneca Canada Inc. Seroquel (quetiapine) Product Monograph. Mississauga, ON 2012.

related toxicity (excessive sedation). Consider starting with a decreased quetiapine dose or 5 select an alternate agent . Risperidone Unlike its active metabolite Potential for ↑ risperidone 4 (CYP2D6, PGP>3A4) paliperidone, risperidone is concentrations. 1 Drug (route of metabolism) Known or Potential Comments primarily metabolized by Interactions with DAAs CYP2D6. However, the elimination of paliperidone may impaired. Use combination Academic copyright: Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON, Alicebe Tseng, Pharm.D., FCSHP, AAHIVP and Sanjeev Sockalingam, MD, FRCPC, University Health Network, Toronto, ON. with caution, and monitor for 1 www.hivclinic.ca 28, 2012 page 1 of 2 Drug (route of metabolism) KnownAugust or Potential Comments possible risperidone-related Interactions with DAAs toxicity. elimination of paliperidone may Ziprasidone (CYP3A4>1A2) Although clinically significant Potential for ↑ ziprasidone be impaired. Use combination Minor CYP dependant pathway interaction unlikely, use concentrations. 3 with caution, with and caution, monitor for (33%). combination and possible risperidone-related monitor for possible ziprasidone6 toxicity. related toxicity (QTc). Legend: CYP (CYP3A4>1A2) = cytochrome P450, P-gp =Potential p-glycoprotein, = Uridine 5'-diphospho-glucuronosyltransferases Ziprasidone Although clinically significant for ↑UGT ziprasidone Minor CYP dependant pathway interaction unlikely, use concentrations. 3 References: (33%). combination with caution, and monitor for possible ziprasidone6 1. Boulton DW, DeVane CL, Liston HL, et al. In vitro P-glycoprotein affinitytoxicity for atypical related (QTc).and Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, Uridine 5'-diphospho-glucuronosyltransferases conventional antipsychotics. Life Sci 2002UGT May= 31;71(2):163-9.

Interactions with Other Drug Classes - benzodiazepines

79 80 Interactions with Other Drug Classes - benzodiazepines

concentrations.

monitor for benzodiazepine-related

efficacy or toxicity. Consider an Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP, Sanjeev Sockalingam, MD, FRCPC, University Health Network, alternate agent such as lorazepam, Toronto, ON, and Pierre Giguere, M.Sc.Phm., The AUC Ottawa↓Hospital, Ottawa, ON. Zolpidem 47% with 5 www.hivclinic.ca August 28, 2012 page 1 of 2 oxazepam or temazepam.

1A2 >> 2D6, 2C19)

Drug Known or Potential Interactions Comments (route of metabolism) with DAAs Lorazepam, oxazepam, No interaction expected based on (DAAs) Preferred due to lower Drug Interactions Between Directly Acting Antivirals andagents Benzodiazepines temazepam (UGT) known pharmacologic interaction potential with DAAs. characteristics. and titrate dose according to Drug Known or Potential Interactions Monitor Comments clinical response. (route of metabolism) with DAAs Alprazolam Use combination caution, Potential for ↑ expected benzodiazepine Lorazepam,(CYP3A4) oxazepam, No interaction based on Preferred agents with due to lower and monitor for benzodiazepine-related concentrations. temazepam (UGT) known pharmacologic interaction potential with DAAs. toxicity. and Consider alternate agent characteristics. Monitor titrate an dose according to such asresponse. lorazepam, oxazepam or clinical temazepam. Alprazolam (CYP3A4) Use combination with caution, and Potential for ↑ benzodiazepine Buspirone (CYP3A4) Use combination with caution, and Potential for ↑ benzodiazepine monitor for benzodiazepine-related concentrations. monitor for benzodiazepine-related concentrations. toxicity. Consider an alternate agent toxicity. Consider anoxazepam alternate agent such as lorazepam, or such as lorazepam, oxazepam or temazepam. temazepam. Buspirone (CYP3A4) Use combination with caution, and Potential for ↑ benzodiazepine Diazepam (CYP2C19>3A) Use combination with caution, and Potential for ↑ benzodiazepine monitor for benzodiazepine-related concentrations. monitor for benzodiazepine-related concentrations. toxicity. Consider an alternate agent toxicity. Consider starting with aor such as lorazepam, oxazepam decreased benzodiazepine dose or temazepam. select an alternatewith agent such and as Diazepam (CYP2C19>3A) Use combination caution, Potential for ↑ benzodiazepine lorazepam, oxazepam or monitor for benzodiazepine-related concentrations. temazepam. toxicity. Consider starting with a Midazolam – oral (3A4) Oral midazolam is contraindicated Midazolam Cmax ↑ 177% and decreased benzodiazepine dose or with boceprevir andagent telaprevir. AUC ↑ 430% ↑ AUC0-24 h with select an alternate such as 1 boceprevir lorazepam, oxazepam or temazepam. AUC ↑↑8.96-fold and Midazolam – oral (3A4) Oral midazolam is contraindicated Midazolam Cmax 177% and 2 Cmax 2.86-fold with telaprevir with boceprevir and telaprevir. AUC ↑↑430% ↑ AUC 0-24 h with 1 Midazolam – IV (3A4) Co-administration of telaprevir and Midazolam boceprevir AUC ↑ 3.4 fold with 2 parenteral midazolam should be telaprevir done in a setting which ensures Midazolam AUC ↑ 8.96-fold and No interaction studies been2 clinical monitoring and appropriate Cmax ↑ 2.86-fold with have telaprevir medical management in case of done with boceprevir Midazolam – IV (3A4) Co-administration of telaprevir and Midazolam AUC ↑ 3.4and fold with 2 respiratory midazolam depressionshould and/or be intravenous parenteral telaprevir benzodiazepines 3 prolonged sedation . ensures (alprazolam, midazolam, done in a setting which triazolam). clinical monitoring and appropriate No interaction studies have been Close clinical monitoring for of medical management in case done with boceprevir and respiratory depression and/or respiratory depression and/or intravenous benzodiazepines 3 prolonged sedation sedation should be . prolonged (alprazolam, midazolam, exercised during co-administration of triazolam). boceprevir with intravenous Close clinical monitoring for benzodiazepines. Dose adjustment respiratory depression and/or of the benzodiazepine should prolonged sedation should be be 4 consideredduring . exercised co-administration of Triazolam (3A4) Triazolam iswith contraindicated Potential for ↑ benzodiazepine boceprevir intravenous with 4 boceprevir and telaprevir. concentrations benzodiazepines. Dose adjustment Zolpidem (CYP3A >> 2C9, Use with caution, and Potential for ↑/↓ benzodiazepine of thecombination benzodiazepine should be 4 1A2 >> 2D6, 2C19) monitor for benzodiazepine-related concentrations. . considered efficacy or is toxicity. Considerwith an Triazolam contraindicated Triazolam (3A4) Potential for ↑ benzodiazepine alternate agent such as lorazepam, Zolpidem AUC4↓ 47% with boceprevir and telaprevir. concentrations 5 oxazepam or temazepam. steady-state telaprevir Zolpidem (CYP3A >> 2C9, Use combination with caution, and Potential for ↑/↓ benzodiazepine

Drug Interactions Between Directly Acting Antivirals (DAAs) and Benzodiazepines

Interactions with Other Drug Classes - benzodiazepines

81 82 Interactions with Other Drug Classes - benzodiazepines

5.

4.

5. 3.

2. 4.

Luo X, Van Heeswijk RPG, Alves K, et al. The effect of telaprevir on the pharmacokinetics of alprazolam and zolpidem in healthy volunteers [abstract PK_11]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA.

Garg V,Canada Chandorkar G, Farmer HF, et al.Product Effect ofMonograph. telaprevir onKirkland, the pharmacokinetics of Merck Inc. Victrelis (boceprevir) QC July 27, 2011. midazolam and digoxin. J Clin Pharmacol 2012;Jan 26 [Epub ahead of print]. Luo X, Van Heeswijk RPG, Alves K, et al. The effect of telaprevir on the pharmacokinetics of Vertex Pharmaceuticals Incivek volunteers (telaprevir)[abstract Product Monograph. Cambridge, MA May, 2011. alprazolam and zolpidemInc. in healthy PK_11]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.

References: 2. Garg V, Chandorkar G, Farmer HF, et al. Effect of telaprevir on the pharmacokinetics of 1. Kasserra C,and Hughes E, Treitel et al. Clinical pharmacology of boceprevir: midazolam digoxin. J Clin M, Pharmacol 2012;Jan 26 [Epub ahead of print]. metabolism, excretion, and drug-drug interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Inc. FebIncivek 27-Mar(telaprevir) 2, 2011, Boston, USA. 3. Vertex Pharmaceuticals Product Monograph. Cambridge, MA May, 2011.

of the benzodiazepine should be 4 considered . Triazolam (3A4) Triazolam is contraindicated with Potential for ↑ benzodiazepine 4 boceprevir and telaprevir. concentrations Zolpidem (CYP3A >> 2C9, Use combination with caution, and Potential for ↑/↓ benzodiazepine 1A2 >> 2D6, 2C19) monitor for benzodiazepine-related concentrations. efficacy or toxicity. Consider an Drug Known Potential Comments alternate agent such as lorazepam, ZolpidemorAUC ↓ 47%Interactions with (route of metabolism) with DAAs telaprevir5 oxazepam or temazepam. steady-state Clinical monitoring and dose titration of zolpidem is recommended to Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP, Sanjeev Sockalingam, MD, FRCPC, University Health Network, achieve the desired clinical response Toronto, ON, and Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON. Drug Known or Potential Interactions Comments when coadministeringpage with1 telaprevir. www.hivclinic.ca August 28, 2012 of 2 (route of metabolism) DAAs Use combination with caution, and Zopiclone (3A4> 2C8, 2C9) with Potential for ↑ benzodiazepine Clinical and dose titration monitor monitoring for benzodiazepine-related concentrations. of zolpidem is recommended to efficacy or toxicity. Consider an achieve desired response alternatethe agent suchclinical as lorazepam, when coadministering with telaprevir. oxazepam or temazepam. Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, UGT = Uridine 5'-diphospho-glucuronosyltransferases Zopiclone (3A4> 2C8, 2C9) Use combination with caution, and Potential for ↑ benzodiazepine monitor for benzodiazepine-related concentrations. efficacy or toxicity. Consider an References: alternate agent such as lorazepam, 1. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, oxazepam or temazepam. Legend: CYP = cytochrome P450, P-gpinteractions = p-glycoprotein, UGT =118]. Uridine 5'-diphospho-glucuronosyltransferases excretion, and drug-drug [abstract 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.

ADDITIONAL INFORMATION Antiretroviral Treatment Options for Patients on DAAs��83

antiretroviral treatment options for patients on DAAs - summary

83 84 antiretroviral treatment options for patients on DAAs - summary

Atazanavir/ritonavir OK3 Etravirine OK10

3, 8 10 efavirenz Dose ↑ to 1125 mg q8hOK* with Rilpivirine

Etravirine OK10

5 Possible atazanavir/ritonavir? Etravirine (?)9

6, 7 AvoidNo efavirenz data

Etravirine (?)9

6, 14

pharmacokinetic properties.13 Tenofovir Avoid combination OK6, 14 until further data available. No data Avoid AZT (anemia) potential ↓/↑ maraviroc; potential benefit on fibrosis?

No data Rilpivirine OK*10 Elvitegravir/cobicistat: no data but potential for interaction based on pharmacokinetic properties.13Raltegravir Avoid combination OK11, 12 until further data available. No data potential benefit on fibrosis? potential ↓/↑ maraviroc; Elvitegravir/cobicistat: no data but potential for interaction based on

Raltegravir OK11, 12

atazanavir/ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir, 3, 8 4 Avoid efavirenz6,1,72 Dose ↑ to 1125 mg q8h with3, efavirenz lopinavir/ritonavir lopinavir/ritonavir

Avoid darunavir/ritonavir, fosamprenavir/ritonavir, Telaprevir (Incivek®) 3, 4 lopinavir/ritonavir 750 mg po q8h with food3 Atazanavir/ritonavir OK Avoid darunavir/ritonavir,

Not recommended with atazanavir/ritonavir, darunavir/ritonavir, Boceprevir (Victrelis®) 1, 2 lopinavir/ritonavir 800 mg q8h with food 5 Possible atazanavir/ritonavir? Not recommended with

Hulskotte EGJ, Feng H-P, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and=ritonavir-boosted HIV-1 protease=inhibitors atazanavir, lopinavir, and darunavir [abstract 771LB] Key: avoid combination caution/dose adjustment = combination OK 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle, WA.

Vertex Pharmaceuticals Inc. Incivek (telaprevir) Product Monograph. Cambridge, MA May, 2011. Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactionsMedicines [abstract Agency. 118]. 18th Conference Retroviruses Opportunistic Infections, Feb 27-Mar 2, 2011, European Questions andon answers on drugand interactions between Victrelis (boceprevir) and Boston, USA. ritonavir-boosted HIV protease inhibitors. 2012 February 16. Report No.: EMA/CHMP/117973/2012. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.excretion, and drug-drug Kasserra C, Hughes E, Treitel M, et al. Clinical pharmacology of boceprevir: metabolism, interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Garg V, USA. Chandorkar G, Yang Y, et al. The effect of CYP3A inhibitors and inducers on the pharmacokinetics of Boston, telaprevir [abstract PK_13]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA. Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.

4. 6.

7. 6.

Garg V, Chandorkar G, Yang Y, et al. The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir [abstract PK_13]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, Academic 2011, copyright: Alice Tseng, Toronto General Hospital, Toronto, ON Cambridge, MA.Pharm.D., FCSHP, AAHIVP.

8.

7.

8.

5.

5.

Vertex Pharmaceuticals Inc. Incivek Cambridge, MA May, 2011.ARV agents and Van Heeswijk RPG, Vandevoorde A,(telaprevir) Boogaerts Product G, et al. Monograph. Pharmacokinetic interactions between the investigational HCV protease inhibitor TVR in healthy volunteers [abstract 119]. 18th Conference on European Medicines Agency. Questions and answers drug interactions between Victrelis (boceprevir) and Retroviruses and Opportunistic Infections, Feb 27-Maron 2, 2011, Boston, USA. ritonavir-boosted HIV protease inhibitors. 2012 February 16. Report No.: EMA/CHMP/117973/2012.

4. 3.

References: 2. Schering Corporation a subsidiary & Co. Victrelisinteraction (boceprevir) prescribing information. 1. Hulskotte EGJ, Feng H-P, Xuan F, of et Merck al. Pharmacokinetic between the HCV proteaseWhitehouse inhibitor Station, NJ April, 2012. boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir [abstract 771LB] 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle, WA. 3. Van Heeswijk RPG, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy [abstract 119]. information. 18th Conference on 2. Schering Corporation a subsidiary of Merck & Co. Victrelisvolunteers (boceprevir) prescribing Whitehouse Retroviruses and 2012. Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA. Station, NJ April,

1.

Key: = avoid combination = caution/dose adjustment = combination OK *caution in patients on other drugs which may ↑ rilpivirine concentrations, prolong QTc, or who are at risk for Torsade de Pointes References:

Avoid AZT (anemia)

NRTIs in patients on other drugs which may ↑ rilpivirine Tenofovir OK *caution concentrations, prolong QTc, or who are at risk for Torsade de Pointes

NRTIs Maraviroc

InSTIs Maraviroc

NNRTIs InSTIs

NNRTIs

PIs

PIs

Telaprevir (Incivek®)

800 mg q8hOptions with food for Patients on Boceprevir 750 mg po q8h food Antiretroviral Treatment orwith Telaprevir

Boceprevir (Victrelis®)

Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir

antiretroviral treatment options for patients on DAAs - summary

85 86 antiretroviral treatment options for patients on DAAs - summary

Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV seronegative volunteers. J Acq Immune Def Syndr 2012;Oct 15 [Epub ahead of print].

9.

de Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase Inhibitor raltegravir [abstract 772LB]. 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, WA. Van Heeswijk RPG, Garg V, Boogaerts G, et al. The pharmacokinetic interaction between telaprevir and raltegravir in healthy volunteers [abstract A1-1738a]. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2011, Chicago, IL. Gilead Sciences Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Prescribing Information. Foster City, CA August, 2012. Van Heeswijk R, Gysen V, Googaerts G, et al. The pharmacokinetic interaction between tenofovir disoproxil fumarate and the investigational HCV protease inhibitor telaprevir [abstract A-966]. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 25-28, 2008, Washington, DC.

11.

12.

13. 14.

randomised, two-way crossover trial [abstract O_18]. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain.

Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. Toronto General Hospital, Toronto, ON www.hivclinic.ca October 24, 2012 of 2 10. Kakuda TN, Leopold L, Nijs S, et al. Pharmacokinetic interaction between etravirine or rilpivirinepage and 1telaprevir: a

Garg V, Chandorkar G, Yang Y, et al. The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir [abstract PK_13]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA.

Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC June 13, 2012.

8.

7.

interactions [abstract 118]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.

GLOSSARY Glossary��87

aa

apply as directed

IV

intravenous

AD

alcohol dehydrogenase

LFTs

liver function tests

ALT

alkaline phosphatase

MD

medical doctor

ANC

absolute neutrophil count

mcg

micrograms

AUC

area under the curve

MCV

mean corpuscular volume

BID

twice a day

mg

milligrams

BM

bowel movement

MU

million units

BOC

boceprevir

PBMC

peripheral blood mononuclear cells

BW

body weight

PI

protease inhibitor

CAPD

continuous ambulatory peritoneal dialysis

pk

pharmacokinetics

CBC/diff

complete blood count/differential

plts

platelets

CK

creatine kinase

po

by mouth

Cmax

maximum (peak) concentration

pr

per rectum

Cmin

minimum (trough) concentration

prn

as required

CNS

central nervous system

pts

patients

Css

concentration at steady-state

q6h

every 6 hours

CTZ

chemoreceptor-trigger zone

q8h

every 8 hours

CYP

hepatic Cytochrome P450 isoenzyme

QID

four times daily

D/C

discontinue

Rx

prescription

Derm

dermatologic

S&S

swish and swallow

ESRD

end stage renal disease

SC

subcutaneous

F/A

facilitated Access (via ODB)

SJS

Stevens-Johnson Syndrome

GGT

gamma glutamyl transferase

SGC

soft gel capsule

GT

glucuronyl transferase

ss

steady-state

gtts

drops

Sx

symptoms

HCV

hepatitis C virus

TID

three times daily

HGC

hard gel capsule

TVR

telaprevir

Hgb

hemoglobin

ULN

upper limit of normal

hs

at bedtime

Vd

volume of distribution

i DS

one double strength tablet

wks

weeks

i SS

one single strength tablet

[ ]

concentration

IM

intramuscular

GLOSSARY

87

88

GLOSSARY

PRINTED WITH THE ASSISTANCE OF AN UNRESTRICTED EDUCATIONAL GRANT FROM:

Copyright 2013, A. Tseng