Drug Drug Interactions with VICTRELIS® (boceprevir) Informative ...

Updated version: 

March 2013 

Drug Drug Interactions 

with VICTRELIS ® (boceprevir) 

This document was developped in collaboration with Prof. Isabelle Colle 

The classifications in this document are a guideline only based on the current information available on March 2013. The relevance of a particular drug 

interaction to a specific patient is difficult to determine using this tool alone given the large number of variables that may apply. 

Any therapeutic decision remains the responsibility of the prescribing physician. Please consult the scientific product circulars of any of the products mentioned 

in this document before prescribing. 

Informative document 

March 2013 

For an electronic version of this document, 

please consult www.victrelis.be

2 

Table of contents 

Class of drug Page number 

A2RB (Angiotensin 2 Receptor Blockers) 14 

ACEI (Angiotensin Converting Enzyme Inhibitors) 13 

Analgesics 4 

Anti Hep.B/Hep.C drugs 31 

Antiarrhythmics 6 

Antibiotics 25 

Anticoagulants 17 

Anticonvulsants 7 

Antidepressants 9-10 

Antifungals 26 

Antimigraine 8 

Antipsychotics 8 

Antiretrovirals 29-30 

Antivirals 29 

Anxiolytics / Sedatives/Hypnotics 11-12 

Asthma medication 22 

Beta Blockers 16 

Calcium channel blockers 15 

Contraceptives 27 

Diuretics 15 

Erectile dysfunction medication 28 

Fibrates 17 

Gastro-intestinal medication 20 

Hypoglycaemic Agents 21 

Immunosuppressants 23-24 

Opioid Substitution Therapy 5 

Statins 18-19 

Other Drugs Rifampicin 

Alfuzosin 

Colchicine 

Grapefruit Juice 

32

3 

Legend 

No clinically significant interaction expected as defined by the 

Liverpool University website (www.hep-druginteractions.org) 

Potential interaction (may require close monitoring, alteration 

of drug dosage or timing of administration) as defined by the 


These drugs should not be coadministered as defined by the 


No information available 

* Information obtained from www.hep-druginteractions.org 

† Information provided by the VICTRELIS ® (boceprevir) 

Scientific leaflet 

$ Drug’s Product Information (Published in MIMs Annual 2011) 

[drug] Drug concentration 

¥ Non exhaustive list of commercial names 

Association of several molecules 

k Information from the publication: Kiser et al., Hepatology 2012 

a Data from abstracts (complete reference at the bottom of the page) 

b Information from the publication: Burger et al., Journal of Hepatology 2013 

AUC Area Under the Curve 

BOC Boceprevir 

DAA Direct Acting Antiviral Agent

Drug to Drug Interactions with VICTRELIS ® (boceprevir) 

Class of 

Drug 

4 

ANALGESICS 

Substrate 

class 

Opioid 

NSAID 

Narcotic 

Drug Brand name (non 

exhaustive list, 

generics not listed). 

For a complete list, 

please consult 

www.bcfi.be or 

www.cbip.be 

Codeine 

Morphine 

Fentanyl 

Ibuprofen 

Paracetamol 

Tramadol 

Dafalgan Codeine ® , 

Paracod Mylan ® , Panadol 

Codeine ® , Algocod ® , 

Nevrine Codeine ® 

MS Direct ® , Oramorph ® , 

MS Contin ® , Morphine HCL 

Sterop ® 

Durogesic ® , Matrifen ® , 

Instanyl ® , Abstral ® 

Nurofen ® , Brufen ® , 

Buprophar ® , Dolofin ® , 

Ibumed ® , Malafene ® , ¥ 

Dafalgan ® , Dolprone ® , 

Panadol ® , Perdolan ® , 

Mersyndol ® , Lemsip ® , ¥ 

Contramal ® , Dolzam ® , 

Tradonal ® , Tramium ® , 

Zaldiar ® , Pontalsic ® 

Liverpool University (*) / 

Extra-information 

Potential 

Interaction 

Not Clinically 

Significant 

Potential 

Interaction 


Significant 


Significant 

Potential 

Interaction 

May 

[codeine]* 

Could 

morphine 

exposure* 

Could 

fentanyl 

exposure* 

May 

[tramadol]* 

Recommendations SmPC/ 

Scientific Literature 

Monitor carefully for 

an extended period 

of time. Dosage 

adjustment should be 

made if warranted* 

CYP pathway(s) 

(www.cbip/bcfi.be) 

(www.mims.com.au) 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP3A4 / CYP2D6 Substrate 

CYP2D6 

CYP3A4 Substrate 

CYP2C9 

CYP1A2 / CYP2E1 / 

CYP3A4 

Substrate 

CYP2D6 / CYP3A4 Substrate

Class of 


5 

OPIOID SUBSTITUTION 

THERAPy 

Substrate 

class 







www.cbip.be 

Methadone Mephenon ® Potential 

Interaction 

Buprenorphine Subutex ® , Suboxone ® Not clinically 

significant 

Naloxone Valtran ® , Tinalox ® , 

Targinact ® , Suboxone ® 



No information 

available 

R-methadone 

AUC, Cmax and 

Cmin by 15%, 

10% and 19% 

S-methadone 

AUC , Cmax and 

Cmin by 22%, 

17% and 26% † 

Buprenorphine 

AUC, Cmax 

and Cmin, by 

19%, 18% and 

31%. 

Naloxone AUC 

and Cmax by 

33% and 9% † 



Individual patients 

may require additional 

titration of their 

methadone dosage 

when BOC is started 

or stopped to ensure 

clinical effect of 

methadone † 

Caution should 

be exercised with 

medicines 

known to prolong the 

QT interval such as 

methadone* 

No dose adjustment 

of buprenorphine/ 

naloxone or BOC is 

recommended. Patients 

should be monitored 

for signs of opiate 

toxicity associated with 

buprenorphine † 

smpc: Individual patients may 

require additional titration of 

their methadone dosage when 

BOC is started or stopped 

to ensure clinical effect of 

methadone 

smpc: No dose adjustment 

of buprenorphine/naloxone or 

BOC is recommended. Patients 

should be monitored for signs 

of opiate toxicity associated 

with buprenorphine 




CYP3A4 / CYP2D6 / 

CYP1A2 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Substrate + 

Inhibitor 


Inhibitor

Class of 


6 

ANTIARRHyTHMICS 

Substrate 

class 







www.cbip.be 

Amiodarone Cordarone ® Potential 

Interaction 

Sotalol Sotalex ® Potential 

Interaction 

Digoxin Lanoxin ® Potential 

Interaction 

Lidocaine Xylocard ® Potential 

Interaction 

Flecainide Tambocor ® , Apocard ® Potential 

Interaction 



May 

[amiodarone]* 

AUC and Cmax of 

Digoxin by 19% 

and 18% b 

May 

[lidocaine]* 



Use with caution. 

Monitor concentrations 

of amiodarone* 

Caution should 

be exercised with 

medicines known to 

prolong the QT interval* 


of digoxin or BOC is 

recommended. Patients 

receiving digoxin 


appropriately † 

Use with caution - 

Clinical monitoring is 

recommended* 

May [flecainide]* Monitor the plasma 

concentration of 

Flecainide. Use with 

caution* 

smpc: A clinical drug 

interaction study with digoxin 

demonstrated that BOC is a 

mild P-gp inhibitor in vivo, 

increasing digoxin exposure 

by 19%. An increase in plasma 

concentrations of substrates 

of the P-gp efflux transporter, 

such as digoxin or dabigatran, 

should be anticipated. No 

dose adjustment of digoxin or 

BOC is recommended. Patients 

receiving digoxin should be 

monitored appropriately 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP3A4 Inhibitor + 

Substrate 

CYP3A4 Substrate of 

P-gp 

CYP2D6 Substrate

Class of 


7 

ANTICONVULSANTS 

Substrate 

class 







www.cbip.be 



Carbamazepine Tegretol ® Coadministration 

contraindicated 

Gabapentin Neurontin ® Not Clinically 

Significant 

Lamotrigrine Lamictal ® , Lambipol ® Not Clinically 

Significant 

Levetiracetam Keppra ® Not Clinically 

Significant 

Phenobarbital Gardenal ® , Vethoine ® Coadministration 


Phenytoin Diphantoine ® , 

Epanutin ® , Vethoine ® 

Coadministration 


Valproate Convulex ® , Depakine ® Not Clinically 

Significant 



The concomitant 

use of BOC with 

carbamazepine is not 

recommended † 

The concomitant use of 

BOC with phenobarbital 

is not recommended † 

The concomitant use of 

BOC with phenytoin is 

not recommended † 

smpc: The concomitant use of 

BOC with carbamazepine is not 

recommended. May significantly 

reduce the plasma exposure of 

BOC † 

smpc: The concomitant use of 

BOC with phenobarbital is not 



BOC † 

smpc: The concomitant use 

of BOC with phenytoin is not 



BOC † 




CYP3A4 / CYP1A2 / 

CYP2C9 

CYP3A4 / CYP2C19 / 

CYP1A2 / CYP2C9 


CYP1A2 / CYP2C9 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Inducer + 

Substrate 

Inducer + 

Substrate 

Inducer + 

Substrate

Class of 


8 

ANTIMIGRAINE 

ANTIPSyCHOTICS 

Substrate 

class 







www.cbip.be 

Dihydroergotamine 

‡ Recommendation based on Pr. Colle experience. 

Dihydergot ® , Diergo ® , 

Dystonal ® 








CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Contraindicated † Contraindicated † Do not co-administer † CYP3A4 Substrate 

Ergotamine Cafergot ® Contraindicated † Contraindicated † Do not co-administer † CYP3A4 Substrate 

Naratriptan Naramig ® No information 

available 

Sumatriptan Imitrex ® No information 

available 

Rizatriptan Maxalt ® Not Clinically 

Significant 

Zolmitriptan Zomig ® No information 

available 

Clozapine Leponex ® Potential 

Interaction 

Olanzapine Zyprexa ® , ZypAdhera ® Not Clinically 

Significant 

Quetiapine Seroquel ® Potential 

Interaction 

Aripiprazole Abilify ® Potential 

Interaction 

May 

[quetiapine]* 

May 

[aripiprazole]* 

Follow plasma 

concentration of 

clozapine ‡ 

Pimozide Orap ® Contraindicated † Contraindicated † Do not co-administer † 

Risperidone Risperdal ® Potential 

Interaction 

May 

[risperidone]* 

Kiser et al., hepatology 2012: 

When available and when 

therapeutic concentrations have 

been established (e.g., clozapine 

plasma concentration >350 ng/ 

mL), therapeutic drug 

monitoring of the antipsychotic 

may have clinical utility 


quetiapine use should be avoided 

in patients treated with BOC 

Use with caution* Kiser et al., hepatology 2012: 

aripiprazole dosage should be 

empirically reduced by half when 

BOC is initiated 

CYP1A2 


CYP3A4 

CYP1A2 / CYP2D6 

Substrate 

CYP3A4 Substrate + 

Inhibitor 

CYP2D6 / CYP3A4 Substrate 

CYP2D6

Class of 


9 

ANTIDEPRESSANTS 

Substrate 

class 

SSRI 







www.cbip.be 

Bupropion Zyban ® , Wellbutrin ® Potential 

Interaction 

St John’s Wort Milperinol ® , Hyperiplant ® , 

Perika ® , Zibrine ® , Kira ® 





Citalopram Cipramil ® Potential 

Interaction 

Escitalopram Sipralexa ® Potential 

Interaction 

Paroxetine Seroxat ® Potential 

Interaction 

May 

[bupropion]* 

Citalopram has 

been found to 

cause a dosedependant 

prolongation of 

the QT interval* 

BOC AUC 9% 

BOC Cmax 2% 

escitalopram AUC 

21% 

escitalopram Cmax 

19%* 

May 

[paroxetine], 

clinically 

significant effect 

on BOC exposure 

unlikely* 






CYP2B6 / CYP2D6 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP3A4 Induce 

Caution is warranted* CYP2C19 / CYP2D6 / 

CYP3A4 


of escitalopram is 

anticipated, but doses 

may need to be adjusted 

(increased) based on 

clinical effect † . 

SSRI have a wide 

therapeutic index, but 

dosis may need to be 

adjusted when combined 

with BOC* 

smpc: Exposure of escitalopram 

was slightly decreased when 

co-administered with BOC. No 

dose adjustment of escitalopram is 

anticipated, but doses may need 

to be adjusted (increased) based 

on clinical effect. Kiser et. al, 

hepatology 2012 

Escitalopram AUC by 21%, 

in t1/2 from 31 to 22 hours 

CYP2C19 / CYP2D6 / 

CYP3A4 

CYP2D6 

Substrate

Class of 


10 

ANTIDEPRESSANTS 

Substrate 

class 

SSRI 

SNRI 

5HT 

antagonist 







www.cbip.be 

Sertraline Serlain ® Potential 

Interaction 

Fluoxetine Prozac ® , Fluoxone ® , 

Fontex ® 



Potential 

Interaction 

Fluvoxamine Floxyfral ® Potential 

Interaction 

Duloxetine Cymbalta ® Potential 

Interaction 

Venlafaxine Effexor ® , Venlasand ® Potential 

Interaction 

Mirtazapine Remergon ® Potential 

Interaction 

May [Sertaline], 

clinically 

significant effect 

on BOC exposure 

unlikely* 

Could BOC 

exposure* 

Duloxetine clearance 

reduced in 

case of moderate 

hepatic disease, 

use with caution* 

May 

[venlafaxine]* 

May 

[mirtazapine]* 



Cautions in case of hepatic 

impairment. 

Sertaline should not be 

used in patients with hepatic 

impairment* 

Lower or less frequent 

Fluoxetine dose to be considered 

in case of hepatic 

insufficiency* 




CYP2D6 

CYP2C9 / CYP2C19 / 

CYP2D6 / CYP3A4 



CYP3A4 

Use with caution* CYP1A2 / CYP2D6 

50% dose reduction required 

for mild to moderate 

hepatic insufficiency. More 

than 50% reduction for 

patients with cirrhosis. $ 

CYP2D6, CYP3A4 


CYP3A4 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Inhibitor 

Inhibitor 

Substrate

Class of 


11 

ANxIOLyTICS / SEDATIVES/HyPNOTICS 

Substrate 

class 







www.cbip.be 

Alprazolam Xanax ® , Alpraz ® Potential 

Interaction 

Diazepam Valium ® Potential 

Interaction 

Lorazepam Temesta ® , Lorazetop ® , 

Serenase ® 




Significant 

Midazolam IV Dormicum ® Potential 

Interaction 

May 

[alprazolam]* 



Close monitoring, lower 

dose of alprazolam should 

be considered* 

May [diazepam]* Use with caution as there 

is an increased risk of 

prolonged sedation and 

respiratory depression* 

May 

[midazolam], AUC 

increase by 3,4 

fold, Cmax Status 

Quo* 

Lower dose of midazolam 

IV by 50% (by half)* Close 

clinical monitoring for 

respiratory depression and/ 

or prolonged sedation 

should be exercised during 

co-administration of BOC 

with intravenous midazolam. 

Dose adjustment of the 

benzodiazepine should be 

considered † . 

smpc: Close clinical monitoring 

for respiratory depression and/ 

or prolonged sedation should be 

exercised during co-administration 

of BOC with intravenous 

midazolam. Dose adjustment of 

the benzodiazepine should be 

considered 


Oral midazolam should not be 

used with BOC, but halving the 

dose of IV midazolam could be 

considered with monitoring for 

therapeutic and toxic effects 

Midazolam oral Dormicum ® Contraindicated † Contraindicated † Do not co-administer † Kiser et al., hepatology 2012: 

BOC increases the AUC of oral 

0-12 

midazolam by 430% (5,3 fold) 

Oxazepam Oxazepam generics Not Clinically 

Significant 

Triazolam IV Halcion ® Coadministration 


May [triazolam] Close clinical monitoring 

for respiratory depression 

and/or prolonged sedation 

should be exercised during 

co-administration of BOC 

with intravenous triazolam. 

Dose adjustment of the 

benzodiazepine should be 

considered † 

smpc: Close clinical monitoring 

for respiratory depression and/ 

or prolonged sedation should be 


of BOC with intravenous 

triazolam. Dose adjustment of 

the benzodiazepine should be 

considered 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 



CYP3A4 

Substrate 




CYP3A4 Substrate

Class of 


ANxIOLyTICS / 

SEDATIVES/ 

HyPNOTICS 

12 

Substrate 

class 







www.cbip.be 








CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Triazolam oral Halcion ® Contraindicated † Contraindicated † Do not co-administer † CYP3A4 Substrate 

Trazodone Nestrolan ® , Trazolan ® Potential 

Interaction 

Zolpidem Stilnoct ® , Zolpitop ® Potential 

Interaction 

May 

[trazodone]* 

Use with caution and 

consider a lower dose of 

trazodone* 

Kiser et al., hepatology 

2012: With the HIV protease 

inhibitor, ritonavir, trazodone 

exposures are increased with 

nausea, dizziness, hypotension, 

and syncope 

May [zolpidem]^ CYP1A2 / CYP3A4 Substrate

Class of 


13 

ACEI (ANGIOTENSIN CONVERTING 

ENzyME INHIBITORS) 

Substrate 

class 







www.cbip.be 



Captopril Capoten ® No information 

available but 

interaction 

unlikely 

Enalapril Renitec ® , Co-Renitec ® , 

Zanicombo ® , Lercaprel ® 


available but 

interaction 

unlikely 

Fosinopril Fosinil ® No information 

available but 

interaction 

unlikely 

Lisinopril Zestril ® , Zestoretic ® No information 

available but 

interaction 

unlikely 

Quinapril Accupril ® , Accuretic ® No information 

available but 

interaction 

unlikely 

Ramipril Tritace ® , Tazko ® , Tritazide ® No information 

available but 

interaction 

unlikely 




CYP enzymes are not involved 

in the metabolism of ace 

inhibitors, thus CYP-mediated 

drug interactions with these 

classes of antihypertensives 

and BOC are unlikely 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer

Class of 


A2RB (ANGIOTENSIN 2 RECEPTOR 

BLOCKERS) 

14 

Substrate 

class 







www.cbip.be 



Candesartan Atacand ® , Atacand Plus ® No information 

available but 

interaction 

unlikely 

Eprosartan Teveten ® , Teveten Plus ® No information 

available but 

interaction 

unlikely 

Irbesartan Aprovel ® , Co-Aprovel ® No information 

available 

Olmesartan Olmetec ® , Belsar ® , 

Olmetec Plus ® , Belsar 

Plus ® , Forzaten ® , Forzaten 

/ HCT ® , Sevikar ® , Sevikar 

/ HCT ® 

Telmisartan Micardis ® , Kinzalmono ® , 

Micardis Plus ® , 

Kinzalkomb ® , Twynsta ® 

Losartan Cozaar ® , Loortan ® , Cozaar 

Plus ® , Loortan Plus ® 

Valsartan Diovan ® , Co-Diovane ® , 

Exforge ® , Exforge HCT ® 


available but 

interaction 

unlikely 


available but 

interaction 

unlikely 

Not clinically 

significant 


available but 

interaction 

unlikely 



Dose reduction could 

be considered for 

irbesartan in patients 

initiating BOC k 

Dose reduction could 


losartan in patients 

initiating BOC k 


2012: contribution of CYP3A4 

in the metabolism of A2RB 

irbesartan and losartan. Dose 

reduction could be considered 

for irbesartan and losartan in 

patients initiating BOC 




CYP2C9 

CYP2C9 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer

Class of 


15 

DIURETICS 

CALCIUM CHANNEL 

BLOCKERS 

Substrate 

class 







www.cbip.be 

Furosemide Lasix ® , Frusamil ® Not Clinically 

Significant 

Hydrochlorothiazide 

Emcoretic ® , 

® , ¥ 

Olmetec Plus 

Indapamide Fludex ® , Coversyl Plus ® , 

Preterax ® , Coperindo ® , 

Perindapam ® 




available but interaction 

unlikely 


available but interaction 

unlikely 

Spironolactone Aldactone ® , Aldactazine ® Not Clinically 

Significant 

Amlodipine Amlor ® , Amlogal ®, ¥ Potential 

Interaction 

Diltiazem Tildiem ® , Progor ® Potential 

Interaction 

Felodipine Plendil ® , Logimat ® , 

Tazko ® 

Potential 

Interaction 

Nifedipine Adalat ® , Hypan ® , Tenif ® Potential 

Interaction 

Verapamil Isoptine ® , Lodixal ® Potential 

Interaction 

May 

[amlodipine]* 

May [diltiazem] 

and [BOC]* 

May 

[felodipine]* 

May 

[nifedipine]* 

May [verapamil] 

and [BOC]* 



Clinical monitoring 

recommended* 


recommended* 


recommended* 

Close clinical monitoring 

recommended* 

CYP enzymes are not involved 

in the metabolism of diuretics, 

thus CYP-mediated 

drug interactions with these 

classes of antihypertensives 

and BOC are unlikely k 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 


Inhibitor 

(weak)* 

CYP3A4 Inhibitor / 

Substrate 



CYP1A2 / CYP3A4 Inhibitor / 

Substrate

Class of 


16 

BETA BLOCKERS 

Substrate 

class 







www.cbip.be 

Atenolol Tenormine ® , 

Tenoretic ® , Tenif ® 

Bisoprolol Emconcor ® , Isoten ® , 

Emcoretic ® , Lodoz ® , 

Maxsoten ® 




Significant 


available 

Carvedilol No information 

available 

Nebivolol Tyskiten ® , Nobiten ® , 

Hypoloc ® , Nobiretic ® 

Potential 

Interaction 

Esmolol Brevibloc ® No information 

available 

Metoprolol Seloken ® , Lopresor ® , 

Selozok ® , Logroton 

Divitabs ® , Zok-Zid ® , 

Logimat ® 

Potential 

Interaction 

Pindolol Visken ® , Viskaldix ® No information 

available 

Propanolol Inderal ® Not Clinically 

Significant 



Dose reductions could 


carvedilol in patients 

initiating BOCk Dose reductions could 


nebivolol in patients 

initiating BOCk . 

Nebivolol UE SmPC: 

contraindication in 

patients with hepatic 

insufficiency or impaired 

liver function* 

In patients with severe 

hepatic dysfunction, 

a reduction in dosage 

may be necessary* 


dose reductions could be 

considered for carvedilol and 

nebivolol in patients initiating 

BOC k 




CYP2C9 / CYP 2D6 

CYP2D6 

CYP2D6 

CYP2D6 


CYP2D6 / CYP3A4 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Substrate

Class of 


17 

ANTICOAGULANTS 

FIBRATES 

Substrate 

class 







www.cbip.be 

Dabigatran Pradaxa ® Potential 

Interaction 



Dalteparin Fragmin ® No information 

available 

Enoxaparin Clexane ® No information 

available 

Warfarin Marevan ® Potential 

Interaction 

Fenofibrate Lipanthyl ® , Lipanthylnano ® , 

Fenogal ® , Fenosup ® 


Significant 

Could 

[Dabigatran] * 


may alter 

[warfarin] * 



No dose adjustment of 

dabigatran is recommended. 

Patients 

receiving dabigatran 


appropriately † 

smpc: An increase in plasma 

concentrations of substrates 

of the P-gp efflux transporter, 

such as digoxin or dabigatran, 

should be anticipated. No dose 

adjustment of dabigatran is recommended. 

Patients receiving 

dabigatran should be monitored 

appropriately 




Monitor INR closely* CYP1A2 / CYP2C9 / 

CYP2C19 / CYP3A4 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

BOC 

inhibitor of 

P-gp

Class of 


18 

STATINS 

Substrate 

class 







www.cbip.be 

Atorvastatin Lipitor ® , Totalip ® , 

Atorstatineg ® , 

Atorvastacalc ® 



Potential 

Interaction 

BOC AUC 5%, 

BOC Cmax 4%, 

Atorvastatin AUC 

and Cmax by 

130% and 166% † 



Exposure to atorvastatin 

was increased when 

administered with BOC. 

When co-administration 

is required, starting 

with the lowest possible 

dose of atorvastatin 

should be considered 

with titration up to 

desired clinical effect 

while monitoring 

for safety, without 

exceeding a daily dose 

of 20 mg. 

For patients currently 

taking atorvastatin, the 

dose of atorvastatin 

should not exceed a 

daily dose of 20 mg 

during co-administration 

with BOC † 

smpc: Exposure to atorvastatin 

was increased when 

administered with BOC. When 

co-administration is required, 

starting with the lowest possible 

dose of atorvastatin should be 

considered with titration up 

to desired clinical effect while 

monitoring for safety, without 

exceeding a daily dose of 20 

mg. For patients currently 

taking atorvastatin, the dose of 

atorvastatin should not exceed 

a daily dose of 20 mg during 

co-administration with BOC. 


the lowest dose of atorvastatin 

should be used and then 

titrated to effect. Burger et al., 

Journal of hepatology 2013: 

Statin level 2,3 times and 

this interaction appears to be 

manageable by starting with a 

low dose of atorvastatin 

(10 mg). An alternative option 

might be pravastatin as this 

statin is not a CYP substrate. 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 


Inhibitor

Class of 


19 

STATINS 

Substrate 

class 







www.cbip.be 



Fluvastatin Lescol ® No information 

available 

Pravastatin Prareduct ® , Pravasine ® Potential 

Interaction 

Rosuvastatin Crestor ® Potential 

Interaction 

Simvastatin Zocor ® , Cholemed ® , 

Inegy ® 

BOC AUC 6%, 

BOC Cmax 7%, 

pravastatin AUC 

and Cmax by 

63% and 49% † 

Effect on 

[rosuvastatin] 

unclear* 



Treatment with 

pravastatin can 

be initiated at the 

recommended dose 

when co-administered 

with BOC. Close 

clinical monitoring is 

warranted. † 

Rosuvastatin 

contraindicated in 

patients with active 

liver disease, Cautions 

in patients who have 

a history of liver 

disease*. Could be 

considered for use in 

combination with BOC, 

increased monitoring for 

symptoms of myopathy 

may be necessary k 

smpc: Concomitant 

administration of pravastatin 

with BOC increased exposure 

to pravastatin. Treatment with 

pravastatin can be initiated 

at the recommended dose 

when co-administered with 

BOC. Close clinical monitoring 

is warranted. Burger et al., 

Journal of hepatology 2013: 

An alternative option (to other 

statins) might be pravastatin 

as this statin is not a CYP 

substrate. Pravastatin levels 

were marginally increased when 

combined with BOC (1,5 fold), 

probably caused by inhibition of 

the organic anion-transporting 

polypeptide (OATP) 1B1. 


2012: could be considered 

for use in combination with 

BOC, increased monitoring for 

symptoms of myopathy may be 

necessary 




CYP2C9 

CYP2C9 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Contraindicated † Contraindicated † Do not co-administer † CYP3A4 Substrate

Class of 


20 

GASTROINTESTINAL MEDICATION 

Substrate 

class 







www.cbip.be 

Antiacids Algeldrate Maalox ® Not Clinically 

Significant 

Alginic Acid Gaviscon ® Not Clinically 

Significant 

Magaldrate Riopan ® Not Clinically 

Significant 

H 2 

Antagonists 

Cimetidine Cimetidine generics Potential 

Interaction 

Ranitidine Zantac ® , Acidine ® Potential 

Interaction 

Anti-emetic Domperidone Motilium ® , Zilium ® , 

Oroperidys ® , Touristil ® 

Metoclopramide 

Primperan ® , Dibertil ® , 

Migpriv ® 



Potential 

Interaction 

Potential 

Interaction 

PPIs Esomeprazole Nexium ® , Vimovo ® Not Clinically 

Significant 

Lansoprazole Dakar ® Potential 

Interaction 

Opioide 

derivative 

Omeprazole Losec ® , Sedacid ® , 

Acidcare ® 

Pantoprazole Pantozol ® , Zurcale ® , 

Pantomed ® , Zurcamed ® , 

Pantogastrix ® , Maalox 

Control ® , Yoevid ® 


Significant 


Significant 

Rabeprazole Pariet ® No information 

available 

Loperamide Immodium ® , Transityl ® Potential 

Interaction 





(www.mims.com. 

au) 

May [BOC]* CYP1A2 / CYP2C9 / 


CYP3A4 

May [BOC]* 

May 

[domperidone]* 

If co-administration is judged strictly 

necessary, clinical monitoring including 

ECG assessments is recommended* 

Reduced dosage of Metoclopramide 

recommended in patients with hepatic 

insufficiency* 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Inhibitor 


CYP2C19 / CYP3A4 Substrate 

May [BOC]* CYP2C19 / CYP3A4 Substrate 

BOC AUC and 

Cmax by 8% 

and 6%, BOC 

Cmin by 17% 

Omeprazole 

AUC, Cmax and 

C8h by 6%, 

3% and 12% † 

May 

[loperamide]* 


omeprazole or BOC is 


Use with caution in patients with 

hepatic impairment as reduced first 

pass metabolism may result in relative 

overdose leading to CNS toxicity* 

smpc: No dose adjustment CYP2C19 

of omeprazole or BOC is 

recommended. de Kanter et 

al., J antimicrob chemother 

2013: Omeprazole did not 

have a clinically significant 

effect on BOC exposure, 

and BOC did not 3affect 

omeprazole exposure 

CYP2C19 

CYP2C19

Class of 


21 

HyPOGLyCAEMIC AGENTS 

Substrate 

class 

Biguanide 

Sulfonyl 

Ureas 

DPP4 

Inhibitors 

Insulins 







www.cbip.be 

Metformin Glucophage ® , Metformax 

® , Glucovance ® , 

Eucreas ® , Janumet ® 

Glibenclamide Daonil ® , Euglucon ® , 

Glucovance ® 



Potential 

Interaction 


available 

Gliclazide Uni Diamicron ® No information 

available 

Glimepiride Amarylle ® No information 

available 

Glipizide Glibenese ® , Minidiab ® No information 

available 

Sitagliptin Januvia ® , Janumet ® Potential 

Interaction 

Vildagliptin Galvus ® , Eucreas ® No information 

available 


available but 

interaction 

unlikely 

May 

[sitagliptin]* 

Probably no 

interactions 

as insulin not 

metabolised by 

the liver 



Metformin contraindicated with hepatic 

insufficiency, acute alcohol intoxication 

and alcoholism* 

Burger et al., Journal of 

hepatology 2013: Metformin 

is not expected to cause 

a problem when combined 

with DAAs 



(www.mims.com. 

au) 

No hepatic metabolism 

CYP2C9 

CYP2C9 

CYP2C9 

CYP2C9 

Use with caution* Metabolized to a small 

extent (~ 20%) by 

CYP3A4* 

Not CYP450 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

P-gp 

Substrate

Class of 


22 

ASTHMA MEDICATION 

Substrate 

class 

Anticholinergic 

ß2 

mimetica 

Inhalation 

corticosteroids 







www.cbip.be 



Cromoglycate Lomudal ® No information 

available 

Ipratropium Atrovent ® , Nebu-Trop ® , 

Combivent ® , Duovent ® , 

Nebu-Iprasal ® 

Formoterol Foradil ® , Oxis ® , Formagal ® , 

Formoair ® , Symbicort ® , 

Inuvair ® 

Salbutamol Ventolin ® , Airomir ® , Combivent 

® , Nebu-Iprasal ® 


available 


Significant 


available 

Salmeterol Serevent ® , Seretide ® Potential 

Interaction 

Theophylline Euphyllin ® , Theolair ® , 

Xanthium ® 


Significant 

Fluticasone Flixotide ® , Seretide ® Potential 

Interaction 

Budesonide Miflonide ® , Pulmicort ® , 

Symbicort ® 

Potential 

Interaction 

Ciclesonide Alvesco ® No information 

available 

May 

[Salmeterol]* 

Cautions with 

Peg-IFN 2a* 

May 

[fluticasone]* 

May 

[Budesonide]* 



Coadministration not 

recommended* 

(risk of cardiovascular 

events) 

Avoid coadministration 

if possible, particularly 

for extended durations* 

Avoid coadministration 

if possible, particularly 

for extended durations* 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 


CYP2C9 / CYP2E1 / 

CYP3A4 / CYP1A2 

Substrate 



CYP3A4 Substrate

Class of 


23 

IMMUNOSUPPRESSANTS 

Substrate 

class 







www.cbip.be 

Tacrolimus Prograft ® , Advagraf ® Potential 

interaction* 

Ciclosporin Sandimmun ® , 

Neoral Sandimmun ® 



Potential 

interaction* 

May Tacrolimus 

Cmax (10 fold) and 

AUC (17 fold)* 

BOC AUC 

Cmax 3% 

May 

Ciclosporin Cmax 

(2 fold) and AUC 

(2,7 fold) BOC 

AUC 16% 

BOC Cmax 8%* 



Concomitant 

administration of 

BOC with tacrolimus 

requires significant 

dose reduction and 

prolongation of the 

dosing interval of 

tacrolimus, with close 

monitoring of tacrolimus 

blood concentrations 

and frequent 

assessments of renal 

function and tacrolimus 

related side effects † 

Dose adjustments of 

ciclosporine should 

be anticipated when 

administered with BOC 

and should be guided 

by close monitoring 

of ciclosporine blood 

concentrations, and 

frequent assessments 

of renal function and 

ciclosporine related side 

effects † 

smpc: Concomitant 

administration of BOC 

with tacrolimus requires 

significant dose reduction and 

prolongation of the dosing 

interval of tacrolimus, with close 

monitoring of tacrolimus blood 

concentrations and frequent 

assessments of renal function 

and tacrolimus-related side 

effects. For more information, 

please refer to the paragraph on 

immunosuppressants from Kiser 

et al., hepatology 2012. 

smpc: Dose adjustments 

of cyclosporine should be 

anticipated when administered 

with BOC and should be 

guided by close monitoring 

of cyclosporine blood 

concentrations, and frequent 


and cyclosporine-related side 

effects. For more information, 

please refer to the paragraph 

on immunosuppressants from 


2012. Burger et al., Journal 

of hepatology 2013: The 

combination of ciclosporin 

and BOC causes the smallest 

interaction and could be 

considered a preferred option. 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 


Substrate for 

P-gp 


Substrate for 

P-gp

Class of 


24 

IMMUNOSUPPRESSANTS 

Substrate 

class 

Drug Brand name 

(non exhaustive 

list, generics 

not listed). For 

a complete list, 



www.cbip.be 

Sirolimus Rapamune ® Potential 

Interaction 

Methyl- 

prednisolone 

Prednisone/ 

Prednisolone 

Beclamethasone 

Medrol ® , Depo-Medrol 

® , Solu-Medrol ® 



Potential 

interaction 

Lodotra ® Potential 

interaction 

Clipper ® , Beclophar 

® , Qvar ® , 

Ecobec ® 

Budesonide Budenofalk ® , Entocort 

® 


Significant 

Potential 

Interaction 

Azathioprine Imuran ® Not Clinically 

Significant 


is expected to 

increase sirolimus 

concentrations* 

May [methylprednisolone]* 

Prednisone AUC 

by 22% and 

Cmax by 1% 

Prednisolone 

AUC and Cmax 

by 37% and 

16% † 

May 

[Budesonide]* 



Close monitoring of sirolimus 

blood 

concentrations is 

recommended and frequent 


and sirolimus-related side 

effects † 

The dose of methylprednisolone 

may need to be titrated 

to avoid steroid toxicity* 

No dose adjustment is necessary 

when co-administered 

with BOC. Patients receiving 

prednisone and BOC should 

be monitored appropriately † 

Vigilance is recommended in 

transplant patients, dosage 

modifications are probably 

not necessary but the occurrence 

of a cushing syndrome 

could suggest an increase in 

Prednisolone concentrations ‡ 

Avoid coadministration, 

particularly for extended 

durations* 

smpc: Blood concentrations of sirolimus are 

expected to 

increase significantly when administered 

with BOC. Close monitoring of sirolimus 

blood concentrations is recommended and 

frequent assessments of renal function and 

sirolimus-related side effects. Burger et al., 

Journal of hepatology 2013: There are no 

data on the use of other immunosuppressant 

such as sirolimus and everolimus, but it’s 

expected that the effect are similar to those 

with tacrolimus. 

smpc: No dose adjustment is necessary 

when co-administered with BOC. Patients 

receiving prednisone and BOC should 

be monitored appropriately. abstract: 

No dosage adjustment of Prednisone is 

necessary when coadministered with BOC. 

However, because of the long-term nature 

of corticosteroid therapy, patients receiving 

concomitant prednisone and BOC should be 

monitored appropriately for the Aes of prolonged 

increases in prednisolone exposure. a 

Burger et al., Journal of hepatology 

2013: There are data available suggesting 

that beclomethasone can be used safely in 

patients on strong CYP3A4 inhibitors and 

consequently this could be the corticosteroid 

of choice for patients on HCV protease 

inhibitors 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 


Inhibitor 


CYP3A4 a Substrate a 


a P.Jumes et al., Pharmacokinetic interaction between the hepatitis C Virus Protease Inhibitor Boceprevir and Prednisone in healthy volunteers - Presented at the 63rd Annual meeting of the AASLD, November 9-13, 2012, Boston, MA, USA. ‡ Recommendation based on Pr. Colle experience.

Class of 


25 

ANTIBIOTICS 

Substrate 

class 

Macrolide 

Quinolone 

Tetracyclins 

Other 







www.cbip.be 

Azithromycin Zitromax ® Not Clinically 

Significant 

Clarithromycin Biclar ® , Heliclar ® , 

Maclar ® , Monoclarium ® 

Erythromycin Erythrocine ® , 

Erythroforte ® 



Potential 

interaction 

Potential 

interaction 

Moxifloxacin Avelox ® , Proflox ® Not Clinically 

Significant 

Ciprofloxacin Ciprobel ® , Ciproxine ® Not Clinically 

Significant 

Ofloxacin Tarivid ® Potential 

interaction 

eg: doxycyclin Potential 

interaction 

Trimethoprim/ 

sulfamethoxazole 

Bactrim ® , Eusaprim ® Not Clinically 

Significant 

May 

[Clarithromycin] 

and [BOC]* 

May 

[erythromycin] 

and [BOC]* 




necessary if normal renal 

function* 

Caution is warranted 

and clinical monitoring 

is recommended 

when coadministering 

BOC with medicines 

known to prolong the 

QT interval, such as 

erythromycin* 

Use with caution due to 

the possible prolongation 

of the QT interval* 

Burger et al., Journal of hepatology 2013: 

Plasma concentrations of BOC were only 

marginally increased (+21%) during coadministration 

and therefore, these agents 

(macrolides) can be safely combined without 

dose adjustments 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP3A4 Substrate, 

Inhibitor 


Inhibitor 

CYP1A2 

CYP2C8 / CYP2C9

Class of 


26 

ANTIFUNGALS 

Substrate 

class 

Azole 

derivatives 







www.cbip.be 

Itraconazole Sporanox ® , Spozole ® Potential 

interaction 

Posaconazole Noxafil ® Potential 

interaction 

Ketoconazole Nizoral ® Potential 

interaction 

Voriconazole Vfend ® Potential 

interaction 

Fluconazole Diflucan ® , Fungimed ® , 

Candizole ® , 



Potential 

interaction 

Amphotericine B Abelcet ® , Ambisome ® Not Clinically 

Significant 

Caspofungine Cancidas ® Potential 

interaction 

Terbinafine Lamisil ® Potential 

interaction 

May 

[itraconazole] and 

[BOC]* 

May 

[posaconazole] 

and [BOC]* 

May 

[ketoconazole]. 


of ketoconazole 

(400 mg twice 

daily) and BOC 

(400 mg single 

dose) BOC Cmax 

by 1,4 fold 

and AUC by 2.31fold* 

May 

[voriconazole] 

and [BOC]* 

Could BOC 

exposure* 

May 

[terbinafine]* 



Doses of itraconazole 

should not exceed 200 

mg/day* 

Doses of ketoconazole 

should not exceed 200 

mg/day* 

No dose adjustment is 

required in patients with 

normal hepatic function. 

A dose reduction of 

caspofungin daily dose 

to 35 mg is recommended 

for adults with 

moderate hepatic 

impairment.* 

smpc: Caution should be 

exercised when BOC is 

combined with ketoconazole or 

azole antifungals (itraconazole, 

posaconazole, voriconazole) 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 


Inhibitor 

CYP3A4 Inhibitor 

CYP3A4 Inhibitor 


CYP2C19 

Inhibitor 

CYP3A4 / CYP2C9 Inhibitor 

CYP2D6

Class of 


27 

CONTRACEPTIVES 

Substrate 

class 

See SmPC for guidance on 

contraception 

Combined 

Pill 







www.cbip.be 

Norethisterone 

(NE) / 

Ethinylestradiol 

(EE) 

Drospirenone 

(DRSP) / 

Ethinylestradiol 

(EE) 








• BOC can not be used during pregnancy 

• Female patients: respect a 4 months’ period after stopping treatment before pregnancy 

• Male patients and female partners: respect a 7 months’ period after stopping treatment before pregnancy 

• Possible that hormonal contraceptives are not reliable when using BOC: treated patients and their partners must use 2 methods of effective non-hormonal 

contraception (eg. male/female condoms, contraceptive diaphragm, copper IUD) 

Ovysmen ® , Trinovum ® Potential 

interaction* 

Yaz ® , Yasmin ® , 

Yasminelle ® , Yaz ® , 

Armunia ® , Drospibel ® 

, Rhonya ® 


Contraindicated* 

NE AUC 

and Cmax 

by 4% and 

17% 

EE AUC and 

Cmax 

by 26% 

and 21% † 

DRSP AUC 

and Cmax 

by 99% and 

57%, EE 

AUC 24% 

and EE Cmax 

* 

Co-administration 

of BOC with an oral 

contraceptive containing 

EE and at least 1 mg 

of NE is unlikely to 

alter the contraceptive 

effectiveness † 

Caution should be 

exercised in patients 

with conditions that 

predispose 

them to hyperkalaemia 

or patients taking 

potassium-sparing 

diuretics † 

smpc: Co-administration of BOC with an oral 

contraceptive containing EE and at least 1 

mg of NE is unlikely to alter the contraceptive 

effectiveness. Indeed, serum progesterone, 

luteinizing hormone (LH) and follicle-stimulating 

hormone (FSH) levels indicated that ovulation 

was suppressed during co-administration of NE 

1 mg/EE 0.035 mg with BOC. The ovulation 

suppression activity of oral contraceptives 

containing lower doses of NE/EE and of other 

forms of hormonal contraception during 

co-administration with BOC has not been 

established. Patients using oestrogens as 

hormone replacement therapy should be 

clinically monitored for signs of oestrogen 

deficiency. 

Kiser et al., hepatology 2012: Progestin-only 

contraception is effective, but it is difficult 

to know with certainty whether BOC would 

increase the levels of all progestins or if it is 

unique to drosperinone. There may also be 

more progestin-associated adverse effects with 

increased progestin concentrations. 

Furthermore, because drosperinone Inhibitors 

potassium excretion in the kidneys, the 

increase in drosperinone concentrations could 

theoretically cause hyperkalemia. Thus, 

considering the potential for increased adverse 

effects with BOC. smpc: Caution should be 

exercised in patients with conditions that 

predispose them to hyperkalaemia or 

patients taking potassium-sparing diuretics. 

Alternative contraceptives should be 

considered for these patients. 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP3A4 Substrate

Class of 


ERECTILE DySFUNCTION 

MEDICATION 

28 

Substrate 

class 







www.cbip.be 

Sildenafil Viagra ® Potential 

interaction 

Tadalafil Cialis ® Potential 

interaction 

Vardenafil Levitra ® Potential 

interaction 



Coadministration is 

expected to 

[sildenafil]* 


expected to 

[tadalafil]* 


expected to 

[vardenafil]* 



Use with caution and monitor for 

Sildenafil associated 

adverse events. Do not exceed 

sildenafil 25 mg every 48 hours* 


Tadalafil associated 


tadalafil 10 mg every 72 hours* 


Vardenafil associated 


vardenafil 2.5 mg every 24 hours* 

CYP 

pathway(s) 

(www.cbip/ 

bcfi.be) 

(www.mims. 

com.au) 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 



CYP3A4 Substrate

Class of 


29 

ANTIRETROVIRALS 

Substrate 

class 

NRTI 

NNRTI 

Protease 

Inhibitors 







www.cbip.be 

Tenofovir Viread ® , Truvada ® , 

Atripla ® 




Significant 

Efavirenz Stocrin ® , Atripla ® Potential 

interaction 

Etravirine Intelence ® Potential 

interaction 

Rilpivirine 

(RPV) 

Atazanavir/ 

Ritonavir 

Endurant ® , Eviplera ® Potential 

interaction 

Reyataz ® Potential 

interaction* 

BOC AUC, Cmax 

and Cmin by 8%, 

5% and 8% 

Tenofovir AUC and 

Cmax by 5% and 

32% † 

BOC AUC, Cmax and 

Cmin by 19%, 8% 

and 44%, Efavirenz 

AUC and Cmax by 

20% and 11% † 

BOC AUC and Cmax 

by 10%, BOC Cmin 

12%, Etravirine 

AUC, Cmax and Cmin 

by 23%, 24% and 

29% † 

BOC AUC, Cmax and 

Cmin by 5%, 7% 

and 18%, Atazanavir 

AUC, Cmax and Cmin 

by 35%, 25% and 

49%, Ritonavir AUC, 

Cmax and Cmin by 

36%, 27% and 45% † 



No dose adjustment required 

for BOC or tenofovir † . Patients 

receiving interferon with ribavirin 

and tenofovir should be closely 

monitored for treatment -associated 

toxicities, especially hepatic 

decompensation and anaemia* 

Avoid coadministration as it BOC 

concentrations, which may result in 

loss of therapeutic effect* 

Increased clinical and laboratory 

monitoring for HIV and HCV 

suppression is recommended † 

Co-administration of atazanavir/ 

ritonavir with BOC resulted in 

lower exposure of atazanavir which 

may be associated with lower 

efficacy and loss of HIV control. 

This co-administration might be 

considered on a case by case basis 

if deemed necessary, in patients 

with suppressed HIV viral loads 

and with HIV viral strain without 

any suspected resistance to the 

HIV regimen. Increased clinical 

and laboratory monitoring for HIV 

suppression is warranted † 

a EG. Rhee et al. Absence of a significant pharmacokinetic interaction between the HCV Protease Inhibitor BOC and HIV-1 NNRTI Rilpivirine - Presented at CROI, March 3-6, 2013 

smpc: No dose adjustment required for 

BOC or tenofovir. Kiser et al., hepatology 

2012. Tenofovir does not affect the 

pharmacokinetics of BOC, but the Cmax of 

tenofovir is increased approximately 30% 

with BOC 

smpc: Plasma trough concentrations of 

BOC were decreased when administered 

with efavirenz. The clinical outcome has 

not been directly assessed 

smpc: The clinical significance of the 

reductions in etravirine pharmacokinetic 

parameters and BOC Cmin in the 

setting of combination therapy with 

HIV antiretroviral medicines, which also 

affect the pharmacokinetics of etravirine 

and/or BOC, has not been directly 

assessed. Increased clinical and laboratory 

monitoring for HIV and HCV suppression is 

recommended. 

abstract: BOC 800 mg three-times 

daily and RPV 25 mg once daily can be 

coadministerad without dose adjustmenta smpc: Co-administration of atazanavir/ 

ritonavir with BOC resulted in lower 

exposure of atazanavir which may be 

associated with lower efficacy and loss 

of HIV control. This co-administration 

might be considered on a case by case 

basis if deemed necessary, in patients 

with suppressed HIV viral loads and with 

HIV viral strain without any suspected 

resistance to the HIV regimen. Increased 

clinical and laboratory monitoring for HIV 

suppression is warranted 

CYP 

pathway(s) 

(www.cbip/ 

bcfi.be) 

(www.mims. 

com.au) 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP3A4 Inducer 

CYP3A4 Sustrate, 

Induce 


Inhibitor

Class of 


30 

ANTIRETROVIRALS 

Substrate 

class 

Protease 

Inhibitors 

Integrase 

Inhibitor 







www.cbip.be 

Lopinavir/ 

Ritonavir 

Darunavir/ 

Ritonavir 

Kaletra ® Potential 

interaction 

Prezista ® Potential 

interaction 

Ritonavir Norvir ® Potential 

interaction 

Raltegravir 

(RAL) 

Isentress ® Not Clinically 

Significant 



BOC AUC 45% 

BOC Cmax 50% 

BOC Cmin 57% 

lopinavir AUC 34% 

lopinavir Cmax 30% 

lopinavir Cmin 43% 

ritonavir AUC 22% 

ritonavir Cmax 12% 

ritonavir Cmin 42%* 

BOC AUC 32% 

BOC Cmax 25% 

BOC Cmin 35% 

darunavir AUC 44% 

darunavir Cmax 36% 

darunavir Cmin 59% 


ritonavir Cmax 13% 

ritonavir Cmin 45%* 

BOC AUC 19% 

BOC Cmax 27% 

BOC Cmin 4%* 

Raltegravir AUC and 

Cmax by 4% and 11% 

Raltegravir C by 

12h 

25% † 



Co-administration of 

atazanavir/ritonavir with BOC 

resulted in lower exposure 

of atazanavir which may be 

associated with lower efficacy 

and loss of HIV control. This 

co-administration might be 

considered on a case by case 

basis if deemed necessary, in 

patients with suppressed HIV 

viral loads and with HIV viral 

strain without any suspected 

resistance to the HIV regimen. 

Increased clinical and 

laboratory monitoring for HIV 

suppression is warranted † 

It is not recommended to coadminister 

darunavir/ritonavir 

and BOC † 


for BOC or raltegravir † 

smpc: Co-administration of atazanavir/ 

ritonavir with BOC resulted in lower 

exposure of atazanavir which may be 

associated with lower efficacy and loss 

of HIV control. This co-administration 

might be considered on a case by case 

basis if deemed necessary, in patients 

with suppressed HIV viral loads and with 


resistance to the HIV regimen. Increased 

clinical and laboratory monitoring for 

HIV suppression is warranted 

smpc: It is not recommended to coadminister 

darunavir/ritonavir and BOC. 

smpc: When BOC is administered with 

ritonavir alone, BOC concentrations are 

decreased 

smpc: No dose adjustment required 

for BOC or raltegravir. de Kanter et 

al., cid 2013: Due to the absence of 

a clinically significant drug interaction, 

RAL can be recommended for 

combined HIV/HCV treatment including 

BOC 


(www.cbip/ 

bcfi.be) (www. 

mims.com.au) 

CYP3A4 

CYP3A4 


/ CYP2C9 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

Substrate, 

Inhibitor 

Substrate, 

Inhibitor 

Substrate, 

Inhibitor

Class of 


31 

ANTI HEP.B/HEP.C DRUGS 

Substrate 

class 







www.cbip.be 

Tenofovir Viread ® , Truvada ® , 

Atripla ® 




Significant 

Entecavir Baraclude ® Not Clinically 

Significant 

Lamivudine 

Zeffix ® , Epivir ® , 

Combivir ® , Trizivir ® , 

Kivexa ® 


Significant 

Adefovir Hepsera ® Not Clinically 

Significant 

Cmax of tenofovir is 

increased 

approximately 30% 

with BOC k 




for BOC or tenofovir † . 

Patients receiving interferon 

with ribavirin and Tenofovir 

should be closely monitored 

for treatment -associated 


decompensation and 

anaemia* 

Patients receiving interferon 

with ribavirin and lamivudine 

should be closely monitored 

for treatment-associated 


decompensation and 

anaemia* 

Caution is recommended in 

combination with Peginterferon 

alfa* 

smpc: No dose adjustment required for 

BOC or tenofovir. 


Tenofovir does not affect the 

pharmacokinetics of BOC, but the Cmax 

of tenofovir is 

increased approximately 30% with BOC 


(www.cbip/ 

bcfi.be) (www. 

mims.com.au) 

CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer

Class of 


32 

OTHER DRUGS 

Substrate 

class 







www.cbip.be 



Rifampicin Rifadine ® Coadministration 

Contraindicated 

Alfuzosin Xatral ® Coadministration 

Contraindicated 

Colchicine Colchicine Opocalcium ® Potential 

Interaction 

Grapefruit Juice Potential 

Interaction* 

May [alfuzosin] 

which can result 

in hypotension* 

Significant 

increases in 

colchicine levels 

are expected* 

Could increase 

BOC 

exposure* 



Coadministration not 


Patients with renal or 

hepatic impairment 

should not be given 

colchicine with BOC* 

smpc: The concomitant use 

of BOC with rifampicin is not 

recommended 




CYP3A4 

Substrate/ 

Inhibitor/ 

Inducer 

CYP2B6 / CYP2C9 / induce 

CYP2C19 / CYP3A4 / 




CYP3A4 Inhibitor

33 

No clinically significant interaction expected as defined by the Liverpool 

University website (www.hep-druginteractions.org) 

Potential interaction (may require close monitoring, alteration of drug 

dosage or timing of administration) as defined by the Liverpool University 

website (www.hep-druginteractions.org) 

These drug should not be coadministered as defined by the Liverpool 

University website (www.hep-druginteractions.org) 

No information available 

Legend 

* Information obtained from www.hep-druginteractions.org 

† Information provided by the VICTRELIS ® (boceprevir) Scientific leaflet 

$ Drug’s Product Information (Published in MIMs Annual 2011) 

[drug] Drug concentration 

¥ Non exhaustive list of commercial names 

Association of several molecules 

k Information from the publication: Kiser et al., Hepatology 2012 

a Data from abstracts (complete reference at the bottom of the page) 

b Information from the publication: Burger et al., Journal of Hepatology 2013 

AUC Area Under the Curve 

BOC Boceprevir 

DAA Direct Acting Antiviral Agent

1. NAME OF THE MEDICINAL PRODUCT Victrelis 200 mg hard capsules 2. QUALITATIVE AND 

QUANTITATIVE COMPOSITION Each hard capsule contains 200 mg of boceprevir. Excipient with known 

effect: each capsule contains 56 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM Hard capsule. Each capsule has a yellowish-brown, opaque cap with an 

“MSD” logo imprinted in red ink and off-white, opaque body with the code “314” imprinted in red ink. 

4. CLINICAL PARTICULARS 4.1 Therapeutic indications Victrelis is indicated for the treatment of chronic 

hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients 

with compensated liver disease who are previously untreated or who have failed previous therapy. See 

sections 4.4 and 5.1. 4.2 Posology and method of administration Treatment with Victrelis should be initiated 

and monitored by a physician experienced in the management of chronic hepatitis C. Posology Victrelis must 

be administered in combination with peginterferon alfa and ribavirin. The Summary of Product Characteristics 

of peginterferon alfa and ribavirin (PR) must be consulted prior to initiation of therapy with Victrelis. The 

recommended dose of Victrelis is 800 mg administered orally three times daily (TID) with food (a meal or light 

snack). Maximum daily dose of Victrelis is 2,400 mg. Administration without food could be associated with a 

net loss of efficacy due to sub-optimal exposure. Patients without cirrhosis who are previously untreated or 

who have failed previous therapy The following dosing recommendations differ for some subgroups from the 

dosing studied in the Phase 3 trials (see section 5.1). Table 1 Duration of therapy using Response-Guided 

Therapy (RGT) guidelines in patients without cirrhosis who are previously untreated or who have failed 

previous therapy to interferon and ribavirin therapy Previously Untreated Patients ASSESSMENT* (HCV-RNA 

Results † ) At Treatment Week 8 Undetectable At Treatment Week 24 Undetectable ACTION Treatment 

duration = 28 weeks 1. Administer peginterferon alfa and ribavirin for 4 weeks, and then 2. Continue with all 

three medicines (peginterferon alfa and ribavirin [PR] + Victrelis) and finish through Treatment Week 28 (TW 

28). Previously Untreated Patients ASSESSMENT* (HCV-RNA Results † ) At Treatment Week 8 Detectable At 

Treatment Week 24 Undetectable ACTION Treatment duration = 48 weeks ‡ 1. Administer peginterferon alfa 

and ribavirin for 4 weeks, and then 2. Continue with all three medicines (PR + Victrelis) and finish through TW 

36; and then 3. Administer peginterferon alfa and ribavirin and finish through TW 48. Patients Who have 

Failed Previous Therapy ASSESSMENT* (HCV-RNA Results † ) At Treatment Week 8 Undetectable At Treatment 

Week 24 Undetectable or At Treatment Week 8 Detectable At Treatment Week 24 Undetectable ACTION 

Treatment duration = 48 weeks 1. Administer peginterferon alfa and ribavirin for 4 weeks, and then 2. 

Continue with all three medicines (PR + Victrelis) and finish through TW 36, and then 3. Administer 

peginterferon alfa and ribavirin and finish through TW 48. *Stopping rule If the patient has hepatitis C virus 

ribonucleic acid (HCV-RNA) results greater than or equal to 100 IU/ml at TW 12; then discontinue threemedicine 

regimen. If the patient has confirmed, detectable HCV-RNA at TW 24; then discontinue threemedicine 

regimen. † In clinical trials, HCV-RNA in plasma was measured with the Roche COBAS Taqman 2.0 

assay with a limit of detection of 9.3 IU/ml and a limit of quantification of 25 IU/ml. ‡ This regimen has only 

been tested in subjects who have failed previous therapy who were late responders (see section 5.1). All 

cirrhotic patients and null responders: Recommended treatment duration is 48 weeks: 4 weeks of bitherapy 

with peginterferon alfa+ ribavirin + 44 weeks of tritherapy with peginterferon alfa + ribavirin + Victrelis. (Refer 

to the stopping rule in Table 1 for all patients.) The duration of the tritherapy after the first 4 weeks of 

bitherapy should not be less than 32 weeks. Given the incremental risk of adverse events with Victrelis 

(anaemia notably); in case the patient cannot tolerate the treatment, consideration could be given to pursue 

with 12 weeks of bitherapy for the final 12 weeks of treatment instead of tritherapy (see sections 4.8 and 5.1). 

Missed doses If a patient misses a dose and it is less than 2 hours before the next dose is due, the missed 

dose should be skipped. If a patient misses a dose and it is 2 or more hours before the next dose is due, the 

patient should take the missed dose with food and resume the normal dosing schedule. Dose reduction 

Dose reduction of Victrelis is not recommended. If a patient has a serious adverse reaction potentially related 

to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced. Refer 

to the Summary of Product Characteristics for peginterferon alfa and ribavirin for additional information 

about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. Victrelis must not be 

administered in the absence of peginterferon alfa and ribavirin. Special populations Renal impairment No 

34 

dose adjustment of Victrelis is required in patients with any degree of renal impairment (see section 5.2). 

Hepatic impairment No dose adjustment of Victrelis is required for patients with mild, moderate or severe 

hepatic impairment. Victrelis has not been studied in patients with decompensated cirrhosis (see section 

5.2). Paediatric population The safety and efficacy of Victrelis in children aged below 18 years have not yet 

been established. No data are available. Elderly Clinical studies of Victrelis did not include sufficient numbers 

of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other 

clinical experience has not identified differences in responses between the elderly and younger patients (see 

section 5.2). Method of administration To obtain the hard capsules the foil of the blister should be peeled off. 

Victrelis is to be taken orally with food (a meal or light snack). 4.3 Contraindications Victrelis, in combination 

with peginterferon alfa and ribavirin, is contraindicated in: Patients with hypersensitivity to the active 

substance or any of the excipients listed in section 6.1. Patients with autoimmune hepatitis. Co-administration 

with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma 

concentrations are associated with serious and/or life-threatening events such as orally administered 

midazolam and triazolam, bepridil, pimozide, lumefantrine, halofantrine, tyrosine kinase inhibitors, 

simvastatin, lovastatin, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) 

(see section 4.5). Pregnancy (see section 4.6). Refer to the Summary of Product Characteristics for 

peginterferon alfa and ribavirin for additional information. 4.8 Undesirable effects The safety profile 

represented by approximately 1,500 patients for the combination of Victrelis with peginterferon alfa 2b and 

ribavirin was based on pooled safety data in two clinical trials: one in patients who were previously untreated, 

and one in patients who had failed prior therapy (see section 5.1). The most frequently reported adverse 

reactions were fatigue, anaemia (see section 4.4), nausea, headache, and dysgeusia. The most common 

reason for dose reduction was anaemia, which occurred more frequently in subjects receiving the combination 

of Victrelis with peginterferon alfa 2b and ribavirin than in subjects receiving peginterferon alfa 2b and 

ribavirin alone. Adverse reactions are listed by System Organ Class (see Table 3). Within each system organ 

class, adverse reactions are listed under headings of frequency using the categories: very common (≥ 1/10); 

common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known 

(cannot be estimated from the available data). Table 3 Adverse reactions in combination with Victrelis with 

peginterferon alfa 2b and ribavirin reported during clinical trials † and ‡ System Organ Class Infections and 

infestations Adverse Reactions Common: Bronchitis*, cellulitis*, herpes simplex, influenza, oral fungal 

infection, sinusitis Uncommon: Gastroenteritis*, pneumonia*, staphylococcal infection*, candidiasis, ear 

infection, fungal skin infection, nasopharyngitis, onychomycosis, pharyngitis, respiratory tract infection, 

rhinitis, skin infection, urinary tract infection Rare: Epiglottitis*, otitis media, sepsis System Organ Class 

Neoplasms benign, malignant and unspecified (including cysts and polyps) Adverse Reactions Rare: Thyroid 

neoplasm (nodules) System Organ Class Blood and lymphatic system disorders Adverse Reactions Very 

common: Anaemia*, neutropenia* Common: Leukopenia*, thrombocytopenia* Uncommon: Haemorrhagic 

diathesis, lymphadenopathy, lymphopenia Rare: Haemolysis System Organ Class Immune system disorders 

Adverse Reactions Rare: Sarcoidosis*, porphyria non-acute System Organ Class Endocrine disorders Adverse 

Reactions Common: Goitre, hypothyroidism Uncommon: Hyperthyroidism System Organ Class Metabolism 

and nutrition disorders Adverse Reactions Very common: Decreased appetite* Common: Dehydration*, 

hyperglycaemia*, hypertriglyceridaemia, hyperuricaemia Uncommon: Hypokalaemia*¸ appetite disorder, 

diabetes mellitus, gout, hypercalcaemia System Organ Class Psychiatric disorders Adverse Reactions Very 

common: Anxiety*, depression*, insomnia, irritability Common: Affect lability, agitation, libido disorder, 

mood altered, sleep disorder Uncommon: Aggression*, homicidal ideation*, panic attack*, paranoia*, 

substance abuse*, suicidal ideation*, abnormal behaviour, anger, apathy, confusional state, mental status 

changes, restlessness Rare: Bipolar disorder*, completed suicide*, suicide attempt*, hallucination auditory, 

hallucination visual, psychiatric decompensation System Organ Class Nervous system disorders Adverse 

Reactions Very common: Dizziness*, headache* Common: Hypoaesthesia*, paraesthesia*, syncope*, 

amnesia, disturbance in attention, memory impairment, migraine, parosmia, tremour, vertigo Uncommon: 

Neuropathy peripheral*, cognitive disorder, hyperaesthesia, lethargy, loss of consciousness, mental 

impairment, neuralgia, presyncope Rare: Cerebral ischaemia*, encephalopathy System Organ Class Eye

disorders Adverse Reactions Common: Dry eye, retinal exudates, vision blurred, visual impairment 

Uncommon: Retinal ischaemia*, retinopathy*, abnormal sensation in eye, conjunctival haemorrhage, 

conjunctivitis, eye pain, eye pruritus, eye swelling, eyelid oedema, lacrimation increased, ocular hyperaemia, 

photophobia Rare: Papilloedema System Organ Class Ear and labyrinth disorders Adverse Reactions 

Common: Tinnitus Uncommon: Deafness*, ear discomfort, hearing impaired System Organ Class Cardiac 

disorders Adverse Reactions Common: Palpitations Uncommon: Tachycardia*, arrhythmia, cardiovascular 

disorder Rare: Acute myocardial infarction*, atrial fibrillation*, coronary artery disease*, pericarditis*, 

pericardial effusion System Organ Class Vascular disorders Adverse Reactions Common: Hypotension*, 

hypertension Uncommon: Deep vein thrombosis*, flushing, pallor, peripheral coldness Rare: Venous 

thrombosis System Organ Class Respiratory, thoracic and mediastinal disorders Adverse Reactions Very 

common: Cough*, dyspnoea* Common: Epistaxis, nasal congestion, oropharyngeal pain, respiratory tract 

congestion, sinus congestion, wheezing Uncommon: Pleuritic pain*, pulmonary embolism*, dry throat, 

dysphonia, increased upper airway secretion, oropharyngeal blistering Rare: Pleural fibrosis*, orthopnoea, 

respiratory failure System Organ Class Gastrointestinal disorders Adverse Reactions Very common: 

Diarrhoea*, nausea*, vomiting* dry mouth, dysgeusia Common: Abdominal pain*, abdominal pain upper*, 

constipation*, gastrooesophageal reflux disease*, haemorrhoids*, abdominal discomfort, abdominal 

distention, anorectal discomfort, aphthous stomatitis, cheilitis, dyspepsia, flatulence, glossodynia, mouth 

ulceration, oral pain, stomatitis, tooth disorder Uncommon: Abdominal pain lower*, gastritis*, pancreatitis*, 

anal pruritus, colitis, dysphagia, faeces discoloured, frequent bowl movements, gingival bleeding, gingival 

pain, gingivitis, glossitis, lip dry, odynophagia, proctalgia, rectal haemorrhage, salivary hypersecretion, 

sensitivity of teeth, tongue discolouration, tongue ulceration Rare: Pancreatic insufficiency System Organ 

Class Hepatobiliary disorders Adverse Reactions Uncommon: Hyperbilirubinaemia Rare: Cholecystitis* 

System Organ Class Skin and subcutaneous tissue disorders Adverse Reactions Very common: Alopecia, dry 

skin, pruritus, rash Common: Dermatitis, eczema, erythema, hyperhidrosis, night sweats, oedema peripheral, 

psoriasis, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, skin lesion 

Uncommon: Photosensitivity reaction, skin ulcer, urticaria (see section 4.4) Not known: Angioedema (see 

section 4.4), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome System Organ Class 

Musculoskeletal and connective tissue disorders Adverse Reactions Very common: Arthralgia, myalgia 

Common: Back pain*, pain in extremity*, muscle spasms, muscular weakness, neck pain Uncommon: 

Musculoskeletal chest pain*, arthritis, bone pain, joint swelling, musculoskeletal pain System Organ Class 

Renal and urinary disorders Adverse Reactions Common: Pollakiuria Uncommon: Dysuria, nocturia System 

Organ Class Reproductive system and breast disorders Adverse Reactions Common: Erectile dysfunction 

Uncommon: Amenorrhoea, menorrhagia, metrorrhagia Rare: Aspermia System Organ Class General 

disorders and administration site conditions Adverse Reactions Very common: Asthenia*, chills, fatigue*, 

pyrexia*, influenza-like illness Common: Chest discomfort*, chest pain*, malaise*, feeling of body temperature 

change, mucosal dryness, pain Uncommon: Feeling abnormal, impaired healing, non-cardiac chest pain 

System Organ Class Investigations Adverse Reactions Very common: Weight decreased Uncommon: Cardiac 

murmur, heart rate increased * Includes adverse reactions which may be serious as assessed by the 

investigator in clinical trial subjects. † Since Victrelis is prescribed with peginterferon alfa and ribavirin, please 

also refer to the respective Summary of Product Characteristics of peginterferon alfa and ribavirin. ‡ Injectionsite 

reactions have not been included since Victrelis is administered orally. Description of selected adverse 

reactions Anaemia (see section 4.4) Anaemia was observed in 49% of subjects treated with the combination 

of Victrelis with peginterferon alfa 2b and ribavirin compared with 29% of subjects treated with peginterferon 

alfa 2b and ribavirin alone. Victrelis was associated with an additional decrease of approximately 1 g/dl in 

haemoglobin concentration (see section 4.4). The mean decreases in haemoglobin values from baseline 

were larger in previously treated patients compared to patients who had never received prior therapy. Dose 

modifications due to anaemia/hemolytic anaemia occurred twice as often in patients treated with the 

35 

combination of Victrelis with peginterferon alfa 2b and ribavirin (26%) compared to peginterferon alfa 2b and 

ribavirin alone (13%). In clinical trials, the proportion of subjects who received erythropoietin for the 

management of anaemia was 43% (667/1,548) of subjects in the Victrelis-containing arms compared to 24% 

(131/547) of subjects receiving peginterferon alfa 2b and ribavirin alone. The majority of the anaemia subjects 

received erythropoietin when haemoglobin levels were ≤ 10 g/dl (or 6.2 mmol/l). The proportion of subjects 

who received a transfusion for the management of anaemia was 3% of subjects in the Victrelis-containing 

arms compared to < 1% of subjects receiving peginterferon alfa 2b and ribavirin alone. Neutrophils (see 

section 4.4) The proportion of subjects with decreased neutrophils was higher in the Victrelis-containing arms 

compared to subjects receiving only peginterferon alfa 2b and ribavirin. The percentage of patients with 

Grades 3-4 neutropenia (neutrophil counts < 0.75 x 109/l) was higher in boceprevir treated patients (29%) 

than in placebo-treated patients (17%), in combination with peginterferon alfa 2b and ribavirin. Seven 

percent of subjects receiving the combination of Victrelis with peginterferon alfa 2b and ribavirin had 

neutrophil counts of < 0.5 x 109/l (Grade 4 neutropenia) compared to 4% of subjects receiving only 

peginterferon alfa 2b and ribavirin. Combined use with peginterferon alfa–2a see specific section in section 

4.4. Platelets Platelet counts were decreased for subjects in the Victrelis containing-arms (3%) compared to 

subjects receiving peginterferon alfa 2b and ribavirin alone (1%). In both treatment arms, patients with 

cirrhosis were at a higher risk to experience Grade 3-4 thrombocytopenia compared with non cirrhotic 

patients. Other laboratory findings The addition of Victrelis to peginterferon alfa–2b and ribavirin was 

associated to higher incidences of increase in uric acid, triglycerides and cholesterol total compared to 

peginterferon alfa–2b and ribavirin only. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme 

Ltd Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom 8. MARKETING AUTHORISATION 

NUMBER(S) EU/1/11/704/001 EU/1/11/704/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE 

AUTHORISATION Date of first authorisation: 18 July 2011 10. DATE OF REVISION OF THE TEXT 03/2013 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency: http://www.ema.europa.eu Legal status of delivery: on medical prescription only. Extract from the 

Victrelis ® Summary of the Product Characteristics. 4.5 Interaction with other medicinal products and other 

forms of interaction. Legal status of delivery: on medical prescription only. Extract from the Victrelis ® Summary 

of the Product Characteristics. Victrelis is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by 

CYP3A4/5 may have increased exposure when administered with Victrelis, which could increase or prolong 

their therapeutic and adverse reactions (see Table 2). Victrelis does not inhibit or induce the other enzymes 

of the CYP450. Boceprevir has been shown to be a p-glycoprotein (P-gp) and breast cancer resistant protein 

(BCRP) substrate in vitro. There is potential for inhibitors of these transporters to increase concentrations of 

boceprevir; the clinical implications of these interactions are not known. A clinical drug interaction study with 

digoxin demonstrated that boceprevir is a mild P-gp inhibitor in vivo, increasing digoxin exposure by 19%. 

An increase in plasma concentrations of substrates of the P-gp efflux transporter, such as digoxin or 

dabigatran, should be anticipated (see table 2). Victrelis is partly metabolized by CYP3A4/5. Co-administration 

of Victrelis with medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure to Victrelis 

(see section 4.4). Victrelis, in combination with peginterferon alfa and ribavirin, is contraindicated when coadministered 

with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated 

plasma concentrations are associated with serious and/or life-threatening events such as orally administered 

midazolam and triazolam, bepridil, pimozide, lumefantrine, halofantrine, tyrosine kinase inhibitors, 

simvastatin, lovastatin, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) 

(see section 4.3). Boceprevir is primarily metabolized by aldoketo reductase (AKR). In medicine interaction 

trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not increase to a 

clinically significant extent. Victrelis may be co-administered with AKR inhibitors. The concomitant use of 

Victrelis with rifampicin or anticonvulsants (such as phenytoin, phenobarbital or carbamazepine) may 

significantly reduce the plasma exposure of Victrelis. No data are available, therefore, the combination of

oceprevir with these medicines is not-recommended (see section 4.4). Caution should be exercised with 

medicines known to prolong QT interval such as amiodarone, quinidine, methadone, pentamidine and some 

neuroleptics. Table 2 provides dosing recommendations as a result of drug interactions with Victrelis. These 

recommendations are based on either drug interaction studies (indicated with *) or predicted interactions 

due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy. 

The percent change and arrows ( = increase, = decrease, = no change) are used to show the magnitude 

and direction of change in mean ratio estimate for each pharmacokinetic parameter. 

36 

Medicinal products by 

therapeutic areas 

interaction 

(postulated mechanism of 

action, if known) 

anaLGesic 

Narcotic analgesic/Opioid Dependence 

Buprenorphine/Naloxone* buprenorphine AUC 19% 

(buprenorphine/naloxone 8/2 – buprenorphine C 18% 

max 

24/6 mg daily + Victrelis 800 mg buprenorphine C 31% 

min 

three times daily) 

naloxone AUC 33% 

naloxone C 9% 

max 

Methadone* 

(methadone 20-150 mg daily 

+ Victrelis 800 mg three times 

daily) 

anti-arrYthMics 

Digoxin* 

(0.25 mg digoxin single dose 


daily) 

(CYP3A inhibition) 

R-methadone AUC 15% 

R-methadone C 10% 

max 

R-methadone C 19% 

min 

S-methadone AUC 22% 

S-methadone C max 17% 

S-methadone C min 26% 


digoxin AUC 19% 

digoxin C max 18% 

(effect on P-gp transport in 

the gut) 

recommendations concerning 

co-administration 


buprenorphine/naloxone or Victrelis 

is recommended. Patients should be 

monitored for signs of opiate toxicity 

associated with buprenorphine. 

Individual patients may require 

additional titration of their 

methadone dosage when Victrelis is 

started or stopped to ensure clinical 

effect of methadone. 

No dose adjustment of digoxin or 

Victrelis is recommended. Patients 

receiving digoxin should be 

monitored appropriately. 

anti-depressants 

Escitalopram* 

(escitalopram 10 mg single dose 


daily) 

anti-inFectives 

Antifungals 

Ketoconazole* 

(ketoconazole 400 mg two times 

daily + 

Victrelis 400 mg single dose) 

boceprevir AUC 9% 

boceprevir C max 2% 

escitalopram AUC 21% 

escitalopram C max 19% 



boceprevir C min N/A 

(CYP3A inhibition and/or 

P-gp inhibition) 

Itraconazole, Posaconazole, Not studied 

Voriconazole 

antiretroviraL 

HIV Nucleoside Reverse Transcriptase Inhibitor (NRTI) 

Tenofovir* 

(tenofovir 300 mg daily + 

Victrelis 800 mg three times 

daily) 

boceprevir AUC 8%** 


boceprevir C min 8% 

tenofovir AUC 5% 

tenofovir C 32% 

max 

HIV Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) 

Efavirenz* 

(efavirenz 600 mg daily + Victrelis 

800 mg three times daily) 




efavirenz AUC 20% 

efavirenz C max 11% 

(CYP3A induction - effect on 

boceprevir) 

Exposure of escitalopram was slightly 

decreased when co-administered 

with Victrelis. No dose adjustment of 

escitalopram is anticipated, but doses 

may need to be adjusted based on 

clinical effect. 

Caution should be exercised 

when boceprevir is combined with 

ketoconazole or azole antifungals 

(itraconazole, posaconazole, 

voriconazole). 

No dose adjustment required for 

Victrelis or tenofovir. 

Plasma trough concentrations of 

Victrelis were decreased when 

administered with efavirenz. The 

clinical outcome of this observed 

reduction of Victrelis trough 

concentrations has not been directly 

assessed.

Etravirine* 

(etravirine 200 mg every 12 hours 


daily) 

HIV Protease Inhibitor (PI) 

Atazanavir/Ritonavir* 

(atazanavir 300 mg / ritonavir 

100 mg daily + Victrelis 800 mg 


Darunavir/Ritonavir* 

(darunavir 600 mg / ritonavir 

100 mg two times daily + 


daily) 

37 




etravirine AUC 23% 

etravirine C max 24% 

etravirine C min 29% 




atazanavir AUC 35% 

atazanavir C max 25% 

atazanavir C min 49% 


ritonavir C max 27% 

ritonavir C min 45% 




darunavir AUC 44% 

darunavir C max 36% 

darunavir C min 59% 


ritonavir C max 13% 

ritonavir C min 45% 

The clinical significance of 

the reductions in etravirine 

pharmacokinetic parameters and 

boceprevir C min in the setting of 

combination therapy with HIV 

antiretroviral medicines, which 

also affect the pharmacokinetics of 

etravirine and/or boceprevir, has not 

been directly assessed. Increased 

clinical and laboratory monitoring 

for HIV and HCV suppression is 

recommended. 

Co-administration of atazanavir/ 

ritonavir with boceprevir resulted 

in lower exposure of atazanavir 

which may be associated with lower 

efficacy and loss of HIV control. 

This co-administration might be 

considered on a case by case basis if 

deemed necessary, in patients with 

suppressed HIV viral loads and with 


resistance to the HIV regimen. 

Increased clinical and laboratory 

monitoring for HIV suppression is 

warranted. 


darunavir/ritonavir and 

Victrelis. 

Lopinavir/Ritonavir* 

(lopinavir 400 mg / ritonavir 

100 mg two times daily + 


daily) 

Ritonavir* 

(ritonavir 100 mg daily + Victrelis 





lopinavir AUC 34% 

lopinavir C max 30% 

lopinavir C min 43% 


ritonavir C 12% 

max 

ritonavir C 42% 

min 


boceprevir C 27% 

max 


min 


Integrase Inhibitor 

Raltegravir* 

raltegravir AUC 4%*** 

(raltegravir 400 mg single dose raltegravir C 11% 

max 

+ Victrelis 800 mg three times raltegravir C12h 25% 

daily) 

corticosteroids 

Prednisone* 

prednisone AUC 22% 

(prednisone 40 mg single dose prednisone C 1% 

max 


daily) 

prednisolone AUC 37% 

prednisolone C 16% 

max 

hMG coa redUctase inhiBitors 

Atorvastatin* 


(atorvastatin 40 mg single dose boceprevir C 4% 

max 


daily) 

atorvastatin AUC 130% 

atorvastatin C 166% 

max 

(CYP3A and OATPB1 

inhibition) 


lopinavir/ritonavir and 

Victrelis. 

When boceprevir is administered 

with ritonavir alone, boceprevir 

concentrations are decreased. 

No dose adjustment required for 

Victrelis or raltegravir. 

No dose adjustment is necessary 

when co-administered with Victrelis. 

Patients receiving prednisone 

and Victrelis should be monitored 

appropriately. 

Exposure to atorvastatin was 

increased when administered with 

Victrelis. When co-administration is 

required, starting with the lowest 

possible dose of atorvastatin 

should be considered with titration 

up to desired clinical effect while 

monitoring for safety, without 

exceeding a daily dose of 20 mg. 

For patients currently taking 

atorvastatin, the dose of atorvastatin 

should not exceed a daily dose of 

20 mg during co-administration with 

Victrelis.

Pravastatin* 

(pravastatin 40 mg single dose 


daily) 

iMMUnosUppressants 

Cyclosporine* 

(cyclosporine 100 mg single dose 

+ Victrelis 800 mg single dose) 

(cyclosporine 100 mg single dose 


daily multiple doses) 

Tacrolimus* 

(tacrolimus 0.5 mg single dose + 

Victrelis 800 mg single dose) 

(tacrolimus 0.5 mg single dose + 

Victrelis 800 mg three times daily 

multiple doses) 

38 



pravastatin AUC 63% 

pravastatin C max 49% 

(OATPB1 inhibition) 



cyclosporine AUC 168% 

cyclosporine C max 101% 

(CYP3A inhibition - effect on 

cyclosporine) 

boceprevir AUC 


max 

tacrolimus AUC 1610% 

tacrolimus C max 890% 

(CYP3A inhibition - effect on 

tacrolimus) 

Sirolimus Not studied 


oraL anticoaGULants 

Dabigatran Interaction not studied. 

(effect on P-gp transport in 

the gut) 

Concomitant administration of 

pravastatin with Victrelis increased 

exposure to pravastatin. Treatment 

with pravastatin can be initiated 

at the recommended dose when 

co-administered with Victrelis. Close 

clinical monitoring is warranted. 

Dose adjustments of cyclosporine 

should be anticipated when 

administered with Victrelis and should 

be guided by close monitoring of 

cyclosporine blood concentrations, 

and frequent assessments of renal 

function and cyclosporine-related 

side effects. 

Concomitant administration of 

Victrelis with tacrolimus requires 

significant dose reduction and 

prolongation of the dosing interval 

of tacrolimus, with close monitoring 

of tacrolimus blood concentrations 


function and tacrolimus-related side 

effects. 

Blood concentrations of sirolimus 

are expected to increase significantly 

when administered with Victrelis. 

Close monitoring of sirolimus blood 

concentrations is recommended 


function and sirolimus-related side 

effects. 

No dose adjustment of dabigatran 

is recommended. Patients receiving 

dabigatran should be monitored 

appropriately. 

oraL contraceptives 

Drospirenone/Ethinyl estradiol*: 

(drospirenone 

3 mg daily + ethinyl estradiol 

0.02 mg daily + Victrelis 800 mg 


Norethindrone † / 

Ethinyl estradiol 

(norethindrone 1 mg daily + 

ethinyl estradiol 0.035 mg daily 


daily) 

proton pUMp inhiBitor 

Omeprazole*: 

(omeprazole 40 mg daily + 


daily) 

drospirenone AUC 99% 

drospirenone C max 57% 

ethinyl estradiol AUC 24% 

ethinyl estradiol C max 

(drospirenone - CYP3A 

inhibition) 

norethindrone AUC 4% 

norethindrone C 17% 

max 

ethinyl estradiol AUC 26% 

ethinyl estradiol C max 21% 




omeprazole AUC 6%** 

omeprazole C max 3% 

omeprazole C8h 12% 

Caution should be exercised 

in patients with conditions that 

predispose them to hyperkalaemia 

or patients taking potassium-sparing 

diuretics (see section 4.4). Alternative 

contraceptives should be considered 

for these patients. 

Co-administration of Victrelis with 

an oral contraceptive containing 

ethinyl estradiol and at least 1 mg of 

norethindrone is unlikely to alter the 

contraceptive effectiveness. Indeed, 

serum progesterone, luteinizing 

hormone (LH) and follicle-stimulating 

hormone (FSH) levels indicated that 

ovulation was suppressed during coadministration 

of norethindrone 

1 mg/ethinyl estradiol 0.035 mg with 

Victrelis (see section 4.6). 

The ovulation suppression activity 

of oral contraceptives containing 

lower doses of norethindrone/ethinyl 

estradiol and of other forms of 

hormonal contraception during coadministration 

with Victrelis has not 

been established. 

Patients using oestrogens as 

hormone replacement therapy should 

be clinically monitored for signs of 

oestrogen deficiency. 

No dose adjustment of omeprazole 

or Victrelis is recommended.

sedatives 

Midazolam* (oral administration) 

(4 mg single oral dose + Victrelis 


Triazolam 

(oral administration) 

Alprazolam, midazolam, 

triazolam (intravenous 

administration) 

** 0-8 hours 

*** 0-12 hours 

† Also known as norethisterone. 

39 

midazolam AUC 430% 

midazolam C max 177% 


Interaction not studied 


Interaction not studied 


Co-administration of oral midazolam 

and oral triazolam with Victrelis is 

contraindicated (see section 4.3). 

Close clinical monitoring for 

respiratory depression and/or 

prolonged sedation should be 


of Victrelis with intravenous 

benzodiazepines (alprazolam, 

midazolam, triazolam). Dose 

adjustment of the benzodiazepine 

should be considered.

MSD Belgium BVBA/SPRL 

Lynx Binnenhof, 5, Clos du Lynx 

Brussel 1200 Bruxelles 

GAST-1056499-0002

Drug Drug Interactions with VICTRELIS® (boceprevir) Informative ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?