TGH Hep C Handbook

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

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

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, alice.tseng@uhn.ca.

Additional information and updates may be found at: www.hcvdruginfo.ca

ACKNOWLEDGEMENTS 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 Canada Inc.

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 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.

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 . . . . . . . . . . . . . . . . . 34

Interactions with Other Drug Classes Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66 71 75 79

III. ADDITIONAL INFORMATION

Antiretroviral Treatment Options for Patients on DAAs . . 84

IV. GLOSSARY ������������������������������������������������������������������������� 88

BOCEPREVIR

1

Merck Canada Inc.

Equal mixture of two diastereoisomers; the pharmacologically active SCH 534128 (S-isomer) and SCH 534129 (R-isomer).

Mechanism of Action: Boceprevir is an inhibitor of the HCV NS3/4A protease. Boceprevir covalently, yet reversibly, binds to the NS3/4A protease active site serine (Ser139) through a (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells.

Manufacturer

Pharmacology/

Activity

Boceprevir cell culture anti-HCV activity was approximately 2-fold lower for an HCV replicon derived from a single genotype 1a isolate, relative to the 1b isolate-derived replicon. Boceprevir had approximately 2-fold reduced activity against a genotype 2a isolate

The IC50 and IC90 values for BOC were approximately 200 nM and 400 nM, respectively, in a 72-hour cell culture assay. Loss of replicon 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 RNA. Prolonged exposure resulted in a 2-log decrease in RNA levels

by Day 15.

TM

Mechanism of action

Victrelis Combination formulation: TM Victrelis Triple : boceprevir/ribavirin/peginterferon alfa-2b

Other Names

Selected Properties of Boceprevir

2

BOCEPREVIR

Resistance – genotypic

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.

A greater than 15-fold reduction in boceprevir anti-HCV activity was conferred by the substitutions: T54C, R155G/I/T and A156S/T/V.

The activity of boceprevir against the HCV NS3/4A protease or genotype 1b replicon was reduced (2-to 10- fold) by the following amino acid substitutions in the NS3/4A protease domain: V36A/I/M, Q41R, F43C/S, T54A/S, V55A/I, R155K/M/Q, V158I, V170A/T and M175L.

Boceprevir cell culture anti-HCV activity was approximately 2-fold lower for an HCV replicon derived from a single genotype 1a isolate, relative to the 1b isolate-derived replicon. Boceprevir had approximately 2-fold reduced activity against a genotype 2a isolate relative to genotype 1a and 1b replicon isolates. In a biochemical assay, boceprevir had approximately 3- and 2- fold reduced activity against NS3/4A proteases derived from single isolates representative of HCV genotypes 2 and 3a, respectively, relative to a genotype 1bderived NS3/4A protease. The presence of 50 % human serum reduced the cell culture anti-HCV activity of BOC by approximately 3fold.

Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90 % suppression of replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.

BOCEPREVIR

3

In a pooled analysis of patients who are previously untreated and patients who have failed previous therapy who received four weeks of PegIFNα2b/RBV followed by boceprevir 800 mg TID in combination with PegIFNα2b/RBV in two Phase 3 studies, post-baseline RAVs were detected in 53 % of non-SVR patients. Interferon responsiveness was associated with detection of fewer RAVs.

Baseline resistance associated polymorphisms were detected in 7 % of subjects by a population based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates. However, among subjects with a relatively poor response to PegINFα2b/RBV during the 4-week lead-in period, the efficacy of boceprevir appeared to be reduced for those who had V36M, T54A, T54S, V55A or R155K at baseline.

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 the beginning, stopping or modifying drug therapy. combination of BOC with PegIFNα2b/RBV. Updated July 2012 www.hivclinic.ca Page 1 of 7

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.

4

BOCEPREVIR

Oral Bioavailability

Cross-resistance

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.

Many of the treatment-emergent NS3/4A amino acid substitutions detected in boceprevir-treated subjects who did not achieve SVR in the Phase 3 clinical trials have been demonstrated to reduce the antiHCV activity of other HCV NS3/4A Protease Inhibitors (PIs)

No data are available regarding the efficacy of boceprevir among subjects who were previously exposed to boceprevir, or who previously failed treatment with a boceprevir-containing regimen.

One or more boceprevir-treatment-emergent substitutions remained detectable with a population-based sequencing assay in 25% of subjects after 2.5 years of follow-up. The most common NS3/4A substitutions detected after 2.5 years of follow-up were T54S and R155K.

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

was associated with detection of fewer RAVs.

BOCEPREVIR

5

75 %

Protein Binding

Drug concentrations

PPK individual prediction from sparse data in HCV patients

AUC, Cmax and Cmin increased in a less-than dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1,200 mg, suggesting diminished absorption at higher doses.

In general, PK results were similar between healthy and HCV subjects.

In the plasma the diastereoisomer ratio is about 2:1 in favour of the active diastereoisomer, SCH 534128. The plasma concentrations of boceprevir described below consist of both diastereoisomers.

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

Oral Bioavailability

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.

6

BOCEPREVIR

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)

(for wildtype virus)

Minimum trough concentration

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

Healthy subjects (non-compartmental analysis)(boceprevir 800 mg TID): Cmax: 1723 ng/mL Cmin: 88 ng/mL AUC: 5408 ng.hr/mL

Population PK estimates HCV patients (boceprevir 800 mg TID): Cmax: 1084 ng/mL Cmin: 218 ng/mL AUC: 4642 ng.hr/mL

PPK individual prediction from sparse data in HCV patients (boceprevir 800 mg TID): Cmax: 1013 ng/mL Cmin: 213 ng/mL AUC: 4403 ng.hr/mL

and 1,200 mg, suggesting diminished absorption at higher doses.

BOCEPREVIR

7

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.

A) Patients without cirrhosis who are previously untreated or who are previous partial responders or relapsers to PegIFNα/RBV therapy:

strategies.

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)

8

BOCEPREVIR

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

C) Patients without cirrhosis who are previously untreated with a poor interferon response (less than a 1.0-log10 decline in HCV-RNA at TW 4 with PegIFNα/RBV alone)

If considered for treatment, these subjects should receive 4 weeks of PegIFNα/RBV followed by 44 weeks of boceprevir 800mg (four 200 capsules) orally TID (every 7-9 hours) in combination with PegIFNα/RBV

B) Patients with prior null response

Treatment duration is based on whether patients are previously untreated or had previous treatment failures and their HCV-RNA levels at TW 8, TW 12 and TW 24

2) Add boceprevir 800 mg (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).

A) Patients without cirrhosis who are previously untreated or who are previous partial responders or relapsers to PegIFNα/RBV therapy:

BOCEPREVIR

9

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

Academic copyright. Prepared by Dominic Martel, M.Sc.Phm. Reviewed by A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please

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)

10

BOCEPREVIR

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)

BOCEPREVIR

11

Pregnancy & Lactation

Toxicity

No studies in pregnant women are available.

Because boceprevir is used in combination with PegIFNα/RBV, it is therefore contraindicated in pregnant women and men whose female partners are pregnant.

Abdominal pain, constipation, diarrhea, dry mouth, vomiting, GERD Fever, chills, weight loss, decrease appetite, myalgia/arthralgia, dizziness Anxiety, depression, insomnia, irritability, mood alteration Cough, dyspnea Dry skin, pruritus, rash Neutropenia, Thrombocytopenia Blurred vision

Most common: Anemia (49% when used with PegIFNα2b/RBV) Fatigue, anemia, nausea, headache, and dysgeusia (> 35% when used with PegIFNα2b/RBV)

Many of the side effects may be related to PegIFNα2b/RBV

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

impairment.

12

BOCEPREVIR

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 effects on fetal development have been observed in rats and rabbits with boceprevir exposures 11.8- and 2.0-fold higher, respectively, than those in humans at the recommended dose of 800 TID. Boceprevir has been shown in animals to distribute across the placenta to to fetal fetal blood blood and and tissues. tissues. placenta

Pregnancy risk category B (all trimesters).

No studies in pregnant women are available.

partners are pregnant.

BOCEPREVIR

13

HCV-RNA levels should be monitored at Treatment Weeks (TWs) 8, 12, and 24, at the End of Treatment (EOT), during treatment follow-up, and for other time points as clinically indicated. In previously untreated subjects without cirrhosis, monitoring of HCV-RNA levels at TW 4 is recommended to determine interferon responsiveness.

Routine Labs

CBC (with WBC differential count) should be obtained at TWs 4, 8 and

CBC (with WBC differential count) Pregnancy test in female patients and in female partners of male patients

Baseline assessment

Contraindicated Drugs: alfuzosin, amiodarone, propafenone, quinidine, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John始s Wort, lovastatin, simvastatin, sildenafil or tadalafil when used for the treatment of pulmonary arterial hypertension, pimozide, drospirenone, astemizole, terfenadine, midazolam (orally administered), and triazolam (orally administered).

See separate drug interaction chart.

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

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

14

BOCEPREVIR

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 REDIPENÂŽ 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

Capsules (Hard-gelatin): 200 mg (yellowish-brown) DIN 02370816 Peelable aclar/PVC/aluminium blisters containing 12 capsules. 7 Academic copyright. Prepared by Dominicblisters Martel, M.Sc.Phm. Reviewed A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please per folding cartonby and 2 folding cartons per outer carton

Dosage Forms

Monthly pregnancy test in female patients and in female partners of male patients

Decreases in the neutrophil counts may require dose reduction or discontinuation of PegIFNÎą/RBV.

If serum hemoglobin is < 100 g/L, a decrease in dose or interruption of RBV may be warranted.

CBC (with WBC differential count) should be obtained at TWs 4, 8 and 12 and should be closely monitored at other time points as considered clinically appropriate.

determine interferon responsiveness.

BOCEPREVIR

15

Deliverable Dose 80 mcg/0.5 mL A carton containing two boxes of 84 BOC capsules each for a total of 168 BOC capsules, two boxes of 28 RBV capsules each for a total of 56 RBV capsules, plus two PegIFNα2b REDIPEN® single dose delivery systems, 80 mcg/REDIPEN®, with two 30-gauge needles (0.3 x 8 mm), 4 alcohol swabs and two pen holders.

Deliverable Dose 100 mcg/0.5 mL A carton containing two boxes of 84 BOC capsules each for a total of 168 BOC capsules, two boxes of 28 RBV capsules each for a total of 56 RBV capsules, plus two PegIFNα2b REDIPEN® single dose delivery systems, 100 mcg/REDIPEN®, with two 30-gauge needles (0.3 x 8 mm), 4 alcohol swabs and two pen holders.

Deliverable Dose 120 mcg/0.5 mL A carton containing two boxes of 84 BOC capsules each for a total of 168 BOC capsules, two boxes of 35 RBV capsules each for a total of 70 RBV capsules, plus two PegIFNα2b REDIPEN® single dose delivery systems, 120 mcg/REDIPEN®, with two 30-gauge needles (0.3 x 8 mm), 4 alcohol swabs and two pen holders.

Deliverable Dose 150 mcg/0.5 mL 1. A carton containing two boxes of 84 BOC capsules each for a total of 168 BOC capsules, two boxes of 42 RBV capsules each for a total of 84 RBV capsules, plus two PegIFNα2b REDIPEN® single dose delivery systems, 150 mcg/REDIPEN®, with two 30-gauge needles (0.3 x 8 mm), 4 alcohol swabs and two pen holders.

2. A carton containing two boxes of 84 BOC capsules each for a total of 168 BOC capsules, two boxes of 49 RBV capsules each for a total

DIN: 02371448; 02371456; 02371464; 02371472

delivery system

16

BOCEPREVIR

o

o

Can also be stored at room temperature (15°C – 30°C ) for up to 3 months.

Store in the original container.

Boceprevir capsules should be refrigerated at 2 C – 8 C.

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 7 of 7

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

Storage

delivery systems, 150 mcg/REDIPEN®, with two 30-gauge needles (0.3 x 8 mm), 4 alcohol swabs and two pen holders.

2. A carton containing two boxes of 84 BOC capsules each for a total of 168 BOC capsules, two boxes of 49 RBV capsules each for a total of 98 RBV capsules, plus two PegIFNα2b REDIPEN® single dose delivery systems, 150 mcg/REDIPEN®, with two 30-gauge needles (0.3 x 8 mm), 4 alcohol swabs and two pen holders.

TELAPREVIR

17

Telaprevir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. This agent is a specific inhibitor of the HCV NS3·4A protease which is essential for viral replication.

Pharmacology/ Mechanism of Action

Resistance – genotypic

Activity

Vertex Pharmaceuticals Incorporated

Manufacturer

Variants V36A/M, T54A/S, R155K/T, and A156S conferred lower levels of in vitro resistance to telaprevir (3- to 25-fold increase in telaprevir IC50), and the A156V/T and V36M+R155K variants conferred higher levels of in vitro resistance to telaprevir (>25-fold increase in telaprevir IC50). All telaprevir-resistant variants

In Vitro Studies

The approved indication for telaprevir is for HCV genotype 1 infection only.

Telaprevir inhibits genotype 2 HCV NS3 serine protease with similar potency to genotype 1a or 1b HCV proteases while its activity against genotype 3 and 4 HCV proteases is reduced.

The slow binding mechanism for the interaction of telaprevir with the HCVNS3•4A protease occurs in 2 steps, with formation of a weaker complex followed by rearrangement to the tightly bound form (covalent complex).

TVR, Incivek®

Other names

Selected Properties of Telaprevir

18

TELAPREVIR

Sequence analyses of HCV in subjects treated with telaprevir who had ontreatment virologic failure or relapse identified amino acid substitutions at 4 positions in the NS3-4A protease region, consistent with the mechanism of action for telaprevir (V36A/M, T54A/S, R155K/T, and A156S/T/V). On-treatment virologic failure during telaprevir treatment was predominantly associated with higher-level resistant variants, and relapse was predominantly associated with lower-level resistant variants or wild-type virus.

Subjects with HCV genotype 1a predominately had V36M and R155K single and combination variants, while subjects with HCV genotype 1b predominately had V36A, T54A/S, and A156S/T/V variants. This difference is likely due to the higher genetic barrier for the V36M and R155K substitutions for genotype 1b than 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 na誰ve, 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.

Clinical Virology Studies Predominant telaprevir-resistant variants at baseline (pre-treatment) were rare (V36M, T54A and R155K <1% and T54S 2.7%).

Predominant baseline resistance to telaprevir did not preclude subjects from achieving an SVR with a telaprevir, peginterferon-alfa, and ribavirin regimen.

resistance to telaprevir (3- to 25-fold increase in telaprevir IC50), and the A156V/T and V36M+R155K variants conferred higher levels of in vitro resistance to telaprevir (>25-fold increase in telaprevir IC50). All telaprevir-resistant variants studied remained fully sensitive to interferon-alfa and ribavirin.

TELAPREVIR

19

Telaprevir V36A/M T54A/S R155K/T A156T/V

Boceprevir V36M T54A R155K A156T

Effect of Food

Oral Bioavailability

The systemic exposure (AUC) to telaprevir was decreased by about 73% when telaprevir was administered under fasting conditions compared to when telaprevir was administered following a standard fat meal (533 kcal, 21 g fat). The telaprevir

Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telapreviralone.

Orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon.

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.

20

TELAPREVIR

In clinical studies in healthy subjects in which a single 750-mg dose of telaprevir was administered after a regular breakfast, the median time of maximum concentration (tmax) ranged from 4.0 to 5.0 hours.

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

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

Tmax

Serum T ½

Drug Concentrations

CHC treatmentexperienced patients (n=191)

Typical apparent volume of distribution is estimated to be 252 L with an interindividual variability of 72%.

Vd

CHC treatmentnaĂŻve patients (n=641)

Telaprevir is approximately 59% to 76% bound to human plasma proteins.

Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding is concentration dependent, decreasing with increasing concentrations of telaprevir.

Protein Binding

Healthy Volunteers (n=39)

The systemic exposure (AUC) to telaprevir was decreased by about 73% when telaprevir was administered under fasting conditions compared to when telaprevir 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), while exposure was increased by about 20% with a high-fat meal (928 kcal, 56 g fat), compared to telaprevir administration with a standard fat meal. Therefore, telaprevir should always be taken with food (not low fat; ~ 20g fat content).

Effect of Food

TELAPREVIR

21

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.

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:

Excretion

82% of dose recovered in feces 9% of dose recovered in expired air 1% of dose recovered in urine (within 96 hours following administration of a single radiolabeled dose of telaprevir 750 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

22

TELAPREVIR

Dosing â&#x20AC;&#x201C; Adult

HCV-RNA

Treatment-NaĂŻve and Prior Relapse Patients Triple Therapy Dual Therapy Total Treatment Duration (telaprevir, (peginterferon peginterferon alfa and ribavirin) alfa and ribavirin) Undetectable at First 12 weeks Additional 12 24 weeks Weeks 4 and 12 weeks Detectable (1000 First 12 weeks Additional 36 48 weeks

Treatment Duration The recommended duration of treatment with telaprevir is 12 weeks in combination with peginterferon alfa and ribavirin:

If taken with efavirenz (not currently approved for use in HIV patients) 1125 mg orally 3 times a day every 7-9 hours with food (not low fat)

The recommended dose of telaprevir is 750 mg (two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food (not low fat). The total daily dose is 6 tablets (2250 mg).

Telaprevir must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin

9% of dose recovered in expired air 1% of dose recovered in urine (within 96 hours following administration of a single radiolabeled dose of telaprevir 750 mg) Apparent total clearance (Cl/F) is estimated to be 32.4 L/h with an inter-individual variability of 27.2%.

TELAPREVIR

23

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

Dual Therapy (peginterferon alfa and ribavirin) Total Treatment Duration

Academic copyright. Prepared by Marie-HÊlène 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

24

TELAPREVIR

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

TELAPREVIR

25

No dose adjustment is necessary for telaprevir in HCV-infected patients with mild, moderate or severe renal impairment.

• After administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl < 30 mL/min), the mean telaprevir Cmax and AUC were increased by 10% and 21%, respectively, compared to healthy subjects.

• The safety and efficacy of telaprevir combination therapy has not been established in HCV-infected subjects with a CrCl ≤ 50 mL/min • Telaprevir has not been studied in patients with end-stage renal disease (ESRD) or on hemodialysis • It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

Common: The most frequent adverse effects when used in combination with peginterferon alfa and ribavirin include:

Toxicity

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 impairment (Child-Pugh B or C, score ≥ 7) or decompensated liver disease.

The pharmacokinetics of telaprevir In HCV-negative subjects with severe hepatic impairment (Child- Pugh Class C) were not studied.

The use of telaprevir in organ transplant patients is not recommended because the safety and efficacy of telaprevir in this patient population has not been established.

Adjust in Renal Failure/ Dialysis

•

•

•

•

26

TELAPREVIR

Common: The most frequent adverse effects when used in combination with peginterferon alfa and ribavirin include: >10-20%: fatigue, pruritus, nausea, headache, influenza-like illness, rash, anemia, insomnia, diarrhea, vomiting, pyrexia, hemorrhoids, and proctalgia

Potential for QT Prolongation:

Serious: The most frequent serious adverse events were anemia and rash • Rash: Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS), were 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 <100 g/L were observed in 33.7% of patients who received telaprevir combination treatment and in 13.6% of patients who received peginterferon alfa and ribavirin. Hemoglobin levels decrease sharply during the first 4 weeks of treatment, with lowest values reached at the end of telaprevir dosing.

Hemoglobin values gradually improve after telaprevir dosing completion.

Toxicity

TELAPREVIR

27

Pregnancy & Lactation

Because telaprevir is to be taken in combination with peginterferon alfa and ribavirin, the warnings applicable to those drugs are also applicable to combination treatment. Refer also to the prescribing information for peginterferon alfa and ribavirin. Ribavirin may cause birth defects and/or death of the exposed fetus.

Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patientsâ&#x20AC;&#x201D;both during treatment and for 6 months after the

U.S. FDA's Pregnancy Category: Category B (All Trimesters)

Potential for QT Prolongation: A study conducted in healthy volunteers (n=41) showed a modest effect of telaprevir at a dose of 1875 mg q8h on the QTcF interval with a placebo-adjusted maximum mean increase of 8.0 msec (90% CI: 5.1-10.9). Exposure at this dose was comparable to the exposure in HCV-infected patients dosed at 750 mg telaprevir q8h plus peginterferon alfa and ribavirin. The potential clinical significance of these findings is uncertain. Use of telaprevir should be avoided in patients with congenital QT prolongation, or a family history of congenital QT prolongation or sudden death. Telaprevir should be used with caution in patients with a history of acquired QT prolongation; clinically relevant bradycardia (persistent heart rate <50 bpm); a history of arrhythmias (especially ventricular arrhythmias or atrial fibrillation); a history of heart failure with reduced leftventricular ejection fraction; myocardial ischemia or infarction; cardiomyopathy; conduction system disease; or a requirement for drugs known to prolong the QT interval without CYP3A4 involvement by telaprevir (e.g., methadone).

treatment compared to peginterferon alfa and ribavirin alone. Hemoglobin values of <100 g/L were observed in 33.7% of patients who received telaprevir combination treatment and in 13.6% of patients who received peginterferon alfa and ribavirin. Hemoglobin levels decrease sharply during the first 4 weeks of treatment, with lowest values reached at the end of telaprevir dosing.

Hemoglobin values gradually improve after telaprevir dosing completion.

28

TELAPREVIR

Telaprevir is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of telaprevir with drugs that are primarily metabolized by CYP3A and/or substrates for P-gpbymay result inIrvine, increased plasma concentrations of such drugs, by which could Academic copyright. Prepared Marie-Hélène Pharm.D. Candidate, University of Toronto.

Reviewed A. Tseng, Pharm.D., AAHIVP, Toronto, ON. Please note: Thistheir chart therapeutic summarizes selected basedreactions on current available data. Please increase or prolong effect properties and adverse consult a health professional whenever beginning, stopping or modifying drug therapy. * See separate Updated January 2012 www.hivclinic.ca Page dependent 5 of 7 when combined with drugs that are highly Telaprevir is contraindicated Drug Interaction on CYP3A for clearance and for which elevated plasma concentrations are Table. associated with serious and/or life-threatening events (narrow therapeutic index).

Telaprevir is also contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir: • Aldosterone antagonists (eplerenone) due to potential for hyperkalemia • Alpha 1-adrenoreceptor antagonists (alfuzosin) due to potential for hypotension or cardiac arrhythmia • Antiarrhythmics (quinidine, flecainide, propafenone, amiodarone) due to

Drug Interactions

Telaprevir treatment alone in mice and rats did not result in harm to the fetus.

Telaprevir treatment alone had effects on fertility parameters in rats. These effects are likely associated with testicular toxicity in male rats but contributions of the female cannot be ruled out.

It is not known whether telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in milk compared to those observed in plasma. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment.

treatment. Refer also to the prescribing information for peginterferon alfa and ribavirin. Ribavirin may cause birth defects and/or death of the exposed fetus.

Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients—both during treatment and for 6 months after the completion of all treatment. Telaprevir combination treatment should not be initiated unless a female patient has a negative pregnancy test immediately prior to initiation of treatment.

TELAPREVIR

29

associated with serious and/or life-threatening events (narrow therapeutic index).

Telaprevir is also contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir: • Aldosterone antagonists (eplerenone) due to potential for hyperkalemia • Alpha 1-adrenoreceptor antagonists (alfuzosin) due to potential for hypotension or cardiac arrhythmia • Antiarrhythmics (quinidine, flecainide, propafenone, amiodarone) due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias • Antimycobacterials (rifampin) because it reduces telaprevir plasma concentrations significantly • Ergot Derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) due to potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia • St. Johnʼs Wort because it reduces telaprevir plasma concentrations • HMG-CoA Reductase Inhibitors (atorvastatin, lovastatin, simvastatin) due to potential for myopathy including rhabdomyolysis • Neuroleptics (pimozide) due to potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics • PDE-5 Inhibitors due to potential for hypotension and/or cardiac arrhythmia (sildenafil: only when used for the treatment of pulmonary arterial hypertension) • Sedatives/Hypnotics (triazolam) due to potential for increased sedation or respiratory depression • Triptans (eletriptan) due to potential for coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation.

30

TELAPREVIR

Antiretroviral Interactions: Telaprevir concentrations are reduced by ritonavir-boosted fosamprenavir, darunavir, lopinavir, and, to a lesser extent, atazanavir. Efavirenz also reduces blood concentrations of telaprevir, an effect that can, in part, be offset by using a Academic copyright. Prepared

by Marie-Hélène Irvine,(1125 Pharm.D. University of Toronto.

Reviewedreduces

by A. Tseng, higher telaprevir dose mgCandidate, q8h). Telaprevir use significantly Pharm.D., AAHIVP, Toronto, ON. Please note: chart summarizes selected properties based on current available data. Please concentrations ofThis darunavir and fosamprenavir. consult a health professional whenever beginning, stopping or modifying drug therapy.

• Avoid coadministration with DRV/r, FPV/r, LPV/r Updated January 2012 www.hivclinic.ca Page 6 of 7 • ATV/r is considered compatible with telaprevir • EFV is considered compatible with telaprevir but with a dose increase of telaprevir (see dosing recommendations in section above)

Other significant DIs: • Anticoagulants (warfarin) concentrations of warfarin may be altered when coadministered with telaprevir. Monitor the INR • Immunosuppressants (cyclosporine, tacrolimus, sirolimus) because concentrations of immunosuppressants may be increased with telaprevir • Long Acting Beta-Adrenoceptor Agonists (salmeterol): Concentrations of salmeterol may be increased with telaprevir. Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

The potential for prolongation of the QT/QTc interval may be increased if telaprevir is administered in the presence of CYP3A4 inhibitors, such as ritonavir, ketoconazole, and erythromycin. Caution should be observed if these drugs are to be used concomitantly with telaprevir. Caution should also be observed when using telaprevir with drugs that can disrupt electrolyte levels.

ventricular fibrillation.

TELAPREVIR

31

Routine Labs

Baseline Assessment

Chemistry (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, TSH, serum cholesterol, and LDL) as frequently as the hematology evaluations or as clinically indicated Hematology (incl. white cell differential count) at week 2, 4, 8, and 12 or as clinically appropriate thereafter

-

-

Hemoglobin at least every 4 weeks

-

These are recommended baseline values for initiation of telaprevir combination treatment: - Hemoglobin: ≥120 g/L (females); ≥130 g/L (males) 3 - Platelet count ≥ 90,000/mm 3 - Absolute neutrophil counts ≥1500/mm - Adequately controlled thyroid function (TSH) - Calculated creatinine clearance ≥50 mL/min - Potassium ≥3.5 mmol/L

The following laboratory evaluations (complete blood count with white blood cell differential counts, electrolytes, serum creatinine, liver function tests, TSH, uric acid, serum cholesterol and LDL) must be conducted in all patients prior to initiating telaprevir combination treatment.

blood concentrations of telaprevir, an effect that can, in part, be offset by using a higher telaprevir dose (1125 mg q8h). Telaprevir use significantly reduces concentrations of darunavir and fosamprenavir.

• Avoid coadministration with DRV/r, FPV/r, LPV/r • ATV/r is considered compatible with telaprevir • EFV is considered compatible with telaprevir but with a dose increase of telaprevir (see dosing recommendations in section above) • TDF is considered compatible with telaprevir • RAL is considered compatible with telaprevir

32

TELAPREVIR

Store at 25ºC; excursions permitted to 15-30ºC.

Storage

Vertex Pharmaceuticals Inc. INCIVEK Product Monograph. Laval, Qc. August 11, 2011.

Thomas DL, Bartlett JG, Peters MG, et al. Provisional Guidance on the Use of Hepatitis C Virus Protease Inhibitors for Treatment of Hepatitis C in HIV-Infected Persons. CID 2011 (HIV/AIDS)

Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009; 50(6):1709-18.

Butt AA, Kanwal F. Boceprevir and Telaprevir in the Management of Hepatitis C Virus-Infected Patients.

CID 2012; 54(1):96-104.

References: Asselah T, Marcellin P. New direct-acting antiviralsʼ combination for the treatment of chronic hepatitis C. Liver International 2011; 31 suppl 1: 68-77.

375 mg purple film-coated capsule-shaped tablets. Each tablet is debossed with the characters “V 375” on one side.

or as clinically indicated Hematology (incl. white cell differential count) at week 2, 4, 8, and 12 or as clinically appropriate thereafter

Dosage Forms

-

DRUG INTERACTION TABLES DAA Interactions

Hepatitis C Directly Acting Antivirals . . . . . . . . . . . . . . . . . 34

Interactions with Other Drug Classes

Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66 71 75 79

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

34

Effect of hepatic impairment

Kinetic Characteristics

Impact of Food

Adult Dose

Telaprevir should be taken with food or a 2 snack that contains at least 20 g fat.

Substrate and strong inhibitor of CYP3A4 6 and p-glycoprotein.

Therefore, boceprevir may be taken without 1 regard to either meal type or timing.

Boceprevir undergoes biotransformation by CYP3A4, CYP3A5 and 3 aldoketoreductases. Boceprevir appears to be a strong, reversible inhibitor of 4 CYP3A4 and p-glycoprotein. In a healthy volunteer study, boceprevir does not appear to exert significant P-gp inhibition at 5 clinically relevant concentrations.

HCV-negative volunteers with no, mild or moderate hepatic impairment received

Telaprevir (Incivek®, TVR, VX-950) Vertex Pharmaceuticals 750 mg po q8h with food (supplied as 375 mg tablets) Compared to a regular breakfast, telaprevir AUC ↓ by 73%, 39% and 26% after administration under fasting conditions, lowcalorie/low fat breakfast, and lowcalorie/high protein breakfast, respectively.

Telaprevir AUC ↑ 20% with a high-fat breakfast.

Boceprevir (Victrelis®, BOC, SCH 503034) Merck 800 mg po q8h with food (supplied as 200 mg capsules) Boceprevir AUC ↑ 60% when administered with a meal vs on an empty stomach. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal.

Drug Interactions with Hepatitis C Protease Inhibitors

35

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

9

In a population pharmacokinetic analysis, no significant covariate effects on boceprevir pharmacokinetic parameters were identified for age, body weight, BMI, Black race, Asian race, renal function and hepatic function. A modest effect of gender (23% ↑ AUC and 22% ↑ Cmax in females) and HCV status (15-20% ↓ Cmax) was observed, but not anticipated to be clinically 8 meaningful.

1) ANTIRETROVIRALS Atazanavir/ In healthy volunteers, coadministration of ritonavir boceprevir and atazanavir/ritonavir resulted in 49% ↓ Ctrough, 35% ↓ AUC and 25% ↓ Cmax of atazanavir and ↓ 34% ritonavir AUC; boceprevir exposures were not

Other

Effect of hepatic impairment

appear to exert significant P-gp inhibition at 5 clinically relevant concentrations.

In an open-label, randomized, cross-over study, 20 HIV/HCV-negative volunteers received 2 treatments: telaprevir 750 mg every 8 hours for 10 days followed by a washout and ATV/r 300/100 mg once daily for 20 days with co-administration of

HCV-negative volunteers with no, mild or moderate hepatic impairment received telaprevir 750 mg as a single dose, then 750 mg q8h for 5 days. All subjects with hepatic impairment were cirrhotics. Mild hepatic impairment did not have a clinically significant effect on telaprevir AUC and Cmax, while moderate hepatic impairment resulted in 49% ↓ Cmax and 46% ↓ AUC of telaprevir compared to controls. A positive correlation between albumin levels and 7 telaprevir exposure was observed.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

36

The European Medicine Agency stated that coadministration of boceprevir with ritonavir-boosted atazanavir may be considered on a case-by-case basis if deemed necessary in patients with suppressed HIV viral loads and with an HIV strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring is warranted in such 10 cases.

Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. www.hivclinic.ca October 25, 2012

Coadministration of boceprevir and ritonavir-boosted protease inhibitors is not 1 recommended.

meaningful.

1) ANTIRETROVIRALS Atazanavir/ In healthy volunteers, coadministration of ritonavir boceprevir and atazanavir/ritonavir resulted in 49% ↓ Ctrough, 35% ↓ AUC and 25% ↓ Boceprevir Cmax of atazanavir and ↓ 34% ritonavir (Victrelis®, BOC, SCH 503034) AUC; boceprevir exposures were not 9 Merck altered.

In HIV/HCV co-infected subjects participating in a phase 2 randomized study of telaprevir vs. placebo plus pegylatedinterferon plus ribavirin, the kinetics of telaprevir were compared in patients on stable ATV/r therapy to patients not receiving concomitant antiretroviral therapy.

In patients receiving concomitant ATV/r, telaprevir Cavg was 9% ↑ compared to patients not receiving concomitant antiretroviral therapy. Median atazanavir concentrations were 16% higher during telaprevir treatment vs. before HCV treatment. Dose adjustment is not required when atazanavir/ritonavir is administered 12 with telaprevir.

In an open-label, randomized, cross-over study, 20 HIV/HCV-negative volunteers received 2 treatments: telaprevir 750 mg every 8 hours for Telaprevir 10 days followed by a (Incivek®, TVR, VX-950) washout and ATV/r 300/100 mg once daily Vertex Pharmaceuticals for 20 days with co-administration of telaprevir 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. With coadministration, telaprevir AUC ↓ 20% and Cmin ↓ 15%, Toronto General Hospital, Toronto, ON while atazanavir AUC ↑ 17% and Cmin ↑ page 1 of 16 11 85%.

37

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Efavirenz

Darunavir/ ritonavir

Avoid combination.

1

In healthy subjects, there was a slight reduction in BOC AUC(0-8h) and Cmax (19% and 8%, respectively), and a 44% decrease in BOC Cmin when co-administered with efavirenz. BOC slightly increased EFV AUC(0-24h) and Cmax (20% and 11%, 4 respectively).

Coadministration of boceprevir and ritonavir-boosted protease inhibitors is not 1 recommended.

In healthy volunteers, coadministration of boceprevir and darunavir/ritonavir resulted in 59% ↓ Ctrough, 44% ↓ AUC and ↓ 36% Cmax of darunavir and 27% ↓ ritonavir AUC, while boceprevir exposure was ↓ by 9 32%.

In an open-label study, 20 HIV/HCVnegative volunteers started telaprevir 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a washout. Subsequently, volunteers received telaprevir 1125 mg every 8 hours and

Darunavir/ritonavir and telaprevir should not 6 be co-administered.

In healthy volunteers, multiple-dose administration of efavirenz 600 mg daily and telaprevir 750 mg q8h resulted in 9% ↓ Cmax, 47% ↓ Cmin and 26% ↓ AUC of 13 telaprevir.

treatment. Dose adjustment is not required when atazanavir/ritonavir is administered 12 with telaprevir.

In an open-label, randomized, cross-over study, 20 HIV/HCV-negative volunteers received 2 treatments: telaprevir 750 mg every 8 hours for 10 days, followed by a washout and DRV/r 600/100 mg twice daily for 20 days with co-administration of telaprevir 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. With coadministration, telaprevir AUC ↓ 35% and Cmin ↓ 32%, while darunavir AUC ↓ 40% and Cmin ↓ 11 42%.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

38

1

Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. www.hivclinic.ca October 25, 2012

Boceprevir (Victrelis®, BOC, SCH 503034) Merck

Avoid combination.

AUC(0-24h) and Cmax (20% and 11%, 4 respectively).

In HIV/HCV co-infected subjects participating in a phase 2 randomized study of telaprevir vs. placebo plus pegylatedinterferon plus ribavirin, the kinetics of telaprevir 1125 mg q8h were compared in patients on stable efavirenz therapy to patients on telaprevir 750 mg q8h not receiving concomitant antiretroviral therapy.

In an open-label study, 20 HIV/HCVnegative volunteers started telaprevir 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a Telaprevir washout. Subsequently, volunteers received TVR,8 VX-950) telaprevir (Incivek®, 1125 mg every hours and EFV/TDF Vertex 600/300Pharmaceuticals mg once daily for 7 days or telaprevir 1500 mg every 12 hours and EFV/TDF 600/300 mg once daily for 7 days in a randomized order without a washout.

Telaprevir was taken withToronto, food and Toronto General Hospital, ON page 2 of 16 EFV/TDF was taken on an empty stomach in the morning. With TVR 1125 mg q8h plus efavirenz/TDF, telaprevir AUC ↓ 18%, Cmin ↓ 25%, EFV AUC ↓ 18%, Cmin ↓ 10%, and tenofovir AUC ↑ 10% and Cmin ↑ 17%.

With TVR 1500 mg q12h plus EFV/TDF, telaprevir AUC ↓ 20%, Cmin ↓ 48%, EFV AUC ↓ 15%, Cmin ↓ 11%, and tenofovir 11 AUC ↑ 10% and Cmin ↑ 6%.

39

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Fosamprenavir/ ritonavir

Etravirine

Elvitegravir/ cobicistat

Potential for concentrations of DAA and/or elvitegravir/cobicistat to be affected; avoid coadministration until more data are available.

In healthy volunteers, coadministration of boceprevir 800 mg q8h with etravirine 200 mg BID for 11-14 days resulted in ↓ 23% AUC, ↓ 24% Cmax and ↓29% Cmin of etravirine and ↑10% AUC and Cmax and ↓ 12% Cmin of boceprevir compared to either drug administered alone. Impact on boceprevir concentrations not considered clinically relevant; impact on etravirine concentrations could be clinically 14 significant.

In an open-label, randomized, cross-over study, 20 HIV/HCV-negative volunteers

telaprevir 1125 mg q8h were compared in patients on stable efavirenz therapy to patients on telaprevir 750 mg q8h not receiving concomitant antiretroviral therapy.

In patients receiving efavirenz, telaprevir Cavg was 4% ↓ compared to patients not receiving concomitant antiretroviral therapy.

Median efavirenz concentrations were 6% lower during telaprevir treatment vs. before HCV treatment. A higher dose of telaprevir (1125 mg every 8 hours) given with efavirenz provides similar telaprevir exposures as seen in the absence of 12 efavirenz.

Potential for concentrations of DAA and/or elvitegravir/cobicistat to be affected; avoid coadministration until more data are available.

In healthy volunteers, coadministration of telaprevir 750 mg TID with etravirine 200 mg BID for 11 days resulted in ↓ 6% AUC, ↓ 7% Cmax and ↓3% Cmin of etravirine and ↓ 16% AUC, ↓ 10% Cmax and ↓ 25% Cmin of telaprevir compared to either drug administered alone. These changes are not considered clinically relevant, combination 15 may be given without dose adjustment.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

40

Boceprevir (Victrelis®, BOC, SCH 503034) Merck

Lopinavir/ritonavir

Coadministration of boceprevir and ritonavir-boosted protease inhibitors is not 1 recommended.

In healthy volunteers, coadministration of boceprevir and lopinavir/ritonavir resulted in 43% ↓ Ctrough, 34% ↓ AUC and ↓ 30% Cmax of lopinavir and 22% ↓ ritonavir AUC, 9 while boceprevir exposure was ↓ by 45%.

Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. www.hivclinic.ca October 25, 2012

Fosamprenavir/ ritonavir

12% Cmin of boceprevir compared to either drug administered alone. Impact on boceprevir concentrations not considered clinically relevant; impact on etravirine concentrations could be clinically 14 significant.

Fosamprenavir/ritonavir and telaprevir 6 should not be co-administered.

In an open-label, randomized, cross-over study, 20 HIV/HCV-negative volunteers received 2 treatments: telaprevir 750 mg every 8 hours for 10 days, followed by a washout and lopinavir/r 400/100 mg twice daily for 20 days with co-administration of telaprevir 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. With coadministration, telaprevir AUC ↓ 54% and Cmin ↓ 52%,

In an open-label, randomized, cross-over study, 20 HIV/HCV-negative volunteers Telaprevir received 2 treatments: telaprevir 750 mg (Incivek®, TVR, followed VX-950) by a every 8 hours for 10 days, Vertex Pharmaceuticals washout and fosamprenavir/r 700/100 mg twice daily for 20 days with co-administration of telaprevir 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds Toronto Hospital, Toronto, ON were takenGeneral with food.

With coadministration, page 3 of 16 telaprevir AUC ↓ 32% and Cmin ↓ 30%, while amprenavir AUC ↓ 47% and Cmin ↓ 11 56%.

telaprevir compared to either drug administered alone. These changes are not considered clinically relevant, combination 15 may be given without dose adjustment.

41

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Raltegravir

The safe use of raltegravir-based therapy in HIV-patients with HCV-cirrhosis receiving triple therapy with boceprevir (n=2) or telaprevir (n=9) has been reported. Median baseline CD4 was 556 cells/mm3, all subjects had undetectable viral load, and all subjects had compensated cirrhosis (Child-Pugh score ≤6 in 82%). During 12 weeks of triple therapy, HIV viral suppression was maintained in all patients except one due to nonadherence. 73%

In an open-label, randomized, cross-over study, 24 healthy volunteers, received boceprevir 800 mg TID for 10 days plus single dose raltegravir 400 mg on day 10 followed by a wash-out period and singledose raltegravir 400 mg on day 38, or the same medications in reverse order.

Raltegravir exposures were not altered in the presence of boceprevir. The combination may be used without dosage 16 adjustment.

ritonavir-boosted protease inhibitors is not 1 recommended.

The safe use of raltegravir-based therapy in HIV-patients with HCV-cirrhosis receiving triple therapy with boceprevir (n=2) or telaprevir (n=9) has been reported. Median baseline CD4 was 556 cells/mm3, all subjects had undetectable viral load, and all subjects had compensated cirrhosis (ChildPugh score ≤6 in 82%). During 12 weeks of triple therapy, HIV viral suppression was

Lopinavir/ritonavir and telaprevir should not 6 be co-administered.

In an open-label cross-over study in 20 HIV/HCV-negative healthy volunteers, coadministration of raltegravir 400 mg BID and telaprevir 750 mg q8h for 6 days with food did not affect telaprevir pharmacokinetics, while raltegravir exposures were increased (Cmin ↑ 78%, Cmax ↑ 26% and AUC ↑ 31%) possibly due to inhibition of intestinal P-gp by telaprevir. Exposure to raltegravirglucuronide was similarly increased. This effect was not considered to be clinically 18 relevant. No dose adjustment is needed for telaprevir when given with raltegravir.

onwards, or vice versa. All compounds were taken with food. With coadministration, telaprevir AUC ↓ 54% and Cmin ↓ 52%, while lopinavir AUC ↑ 6% and Cmin ↑ 11 14%.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

42

Ritonavir

In human liver microsomes, the metabolism of telaprevir and boceprevir was

Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. www.hivclinic.ca October 25, 2012

Rilpivirine

telaprevir (n=9) has been reported. Median baseline CD4 was 556 cells/mm3, all subjects had undetectable viral load, and all subjects had compensated cirrhosis (Child-Pugh score ≤6 in 82%). During 12 weeks of triple therapy, HIV viral suppression was maintained in all patients except one due to nonadherence. 73% patients achieved complete early HCV Boceprevir virologic response (negative HCV-RNA at BOC, 503034) week (Victrelis®, 12 of therapy) withSCH no breakthrough 17 Merck or recurrence during follow-up.

May wish to avoid using combination in patients at increased risk for Torsade de Pointes, or who are on other drugs that may ↑ rilpivirine levels or that are known to cause QTc prolongation.

In human liver microsomes, the metabolism of telaprevir and boceprevir was

HIV-patients with HCV-cirrhosis receiving triple therapy with boceprevir (n=2) or telaprevir (n=9) has been reported. Median baseline CD4 was 556 cells/mm3, all subjects had undetectable viral load, and all subjects had compensated cirrhosis (ChildPugh score ≤6 in 82%). During 12 weeks of triple therapy, HIV viral suppression was maintained in all patients except one due to Telaprevir nonadherence. 73% patients achieved TVR, VX-950) complete (Incivek®, early HCV virologic response Pharmaceuticals (negative Vertex HCV-RNA at week 12 of therapy) with no breakthrough or recurrence during 17 follow-up.

In healthy volunteers, coadministration of telaprevir mgHospital, TID with rilpivirine Toronto750 General Toronto, ON 25 mg of 16 AUC, ↑ daily for 11 days resultedpage in ↑478% 49% Cmax and ↑ 93% Cmin of rilpivirine and ↓ 8% AUC, ↓ 5% Cmax and ↓ 13% Cmin of telaprevir compared to either drug administered alone. These changes are not considered clinically relevant, combination 15 may be given without dose adjustment.

43

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Ritonavir

In healthy subjects, ritonavir had minimal effects on steady-state BOC exposure.

RTV 100 mg daily plus BOC three times daily resulted in BOC AUC ↓ 19% and Cmax ↓ 27%, while ritonavir 100mg BID plus BOC twice daily resulted in decreased 4 BOC AUCt by 18% and Cmax ↓ 34%.

In human liver microsomes, the metabolism of telaprevir and boceprevir was substantially inhibited in the presence of low concentrations of ritonavir. With codosing of ritonavir in rats, the plasma exposure of both HCV agents was increased by more than 15-fold, and plasma concentrations 8 hours after dosing 19 were increased by > 50-fold.

HIV-negative subjects received telaprevir 750 mg q8h alone, or 250 mg or 750 mg BID with ritonavir 100 mg BID. Doses were given with food for 14 days. Ritonavir did not exert a significant boosting effect on telaprevir exposures: when compared with TVR 750 mg q8h given alone (Group C), TVR PK parameters on Day 14 were 59% to 75% lower when TVR 250 mg q12h was coadministered with RTV 100 mg q12h (Group A) and 15% to 32% lower when TVR 750 mg q12h was co-administered with RTV 100 mg q12h (Group B). Of note, RTV exposures were higher when co-administered with TVR

↑ rilpivirine levels or that are known to cause QTc prolongation.

In human liver microsomes, the metabolism of telaprevir and boceprevir was substantially inhibited in the presence of low concentrations of ritonavir. With co-dosing of ritonavir in rats, the plasma exposure of both HCV agents was increased by more than 15-fold, and plasma concentrations 8 hours after dosing were increased by > 50fold. A human pharmacokinetic model of telaprevir co-administered with low-dose ritonavir suggested that improved efficacy and/or dosing convenience may be feasible by pharmacokinetic enhancement with 19 ritonavir.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

44

www.hivclinic.ca

October 25, 2012

Boceprevir In healthy subjects, there were no clinically (Victrelis速, BOC, 503034) relevant changes in BOCSCH exposure when Merck co-administered with tenofovir. BOC also had no notable effect on tenofovir AUC or renal clearance, but increased tenofovir Cmax by 32%. No BOC dosage adjustment 4 needed co-administration Academic copyright: is Alice Tseng, with Pharm.D., FCSHP, AAHIVP.tenofovir.

Tenofovir

In an open-label study, 20 HIV/HCVpage 5 of 16 negative volunteers started telaprevir 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a washout. Subsequently, volunteers received telaprevir 1125 mg every 8 hours and EFV/TDF 600/300 mg once daily for 7 days or telaprevir 1500 mg every 12 hours and EFV/TDF 600/300 mg once daily for 7 days in a randomized order without a washout.

Telaprevir was taken with food and EFV/TDF was taken on an empty stomach in the morning. With TVR 1125 mg q8h plus

Toronto General Hospital, Toronto, ON

TVR PK parameters on Day 14 were 59% to 75% lower when TVR 250 mg q12h was coadministered with RTV 100 mg q12h (Group A) and 15% to 32% lower when TVR 750 mg q12h was co-administered with RTV 100 mg q12h (Group B). Of note, RTV exposures were higher when co-administered with TVR 750 mg q12h (Group B), compared with 250 q12h (Group A), suggesting that CYP3A 20 inhibition by TVR was dose-dependent.

In a randomized, Telaprevir open-label study, healthy TVR, VX-950) volunteers(Incivek速, received tenofovir 300 mg daily, telaprevir Vertex 750 mgPharmaceuticals q8h, or both drugs, each for 7 days. In the presence of telaprevir, tenofovir AUC24h was increased by 30% 21 while telaprevir kinetics were not affected.

45

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Buprenorphine

In HCV-negative volunteers on stable,

Use combination with caution and monitor for dose-related amlodipine toxicity.

2) OTHER MEDICATIONS Alprazolam No interaction studies have been done with intravenous benzodiazepines. Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of boceprevir with intravenous benzodiazepines (alprazolam, midazolam, triazolam).

Dose adjustment of the benzodiazepine 1 should be considered.

Amlodipine Combination not studied. Potential for ↑ amlodipine concentrations in the presence of boceprevir.

In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, amlodipine Cmax ↑ 27% and AUC ↑ 179%. Monitor for doserelated amlodipine toxicity when 23 coadministering with telaprevir.

In HCV-negative volunteers on stable,

In healthy subjects who received a single dose of alprazolam 0.5 mg alone and in combination with multiple doses of telaprevir 750 mg po q8h, alprazolam AUC ↑ 35% and the mean t1/2 increased from 13.4 hours to 22 18.7 hours in the presence of telaprevir.

Telaprevir was taken with food and EFV/TDF was taken on an empty stomach in the morning. With TVR 1125 mg q8h plus efavirenz/TDF/FTC, telaprevir AUC ↓ 18%, Cmin ↓ 25%, EFV AUC ↓ 18%, Cmin ↓ 10%, and tenofovir AUC ↑ 10% and Cmin ↑ 17%. With TVR 1500 mg q8h plus EFV/TDF/FTC, telaprevir AUC ↓ 20%, Cmin ↓ 48%, EFV AUC ↓ 15%, Cmin ↓ 11%, and 11 tenofovir AUC ↑ 10% and Cmin ↑ 6%.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

46

In HCV-negative volunteers on stable, maintenance doses (8/2 mg to 24/6 mg QD) of buprenorphine/naloxone, coadministration of boceprevir 800 mg q8h for 6 days did not have a clinically Boceprevir significant impact on the pharmacokinetics (Victrelis®, BOC,↑SCH 503034) of buprenorphine (AUC 20%, Cmax ↑ Merck 18%) or naloxone (AUC ↑ 30%, Cmax ↑ 9%). Boceprevir exposures in the presence of buprenorphine/naloxone were Academic copyright: similar Alice Tseng, Pharm.D., controls.

FCSHP, AAHIVP. to historical Dose www.hivclinic.ca October 25,when 2012 adjustment is likely not necessary boceprevir is co-administered with 24 buprenorphine/naloxone.

Clarithromycin In healthy subjects, clarithromycin had minimal effects on steady-state BOC exposure. Clarithromycin (in the presence of diflunisal) increased BOC AUC by 21% 4 and Cmax by 36%.

Corticosteroids Inhaled/nasal fluticasone and budesonide: (oral/inhaled, Potential for ↑ corticosteroid concentrations injectable or resulting in significantly reduced serum topical) cortisol concentrations. Avoid coe.g., administration if possible, particularly for 1 betamethasone, extended durations.

Buprenorphine

Use combination with caution and monitor for dose-related amlodipine toxicity.

of boceprevir.

Inhaled/nasal fluticasone and budesonide: Potential for ↑ corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential

(coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, amlodipine Cmax ↑ 27% and AUC ↑ 179%. Monitor for doserelated amlodipine toxicity when 23 coadministering with telaprevir.

In HCV-negative volunteers on stable, maintenance doses of buprenorphine/naloxone, coadministration of telaprevir 750 mg q8h for 7 days did not have a clinically significant impact on the pharmacokineticsTelaprevir or pharmacodynamic TVR,Telaprevir VX-950) effects of (Incivek®, buprenorphine.

Pharmaceuticals exposure Vertex was consistent with historical control when co-administered with buprenorphine/naloxone.

Dose adjustment is not necessary when telaprevir co-administered withON Torontois General Hospital, Toronto, 25 buprenorphine/naloxone.page 6 of 16

47

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Cyclosporine

injectable or topical) e.g., betamethasone, budesonide, dexamethasone, fluticasone, prednisone, triamcinolone

In healthy volunteers, the kinetics of singledose cyclosporine 100 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, cyclosporine AUC ↑ 2.7-fold and Cmax ↑ 2fold; BOC pharmacokinetics were not affected by cyclosporine. Co-administration of cyclosporine with boceprevir may require dose adjustment of CsA and close monitoring of cyclosporine blood levels as well as frequent assessments of renal

Systemic dexamethasone: Potential for ↓ boceprevir concentrations via CYP3A4 induction by dexamethasone.

Avoid combination if possible, use with 1 caution if necessary.

Inhaled beclomethasone or ciclesonide, or intranasal beclomethasone or triamcinolone may be safer alternatives, but caution is still warranted. Use lowest possible corticosteroid dose and monitor closely for 26 systemic corticosteroid side effects.

resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for 1 extended durations.

Systemic dexamethasone: Potential for ↓ telaprevir concentrations via CYP3A4 induction by dexamethasone. Use combination with caution or consider 6 altenate agents.

In healthy subjects, the pharmacokinetics of single dose cyclosporine was assessed alone at 100 mg and in the presence of steady-state telaprevir 750 mg q8h at a dose of 10 mg on day 1 and day 8. When coadministered with telaprevir, cyclosporine exposure ↑ 4.6-fold and the elimination t1/2 increased from 12 to 42 hours; the effect of first dose of telaprevir on cyclosporine kinetics was similar to the effect of steadystate telaprevir. Telaprevir kinetics were similar to historical data, suggesting no

Inhaled beclomethasone or ciclesonide, or intranasal beclomethasone or triamcinolone may be safer alternatives, but caution is still warranted. Use lowest possible corticosteroid dose and monitor closely for 26 systemic corticosteroid side effects.

resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of 6 systemic corticosteroid side effects.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

48

In five genotype 1 liver transplant patients with HCV recurrence, boceprevir 800 mg Boceprevir three times a day was initiated after a 4BOC, SCH 503034) week (Victrelis®, lead-in phase.

Concomitant Merck immunosuppressant therapy (IT) included cyclosporine (3), tacrolimus (2) and everolimus (1). The mean follow-up period since HCV therapy was 14.8±3.1 weeks. clearances of IT decreased Academic copyright: Estimated Alice Tseng, oral Pharm.D., FCSHP, AAHIVP. on average by 50%, requiring reduced www.hivclinic.ca October 25, 2012 dosing regimens. Anaemia occurred in all patients, with a mean fall in haemoglobin levels between baseline and week 12 of 3.12±2.27g/dL. All patients required administration of β-erythropoietin, three needed ribavirin dose reduction and one a 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).

mg TID. In the presence of BOC, cyclosporine AUC ↑ 2.7-fold and Cmax ↑ 2fold; BOC pharmacokinetics were not affected by cyclosporine. Co-administration of cyclosporine with boceprevir may require dose adjustment of CsA and close monitoring of cyclosporine blood levels as well as frequent assessments of renal 27 function and CsA-related side effects.

In a series of 9 liver transplant HCV patients

In a case series, patients with recurrent HCV post-liver transplant with null response (<2 Telaprevir log ↓) to pegylated-interferon/ribavirin (PR) (Incivek®, TVR, for ≥12 weeks received a 4VX-950) week lead-in Vertex Pharmaceuticals with PEG-IFN α2b with ribavirin 600-1000 mg/d followed by addition of telaprevir 750 mg q8h. Patients on tacrolimus were converted to cyclosporine prior to starting telaprevir.

On theHospital, first day of telaprevir Toronto General Toronto, ON therapy, the cyclosporinepage dose was 7 of 16 decreased from an average of 200 mg to 25 mg per day, with a target CsA trough of 100 ng/mL. To date, 4 subjects have completed 12 weeks of telaprevir therapy. The average CsA dose at week 16 was 68 mg. All patients required ↓ in ribavirin dose; no episodes of renal toxicity secondary to ↑ CsA levels or rejection following the end of 30 telaprevir therapy were observed.

of 10 mg on day 1 and day 8. When coadministered with telaprevir, cyclosporine exposure ↑ 4.6-fold and the elimination t1/2 increased from 12 to 42 hours; the effect of first dose of telaprevir on cyclosporine kinetics was similar to the effect of steadystate telaprevir. Telaprevir kinetics were similar to historical data, suggesting no 29 major effect of cyclosporine on telaprevir.

49

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Digoxin

In an open-label, randomized crossover study, healthy volunteers received single dose digoxin 0.25 mg alone or in combination with multiple-dose boceprevir 800 mg TID. In the presence of boceprevir, digoxin AUC was ↑ 19% and Cmax ↑ 18%, while terminal t½ was unchanged. These results suggest that dosage adjustment of digoxin is not necessary with concomitant boceprevir therapy, and that boceprevir does not appear to exert significant P-gp inhibition at clinically relevant 5 concentrations.

vira load decrease at week 12: 6.64±0.35 28 log(10)IU/mL).

30

Initiate digoxin at the lowest dose, and monitor serum digoxin concentrations to 6 titrate to desired clinical effect.

In a series of 9 liver transplant HCV patients treated with telaprevir, pegylated interferon, and ribavirin in parallel with tacrolimus (n=4), cyclosporine (n=4), or sirolimus (n=1), immunosuppressant dose-reductions were required in all patients (cyclosporine 2.5-fold, sirolimus 7-fold, tacrolimus 22-fold, respectively) during the course of the 12 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.

In an open-label study, healthy subjects received single doses of IV midazolam 0.5 mg, and oral midazolam 2 mg with oral digoxin 0.5 mg administered sequentially alone and in combination with multiple-dose telaprevir 750 mg q8h. In the presence of telaprevir, digoxin Cmax ↑ 50% and AUC ↑ 85%, while renal clearance was not 32 changed.

telaprevir therapy were observed.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

50

Patients receiving treatment with both boceprevir and digoxin should be 1 monitored appropriately.

Escitalopram In healthy volunteers, the kinetics of single dose escitalopram 10 mg were not altered Boceprevir to a clinically significant manner in the (Victrelis®, BOC, SCH 503034)800 presence of multiple dose boceprevir Merck mg TID. The pharmacokinetics of boceprevir were similar with and without coadministration of escitalopram. No dosage adjustment is expected to be with coadministration of this Academic copyright: required Alice Tseng, Pharm.D., FCSHP, AAHIVP. 33 combination. www.hivclinic.ca October 25, 2012 HmgCoA In healthy volunteers, the kinetics of single reductase dose atorvastatin 40 mg in the presence inhibitors (statins): of steady-state BOC 800 mg TID were significantly increased (atorvastatin AUC ↑ atorvastatin 130% and Cmax ↑ 170%) compared to lovastatin administration alone. BOC kinetics were pravastatin not significantly affected by atorvastatin rosuvastatin coadministration. A lower maintenance simvastatin dose of atorvastatin may be warranted with concomitant BOC therapy; additional

while terminal t½ was unchanged. These results suggest that dosage adjustment of digoxin is not necessary with concomitant boceprevir therapy, and that boceprevir does not appear to exert significant P-gp inhibition at clinically relevant 5 concentrations.

Atorvastatin, lovastatin and simvastatin 36 are contraindicated with telaprevir.

In healthy subjects, the kinetics of single dose amlodipine 5 mg/atorvastatin 20 mg (coformulated) were assessed alone and with steady-state telaprevir 750 mg q8h. In the presence of telaprevir, atorvastatin 23 Cmax ↑ 10.6-fold and AUC ↑ 7.88-fold.

Toronto General Hospital, Toronto, ON page 8 of 16

In healthy volunteers, coadministration of escitalopram 10 mg daily with telaprevir 750 mg q8h for 7 daysTelaprevir resulted in 35% ↓ (Incivek®, TVR,telaprevir VX-950) escitalopram AUC, while Pharmaceuticals exposuresVertex were not affected. May need to titrate escitalopram dose according to 34 clinical response.

Initiate digoxin at the lowest dose, and monitor serum digoxin concentrations to 6 titrate to desired clinical effect.

telaprevir, digoxin Cmax ↑ 50% and AUC ↑ 85%, while renal clearance was not 32 changed.

51

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Ketoconazole

rosuvastatin simvastatin

Lovastatin and simvastatin are 36 contraindicated with boceprevir.

In healthy subjects, ketoconazole (KCZ) increased BOC AUC ↑131%, Cmax ↑ 4 41%.

In healthy volunteers, the kinetics of single dose pravastatin 40 mg in the presence of steady-state BOC 800 mg TID were increased (pravastatin AUC ↑ 60% and Cmax ↑ 50%) compared to administration alone. BOC kinetics were not significantly affected by pravastatin coadministration.

This slight increase may reflect potential inhibition of OATP by BOC, since pravastatin is not metabolized to a significant extent by CYP450 and is a substrate of OATP1B1 and OATP2B1, but not of P-gp. It is anticipated that pravastatin treatment can be initiated at the recommended dose when co-administered 35 with BOC, with close clinical monitoring.

coadministration. A lower maintenance dose of atorvastatin may be warranted with concomitant BOC therapy; additional clinical monitoring for symptoms of statin toxicity is recommended if atorvastatin doses of greater than 40 mg daily are 35 used.

In healthy subjects, the effect of single dose ketoconazole 400 mg on the kinetics of single dose (750 mg) or multiple dose (750 mg q8h) telaprevir was studied. When

Atorvastatin, lovastatin and simvastatin 36 are contraindicated with telaprevir.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

52

When coadministration is required, doses of ketoconazole and itraconazole should 1 not exceed 200 mg/day.

35

Boceprevir (Victrelis®, BOC, SCH 503034) Merck on stable, Methadone In HCV-negative volunteers maintenance doses (20-150 mg QD) of methadone, boceprevir 800 mg q8h was coadministered for 6 days. In the presence boceprevir, exposures R-methadone Academic copyright: of Alice Tseng, Pharm.D., FCSHP,ofAAHIVP. www.hivclinic.ca October 25, 2012 were decreased (AUC ↓ 16%, Cmax ↓ 10%) and S-methadone were decreased (AUC ↓ 22%, Cmax ↓ 17%). These changes did not result in clinically significant effects including withdrawal.

Boceprevir exposures in the presence of methadone were similar to historical controls. Dose adjustment is likely not necessary when boceprevir is co24 administered with methadone.

Ketoconazole

Lovastatin and simvastatin are 36 contraindicated with boceprevir.

In healthy subjects, ketoconazole (KCZ) increased BOC AUC ↑131%, Cmax ↑ 4 41%.

with BOC, with close clinical monitoring.

In healthy subjects, the effect of single dose ketoconazole 400 mg on the kinetics of single dose (750 mg) or multiple dose (750 mg q8h) telaprevir was studied. When single doses of both drugs were coadministered, telaprevir Cmax ↑ 24% and AUC ↑ 62%. However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure.

High (>200 mg per day) doses of Telaprevir are not ketoconazole or itraconazole 13 (Incivek®, TVR, VX-950) recommended with telaprevir.

Vertex Pharmaceuticals In HCV-negative volunteers on stable methadone maintenance therapy (median methadone dose 85 mg, range 40-120 mg/day), telaprevir 750 mg q8h was coadministered for 7Hospital, days. Toronto, In the presence of Toronto General ON of 31%, 16 telaprevir, R-methadone page Cmin9 ↓ Cmax ↓ 21% and AUC ↓ 21%. The AUC ratio of S-/R-methadone was comparable before and during coadministration of telaprevir.

The median unbound fraction of Rmethadone ↑ from 7.92% to 9.98% during coadministration with telaprevir, but the median unbound Cmin of R-methadone was similar before and during telaprevir coadministration. A priori methadone dose

53

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Midazolam

No interaction studies have been done with intravenous benzodiazepines. Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of boceprevir with intravenous benzodiazepines (alprazolam, midazolam, triazolam).

Dose adjustment of the benzodiazepine 1 should be considered.

Boceprevir is contraindicated with oral 1 midazolam.

Clinical monitoring is recommended, with dose adjustments of methadone if necessary during concomitant treatment 1 with boceprevir.

In healthy subjects, coadministration of oral midazolam plus steady-state BOC resulted in increased MDZ exposure: 177% ↑ Cmax 4 and 430% ↑ AUC0-24 h.

methadone were similar to historical controls. Dose adjustment is likely not necessary when boceprevir is co24 administered with methadone.

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.

Telaprevir is contraindicated with oral 6 midazolam.

In an open-label study, healthy subjects received single doses of IV midazolam 0.5 mg, and oral midazolam 2 mg with oral digoxin 0.5 mg administered sequentially alone and in combination with multiple-dose telaprevir 750 mg q8h. In the presence of telaprevir, midazolam IV AUC ↑ 3.4 fold, and midazolam oral Cmax ↑ 2.86-fold and AUC ↑ 8.96-fold. In the presence of telaprevir, digoxin Cmax ↑ 50% and AUC ↑ 85%, while 32 renal clearance was not changed.

coadministration with telaprevir, but the median unbound Cmin of R-methadone was similar before and during telaprevir coadministration. A priori methadone dose adjustments are not required when initiating telaprevir, but close monitoring is recommended, with dose adjustments if 37 necessary.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

54

In healthy subjects, co-administration of diflunisal or ibuprofen (aldo ketoreductase inhibitors) had little effect on the steady4 state exposure to BOC. In healthy subjects, there were no clinically relevant changes in BOC exposure when co-administered with drospirenone (DRSP)/ethinyl estradiol (EE). BOC increased DRSPBoceprevir AUC(0-24h) and Cmax (99% (Victrelis®, BOC, and SCHdecreased 503034) EE and 57%, respectively); 4 AUC (24%) with noMerck effect on EE Cmax..

Pegylated interferon alfa-2b

In healthy subjects, there were no clinically relevant changes in either BOC or PEG2b exposure when co-administered with pegylated interferon alfa-2b. No BOC dosage adjustment is needed with co-

Alternative methods of non-hormonal contraception are recommended. Coof BOC withAAHIVP. drospirenone Academic copyright: administration Alice Tseng, Pharm.D., FCSHP, www.hivclinic.ca October 25, 2012 (Yaz®, Yasmin®, Angeliq®) 1 is contraindicated.

Oral contraceptives

NSAIDS

midazolam, triazolam).

Dose adjustment of the benzodiazepine 1 should be considered.

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 exposures were not significantly affected.

LH and FSH concentrations at day 7 also ↑, Toronto General Hospital, ON corresponding with the ↓ Toronto, EE concentrations.

10 of 16 Alternative methods ofpage 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.

55

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

Phosphodiesterase Type 5 (PDE5) Inhibitors • sildenafil (Viagra®, Revatio®); (CYP3A4>>2C9 substrate; weak inhibitor of CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4 - unlikely to cause significant interactions) • tadalafil (Cialis, Adcirca®); CYP3A4 substrate • vardenafil (Levitra); substrate of CYP3A4>3A5, 2C Rifampin

interferon alfa-2b

For treatment of erectile dysfunction: Use with caution and increased monitoring for PDE-5 inhibitor-associated toxicities. Do not exceed the following 6 doses: • 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

Coadministration is contraindicated, as boceprevir concentrations may be

For treatment of pulmonary arterial 6 hypertension (PAH): • Sildenafil use for PAH is (contraindicated with telaprevir.

• Co-administration of tadalafil and telaprevir for PAH treatment is not recommended.

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

For treatment of erectile dysfunction: Use with caution and increased monitoring for PDE-5 inhibitor-associated toxicities. Do not exceed the following 1 doses: • sildenafil: 25 mg every 48 hours • tadalafil: 10 mg every 72 hours • vardenafil: 2.5 mg every 24 hours (NB: this dose not approved in Canada; therefore, combination is not recommended)

For treatment of pulmonary arterial 1 hypertension (PAH): • Sildenafil or tadalafil use for PAH is contraindicated with boceprevir.

relevant changes in either BOC or PEG2b exposure when co-administered with pegylated interferon alfa-2b. No BOC dosage adjustment is needed with co4 administration. ↑ in PDE-5 inhibitor concentrations are expected, and may result in an increase in adverse effects, including hypotension, syncope, visual disturbances, and priapism.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

56

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)

In five genotype 1 liver transplant patients with HCV recurrence, boceprevir 800 mg three times a day was initiated after a 4-

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 reduction of tacrolimus and/or prolongation of the dosing interval, Academic copyright: with Alice close Tseng, monitoring Pharm.D., FCSHP, AAHIVP. of tacrolimus www.hivclinic.ca October 25, 2012 concentrations and frequent assessments of renal function and tacrolimus-related 27 side effects.

Tacrolimus

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

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

General HCV-1a Hospital, Toronto, ONpost-liver In aToronto case series, infected, page pegylated 11 of 16 transplant patients received interferon 2a/b, ribavirin, and telaprevir. All subjects were on stable tacrolimus dosing prior to starting antiviral therapy. Tacrolimus doses were pre-emptively reduced to 50% of pre-treatment doses and given once weekly.

Trough TAC levels were checked q2d for the

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 tacrolimus on telaprevir.

• • •

57

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

In five genotype 1 liver transplant patients with HCV recurrence, boceprevir 800 mg three times a day was initiated after a 4week lead-in phase. Concomitant immunosuppressant therapy (IT) included cyclosporine (3), tacrolimus (2) and everolimus (1). The mean follow-up period since HCV therapy was 14.8±3.1 weeks.

Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anaemia occurred in all patients, with a mean fall in haemoglobin levels between baseline and week 12 of 3.12±2.27g/dL. All patients required administration of β-erythropoietin, three needed ribavirin dose reduction and one a 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).

In a series of 9 liver transplant HCV patients treated with telaprevir, pegylated interferon, and ribavirin in parallel with tacrolimus (n=4), cyclosporine (n=4), or sirolimus (n=1), immunosuppressant dose-reductions were required in all patients (cyclosporine 2.5-fold, sirolimus 7-fold, tacrolimus 22-fold, respectively) during the course of the 12 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.

prior to starting antiviral therapy. Tacrolimus doses were pre-emptively reduced to 50% of pre-treatment doses and given once weekly.

Trough TAC levels were checked q2d for the first 2 weeks, then weekly until telaprevir therapy was complete. Baseline TAC dosing was resumed after 5 days of stopping telaprevir. No episodes of acute rejection or TAC toxicity were noted; 4 patients had early rapid virologic response, 2 patients had complete early virologic response, 1 patient was a non-responder.

The main adverse effect was anemia (n=6 required transfusions); dehydration, renal 39 insufficiency and infections also reported.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

58

Boceprevir (Victrelis®, BOC, SCH 503034) Merck

Combination has not been studied.

Potential for altered warfarin concentrations in the presence of boceprevir. Monitor INR when coadministering warfarin and 1 boceprevir.

Zolpidem

Academic copyright: Alice Tseng, Pharm.D., FCSHP, AAHIVP. www.hivclinic.ca October 25, 2012

Warfarin

Monitor INR when coadministering warfarin 6 and telaprevir.

In healthy subjects who received a single

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.

In vitro, the effect of 14C-telaprevir at various concentrations on the proteinbinding of 3H-warfarin was evaluated in human plasma. Protein-binding of 14Ctelaprevir 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.

Protein binding ofTelaprevir 3H-warfarin in human (Incivek®, VX-950) plasma was 98% andTVR, was unchanged by the Pharmaceuticals presence Vertex of telaprevir over the concentration range of 0.1 to 20 uM. At low 14C-telaprevir concentrations, warfarin and other ligands with high affinity binding to albumin or alpha1-acid glycoprotein may displace 14C-telaprevir General Hospital, Toronto, ON fromToronto protein binding sites and ↑ the free 40 page 12 of 16 fraction of telaprevir.

59

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

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

Merck CanadaRPG, Inc. Victrelis (boceprevir) Product Monograph.

Kirkland, June 13, 2012.

Van Heeswijk Boogaerts G, De Paepe E, et al.

The effect of differentQC types of food on the bioavailability of the investigational HCV protease inhibitor telaprevir [abstract PK_19]. 6th 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]. 6th Cambridge, MA. International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Ghosal A, Yuan Cambridge, MA.Y, Tong W, et al. Characterization of human liver enzymes involved in the

1.2.

3.

2.

References:

1.

Please note: This chart summarizes some of the major drug interactions identified to date, based on current available data; other drugsummarizes interactions some may exist. whenever adding/modifying therapy.

The Please note: This chart of thePlease major use drugcaution interactions identified to date, based on current information in this table is intended for use experienced physicians pharmacists.

It is not intended to available data; other drug interactions mayby exist.

Please use cautionand whenever adding/modifying therapy.

The replace sound professional judgmentfor in use individual situations, physicians and should and be used in conjunction other reliable information in this table is intended by experienced pharmacists.

It is with not intended to 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. users are advised to recheck the information contained herein with the original source before applying it to patient care.

References:

Zolpidem Zolpidem

Monitor INR when coadministering warfarin Monitor INR6 when coadministering warfarin and telaprevir. 6 and telaprevir.

In healthy subjects who received a single In healthy subjects received dose of zolpidem 5 mgwho alone and in a single dose of zolpidem 5 mg750 alone in combination with a single mgand telaprevir combination with a singledoses 750 mg telaprevir dose and multiple telaprevir of 750 andzolpidem multiple telaprevir mgdose po q8h, exposuresdoses were of 750 mg po q8h, zolpidem exposures were unchanged after single dose telaprevir, while unchanged single while zolpidem Cmaxafter ↓ 42% anddose AUC telaprevir, ↓ 47% after zolpidem Cmax and AUC 47% after steady-state dosing↓of42% telaprevir.

The↓ mean 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.

INTERACTIONS WITH DIRECTLY ACTING ANTIVIRALS (DAAS)

60

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.

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Adiwijaya B, Chandorkar G, Van Heeswijk RPG, et al. Effect of mild and moderate hepatic

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Henshaw J, Adiwijaya B, Adda N, et al. The pharmacokinetics of telaprevir and selected ART medications in HCV/HIV co-infected patients [abstract PK_08]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA.

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.

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].

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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].

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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.

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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.

Lee JE, Van Heeswijk RPG, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother 2011;55(10):4569-74.

Hulskotte EGJ, Feng H-P, Bruce RD, et al. Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy [abstract PK_09]. 7th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 27-28, 2012, Cambridge, MA.

Luo X, Trevejo J, Van Heeswijk RPG, et al. Effect of telaprevir on the pharmacokinetics of buprenorphine in volunteers on stable buprenorphine/naloxone maintenance therapy. Antimicrob Agents Chemother 2012;56(7):3641-7.

Foisy MM, Yakiwchuk EMK, Chiu I, et al. Adrenal suppression and Cushingâ&#x20AC;&#x2122;s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9(6):389-96.

Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012;May 11 [Epub ahead of print].

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.

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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.

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Hulskotte EGJ, Gupta S, Xuan F, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin [abstract]. HEP DART, December 4-8, 2011, Koloa, Hawaii.

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Van Heeswijk RPG, Vandevoorde A, Verboven P, et al. The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir [abstract PK_18]. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 22-23, 2011, Cambridge, MA.

Garg V, Van Heeswijk RPG, Yang Y, et al. The pharmacokinetic interaction between an oral contraceptive containing ethinyl estradiol and norethindrone and the HCV protease inhibitor telaprevir. J Clin Pharmacol 2011;Oct 30.

Mantry PS, Hassett MS, Weinstein J, et al. Triple therapy using telaprevir in the treatment of hepatitic C recurrence after liver transplantation: an early single center experience [abstract 90].

HEP DART, December 4-8, 2011, Koloa, Hawaii.

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.

35.

36.

37.

38.

39.

40.

Boston, MA.

INTERACTIONS WITH OTHER DRUG CLASSES - ANTICONVULSANTS

66

Gabapentin (Renal)

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

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

Anticonvulsant (route of metabolism)

Use combination with caution.

Clinical or laboratory monitoring of carbamazepine concentrations and dose titration are recommended to achieve the 3 desired clinical response.

Consider an alternate agent with non-inducing metabolic properties.

No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical

Carbamazepine is 5 contraindicated with boceprevir.

Substrate and strong inhibitor of 3 CYP3A4 and p-glycoprotein.

Substrate of CYP3A4, CYP3A5 1 and aldoketoreductases.

Strong, reversible inhibitor of CYP3A4 and p-glycoprotein in 2 vitro.

Potential for ↓ DAA concentration and/or ↓ 4 anticonvulsant concentration.

Potential for ↓ DAA concentration and/or ↑ 4 anticonvulsant concentration.

Telaprevir (Incivek®, TVR, VX-950) Vertex Pharmaceuticals

Boceprevir (Victrelis®, BOC, SCH 503034) Merck

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

67

INTERACTIONS WITH OTHER DRUG CLASSES - ANTICONVULSANTS

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

Inhibitor of CYPC19 Potent inducer of CYP3A4.

Relative to carbamazepine, oxcarbazepine inducing effect is 6 54% lower Phenobarbital (parent - 2C9/19)

Oxcarbazepine (parent - UGT)

Lithium (renal)

Levetiracetam (24% enzymatic hydrolysis, 66% renal)

Lamotrigine (UGT)

Gabapentin (Renal)

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

Use combination with caution.

Clinical or laboratory monitoring of phenobarbital concentrations

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

Phenobarbital is contraindicated 5 with boceprevir.

non-inducing metabolic properties.

No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.

No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.

No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.

NB: No data exist for levetiracetam for treating psychiatric disorders in the context of HCV. No interaction expected based on known pharmacologic characteristics. Monitor and 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.

INTERACTIONS WITH OTHER DRUG CLASSES - ANTICONVULSANTS

68

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

Pregabalin (renal)

Phenytoin is contraindicated with 5 boceprevir.

Potent inducer of CYP3A4, 2C9/19, UGT

page 1 of 3

Use combination with caution.

Clinical or laboratory monitoring of phenobarbital concentrations and dose titration are recommended to achieve the 3 desired clinical response.

Consider an alternate agent with non-inducing metabolic properties.

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

Consider an alternate agent with non-inducing metabolic properties.

No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical

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

Phenytoin (parent - 70% CYP2C9, minor 2C19)

Sanjeev Sockalingam, MD, FRCPC, University Health Network, Toronto, ON. www.hivclinic.ca August 28, 2012

Phenobarbital is contraindicated 5 Boceprevir with boceprevir.

(Victrelis®, BOC, SCH 503034) Merck

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

Use combination with caution.

Telaprevirmonitoring Clinical or laboratory (Incivek®, TVR, VX-950) of phenobarbital concentrations Pharmaceuticals and Vertex dose titration are recommended to achieve the 3 Academic copyright: Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON, Alicedesired Tseng, Pharm.D., FCSHP, AAHIVP and clinical response.

Potent inducer of CYP3A4, 1A2, 2C9/19, UGT Anticonvulsant (route of metabolism)

54% lower Phenobarbital (parent - 2C9/19)

69

INTERACTIONS WITH OTHER DRUG CLASSES - ANTICONVULSANTS

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.

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

Novartis Pharmaceuticals Canada Inc. Tegretol (Carbamazepine) Product Monograph. Dorval, Que. 2011.

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

2.

3.

4.

5.

References: 1.

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.

Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, UGT = Uridine 5'-diphospho-glucuronosyltransferases

Inhibitor of UGT,CYP2C9/19

Induces 3A4 (mild), inhibits 2C19 Valproic acid, divalproex (Parent â&#x20AC;&#x201C; 50% UGT, <10% CYP)

Topiramate (renal)

Pregabalin (renal)

non-inducing metabolic properties.

No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.

Potential for â&#x2020;&#x201C; DAA concentrations. Monitor and titrate dose according to clinical response.

NB: No data exist for topiramate for treating psychiatric disorders in the context of HCV. No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical 8 response and serum levels. Monitor for potential hepatotoxicity.

INTERACTIONS WITH OTHER DRUG CLASSES - ANTICONVULSANTS

70

Novartis Pharmaceuticals Canada Inc. Tegretol (Carbamazepine) Product Monograph. Dorval, Que. 2011.

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

Andreasen AH, Brosen K, Damkier P. A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on CYP3A4. Epilepsia 2007 Mar;48(3):490-6.

4.

5.

6.

8.

Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut. [Review] 1984 Jun;25(6):673-81.

Academic copyright: H, Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, ON, Alice Tseng,review Pharm.D., AAHIVP and 7.

Hachad Ragueneau-Majlessi I, Levy RH. New Ottawa, antiepileptic drugs: on FCSHP, drug interactions.

Sanjeev Sockalingam, MD, FRCPC, University Health Network, Toronto, ON. Ther Drug Monit. [Review] 2002 Feb;24(1):91-103. www.hivclinic.ca August 28, 2012 page 2 of 3

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

3.

Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIDEPRESSANTS

71

Level 4

Level 2

7, 8

Level of Evidence* 1, 2 Level 1

Nortriptyline (2D6)

Paroxetine (2D6)

Citalopram (CYP2C19, 3A4 >> 2D6)

Antidepressant (route of metabolism) Escitalopram (CYP2C19, 3A4 >> 2D6)

No interaction expected based on known pharmacologic

Potential for ↑ antidepressant concentrations.

No interaction expected based on known pharmacologic characteristics.

35% ↓ escitalopram AUC 4 with telaprevir.

Known or Potential Interactions with DAAs 21% ↓ AUC, 19% ↓ Cmax of escitalopram 3 with boceprevir.

NB: Evidence in RCT for depressed mood component of major depression only Monitor and titrate dose according to clinical response.

Telaprevir: May need to titrate escitalopram dose according to clinical 6 response.

Monitor and titrate dose according to clinical response.

Monitor and titrate dose according to clinical response.

Boceprevir: escitalopram dose may need to be 5 adjusted.

Comments

Antidepressant Use in Hepatitis C: Level of Evidence for Prophylactic and Symptomatic Treatment of Depression in HCV and Actual/Potential Drug Interactions with Directly Acting Antivirals (DAAs)

72

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIDEPRESSANTS

Inconclusive

Level 4

Modafinil (3A4; may induce

Tricyclic antidepressants i.e. desipramine (CYP2D6>>UGT), imipramine (CYP2D6, 1A2, 2C19, 3A > UGT), trazodone (CYP2D6> CYP3A)

Sertraline (CYP2B6 > 2C9/19, 3A4, 2D6, UGT1A1 - possible) Mirtazapine (CYP2D6, 1A2, 3A4) Venlafaxine (CYP2D6 > CYP3A4) Desvenlafaxine (UGT>>3A4)

Bupropion (2B6) Fluoxetine (2D6)

Nortriptyline (2D6)

Potential for ↑ modafinil

Potential for ↑ desvenlafaxine concentrations (clinical significance unknown).

Also, potential for ↓ concentrations of DAAs (clinical significance unknown).

Potential increase in TCA concentrations resulting in dizziness, hypotension and syncope.

No interaction expected based on known pharmacologic characteristics.

No interaction expected based on known pharmacologic characteristics.

Potential for ↑ sertraline, mirtazapine, venlafaxine concentrations (clinical significance unknown).

NB: Trazodone is primarily used clinically for treating insomnia in HCV. Use with caution; monitor

Use with caution with DAAs, lower TCA doses 5, 6 are recommended.

Use with caution; monitor and titrate antidepressant dose according to clinical response. Monitor for efficacy to HCV therapy.

Use with caution; monitor and titrate dose according to clinical response.

Monitor and titrate dose according to clinical response.

depression only Monitor and titrate dose according to clinical response.

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIDEPRESSANTS

73

concentrations resulting in dizziness, hypotension and syncope.

NB: Trazodone is primarily used clinically for treating insomnia in HCV. Use with caution; monitor Comments

DAAs, lower TCA doses 5, 6 are recommended.

Avoid (exceptional circumstances only)

Duloxetine: risk of hepatotoxicity.

Nefazodone: potential for ↑ nefazodone and/or DAA concentrations; also

Nefazodone (3A4)

No interaction expected based on known pharmacologic characteristics.

Potential for ↓ DAA concentrations.

Duloxetine (1A2, 2D6)

St. John's Wort (hypericum perforatum); induces CYP3A4 and P-gp.

Amantadine (minimal metabolism)

6

Duloxetine is contraindicated in liver disease.

St. John’s Wort is contraindicated with 5, boceprevir and telaprevir.

Monitor and titrate dose according to clinical response.

Inconclusive Modafinil (3A4; may induce Potential for ↑ modafinil Level of Antidepressant Known or Potential Academic copyright: Sanjeev Sockalingam, MD, FRCPC, Alice Tseng, Pharm.D., FCSHP, AAHIVP, University Health Network, Evidence* (route of metabolism) Interactions Toronto, ON, and Pierre Giguere, M.Sc.Phm., The Ottawa Hospital, Ottawa, ON.with DAAs evidence as 3A4) and titratepage antidepressant concentrations and/or ↓ www.hcvdruginfo.ca November 21, 2012 1 of 2 monotherapy dose according to clinical DAA concentrations. response. Monitor for efficacy to HCV therapy.

i.e. desipramine (CYP2D6>>UGT), imipramine (CYP2D6, 1A2, 2C19, 3A > UGT), trazodone (CYP2D6> CYP3A)

74

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIDEPRESSANTS

Nefazodone: potential for ↑ nefazodone and/or DAA concentrations; also risk of hepatotoxicity.

References: 1.

Schaefer M, Sarkar R, Knop V, et al. Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease. Ann Intern Med 2012;157:97103.

2. de Knegt RJ, Bezemer G, Van Gool AR, et al. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C. Aliment Pharmacol Ther 2011;34(11-12):1306-17.

3.

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 helathy volunteers. Global Antiviral Journal 2011;7, Suppl 1:108-09 (abstract).

4.

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 International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 23-24, 2010, Boston, MA. 5.

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

6.

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

7.

Kraus MR, Schafer A, Schottker K, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomized, double-blind, placebo-controlled study. Gut 2008;57(4):531-6.

8.

McNutt MD, Liu S, Manatunga A, et al. Neurobehavioral effects of interferon-alpha in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology 2012;37(6):1444-54.

*Level of Evidence for Prophylactic and Symptomatic Treatment of Depression in HCV Criteria Level 1 ≥ 2 randomized controlled trials or meta-analysis Level 2 1 randomized controlled trial Level 3 Prospective open label study (n ≥ 10) Level 4 Anecdotal or expert opinion

Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, UGT = Uridine 5'-diphospho-glucuronosyltransferases

Nefazodone (3A4)

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIPSYCHOTICS

75

1

Weak inhibitor of CYP2D6.

Asenapine does not cause induction of CYP1A2 or CYP3A4 Clozapine (CYP1A2> 3A4, P-gp)

Asenapine (UGT, CYP1A2>> CYP3A4, 2D6)

Aripiprazole (CYP3A4, 2D6)

Drug (route of metabolism)

Potential for â&#x2020;&#x2018; clozapine concentrations

No interaction expected based on known pharmacologic characteristics.

Known or Potential Interactions with DAAs Potential for â&#x2020;&#x2018; aripiprazole concentrations

Clozapine has a narrow therapeutic index. Use combination with caution, and monitor for clozapine-related toxicity (bone marrow suppression, generalized seizures, severe sedation, confusion and delirium).

Consider starting with a decreased aripiprazole dose or select an alternate agent.

Monitor and titrate dose according to clinical response.

Use combination with caution, and monitor for aripiprazolerelated toxicity (sedation, sinus tachycardia, nausea/vomiting, or dystonic reactions).

Comments

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

76

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIPSYCHOTICS

Potential for ↑ olanzapine 4 concentrations.

Potential for ↑ paliperidone 4 concentrations.

Potential for ↑ quetiapine 4 concentrations.

Potential for ↑ risperidone 4 concentrations.

Olanzapine (CYP1A2, UGT, PGP>2D6)

Paliperidone (CYP3A4, PGP>2D6) Minor CYP dependant pathway(41%).

4 Substrate and inhibitor of PGP

Quetiapine (CYP3A4>2D6, PGP)

Risperidone (CYP2D6, PGP>3A4)

Consider starting with a decreased clozapine dose or select an alternate agent.

Clozapine therapeutic drug 2, 3 monitoring is recommended.

Use combination with caution, and monitor for possible olanzapine-related toxicity.

Monitor and titrate dose according to clinical response.

DAAs inhibit both CYP3A4 and PGP, and clinically significant interaction, although unlikely, cannot be ruled out. Use combination with caution, and monitor for possible 4 paliperidone-related toxicity .

Use combination with caution, and monitor for quetiapinerelated toxicity (excessive sedation). Consider starting with a decreased quetiapine dose or 5 select an alternate agent .

Unlike its active metabolite paliperidone, risperidone is primarily metabolized by

toxicity (bone marrow suppression, generalized seizures, severe sedation, confusion and delirium).

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIPSYCHOTICS

77

Boulton DW, DeVane CL, Liston HL, et al. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci 2002 May 31;71(2):163-9.

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. Gov't] 1997 Nov;44(5):439-46.

Spina E, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review.

Basic Clin Pharmacol Toxicol 2007;100:4-22.

1.

2.

3.

References:

Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, UGT = Uridine 5'-diphospho-glucuronosyltransferases

related toxicity (excessive sedation). Consider starting with a decreased quetiapine dose or 5 select an alternate agent .

Risperidone Unlike its active metabolite Potential for â&#x2020;&#x2018; 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 www.hivclinic.ca August 28, 2012 page 1 of 2 possible risperidone-related toxicity.

Ziprasidone (CYP3A4>1A2) Although clinically significant Potential for â&#x2020;&#x2018; ziprasidone Minor CYP dependant pathway interaction unlikely, use concentrations.

3 (33%). combination with caution, and monitor for possible ziprasidone6 related toxicity (QTc).

78

INTERACTIONS WITH OTHER DRUG CLASSES - ANTIPSYCHOTICS

Spina E, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review.

Basic Clin Pharmacol Toxicol 2007;100:4-22.

English BA, Dortch M, Ereshefsky L, et al. Clinically Significant Psychotropic Drug-Drug Interactions in the Primary Care Setting. Curr Psychiatry Rep 2012 Jun 17.

AstraZeneca Canada Inc. Seroquel (quetiapine) Product Monograph. Mississauga, ON 2012.

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.

3.

4.

5.

6.

Gov't] 1997 Nov;44(5):439-46.

INTERACTIONS WITH OTHER DRUG CLASSES - BENZODIAZEPINES

79

Potential for ↑ benzodiazepine concentrations.

Potential for ↑ benzodiazepine concentrations.

Buspirone (CYP3A4)

Diazepam (CYP2C19>3A)

Midazolam Cmax ↑ 177% and AUC ↑ 430% ↑ AUC0-24 h with

Potential for ↑ benzodiazepine concentrations.

Alprazolam (CYP3A4)

Midazolam – oral (3A4)

Known or Potential Interactions with DAAs No interaction expected based on known pharmacologic characteristics.

Drug (route of metabolism) Lorazepam, oxazepam, temazepam (UGT)

Preferred agents due to lower interaction potential with DAAs. Monitor and titrate dose according to clinical response.

Use combination with caution, and monitor for benzodiazepine-related toxicity. Consider an alternate agent such as lorazepam, oxazepam or temazepam.

Use combination with caution, and monitor for benzodiazepine-related toxicity. Consider an alternate agent such as lorazepam, oxazepam or temazepam.

Use combination with caution, and monitor for benzodiazepine-related toxicity. Consider starting with a decreased benzodiazepine dose or select an alternate agent such as lorazepam, oxazepam or temazepam.

Oral midazolam is contraindicated with boceprevir and telaprevir.

Comments

Drug Interactions Between Directly Acting Antivirals (DAAs) and Benzodiazepines

80

INTERACTIONS WITH OTHER DRUG CLASSES - BENZODIAZEPINES

Zolpidem (CYP3A >> 2C9, 1A2 >> 2D6, 2C19)

Triazolam (3A4)

Midazolam – IV (3A4)

Midazolam – oral (3A4)

5

Zolpidem AUC ↓ 47% with

Potential for ↑ benzodiazepine 4 concentrations Potential for ↑/↓ benzodiazepine concentrations.

No interaction studies have been done with boceprevir and intravenous benzodiazepines (alprazolam, midazolam, triazolam).

Midazolam AUC ↑ 8.96-fold and 2 Cmax ↑ 2.86-fold with telaprevir Midazolam AUC ↑ 3.4 fold with 2 telaprevir

Midazolam Cmax ↑ 177% and AUC ↑ 430% ↑ AUC0-24 h with 1 boceprevir

Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of boceprevir with intravenous benzodiazepines. Dose adjustment of the benzodiazepine should be 4 considered .

Triazolam is contraindicated with boceprevir and telaprevir.

Use combination with caution, and monitor for benzodiazepine-related efficacy or toxicity. Consider an alternate agent such as lorazepam, oxazepam or temazepam.

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 3 prolonged sedation .

lorazepam, oxazepam or temazepam.

Oral midazolam is contraindicated with boceprevir and telaprevir.

INTERACTIONS WITH OTHER DRUG CLASSES - BENZODIAZEPINES

81

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].

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

2.

3.

References: 1.

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.

Legend: CYP = cytochrome P450, P-gp = p-glycoprotein, UGT = Uridine 5'-diphospho-glucuronosyltransferases

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. when coadministeringpage with1 telaprevir. www.hivclinic.ca August 28, 2012 of 2 Use combination with caution, and Zopiclone (3A4> 2C8, 2C9) Potential for ↑ benzodiazepine monitor for benzodiazepine-related concentrations. efficacy or toxicity. Consider an alternate agent such as lorazepam, oxazepam or temazepam.

82

INTERACTIONS WITH OTHER DRUG CLASSES - BENZODIAZEPINES

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

Merck Canada Inc. Victrelis (boceprevir) Product Monograph. Kirkland, QC July 27, 2011.

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.

4.

5.

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].

3.

2.

ADDITIONAL INFORMATION Antiretroviral Treatment Options for Patients on DAAs �������������84

ANTIRETROVIRAL TREATMENT OPTIONS FOR PATIENTS ON DAAS - SUMMARY

84

NRTIs

Maraviroc

InSTIs

NNRTIs

PIs

Dose ↑ to 1125 mg q8h with efavirenz3, 8 Etravirine OK10 Rilpivirine OK*10

Avoid efavirenz6, 7

Etravirine (?)9

No data

Avoid AZT (anemia)

Tenofovir OK6, 14

Elvitegravir/cobicistat: no data but potential for interaction based on pharmacokinetic properties.13 Avoid combination until further data available.

No data potential ↓/↑ maraviroc; potential benefit on fibrosis?

Raltegravir OK11, 12

Telaprevir (Incivek®) 750 mg po q8h with food Avoid darunavir/ritonavir, fosamprenavir/ritonavir, lopinavir/ritonavir3, 4 Atazanavir/ritonavir OK3

Boceprevir (Victrelis®) 800 mg q8h with food Not recommended with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir1, 2 Possible atazanavir/ritonavir?5

Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir

85

ANTIRETROVIRAL TREATMENT OPTIONS FOR PATIENTS ON DAAS - SUMMARY

Avoid AZT (anemia)

Tenofovir OK6, 14

= avoid combination

= caution/dose adjustment

= combination OK

Schering Corporation a subsidiary of Merck & Co. Victrelis (boceprevir) prescribing information. Whitehouse Station, NJ April, 2012.

Van Heeswijk RPG, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers [abstract 119]. 18th Conference on Retroviruses and Opportunistic Infections, Feb 27-Mar 2, 2011, Boston, USA.

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

European Medicines Agency. Questions and answers on drug interactions between Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitors. 2012 February 16. Report No.: EMA/CHMP/117973/2012.

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.

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

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.

2.

3.

4.

5.

6.

7.

8.

References: 1.

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] 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle, WA.

Key:

*caution in patients on other drugs which may â&#x2020;&#x2018; rilpivirine concentrations, prolong QTc, or who are at risk for Torsade de Pointes

NRTIs

ANTIRETROVIRAL TREATMENT OPTIONS FOR PATIENTS ON DAAS - SUMMARY

86

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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.

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GLOSSARY Glossary �����������������������������������������������������������������������������������������88

ALP

alkaline phosphatase

ALT

alanine aminotransferase

AST:

aspartate aminotransferase

AUC

area under the curve

BID

twice a day

BOC

boceprevir

CBC/diff

complete blood count/differential

CI

confidence interval

CK

creatine kinase

Cmax

maximum (peak) concentration

Cmin

minimum (trough) concentration

CNS

central nervous system

CSF

cerebrospinal fluid

Css

concentration at steady-state

CYP

hepatic cytochrome P450 isoenzyme

D/C

discontinue

ESRD

end stage renal disease

GGT

gamma glutamyl transferase

GT

glucuronyl transferase

HCV

hepatitis C virus

HCV-RNA

hepatitis C viral load

Hgb

hemoglobin

hs

at bedtime

IV

intravenous

LFTs

liver function tests

MD

medical doctor

mcg

micrograms

mg

milligrams

PEG-IFN

pegylated interferon

PI

protease inhibitor

GLOSSARY

88

89

PK

pharmacokinetics

po

by mouth

PR

partial response

prn

as required

q8h

every 8 hours

QID

four times daily

RBV

ribavirin

RVR

rapid virologic response

SC

subcutaneous

SJS

Stevens-Johnson Syndrome

ss

steady-state

SVR

sustained virologic response

Sx

symptoms

T½

half-life

TID

three times daily

Tmax

time to reach maximum concentration

TVR

telaprevir

ULN

upper limit of normal

Vd

volume of distribution

wks

weeks

GLOSSARY

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Copyright 2013, A. Tseng