Olysio

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

OLYSIO 150 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains simeprevir sodium equivalent to 150 mg of simeprevir.

Excipient with known effect: each capsule contains 78.4 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule)

White gelatin capsule of approximately 22 mm in length, marked with “TMC435 150” in black ink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

OLYSIO is indicated in combination with other medicinal products for the treatment of chronic 
hepatitis C (CHC) in adult patients (see sections 4.2, 4.4 and 5.1).

For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.

4.2 Posology and method of administration

Treatment with OLYSIO should be initiated and monitored by a physician experienced in the 
management of CHC.

Posology
The recommended dosage of OLYSIO is one capsule of 150 mg once daily, taken with food.

OLYSIO must be used in combination with other medicinal products for the treatment of CHC (see 
section 5.1). When considering OLYSIO combination treatment with peginterferon alfa and ribavirin 
in HCV genotype 1a patients, patients should be tested for the presence of virus with the NS3 Q80K 
polymorphism before starting treatment (see section 4.4).
Refer also to the Summary of Product Characteristics of the medicinal products that are used in 
combination with OLYSIO.

The recommended co-administered medicinal product(s) and treatment duration for OLYSIO
combination therapy are provided in tables 1 and 2.

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Table 1: Recommended treatment duration for OLYSIO combination therapy with 
sofosbuvir with or without ribavirin in patients with HCV genotype 1 or 4

Patient population Treatment duration
Patients without cirrhosis 12 weeks OLYSIO + sofosbuvir
Patients with cirrhosis1 24 weeks OLYSIO + sofosbuvir

or
12 weeks OLYSIO + sofosbuvir + ribavirin2

12 weeks OLYSIO + sofosbuvir (without ribavirin) may be considered 
for patients deemed at low risk for clinical disease progression and 
who have subsequent retreatment options (see sections 4.4 and 5.1)

1
In HCV genotype 1a infected patients with cirrhosis, testing for the presence of the Q80K polymorphism may be 
considered prior to initiation of therapy with OLYSIO in combination with sofosbuvir (see section 4.4).

2
The daily dose of ribavirin is weight based (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg) and administered orally in 
two divided doses with food; also refer to the Summary of Product Characteristics of ribavirin.

Table 2: Recommended treatment duration for OLYSIO combination therapy with 
peginterferon alfa and ribavirin1 in HCV genotype 1 or 4

Patient population Treatment duration
Treatment-naïve and prior relapse patients2

with or without cirrhosis, who are 
not co-infected with HIV

24 weeks3

Treatment with OLYSIO must be initiated in combination 
with peginterferon alfa + ribavirin and administered for 
12 weeks and then followed by an additional 12 weeks of 
peginterferon alfa + ribavirin.

without cirrhosis, who are 
co-infected with HIV

with cirrhosis, who are 
co-infected with HIV

48 weeks3

Treatment with OLYSIO must be initiated in combination 
with peginterferon alfa + ribavirin and administered for 
12 weeks and then followed by an additional 36 weeks of 
peginterferon alfa and + ribavirin.

Prior non-responder patients (including partial and null responders)2

with or without cirrhosis, with or 
without HIV co-infection

48 weeks3

Treatment with OLYSIO must be initiated in combination 
with peginterferon alfa + ribavirin and administered for 
12 weeks and then followed by an additional 36 weeks of 
peginterferon alfa + ribavirin.

1
When considering OLYSIO combination treatment with peginterferon alfa and ribavirin in HCV genotype 1a patients, 
testing for NS3 Q80K polymorphism should be performed before starting treatment (see section 4.4).

2
Following prior treatment with interferon (pegylated or non-pegylated), with or without ribavirin (see section 5.1).

3
Recommended duration of treatment provided that patient does not meet a stopping rule (see table 3).

Refer to table 3 for treatment stopping rules based on HCV RNA levels at weeks 4, 12 and 24 for
patients receiving treatment with OLYSIO, peginterferon alfa and ribavirin.

Treatment discontinuation in patients with inadequate on-treatment virologic response
OLYSIO in combination with sofosbuvir
There are no virologic treatment stopping rules that apply to the combination of OLYSIO with 
sofosbuvir.

OLYSIO in combination with peginterferon alfa and ribavrin
It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained 
virologic response (SVR), therefore discontinuation of treatment is recommended in these patients. 

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The HCV RNA thresholds that trigger discontinuation of treatment (i.e., treatment stopping rules) are 
presented in table 3.

Table 3: Treatment stopping rules in patients receiving OLYSIO in combination with 
peginterferon alfa and ribavirin with inadequate on-treatment virologic response

HCV RNA Action
Treatment week 4: ≥ 25 IU/ml Discontinue OLYSIO, peginterferon alfa and ribavirin
Treatment week 12: ≥ 25 IU/ml1 Discontinue peginterferon alfa and ribavirin (treatment with 

OLYSIO is complete at week 12)
Treatment week 24: ≥ 25 IU/ml1 Discontinue peginterferon alfa and ribavirin
1

Re-evaluation of HCV RNA is recommended in case of HCV RNA ≥ 25 IU/ml after previous undetectable HCV RNA 
to confirm HCV RNA levels prior to discontinuing HCV treatment.

Dosage adjustment or interruption of OLYSIO treatment
To prevent treatment failure, the dose of OLYSIO must not be reduced or interrupted. If treatment 
with OLYSIO is discontinued because of adverse reactions or inadequate on-treatment virologic
response, OLYSIO treatment must not be reinitiated.

Dosage adjustment or interruption of medicinal products used in combination with OLYSIO for the 
treatment of CHC
If adverse reactions, potentially related to the medicinal products that are used in combination with 
OLYSIO for the treatment of CHC, require dosage adjustment or interruption of the medicinal 
product(s), refer to the instructions outlined in the respective Summary of Product Characteristics for 
these medicinal products.
If other medicinal products used in combination with OLYSIO for the treatment of CHC are 
permanently discontinued for any reason, OLYSIO must also be discontinued. When ribavirin is
added to the combination of OLYSIO and sofosbuvir, and ribavirin needs to be discontinued, 
treatment of OLYSIO with sofosbuvir without ribavirin can be continued (see section 5.1).

Missed dose
If a dose of OLYSIO is missed, and the patient notices within 12 hours of the usual dosing time, the 
patient should take the missed dose of OLYSIO with food as soon as possible and then take the next 
dose of OLYSIO at the regularly scheduled time.

If a dose of OLYSIO is missed by more than 12 hours after the usual dosing time, the patient should 
not take the missed dose of OLYSIO and should resume dosing of OLYSIO with food at the regularly 
scheduled time.

Special populations
Elderly (over 65 years of age)
There are limited data on the safety and efficacy of OLYSIO in patients older than 65 years. There are
no safety and efficacy data of OLYSIO in patients over the age of 75 years. No dose adjustment of 
OLYSIO is required in elderly patients (see section 5.2).

Renal impairment
No dose adjustment of OLYSIO is required in patients with mild or moderate renal impairment. 
Increased simeprevir exposures have been observed in individuals with severe renal impairment.
OLYSIO has not been studied in HCV infected patients with severe renal impairment (creatinine 
clearance below 30 ml/min) or end stage renal disease, including patients requiring haemodialysis. As 
exposure may be increased in HCV infected patients with severe renal impairment, caution is 
recommended when prescribing OLYSIO to these patients (see section 5.2).
Refer to the respective Summary of Product Characteristics of the medicinal products used in 
combination with OLYSIO regarding their use in patients with renal impairment.

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Hepatic impairment
No dose adjustment of OLYSIO is required in patients with mild hepatic impairment (Child-Pugh A).
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B 
or C) (see sections 4.4 and 5.2).

Race
No dose adjustment is necessary based on race (see section 5.2).

Paediatric population
The safety and efficacy of OLYSIO in children aged below 18 years have not yet been established. No 
data are available.

HCV/Human immunodeficiency virus type 1 (HIV-1) co-infection
No dose adjustment of OLYSIO is required in HCV/HIV-1 co-infected patients (see sections 4.8, 5.1 
and 5.2).

OLYSIO in combination with sofosbuvir: HCV/HIV-1 co-infected patients should be treated for the 
same duration as HCV mono-infected patients.

OLYSIO in combination with peginterferon alfa and ribavirin: HCV/HIV-1 co-infected patients 
should be treated for the same duration as HCV mono-infected patients, except for co-infected patients 
with cirrhosis who should receive 36 weeks of treatment with peginterferon alfa and ribavirin after 
completing 12 weeks of treatment with OLYSIO, peginterferon alfa and ribavirin (total treatment 
duration of 48 weeks).

Please refer to sections 4.4 and 4.5 for relevant interactions with antiretroviral agents.

Method of administration
OLYSIO must be taken orally once a day with food (see section 5.2). The capsule should be 
swallowed as a whole.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

General
The efficacy of OLYSIO has not been studied in patients with HCV genotypes 2, 3, 5 or 6; therefore 
OLYSIO should not be used in these patients (see section 5.1).

OLYSIO must not be administered as monotherapy and must be prescribed in combination with other 
medicinal products for the treatment of CHC.

Consult the Summary of Product Characteristics of the co-prescribed medicinal products before 
starting therapy with OLYSIO. Warnings and precautions related to these medicinal products also 
apply to their use in OLYSIO combination treatment.

There are no clinical data on the use of OLYSIO in re-treating patients who have failed an HCV 
NS3-4A protease inhibitor-based therapy (see sections 5.1 and 5.3).

Hepatic decompensation and hepatic failure
Hepatic decompensation and hepatic failure, including fatal cases, have been reported post-marketing 
in patients treated with OLYSIO in combination with peginterferon alfa and ribavirin and in 
combination with sofosbuvir. Although causality is difficult to establish due to background advanced 
liver disease, a potential risk cannot be excluded.

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Therefore, in patients who are at high risk for hepatic decompensation or hepatic failure, liver function 
tests should be monitored before and as clinically indicated during OLYSIO combination therapy.

Hepatic impairment
OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B 
or C) (see sections 4.2, 4.8 and 5.2).

Severe bradycardia and heart block
Cases of bradycardia have been observed when OLYSIO is used in combination with sofosbuvir and 
concomitant amiodarone. The mechanism is not established.
Cases are potentially life threatening, therefore amiodarone should only be used in patients on 
OLYSIO combination treatment with sofosbuvir when other alternative antiarrhythmic treatments are 
not tolerated or are contraindicated.
Should concomitant use of amiodarone be considered necessary, it is recommended that patients are 
closely monitored when initiating OLYSIO combination treatment with sofosbuvir. Patients who are 
identified as being at high risk of bradyarrhythmia should be continuously monitored for 48 hours in 
an appropriate clinical setting.
Due to the long elimination half-life of amiodarone, appropriate monitoring should also be carried out 
for patients who have discontinued amiodarone within the past few months and are to be initiated on 
OLYSIO combination treatment with sofosbuvir.
All patients receiving OLYSIO combination treatment with sofosbuvir in combination with 
amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms 
of bradycardia and heart block and should be advised to seek medical advice urgently should they 
experience them.

Pre-treatment testing for NS3 Q80K polymorphism in patients infected with HCV genotype 1a
OLYSIO in combination with sofosbuvir
In HCV genotype 1a infected patients with cirrhosis, testing for the presence of the NS3 Q80K 
polymorphism may be considered prior to initiation of therapy with OLYSIO in combination with 
sofosbuvir (see section 5.1).
In HCV genotype 1a infected patients without cirrhosis, simeprevir efficacy in combination with 
sofosbuvir at the recommended 12-week treatment duration was not impacted by the presence of the 
NS3 Q80K polymorphism (see section 5.1).

OLYSIO in combination with peginterferon alfa and ribavirin
Simeprevir efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in 
patients infected with hepatitis C genotype 1a with the NS3 Q80K polymorphism at baseline 
compared to patients with hepatitis C genotype 1a without the Q80K polymorphism (see section 5.1). 
Testing for the presence of the Q80K polymorphism in patients with HCV genotype 1a is strongly 
recommended when considering therapy with OLYSIO in combination with peginterferon alfa and 
ribavirin. Alternative therapy should be considered for patients infected with HCV genotype 1a with 
the Q80K polymorphism or in cases where testing is not accessible.

Co-administration with other direct acting antivirals against HCV
OLYSIO should only be co-administered with other direct acting antiviral medicinal products if the 
benefits are considered to outweigh the risks based upon available data. There are no data to support 
the co-administration of OLYSIO and telaprevir or boceprevir. These HCV protease inhibitors are 
anticipated to be cross-resistant, and co-administration is not recommended (see also section 4.5).

OLYSIO in combination with peginterferon alfa-2b
In the clinical studies, patients randomised to simeprevir in combination with peginterferon alfa-2b 
and ribavirin obtained numerically lower SVR12 rates and also experienced viral breakthrough and 
viral relapse more frequently than those treated with simeprevir in combination with peginterferon 
alfa-2a and ribavirin (see section 5.1).

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Pregnancy and contraception
OLYSIO should only be used during pregnancy or in women of childbearing potential if the benefit 
justifies the risk. Female patients of childbearing potential must use an effective form of contraception 
(see section 4.6).

The contraindications and warnings regarding pregnancy and contraception requirements applicable to 
the co-administered medicinal products also apply to their use in OLYSIO combination treatment.

Ribavirin may cause birth defects and/or death of the exposed foetus. Therefore, extreme care must be 
taken to avoid pregnancy in female patients and in female partners of male patients (see section 4.6).

Photosensitivity
Photosensitivity reactions have been observed with OLYSIO combination treatment (see section 4.8).
Patients should be informed of the risk of photosensitivity reactions and on the importance of applying 
appropriate sun protective measures during treatment with OLYSIO. Excess exposure to sun and use 
of tanning devices during treatment with OLYSIO should be avoided. If photosensitivity reactions
occur, discontinuation of OLYSIO should be considered and patients should be monitored until the 
reaction has resolved.

Rash
Rash has been observed with OLYSIO combination treatment (see section 4.8). Patients with mild to 
moderate rashes should be monitored for possible progression of rash, including the development of 
mucosal signs or systemic symptoms. In case of severe rash, OLYSIO and other co-administered 
medicinal products for the treatment of CHC should be discontinued and the patients should be 
monitored until the symptoms have resolved.

Laboratory testing during treatment with OLYSIO, peginterferon alfa and ribavirin
HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated (see also 
guidelines for treatment duration and stopping rules; section 4.2). Use of a sensitive quantitative 
HCV RNA assay for monitoring HCV RNA levels during treatment is recommended.
Refer to the Summary of Product Characteristics of peginterferon alfa and ribavirin for pre-treatment, 
on-treatment and post-treatment laboratory testing requirements including haematology, biochemistry 
(including hepatic enzymes and bilirubin), and pregnancy testing requirements.

Interactions with medicinal products
Co-administration of OLYSIO with substances that moderately or strongly induce or inhibit 
cytochrome P450 3A (CYP3A4) is not recommended as this may lead to significantly lower or higher
exposure of simeprevir, respectively.
Please refer to section 4.5 for information on interactions with medicinal products.

Hepatitis B virus (HBV) co-infection
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before 
initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should 
therefore be monitored and managed according to current clinical guidelines.

Organ transplant patients
Co-administration of OLYSIO with ciclosporin is not recommended as this leads to significantly 
higher exposure of simeprevir (see section 4.5).

Excipient of OLYSIO capsules
OLYSIO capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine.

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4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products that affect simeprevir exposure
The primary enzyme involved in the biotransformation of simeprevir is CYP3A4 (see section 5.2) and 
clinically relevant effects of other medicinal products on simeprevir pharmacokinetics via CYP3A4
may occur. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A4 may 
significantly increase the plasma exposure of simeprevir, while co-administration with moderate or 
strong inducers of CYP3A4 may significantly reduce the plasma exposure of simeprevir and lead to 
loss of efficacy (see table 4). Therefore, co-administration of OLYSIO with substances that 
moderately or strongly inhibit or induce CYP3A4 is not recommended.
Hepatic uptake of simeprevir is mediated by OATP1B1/3. Inhibitors of OATP1B1/3 such as 
eltrombopag or gemfibrozil may result in increases in simeprevir plasma concentrations.

Medicinal products that are affected by the use of simeprevir
Simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not 
affect hepatic CYP3A4 activity. Co-administration of OLYSIO with medicinal products that are 
primarily metabolised by CYP3A4 may result in increased plasma concentrations of such medicinal 
products (see table 4). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo.
Simeprevir inhibits OATP1B1/3, P-gp and BCRP transporters. Co-administration of OLYSIO with 
medicinal products that are substrates for OATP1B1/3, P-gp and BCRP transport may result in 
increased plasma concentrations of such medicinal products (see table 4).

Patients treated with vitamin K antagonists
As liver function may change during treatment with OLYSIO, close monitoring of International 
Normalised Ratio (INR) values is recommended.

Interaction table
Established and theoretical interactions between simeprevir and selected medicinal products are listed 
in table 4 (least square mean ratios with 90% confidence intervals (90% CI) are presented, increase is 
indicated as “↑”, decrease as “↓”, no change as “↔”). Interaction studies have been performed in 
healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted.

Table 4: Interactions and dose recommendation with other medicinal products

Medicinal products 
by therapeutic areas

Effect on drug levels
Least Squares Mean Ratio (90%CI)

Recommendation for 
co-administration

ANALEPTIC
Caffeine
150 mg

caffeine AUC 1.26 (1.21-1.32) ↑
caffeine Cmax 1.12 (1.06-1.19) ↔
caffeine Cmin not studied

No dose adjustment is 
required.

ANTIARRHYTHMICS
Digoxin
0.25 mg

digoxin AUC 1.39 (1.16-1.67) ↑
digoxin Cmax 1.31 (1.14-1.51) ↑
digoxin Cmin not studied

(inhibition of P-gp transporter)

Concentrations of digoxin 
should be monitored and 
used for titration of 
digoxin dose to obtain the 
desired clinical effect.

Amiodarone Not studied. Mild increases in concentrations of 
amiodarone may be expected when amiodarone 
is administered orally.

(intestinal CYP3A4 enzyme inhibition)

Mild increases in simeprevir concentrations may 
occur due to inhibition of CYP3A4 by 
amiodarone.

Treatment regimen not 
containing sofosbuvir:
Caution is warranted and 
therapeutic drug 
monitoring for 
amiodarone and/or clinical 
monitoring (ECG etc.) 
when orally administered 
are recommended.

Treatment regimen with 

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sofosbuvir:
Use only if no other 
alternative is available. 
Close monitoring is 
recommended if this 
medicinal product is 
administered with 
OLYSIO in combination 
with sofosbuvir (see 
section 4.4).

Disopyramide
Flecainide
Mexiletine
Propafenone
Quinidine

Not studied. Mild increases in concentrations of 
these antiarrhythmics may be expected when 
these medicinal products are administered orally.

(intestinal CYP3A4 enzyme inhibition)

Caution is warranted and 
therapeutic drug 
monitoring for these 
antiarrhythmics and/or 
clinical monitoring (ECG 
etc.) when orally 
administered are 
recommended.

ANTICOAGULANTS
Warfarin and other 
vitamin K antagonists

warfarin 10 mg:
S-warfarin AUC 1.04 (1.00-1.07) ↔
S-warfarin Cmax 1.00 (0.94-1.06) ↔
S-warfarin Cmin not studied

While no change in the 
pharmacokinetics of 
warfarin is expected, close 
monitoring of INR is 
recommended with all 
vitamin K antagonists. 
This is due to potential 
liver function changes 
during treatment with 
OLYSIO.

ANTICONVULSANTS
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin

Not studied. Significant decrease in plasma 
concentrations of simeprevir are expected.

(strong CYP3A4 induction)

It is not recommended to 
co-administer OLYSIO 
with these anticonvulsants 
as co-administration may 
result in loss of 
therapeutic effect of 
OLYSIO.

ANTIDEPRESSANTS
Escitalopram
10 mg once daily

escitalopram AUC 1.00 (0.97-1.03) ↔
escitalopram Cmax 1.03 (0.99-1.07) ↔
escitalopram Cmin 1.00 (0.95-1.05) ↔
simeprevir AUC 0.75 (0.68-0.83) ↓
simeprevir Cmax 0.80 (0.71-0.89) ↓
simeprevir Cmin 0.68 (0.59-0.79) ↓

No dose adjustment is 
required.

ANTIHISTAMINES
Astemizole
Terfenadine

Not studied. Astemizole and terfenadine have 
the potential for cardiac arrhythmias. Mild 
increases in concentrations of these 
antihistamines may be expected.

(intestinal CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with astemizole or 
terfenadine.

ANTI-INFECTIVES
Antibiotics – macrolides (systemic administration)
Azithromycin Not studied. Based on the elimination pathway 

of azithromycin, no drug interactions are 
expected between azithromycin and simeprevir.

No dose adjustment is 
required.

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Erythromycin
500 mg three times a 
day

erythromycin AUC 1.90 (1.53-2.36) ↑
erythromycin Cmax 1.59 (1.23-2.05) ↑
erythromycin Cmin 3.08 (2.54-3.73) ↑
simeprevir AUC 7.47 (6.41-8.70) ↑
simeprevir Cmax 4.53 (3.91-5.25) ↑
simeprevir Cmin 12.74 (10.19-15.93) ↑

(inhibition of CYP3A4 enzymes and P-gp 
transporter by both erythromycin and 
simeprevir)

It is not recommended to 
co-administer OLYSIO 
with systemic 
erythromycin.

Clarithromycin
Telithromycin

Not studied. Increased plasma concentrations of 
simeprevir are expected.

(strong CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with clarithromycin or 
telithromycin.

Antifungals (systemic administration)
Itraconazole
Ketoconazole*
Posaconazole

Not studied. Significant increases in plasma 
concentrations of simeprevir are expected.

(strong CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with systemic 
itraconazole, ketoconazole 
or posaconazole.

Fluconazole
Voriconazole

Not studied. Significant increases in plasma 
concentrations of simeprevir are expected.

(mild to moderate CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with systemic fluconazole 
or voriconazole.

Antimycobacterials
Bedaquiline Not studied. No clinically relevant drug-drug 

interaction is expected.
No dose adjustment is 
required.

Rifampicin1

600 mg once daily
rifampicin AUC 1.00 (0.93-1.08) ↔
rifampicin Cmax 0.92 (0.80-1.07) ↔
rifampicin Cmin not studied
25-desacetyl-rifampicin AUC 1.24 (1.13-1.36) ↑
25-desacetyl-rifampicin Cmax 1.08 (0.98-1.19) ↔
25-desacetyl-rifampicin Cmin not studied
simeprevir AUC 0.52 (0.41-0.67) ↓
simeprevir Cmax 1.31 (1.03-1.66) ↑
simeprevir Cmin 0.08 (0.06-0.11) ↓

(CYP3A4 enzyme induction)

It is not recommended to 
co-administer OLYSIO 
with rifampicin as 
co-administration may 
result in loss of 
therapeutic effect of 
OLYSIO.

Rifabutin
Rifapentine

Not studied. Significant decreases in plasma 
concentrations of simeprevir are expected.

(CYP3A4 enzyme induction)

It is not recommended to 
co-administer OLYSIO 
with rifabutin or 
rifapentine as 
co-administration may 
result in loss of 
therapeutic effect of 
OLYSIO.

ANTITUSSIVE
Dextromethorphan 
(DXM)
30 mg

DXM AUC 1.08 (0.87-1.35) ↑
DXM Cmax 1.21 (0.93-1.57) ↑
DXM Cmin not studied
dextrorphan AUC 1.09 (1.03-1.15) ↔
dextrorphan Cmax 1.03 (0.93-1.15) ↔
dextrorphan Cmin not studied

No dose adjustment is 
required.Me

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CALCIUM CHANNEL BLOCKERS (oral administration)
Amlodipine
Bepridil
Diltiazem
Felodipine
Nicardipine
Nifedipine
Nisoldipine
Verapamil

Not studied. Increased plasma concentrations of 
orally administered calcium channel blockers 
may be expeced.

(intestinal CYP3A4 enzyme and P-gp transporter 
inhibition)

Increased simeprevir concentrations may occur 
due to mild inhibition of CYP3A4 by amlodipine 
and moderate inhibition of CYP3A4 by 
diltiazem and verapamil.

Caution is warranted and 
clinical monitoring of 
patients is recommended
when these calcium 
channel blockers are given 
orally.

GLUCOCORTICOIDS
Dexamethasone 
(systemic)

Not studied. Decreased plasma concentrations of 
simeprevir are expected.

(moderate CYP3A4 enzyme induction)

It is not recommended to 
co-administer OLYSIO 
with systemic 
dexamethasone as 
co-administration may 
result in loss of 
therapeutic effect of 
OLYSIO.

Budesonide
Fluticasone
Methylprednisolone
Prednisone

Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

GASTROINTESTINAL PRODUCTS
Antacid
Aluminium or 
Magnesium hydroxide
Calcium carbonate

Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

H2-receptor antagonists
Cimetidine
Nizatidine
Ranitidine

Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

Propulsive
Cisapride Not studied. Cisapride has the potential to cause 

cardiac arrhythmias. Increased concentrations of 
cisapride may be possible.

(intestinal CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with cisapride.

Proton pump inhibitors
Omeprazole
40 mg

omeprazole AUC 1.21 (1.00-1.46) ↑
omeprazole Cmax 1.14 (0.93-1.39) ↑
omeprazole Cmin not studied

No dose adjustment is 
required.

Dexlansoprazole
Esomeprazole
Lansoprazole
Pantoprazole
Rabeprazole

Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

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HCV PRODUCTS
Antiviral 
Daclatasvir
60 mg once daily

daclatasvir AUC 1.96 (1.84-2.10) ↑
daclatasvir Cmax 1.50 (1.39-1.62) ↑
daclatasvir Cmin 2.68 (2.42-2.98) ↑
simeprevir AUC 1.44 (1.32-1.56) ↑
simeprevir Cmax 1.39 (1.27-1.52) ↑
simeprevir Cmin 1.49 (1.33-1.67) ↑

No dose adjustment of 
daclatasvir or OLYSIO is 
required.

Ledipasvir2

90 mg once daily
ledipasvir AUC 1.75 (1.56-1.96) ↑
ledipasvir Cmax 1.64 (1.45-1.86) ↑
ledipasvir Cmin 1.74 (1.55-1.97) ↑
simeprevir AUC 3.05 (2.43-3.84) ↑
simeprevir Cmax 2.34 (1.95-2.81) ↑
simeprevir Cmin 4.69 (3.40-6.47) ↑

It is not recommended to 
co-administer OLYSIO 
with a 
ledipasvir-containing 
medicinal product.

Sofosbuvir3

400 mg once daily
sofosbuvir AUC 3.16 (2.25-4.44) ↑
sofosbuvir Cmax 1.91 (1.26-2.90) ↑
sofosbuvir Cmin not studied
GS-331007 AUC 1.09 (0.87-1.37) ↔
GS-331007 Cmax 0.69 (0.52-0.93) ↓
GS-331007 Cmin not studied
simeprevir AUC 0.94 (0.67-1.33) ↔
simeprevir Cmax 0.96 (0.71-1.30) ↔
simeprevir Cmin not studied

Increase in sofosbuvir 
exposure observed in the 
pharmacokinetic substudy 
is not clinically relevant.

HERBAL PRODUCTS
Milk thistle (Silybum 
marianum)

Not studied. Increased plasma concentrations of 
simeprevir are expected.

(CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with milk thistle.

St John's wort 
(Hypericum 
perforatum)

Not studied. Significantly decreased plasma 
concentrations of simeprevir are expected.

(CYP3A4 enzyme induction)

It is not recommended to 
co-administer OLYSIO 
with products containing 
St John’s wort as 
co-administration may 
result in loss of 
therapeutic effect of 
OLYSIO.

HIV PRODUCTS
Antiretroviral – CCR5 antagonist
Maraviroc Not studied. No clinically relevant drug-drug 

interaction is expected.
No dose adjustment is 
required for either drug 
when OLYSIO is 
co-administered with 
maraviroc.

Antiretroviral – integrase inhibitor
Raltegravir
400 mg twice a day

raltegravir AUC 1.08 (0.85-1.38) ↑
raltegravir Cmax 1.03 (0.78-1.36) ↔
raltegravir Cmin 1.14 (0.97-1.36) ↑
simeprevir AUC 0.89 (0.81-0.98) ↔
simeprevir Cmax 0.93 (0.85-1.02) ↔
simeprevir Cmin 0.86 (0.75-0.98) ↓

No dose adjustment is 
required.

Dolutegravir Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

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Antiretroviral – non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily

efavirenz AUC 0.90 (0.85-0.95) ↔
efavirenz Cmax 0.97 (0.89-1.06) ↔
efavirenz Cmin 0.87 (0.81-0.93) ↔
simeprevir AUC 0.29 (0.26-0.33) ↓
simeprevir Cmax 0.49 (0.44-0.54) ↓
simeprevir Cmin 0.09 (0.08-0.12) ↓

(CYP3A4 enzyme induction)

It is not recommended to 
co-administer OLYSIO 
with efavirenz as 
co-administration may 
result in loss of 
therapeutic effect of 
OLYSIO.

Rilpivirine
25 mg once daily

rilpivirine AUC 1.12 (1.05-1.19) ↔
rilpivirine Cmax 1.04 (0.95-1.13) ↔
rilpivirine Cmin 1.25 (1.16-1.35) ↑
simeprevir AUC 1.06 (0.94-1.19) ↔
simeprevir Cmax 1.10 (0.97-1.26) ↑
simeprevir Cmin 0.96 (0.83-1.11) ↔

No dose adjustment is 
required.

Other NNRTIs
(Delavirdine, 
Etravirine,
Nevirapine)

Not studied. Altered plasma concentrations of 
simeprevir are expected.

(CYP3A4 enzyme induction [etravirine or 
nevirapine] or inhibition [delavirdine])

It is not recommended to 
co-administer OLYSIO 
with delavirdine, 
etravirine or nevirapine.

Antiretroviral – nucleoside or nucleotide reverse transcriptase inhibitors (N(t)RTIs)
Tenofovir disoproxil 
fumarate
300 mg once daily

tenofovir AUC 1.18 (1.13-1.24) ↔
tenofovir Cmax 1.19 (1.10-1.30) ↑
tenofovir Cmin 1.24 (1.15-1.33) ↑
simeprevir AUC 0.86 (0.76-0.98) ↓
simeprevir Cmax 0.85 (0.73-0.99) ↓
simeprevir Cmin 0.93 (0.78-1.11) ↓

No dose adjustment is 
required.

Other NRTIs
(Abacavir, 
Didanosine, 
Emtricitabine,
Lamivudine, 
Stavudine, 
Zidovudine)

Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

Antiretroviral – protease inhibitors (PIs)
Darunavir/ritonavir4

800/100 mg once 
daily

darunavir AUC 1.18 (1.11-1.25) ↑
darunavir Cmax 1.04 (0.99-1.10) ↔
darunavir Cmin 1.31 (1.13-1.52) ↑
ritonavir AUC 1.32 (1.25-1.40) ↑
ritonavir Cmax 1.23 (1.14-1.32) ↑
ritonavir Cmin 1.44 (1.30-1.61) ↑
simeprevir AUC 2.59 (2.15-3.11) ↑*
simeprevir Cmax 1.79 (1.55-2.06) ↑*
simeprevir Cmin 4.58 (3.54-5.92) ↑*

* darunavir/ritonavir + 50 mg simeprevir compared to 
150 mg simeprevir alone.

(strong CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with darunavir/ritonavir.

Ritonavir1

100 mg twice daily
simeprevir AUC 7.18 (5.63-9.15) ↑
simeprevir Cmax 4.70 (3.84-5.76) ↑
simeprevir Cmin 14.35 (10.29-20.01) ↑

(strong CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with ritonavir.

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Other 
ritonavir-boosted or 
unboosted HIV PIs 
(Atazanavir, 
(Fos)amprenavir, 
Lopinavir, Indinavir, 
Nelfinavir, 
Saquinavir, 
Tipranavir)

Not studied. Altered plasma concentrations of 
simeprevir are expected.

(CYP3A4 enzyme induction or inhibition)

It is not recommended to 
co-administer OLYSIO 
with any HIV PI, with or 
without ritonavir.

Cobicistat-containing 
medicinal products

Not studied. Significantly increased plasma 
concentrations of simeprevir are expected.

(strong CYP3A4 enzyme inhibition)

It is not recommended to 
co-administer OLYSIO 
with cobicistat-containing 
medicinal products.

HMG CO-A REDUCTASE INHIBITORS
Rosuvastatin
10 mg

rosuvastatin AUC 2.81 (2.34-3.37) ↑
rosuvastatin Cmax 3.17 (2.57-3.91) ↑
rosuvastatin Cmin not studied

(OATP1B1/3, BCRP transporter inhibition)

Titrate the rosuvastatin 
dose carefully and use the 
lowest necessary dose 
while monitoring for 
safety when 
co-administered with 
OLYSIO.

Pitavastatin
Pravastatin

Not studied. Increased plasma concentrations of 
pitavastatin and pravastatin are expected.

(OATP1B1/3 transporter inhibition)

Titrate the pitavastatin and 
pravastatin dose carefully 
and use the lowest 
necessary dose while 
monitoring for safety 
when co-administered 
with OLYSIO.

Atorvastatin
40 mg

atorvastatin AUC 2.12 (1.72-2.62) ↑
atorvastatin Cmax 1.70 (1.42-2.04) ↑
atorvastatin Cmin not studied
2-OH-atorvastatin AUC 2.29 (2.08-2.52) ↑
2-OH-atorvastatin Cmax 1.98 (1.70-2.31) ↑
2-OH-atorvastatin Cmin not studied

(OATP1B1/3 transporter and/or CYP3A4 
enzyme inhibition)

Increased simeprevir concentrations may occur 
due to inhibition of OATP1B1 by atorvastatin.

Titrate the atorvastatin 
dose carefully and use the 
lowest necessary dose 
while monitoring for 
safety when 
co-administered with 
OLYSIO.

Simvastatin
40 mg

simvastatin AUC 1.51 (1.32-1.73) ↑
simvastatin Cmax 1.46 (1.17-1.82) ↑
simvastatin Cmin not studied
simvastatin acid AUC 1.88 (1.63-2.17) ↑
simvastatin acid Cmax 3.03 (2.49-3.69) ↑
simvastatin acid Cmin not studied

(OATP1B1 transporter and/or CYP3A4 enzyme 
inhibition)

Titrate the simvastatin 
dose carefully and use the 
lowest necessary dose 
while monitoring for 
safety when 
co-administered with 
OLYSIO.

Lovastatin Not studied. Increased plasma concentrations of 
lovastatin are expected.

(OATP1B1 transporter and/or CYP3A4 enzyme 
inhibition)

Titrate the lovastatin dose 
carefully and use the 
lowest necessary dose 
while monitoring for 
safety when 
co-administered with 
OLYSIO.

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Fluvastatin Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

HORMONAL CONTRACEPTIVES
Ethinylestradiol and 
norethindrone
0.035 mg once daily/
1 mg once daily

ethinylestradiol AUC 1.12 (1.05-1.20) ↔
ethinylestradiol Cmax 1.18 (1.09-1.27) ↑
ethinylestradiol Cmin 1.00 (0.89-1.13) ↔
norethindrone AUC 1.15 (1.08-1.22) ↔
norethindrone Cmax 1.06 (0.99-1.14) ↔
norethindrone Cmin 1.24 (1.13-1.35) ↑

No dose adjustment is 
required.

IMMUNOSUPPRESSANTS
Ciclosporin
100 mg

patient individualised 
dose5

ciclosporin AUC 1.19 (1.13-1.26) ↑
ciclosporin Cmax 1.16 (1.07-1.26) ↑
ciclosporin Cmin not studied
simeprevir AUC 5.68 (3.58-9.00) ↑6

simeprevir Cmax 4.53 (3.05-6.74) ↑
6

simeprevir Cmin not studied
6

(OATP1B1/3, P-gp and CYP3A inhibition by 
ciclosporin)

It is not recommended to 
co-administer OLYSIO 
with ciclosporin.

Tacrolimus
2 mg

patient individualised 
dose5

tacrolimus AUC 0.83 (0.59-1.16) ↓
tacrolimus Cmax 0.76 (0.65-0.90) ↓
tacrolimus Cmin not studied
simeprevir AUC 1.90 (1.37-2.63) ↑7

simeprevir Cmax 1.85 (1.40-2.46) ↑
7

simeprevir Cmin not studied
7

(OATP1B1 inhibition by tacrolimus)

No dose adjustment is 
required for either drug 
when OLYSIO is 
co-administered with 
tacrolimus. Monitoring of 
blood concentrations of 
tacrolimus is 
recommended.

Sirolimus Not studied. Mild increased or decreased plasma 
concentrations of sirolimus may occur.

Monitoring of blood 
concentrations of 
sirolimus is 
recommended.

NARCOTIC ANALGESICS
Methadone8

30-150 mg once daily, 
individualised dose

R(-) methadone AUC 0.99 (0.91-1.09) ↔
R(-) methadone Cmax 1.03 (0.97-1.09) ↔
R(-) methadone Cmin 1.02 (0.93-1.12) ↔

No dose adjustment is 
required.

Buprenorphine
Naloxone

Not studied. No clinically relevant drug-drug 
interaction is expected.

No dose adjustment is 
required.

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PHOSPHODIESTERASE TYPE 5 INHIBITORS
Sildenafil
Tadalafil
Vardenafil

Not studied. Mild increases in concentrations of 
PDE-5 inhibitors may be expected.

(intestinal CYP3A4 enzyme inhibition)

Mild increases in simeprevir concentrations may 
occur due to mild inhibition of OATP1B1 by 
sildenafil.

No dose adjustment is 
required when OLYSIO is 
co-administered with 
doses of sildenafil, 
vardenafil, or tadalafil 
indicated for the treatment 
of erectile dysfunction.

Dose adjustment of the 
PDE-5 inhibitor may be 
required when OLYSIO is 
co-administered with 
sildenafil or tadalafil 
administered chronically 
at doses used for the 
treatment of pulmonary 
arterial hypertension. 
Consider starting with the 
lowest dose of the PDE-5 
inhibitor and increase as 
needed, with clinical 
monitoring as appropriate.

SEDATIVES/ANXIOLYTICS
Midazolam
Oral: 0.075 mg/kg
Intravenous: 
0.025 mg/kg

Oral:
midazolam AUC 1.45 (1.35-1.57) ↑
midazolam Cmax 1.31 (1.19-1.45) ↑
midazolam Cmin not studied

Intravenous:
midazolam AUC 1.10 (0.95-1.26) ↑
midazolam Cmax 0.78 (0.52-1.17) ↓
midazolam Cmin not studied

(mild intestinal CYP3A4 enzyme inhibition)

Plasma concentrations of 
midazolam were not 
affected when 
administered 
intravenously as 
simeprevir does not inhibit 
hepatic CYP3A4.
Caution is warranted when 
this medicinal product 
with narrow therapeutic 
index is co-administered 
with OLYSIO via the oral 
route.

Triazolam (oral) Not studied. Mild increases in concentrations of 
triazolam may be expected.

(intestinal CYP3A4 enzyme inhibition)

Caution is warranted when 
this medicinal product 
with narrow therapeutic 
index is co-administered 
with OLYSIO via the oral 
route.

STIMULANTS
Methylphenidate Not studied. No clinically relevant drug-drug 

interaction is expected.
No dose adjustment is 
required.

The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) for each pharmacokinetic parameter is based on the 
90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 0.80 - 1.25 range.
1

This interaction study has been performed with a dose higher than the recommended dose for simeprevir assessing the 
maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of 
simeprevir 150 mg once daily.

2
The interaction between simeprevir and the medicinal product was evaluated in a phase 2 pharmacokinetic study in 
20 HCV-infected patients.

3
Comparison based on historic controls. The interaction between simeprevir and the medicinal product was evaluated in 
a pharmacokinetic substudy within a phase 2 study in 22 HCV infected patients.

4
The dose of simeprevir in this interaction study was 50 mg when co-administered in combination with 
darunavir/ritonavir, compared to 150 mg in the simeprevir alone treatment group.

5
Patient individualised dose at the discretion of the physician, according to local clinical practice.

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6
Comparison based on historic controls. Data from a phase 2 study in 9 HCV infected post-liver transplant patients.

7
Comparison based on historic controls. Data from a phase 2 study in 11 HCV infected post-liver transplant patients.

8
The interaction between simeprevir and the medicinal product was evaluated in a pharmacokinetic study in 
opioid-dependent adults on stable methadone maintenance therapy.

* Ketoconazole: pending further ATC classification.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no adequate and well-controlled studies with simeprevir in pregnant women. Studies in 
animals have shown reproductive effects (see section 5.3). OLYSIO should only be used during
pregnancy or in women of childbearing potential if the benefit justifies the risk. Female patients of 
childbearing potential must use an effective form of contraception.

Because OLYSIO must be co-administered with other medicinal products, for the treatment of CHC, 
the contraindications and warnings applicable to those medicinal products also apply to their use in 
combination treatment with OLYSIO (see section 4.3).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species 
exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female 
partners of male patients. Female patients of childbearing potential and male patients with female 
partners of childbearing potential must use an effective form of contraception during treatment with 
ribavirin and after completion of ribavirin treatment for a duration as specified in the Summary of 
Product Characteristics for ribavirin.

Breast-feeding
It is not known whether simeprevir or its metabolites are excreted in human milk. When administered 
to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of 
simeprevir via milk (see section 5.3). A risk to the newborn/infant cannot be excluded. A decision 
must be made whether to discontinue breast-feeding or to discontinue/abstain from OLYSIO therapy,
taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility
There are no data on the effect of simeprevir on human fertility. No effects on fertility were observed 
in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

OLYSIO has no or negligible influence on the ability to drive and use machines. Combination 
treatment of OLYSIO with other medicinal products for the treatment of CHC may affect a patient’s 
ability to drive and use machines. Refer to the Summary of Product Characteristics for these 
co-administered medicinal products regarding their potential effect on the ability to drive and use 
machines.

4.8 Undesirable effects

Summary of the safety profile
The overall safety profile of simeprevir is based on data from 580 HCV genotype 1 infected patients 
who received simeprevir in combination with sofosbuvir with or without ribavirin (pooled data from 
the clinical phase 2 study HPC2002 and the clinical phase 3 studies HPC3017 and HPC3018) and
1,486 HCV genotype 1 infected patients who received simeprevir (or placebo) in combination with 
peginterferon alfa and ribavirin (pooled data from the clinical phase 2 studies C205 and C206 and the 
clinical phase 3 studies C208, C216 and HPC3007).

The safety profile of simeprevir is comparable in patients with HCV genotype 4 infection and HCV 
genotype 1 infection, when given either in combination with sofosbuvir or in combination with 
peginterferon alfa and ribavirin.

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Simeprevir in combination with sofosbuvir
The safety profile of simeprevir in combination with sofosbuvir in patients with HCV genotype 1 
infection with or without cirrhosis is based on pooled data from the phase 2 study HPC2002 and the 
phase 3 studies HPC3017 and HPC3018 which included 472 patients who received simeprevir with 
sofosbuvir without ribavirin (155, 286 and 31 patients received 8, 12 or 24 weeks of treatment, 
respectively) and 108 patients who received simeprevir with sofosbuvir and ribavirin (54 patients each 
received 12 or 24 weeks of treatment).

The majority of the adverse reactions reported were grade 1 in severity. Grade 2 and 3 adverse 
reactions were reported in 3.5% (n = 10) and 0.3% (n = 1) of patients, respectively, receiving 12 weeks 
simeprevir with sofosbuvir; no grade 4 adverse reactions were reported. In patients receiving 24 weeks 
simeprevir with sofosbuvir, no grade 2 or 3 adverse reactions were reported; one patient (3.2%) 
experienced a grade 4 adverse reaction (‘blood bilirubin increased’). No serious adverse reactions 
were reported.

The most frequently reported adverse reactions (incidence ≥ 5% following 12 or 24 weeks of 
treatment) were rash, pruritus, constipation and photosensitivity reaction (see section 4.4).

One patient in the 12-week treatment group (0.3%) and none of the patients in the 24-week treatment 
group discontinued treatment due to adverse reactions.

Simeprevir in combination with peginterferon alfa and ribavirin
The safety profile of simeprevir in combination with peginterferon alfa and ribavirin in patients with 
HCV genotype 1 infection is based on the pooled data from the phase 2 studies and phase 3 
studies C205, C206, C208, C216 and HPC3007 which included 924 patients who received simeprevir 
150 mg once daily for 12 weeks and 540 patients who received placebo with peginterferon alfa and 
ribavirin.

In the pooled phase 3 safety data, the majority of the adverse reactions reported during 12 weeks 
treatment with simeprevir were grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported 
in 3.1% of patients receiving simeprevir with peginterferon alfa and ribavirin versus 0.5% of patients 
receiving placebo with peginterferon alfa and ribavirin. Serious adverse reactions were reported in 
0.3% of simeprevir-treated patients (2 photosensitivity events requiring hospitalisation) and in none of 
the patients receiving placebo with peginterferon alfa and ribavirin.

During the first 12 weeks of treatment, the most frequently reported adverse reactions (incidence 
≥ 5%) were nausea, rash, pruritus, dyspnoea, blood bilirubin increase and photosensitivity reaction 
(see section 4.4).

Discontinuation of simeprevir due to adverse reactions occurred in 0.9% of patients receiving 
simeprevir with peginterferon alfa and ribavirin.

Tabulated list of adverse reactions
Adverse reactions of simeprevir in combination with sofosbuvir or in combination with peginterferon 
alfa and ribavirin reported in adult patients with HCV genotype 1 infection are listed in table 5. The 
adverse reactions are listed by system organ class (SOC) and frequency: 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), very 
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Table 5: Adverse reactions identified with simeprevir in combination with sofosbuvir or 
simeprevir in combination with peginterferon alfa and ribavirin1

SOC
Frequency 
Category

simeprevir + sofosbuvir simeprevir + 
peginterferon alfa + 

ribavirin
N = 781

12 weeks
N = 286

24 weeks
N = 31

Respiratory, thoracic and mediastinal disorders:
very common dyspnoea*
Gastrointestinal disorders:
very common nausea
common constipation constipation constipation
Hepatobiliary disorders:
common blood bilirubin increased* blood bilirubin increased* blood bilirubin increased*
Skin and subcutaneous tissue disorders:
very common rash* rash*, pruritus*
common rash*, pruritus*, 

photosensitivity reaction*
pruritus*, photosensitivity 
reaction*

photosensitivity reaction*

1
Simeprevir in combination with sofosbuvir: pooled studies HPC2002, HPC3017 and HPC3018 (12 weeks) or
study HPC2002 (24 weeks); simeprevir in combination with peginterferon alfa and ribavirin: pooled phase 3 
studies C208, C216 and HPC3007 (first 12 weeks of treatments).

* see section below for further details.

Description of selected adverse reactions
Rash and pruritus
Most of the rash and pruritus events in simeprevir-treated patients were of mild or moderate severity 
(grade 1 or 2).

Simeprevir in combination with sofosbuvir: Rash and pruritus were reported in 8.0% and 8.4%, 
respectively, of patients receiving 12 weeks of treatment compared to 12.9% and 3.2%, respectively,
of patients receiving 24 weeks of treatment (all grades). Grade 3 rash was reported in one patient 
(0.3%; 12-week treatment group) which led to treatment discontinuation; none of the patients 
experienced grade 4 rash. None of the patients experienced grade 3 or 4 pruritus; none of the patients 
discontinued treatment due to pruritus.

In study HPC2002, rash (grouped term) was reported in 10.7% of patients receiving 12 weeks of 
simeprevir and sofosbuvir without ribavirin versus 20.4% of patients receiving 12 weeks of simeprevir 
and sofosbuvir with ribavirin.

Simeprevir in combination with peginterferon alfa and ribavirin: During the 12 weeks treatment with
simeprevir, rash and pruritus were reported in 21.8% and 21.9% of simeprevir-treated patients, 
compared to 16.6% and 14.6% in placebo-treated patients, respectively (all grades; pooled phase 3). 
Grade 3 rash or pruritus occurred in 0.5% and 0.1% of simeprevir-treated patients, respectively.
Discontinuation of simeprevir due to rash or pruritus occurred in 0.8% and 0.1% of simeprevir-treated 
patients, compared to 0.3% and 0% of placebo-treated patients, respectively.

Blood bilirubin increased
Elevations in direct and indirect bilirubin have been reported in patients treated with simeprevir and 
were mostly of mild or moderate severity. Bilirubin elevations were generally not associated with 
elevations in liver transaminases and bilirubin levels normalised after end of treatment.

Simeprevir in combination with sofosbuvir: ‘Blood bilirubin increased’ was reported in 1.0% of 
patients receiving 12 weeks of treatment compared to 3.2% in patients receiving 24 weeks of treatment 
(all grades). Grade 2 ‘blood bilirubin increased’ was reported in one patient (0.3%) receiving 12 weeks 
of treatment. There were no grade 3 events reported. One patient (3.2%) receiving 24 weeks of 
treatment experienced a grade 4 ‘blood bilirubin increased’ event. None of the patients discontinued 
treatment due to ‘blood bilirubin increased’.

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In study HPC2002, increased bilirubin was reported in 0% of patients receiving 12 weeks of 
simeprevir and sofosbuvir without ribavirin versus 9.3% of patients receiving 12 weeks of simeprevir 
and sofosbuvir with ribavirin.

Simeprevir in combination with peginterferon alfa and ribavirin: During the 12 weeks treatment with 
simeprevir, ‘blood bilirubin increased’ was reported in 7.4% of simeprevir-treated patients, compared 
to 2.8% in placebo-treated patients (all grades; pooled phase 3). In 2% and 0.3% of the 
simeprevir-treated patients grade 3 or 4 ‘blood bilirubin increased’ was reported, respectively (pooled 
phase 3 studies). Discontinuation of simeprevir due to ‘blood bilirubin increased’ was rare (0.1%; 
n = 1).

Photosensitivity reactions
Simeprevir in combination with sofosbuvir: Photosensitivity reactions were reported in 3.1% of 
simeprevir-treated patients receiving 12 weeks of treatment compared to 6.5% in patients receiving 
24 weeks of treatment (all grades). Most of the photosensitivity reactions were of mild severity 
(grade 1); grade 2 photosensitivity reactions were reported in two patients (0.7%) receiving 12 weeks 
of treatment. There were no grade 3 or 4 photosensitivity reactions reported and none of the patients 
discontinued treatment due to photosensitivity reactions.

In study HPC2002, photosensitivity reactions (grouped term) was reported in 7.1% of patients 
receiving 12 weeks of simeprevir and sofosbuvir without ribavirin versus 5.6% of patients receiving 
12 weeks of simeprevir and sofosbuvir with ribavirin.

Simeprevir in combination with peginterferon alfa and ribavirin: During the 12 weeks treatment with
simeprevir, photosensitivity reactions were reported in 4.7% of simeprevir-treated patients compared 
to 0.8% in placebo-treated patients (all grades; pooled phase 3). Most photosensitivity reactions in 
simeprevir-treated patients were of mild or moderate severity (grade 1 or 2); 0.3% of the 
simeprevir-treated patients experienced serious reactions leading to hospitalisation (see section 4.4).

Dyspnoea
Simeprevir in combination with peginterferon alfa and ribavirin: During the first 12 weeks treatment 
with simeprevir, dyspnoea was reported in 11.8% of simeprevir-treated patients, compared to 7.6% in 
placebo-treated patients (all grades; pooled phase 3). Only grade 1 and 2 events were reported and 
there were no events leading to discontinuation of any of the study drugs. In patients aged > 45 years, 
dyspnoea was reported in 16.4% of simeprevir-treated patients compared to 9.1% in placebo-treated 
patients (all grades; pooled phase 3).

Cardiac arrhythmias
Cases of bradycardia have been observed when OLYSIO is used in combination with sofosbuvir and 
concomitant amiodarone (see sections 4.4 and 4.5).

Laboratory abnormalities
Simeprevir in combination with sofosbuvir
Treatment-emergent laboratory abnormalities in amylase and lipase have been observed in patients 
treated with simeprevir in combination with sofosbuvir (table 6). Elevations in amylase and lipase 
were transient and mostly of mild or moderate severity. Amylase and lipase elevations were not 
associated with pancreatitis.

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Table 6: Treatment-emergent laboratory abnormalities in amylase and lipase in patients 
receiving 12 or 24 weeks of simeprevir in combination with sofosbuvir (12 weeks: 
pooled studies HPC2002, HPC3017 and HPC3018; 24 weeks: study HPC2002)

Laboratory parameter WHO toxicity range1 12 weeks simeprevir + 
sofosbuvir

N = 286
n (%)

24 weeks simeprevir + 
sofosbuvir

N = 31
n (%)

Chemistry
Amylase

Grade 1 ≥ 1.1 to ≤ 1.5 x ULN 34 (11.9%) 8 (25.8%)
Grade 2 > 1.5 to ≤ 2.0 x ULN 15 (5.2%) 2 (6.5%)
Grade 3 > 2.0 to ≤ 5.0 x ULN 13 (4.5%) 3 (9.7%)

Lipase
Grade 1 ≥ 1.1 to ≤ 1.5 x ULN 13 (4.5%) 1 (3.2%)
Grade 2 > 1.5 to ≤ 3.0 x ULN 22 (7.7%) 3 (9.7%)
Grade 3 > 3.0 to ≤ 5.0 x ULN 1 (0.3%) 1 (3.2%)
Grade 4 > 5.0 x ULN 1 (0.3%) 1 (3.2%)

1
WHO worst toxicity grades 1 to 4.

ULN = Upper Limit of Normal.

Simeprevir in combination with peginterferon alfa and ribavirin
There were no differences in haemoglobin, neutrophils or platelets between both treatment groups. 
Treatment-emergent laboratory abnormalities that were observed at a higher incidence in 
simeprevir-treated patients than in patients treated with placebo, peginterferon alfa and ribavirin are 
given in table 7.

Table 7: Treatment-emergent laboratory abnormalities observed at a higher incidence in 
patients receiving simeprevir in combination with peginterferon alfa and ribavirin 
(pooled phase 3 studies C208, C216 and HPC3007; first 12 weeks of treatments)

Laboratory 
parameter

WHO toxicity range1 simeprevir + peginterferon alfa + ribavirin
N = 781
n (%)

Chemistry
Alkaline phosphatase

Grade 1 ≥ 1.25 to ≤ 2.50 x ULN 26 (3.3%)
Grade 2 > 2.50 to ≤ 5.00 x ULN 1 (0.1%)

Hyperbilirubinemia
Grade 1 ≥ 1.1 to ≤ 1.5 x ULN 208 (26.7%)
Grade 2 > 1.5 to ≤ 2.5 x ULN 143 (18.3%)
Grade 3 > 2.5 to ≤ 5.0 x ULN 32 (4.1%)
Grade 4 > 5.0 x ULN 3 (0.4%)

1
WHO worst toxicity grades 1 to 4.

ULN = Upper Limit of Normal.

Other special populations
Patients co-infected with HIV-1
The safety profile of simeprevir in combination with peginterferon alfa and ribavirin is comparable 
between HCV genotype 1 infected patients with and without HIV-1 co-infection.

Asian patients
The safety profile of OLYSIO 150 mg in combination with peginterferon alfa and ribavirin in a 
phase 3 study conducted in Asian patients in China and South-Korea is comparable to non-Asian 
patients from a pooled phase 3 population from global studies, except for higher frequencies for ‘blood 
bilirubin increased’ events (see table 8).

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Table 8: ‘Blood bilirubin increased’ events observed in Asian patients from the phase 3 
study HPC3005 versus the pooled phase 3 studies C208, C216 and HPC3007 
receiving simeprevir or placebo in combination with peginterferon alfa and 
ribavirin (first 12 weeks of treatment)

Blood bilirubin 
increased

Phase 3 study in Asian patients Pooled phase 3 studies
simeprevir + 

peginterferon alfa 
+ ribavirin

N = 152
n (%)

placebo + 
peginterferon alfa 

+ ribavirin
N = 152
n (%)

simeprevir + 
peginterferon alfa 

+ ribavirin
N = 781
n (%)

placebo + 
peginterferon alfa 

+ ribavirin
N = 397
n (%)

All grades 67 (44.1%) 28 (18.4%) 58 (7.4%) 11 (2.8%)
Grade 3 10 (6.6%) 2 (1.3%) 16 (2.0%) 2 (0.5%)
Grade 4 0 (0%) 0 (0%) 2 (0.3%) 0 (0%)
Related 
discontinuations

1 (0.7%) 0 (0%) 1 (0.1%) 0 (0%)

During administration of simeprevir with peginterferon alfa and ribavirin, the elevations in direct and 
indirect bilirubin were generally not associated with elevations in liver transaminases and normalised 
after end of treatment.

Hepatic impairment
Simeprevir exposure is significantly increased in patients with severe hepatic impairment (see 
section 5.2). A trend for a higher incidence of increased bilirubin levels with increasing simeprevir 
plasma exposure was observed. These increases in bilirubin levels were not associated with any 
adverse liver safety finding. However, reports of hepatic decompensation and hepatic failure during 
OLYSIO combination therapy have been received in the post marketing setting (see section 4.4).
A higher incidence of anaemia in patients with advanced fibrosis receiving simeprevir in combination 
with peginterferon alfa and ribavirin has been reported.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Human experience of overdose with simeprevir is limited. In healthy adult subjects receiving single 
doses up to 600 mg or once daily doses up to 400 mg for 5 days, and in HCV infected adult patients 
receiving 200 mg once daily for 4 weeks, adverse reactions were consistent with those observed in 
clinical studies at the recommended dose (see section 4.8).

There is no specific antidote for overdose with OLYSIO. In the event of an overdose with OLYSIO, it 
is recommended to employ the usual supportive measures and observe the patient’s clinical status.

Simeprevir is highly protein bound, therefore dialysis is unlikely to result in significant removal of 
simeprevir (see section 5.2).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AE14.

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


23

Mechanism of action
Simeprevir is a specific inhibitor of the HCV NS3/4A serine protease, which is essential for viral 
replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant 
genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, 
respectively.

Antiviral activity in vitro
The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM 
(7.05 ng/ml) and 19 nM (14.25 ng/ml), respectively. Chimeric replicons carrying NS3 sequences 
derived from HCV PI treatment-naïve genotype 1a and genotype 1b patients displayed median fold 
change (FC) in simeprevir EC50 values of 1.4 (N = 78) and 0.4 (N = 59) compared to reference 
genotype 1b replicon, respectively. Genotype 1a and 1b isolates with a baseline Q80K polymorphism 
resulted in median FC in simeprevir EC50 of 11 (N = 33) and 8.4 (N = 2), respectively. Median 
simeprevir FC values against genotype 2 and genotype 3 baseline isolates tested were 25 (N = 4) and 
1,014 (N = 2), respectively. Median simeprevir FC values against baseline isolates of genotype 4a, 
genotype 4d and genotype 4other were 0.5 (N = 38), 0.4 (N = 24), and 0.8 (N = 29), respectively. The 
presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. In vitro combination 
of simeprevir with interferon, ribavirin, NS5A or NS5B inhibitors resulted in additive or synergistic 
effects.

Antiviral activity in vivo
Short term monotherapy data of simeprevir from studies C201 (genotype 1) and C202 (genotype 2, 3, 
4, 5 and 6) in patients receiving 200 mg once daily simeprevir for 7 days is presented in table 9.

Table 9: Antiviral activity of simeprevir 200 mg monotherapy (studies C201 and C202)

Genotype Mean (SE) change in HCV RNA at day 7/8
(log10 IU/mL)

Genotype 1 (N = 9) -4.18 (0.158)
Genotype 2 (N = 6) -2.73 (0.71)
Genotype 3 (N = 8) -0.04 (0.23)
Genotype 4 (N = 8) -3.52 (0.43)
Genotype 5 (N = 7) -2.19 (0.39)
Genotype 6 (N = 8) -4.35 (0.29)

Resistance
Resistance in cell culture
Resistance to simeprevir was characterised in HCV genotype 1a and 1b replicon-containing cells. 
Ninety-six percent of simeprevir-selected genotype 1 replicons carried one or multiple amino acid 
substitutions at NS3 protease positions 43, 80, 155, 156, and/or 168, with substitutions at NS3 position 
D168 being most frequently observed (78%). Additionally, resistance to simeprevir was evaluated in 
HCV genotype 1a and 1b replicon assays using site-directed mutants and chimeric replicons carrying 
NS3 sequences derived from clinical isolates. Amino acid substitutions at NS3 positions 43, 80, 122, 
155, 156, and 168 reduced in vitro simeprevir activity. Substitutions such as D168V or A, and R155K 
were usually associated with large reductions in susceptibility to simeprevir in vitro (FC in EC50 > 50), 
whereas other substitutions such as Q80K or R, S122R, and D168E displayed in vitro low level 
resistance (FC in EC50 between 2 and 50). Other substitutions such as Q80G or L, S122G, N or T did 
not reduce simeprevir activity (FC in EC50 ≤ 2). Amino acid substitutions at NS3 positions 80, 122, 
155, and/or 168, associated with in vitro low level resistance to simeprevir when occurring alone, 
reduced simeprevir activity by more than 50-fold when present in combination.

Resistance in clinical studies
In a pooled analysis of patients treated with 150 mg simeprevir in combination with peginterferon alfa 
and ribavirin who did not achieve SVR in the controlled phase 2 and phase 3 clinical studies (studies 
C205, C206, C208, C216, HPC3007), emerging amino acid substitutions at NS3 positions 80, 122, 
155 and/or 168 were observed in 180 out of 197 (91%) patients. Substitutions D168V and R155K 
alone or in combinations with other mutations at these positions emerged most frequently (table 10). 

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Most of these emerging substitutions have been shown to reduce simeprevir anti-HCV activity in cell 
culture replicon assays.

HCV genotype 1 subtype-specific patterns of simeprevir treatment-emergent amino acid substitutions 
were observed in patients not achieving SVR. Patients with HCV genotype 1a predominantly had 
emerging R155K alone or in combination with amino acid substitutions at NS3 positions 80, 122 
and/or 168, while patients with HCV genotype 1b had most often an emerging D168V substitution 
(table 10). In patients with HCV genotype 1a with a baseline Q80K amino acid substitution an 
emerging R155K substitution was observed most frequently at failure.

Table 10: Treatment-emergent amino-acid substitutions in pooled phase 2 and phase 3 
studies: patients who did not achieve SVR with 150 mg simeprevir in combination 
with peginterferon alfa and ribavirin

Emerging amino-acid
substitutions in NS3

All HCV genotypes
N = 197
% (n)

Genotype 1a1

N = 116
% (n)

Genotype 1b
N = 81
% (n)

Any substitution at NS3 position 
43, 80, 122, 155, 156, or 1682

91.4% (180) 94.8% (110) 86.4% (70)

D168E 15.7% (31) 14.7% (17) 17.3% (14)
D168V 31.0% (61) 10.3% (12) 60.5% (49)
Q80R3 7.6% (15) 4.3% (5) 12.3% (10)
R155K 45.2% (89) 76.7% (89) 0% (0)
Q80X+D168X4 8.1% (16) 4.3% (5) 13.6% (11)
R155X+ D168X4 9.1% (18) 12.9% (15) 3.7% (3)
Q80K3, S122A/G/I/T3, S122R, 
R155Q3, D168A, D168F3, D168H, 
D168T, I170T5

Less than 10% Less than 10% Less than 10%

1
May include few patients with HCV non-genotype 1a/1b.

2
Alone or in combination with other substitutions (includes mixtures).

3
Substitutions only observed in combinations with other emerging substitutions at one or more of the NS3 positions 80, 
122, 155 and/or 168.

4
Patients with these combinations are also included in other rows describing the individual substitutions. X represents 
multiple amino acids. Other double or triple mutations were observed with lower frequencies.

5
Two patients had emerging single substitution I170T.

Note, substitutions at NS3 position 43 and 156 associated with reduced simeprevir activity in vitro were not observed at 
time of failure.

In study HPC3011 in HCV genotype 4 infected patients, 28 of 32 (88%) patients who did not achieve 
SVR had emerging amino acid substitutions at NS3 positions 80, 122, 155, 156 and/or 168 (mainly 
substitutions at position 168; 24 out of 32 [75%] patients), similar to the emerging amino acid 
substitutions observed in genotype 1 infected patients.

The majority of HCV genotype 1 infected patients treated with simeprevir in combination with 
sofosbuvir (with or without ribavirin) for 12 or 24 weeks who did not achieve SVR due to virologic 
reasons and with sequencing data available had emerging NS3 amino acid substitutions at position 168 
and/or emerging R155K: 5 out of 6 patients in study HPC2002, 1 out of 3 patients in study HPC3017 
and 11 out of 13 patients in study HPC3018. The emerging NS3 amino acid substitutions were similar 
to those observed in patients who did not achieve SVR following treatment with simeprevir in 
combination with peginterferon alfa and ribavirin. No emerging NS5B amino acid substitutions
associated with sofosbuvir resistance were observed in patients who did not achieve SVR following 
treatment of simeprevir in combination with sofosbuvir (with or without ribavirin) for 12 or 24 weeks.

Persistence of resistance–associated substitutions
The persistence of simeprevir-resistant NS3 amino acid substitutions was assessed following treatment 
failure.

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In the pooled analysis of patients receiving 150 mg simeprevir in combination with peginterferon alfa 
and ribavirin in the controlled phase 2 and phase 3 studies, treatment-emergent simeprevir-resistance 
variants were no longer detectable in 90 out of 180 patients (50%) at the end of the studies after a 
median follow-up of 28 weeks (range 0-70 weeks). In 32 out of 48 patients (67%) with emerging 
single D168V and in 34 out of 66 (52%) patients with emerging single R155K, the respective 
emerging variants were no longer detected at end of the studies.

Data from a 3-year follow-up study in patients who did not achieve SVR with simeprevir in 
combination with peginterferon alfa and ribavirin in a previous phase 2 or phase 3 study showed that 
in 86% (37/43) of these patients the emerging mutations at time of failure in the previous study were 
no longer detected after a median follow-up of 180 weeks (range 47-230 weeks) (study HPC3002).

The long-term clinical impact of the emergence or persistence of simeprevir-resistance-associated 
substitutions is unknown.

Effect of baseline HCV polymorphisms on treatment response
Analyses were conducted to explore the association between naturally-occurring baseline NS3/4A 
amino acid substitutions (polymorphisms) and treatment outcome.

Baseline polymorphisms at NS3 positions 43, 80, 122, 155, 156, and/or 168, associated with reduced 
simeprevir activity in vitro were generally uncommon (1.3%) in patients with HCV genotype 1
infection (n = 2,007; pooled phase 2 and phase 3 studies with simeprevir in combination with 
peginterferon alfa and ribavirin), with exception of the substitution Q80K in HCV genotype 1a 
patients which was seen in 30% of patients with HCV genotype 1a and in 0.5% of patients with HCV 
genotype 1b. In Europe, the prevalence was lower, 19% (73/377) in patients with HCV genotype 1a 
and 0.3% (3/877) in genotype 1b.

The Q80K polymorphism was not observed in patients with genotype 4 infection.

The presence of Q80K at baseline was associated with lower SVR rates in HCV genotype 1a patients 
treated with simeprevir in combination with peginterferon alfa and ribavirin (tables 19, 21, 22).

Cross-resistance
Some of the treatment-emergent NS3 amino acid substitutions detected in simeprevir-treated patients 
who did not achieve SVR in clinical studies (e.g., R155K) have been shown to reduce anti-HCV 
activity of telaprevir, boceprevir, and other NS3/4A PIs. The impact of prior exposure to simeprevir in 
patients not achieving SVR on the efficacy of subsequent HCV NS3/4A PI-based treatment regimens 
has not been established. There are no clinical data on the efficacy of simeprevir in patients with a 
history of exposure to the NS3/4A PIs telaprevir or boceprevir.

Cross-resistance is not expected between direct-acting antiviral agents with different mechanisms of 
action. Simeprevir-resistant variants studied remained susceptible to representative HCV nucleoside 
and non-nucleoside polymerase inhibitors, and NS5A inhibitors. Variants carrying amino-acid 
substitutions conferring reduced susceptibility to NS5A inhibitors (L31F/V, Y93C/H), nucleoside 
polymerase inhibitors (S282T) and non-nucleoside polymerase inhibitors (C316N, M414I/L, P495A) 
remained susceptible to simeprevir in vitro.

Clinical efficacy and safety
Sustained virologic response (SVR) was the primary endpoint in all studies and was defined as 
HCV RNA less than the lower limit of quantification (LLOQ) detectable or undetectable 12 weeks 
(SVR12) or 24 weeks (SVR24) after the planned end of treatment (studies C206, C208, C212, C216, 
HPC2002, HPC3007 and HPC3011) or after the actual end of treatment (studies HPC2014, HPC3017, 
HPC3018 and HPC3021) (LLOQ of 25 IU/ml and limit of detection of 15 IU/ml, except in 
studies HPC2014 and HPC3021 where LLOQ and limit of detection were 15 IU/ml).

Patients had compensated liver disease (including cirrhosis), HCV RNA of at least 10,000 IU/ml, and 
liver histopathology consistent with CHC (if available).

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Simeprevir in combination with sofosbuvir
The efficacy of simeprevir (150 mg once daily) as part of an interferon-free regimen (sofosbuvir,
400 mg once daily) was evaluated in patients with HCV genotype 1 or 4 infection, who were
treatment-naïve or treatment-experienced patients (following prior interferon-based therapy)
(table 11).

Table 11: Studies conducted with simeprevir + sofosbuvir: population and summary of study 
design

Study1 Population Number 
of patients 
enrolled

Summary of study design

HPC3017
(OPTIMIST-1; 
Phase 3)

Genotype 1, treatment-naïve or 
treatment-experienced2, without 
cirrhosis

310 8 or 12 weeks SMV + 
sofosbuvir

HPC3018
(OPTIMIST-2; 
Phase 3)

Genotype 1, treatment-naïve or 
treatment-experienced2, with 
compensated cirrhosis

103 12 weeks SMV + sofosbuvir

HPC2002
(COSMOS; 
Phase 2)

Genotype 1, treatment-naïve or null 
responders3, with compensated 
cirrhosis or without cirrhosis

167 12 or 24 weeks SMV + 
sofosbuvir, with or without 
ribavirin4

HPC2014
(OSIRIS; 
Phase 2)

Genotype 4, treatment-naïve or 
treatment-experienced2, with 
compensated cirrhosis or without 
cirrhosis

63 patients without cirrhosis: 8 or 
12 weeks SMV + sofosbuvir;
patients with cirrhosis:
12 weeks SMV + sofosbuvir

HPC3021
(PLUTO; 
Phase 3)

Genotype 4, treatment-naïve or 
treatment-experienced2, with 
compensated cirrhosis or without 
cirrhosis

40 12 weeks SMV + sofosbuvir

SMV = simeprevir.
1

Open-label, randomised, except for studies HPC3018 and HPC3021 which were single arm, and study HPC2014 which 
was partly randomised.

2
Includes relapsers, partial and null reponders to prior treatment with interferon (pegylated or non-pegylated), with or 
without ribavirin.

3
To prior treatment with peginterferon alfa and ribavirin.

4
Body-weight based twice daily ribavirin dosing, according to the Summary of Product Characteristics of ribavirin.

Efficacy in patients with HCV genotype 1
OPTIMIST-1 and OPTIMIST-2
In studies HPC3017 (OPTIMIST-1) and HPC3018 (OPTIMIST-2), patients received simeprevir +
sofosbuvir for 8 weeks (HPC3017 only) or 12 weeks (HPC3017 and HPC3018) (see table 11). In 
study HPC3017, patients without cirrhosis were enrolled; in study HPC3018, patients with cirrhosis 
were enrolled (table 12).

Table 12: Demographics and baseline characteristics (studies HPC3017 and HPC3018)

HPC3017
N = 310

HPC3018
N = 103

Age (years)
median (range)
% above 65 yrs

56 (19-70)
6%

58 (29-69)
6%

Male gender 55% 81%
Race

White
Black/African American

80%
18%

81%
19%

Hispanic 16% 16%
BMI ≥ 30 kg/m2 34% 40%

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Median baseline HCV RNA levels (log10 IU/ml) 6.8 6.8
Presence of cirrhosis

no cirrhosis
with cirrhosis

100%
0%

0%
100%

Prior treatment history
treatment-naïve
treatment-experienced1

70%
30%

49%
51%

IL28B genotype
CC
non-CC

27%
73%

28%
72%

HCV geno/subtype and presence of baseline Q80K polymorphism in HCV genotype 1a
HCV genotype 1a

with Q80K
HCV genotype 1b

75%
41%
25%

70%
47%
30%

1
Includes relapsers, partial and null reponders to prior treatment with interferon (pegylated or non-pegylated), with or 
without ribavirin, and interferon-intolerant patients.

The overall SVR12 rate for patients without cirrhosis receiving 8 weeks of simeprevir + sofosbuvir 
was 83% (128/155); all patients not achieving SVR12 had viral relapse (17%; 27/155). The response 
rates for patients with or without cirrhosis receiving 12 weeks of simeprevir + sofosbuvir are shown in 
table 13.

Table 13: Treatment outcome in HCV genotype 1 infected patients receiving 12 weeks 
simeprevir + sofosbuvir (studies HPC3017 and HPC3018)

Treatment outcome Patients without cirrhosis
N = 155
% (n/N)

Patients with cirrhosis
N = 103
% (n/N)

SVR12 97% (150/155)1 83% (86/103)1

Outcome for patients without SVR12
On-treatment failure2 0% (0/155) 3% (3/103)
Viral relapse3 3% (4/154) 13% (13/99)

SVR12 rates for selected subgroups
Prior treatment history

treatment-naïve 97% (112/115) 88% (44/50)
treatment-experienced4 95% (38/40) 79% (42/53)

HCV geno/subtype and presence of baseline Q80K polymorphism in HCV genotype 1a
Genotype 1a

with Q80K
without Q80K

97% (112/116)
96% (44/46)
97% (68/70)

83% (60/72)
74% (25/34)
92% (35/38)

Genotype 1b 97% (38/39) 84% (26/31)
1

Superior versus historical control rate (historical SVR rates of approved combination treatments of direct acting 
antivirals with peginterferon alfa and ribavirin).

2
Out of the 3 patients with on-treatment failure, 2 patients experienced viral breakthrough and one patient discontinued 
treatment early due to an adverse event.

3
Viral relapse rates are calculated with a denominator of patients with undetectable (or unconfirmed detectable) 
HCV RNA at EOT.

4
Includes relapsers, partial and null reponders to prior treatment with interferon (pegylated or non-pegylated), with or 
without ribavirin.

COSMOS
In study HPC2002 (COSMOS), prior null responders with METAVIR fibrosis score F0-F2, or 
treatment-naïve and prior null responder patients with METAVIR fibrosis score F3-F4 and 
compensated liver disease received simeprevir + sofosbuvir, with or without ribavirin, for 12 or 
24 weeks (see table 11). The 167 enrolled patients had a median age of 57 years (range 27 to 70 years; 
with 5% above 65 years); 64% were male; 81% were White, 19% Black or African American, and 
21% Hispanic; 37% had a BMI ≥ 30 kg/m2; the median baseline HCV RNA level was 6.7 log10 IU/ml; 

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75% had no cirrhosis (METAVIR fibrosis score F0-3) and 25% had cirrhosis (METAVIR fibrosis 
score F4); 78% had HCV genotype 1a of which 45% carried Q80K at baseline, and 22% had HCV 
genotype 1b; 86% had non-CC IL28B alleles (CT or TT); 76% were prior null responders to 
peginterferon alfa and ribavirin, and 24% were treatment-naïve.

Table 14 shows the response rates for patients without cirrhosis (METAVIR scores F0-3) receiving 
12 weeks of simeprevir +sofosbuvir with or without ribavirin; extending treatment to 24 weeks did not 
increase response rates in comparison with 12 weeks treatment. Ribavirin use and prior treatment 
status (treatment-naïve and prior null responders) did not impact treatment outcome. The overall 
SVR12 rate was similar in patients receiving simeprevir + sofosbuvir with or without ribavirin. The 
response rates for patients with cirrhosis (METAVIR score F4) receiving 12 or 24 weeks of simeprevir 
+ sofosbuvir are shown in table 15.

Table 14: Treatment outcome in HCV genotype 1 infected patients without cirrhosis 
receiving 12 weeks simeprevir + sofosbuvir, with or without ribavirin 
(study HPC2002)

Treatment outcome simeprevir + sofosbuvir
N = 21

% (n/N)

simeprevir + sofosbuvir + ribavirin
N = 43

% (n/N)
SVR12 95% (20/21) 95% (41/43)
Outcome for patients without SVR12
On-treatment failure 0% (0/21) 0% (0/43)
Viral relapse1 5% (1/21) 5%(2/43)
1

Viral relapse rates are calculated with a denominator of patients with undetectable HCV RNA at EOT and with at least 
one follow-up HCV RNA assessment.

Table 15: Treatment outcome in HCV genotype 1 infected patients with cirrhosis receiving 
12 or 24 weeks simeprevir + sofosbuvir, with or without ribavirin 
(study HPC2002)

Treatment outcome 12 weeks 24 weeks
simeprevir + 
sofosbuvir

N = 7
% (n/N)

simeprevir + 
sofosbuvir
+ ribavirin

N = 11
% (n/N)

simeprevir + 
sofosbuvir

N = 10
% (n/N)

simeprevir + 
sofosbuvir
+ ribavirin

N = 13
% (n/N)

SVR12 86% (6/7) 91% (10/11) 100% (10/10) 92% (12/13)
Outcome for patients without SVR12
On-treatment failure1 0% (0/7) 0% (0/11) 0% (0/10) 8% (1/13)
Viral relapse2 14% (1/7) 9% (1/11) 0% (0/10) 0% (0/12)
1

The one patient with on-treatment failure discontinued treatment early due to an adverse event.
2

Viral relapse rates are calculated with a denominator of patients with undetectable HCV RNA at EOT and with at least 
one follow-up HCV RNA assessment.

Efficacy in adults with HCV genotype 4
In study HPC2014 (OSIRIS), patients received simeprevir + sofosbuvir for 8 weeks (patients without 
cirrhosis) or 12 weeks (patients with or without cirrhosis) (see table 11). The 63 enrolled patients had a 
median age of 51 years (range 24 to 68 years; with 2% above 65 years); 54% were male; 43% had a 
BMI ≥ 30 kg/m2; the median baseline HCV RNA level was 6.01 log10 IU/ml; 37% had cirrhosis; 30% 
had HCV genotype 4a, and 56% HCV genotype 4c or 4d; 79% had non-CC IL28B alleles (CT or TT); 
52% were treatment-naïve, and 48% were treatment-experienced.

In study HPC3021 (PLUTO), patients received simeprevir + sofosbuvir for 12 weeks (see table 11).
The 40 enrolled patients had a median age of 51 years (range 29 to 69 years; with 5% above 65 years); 
73% were male; 18% had a BMI ≥ 30 kg/m2; the median baseline HCV RNA level was 
6.35 log10 IU/ml; 18% had cirrhosis; 25% had HCV genotype 4a, and 73% HCV genotype 4d; 85%

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had non-CC IL28B alleles (CT or TT); 33% were treatment-naïve, and 68% were 
treatment-experienced.

The overall SVR12 rate for patients without cirrhosis receiving 8 weeks of simeprevir + sofosbuvir 
was 75% (15/20); all patients not achieving SVR12 had viral relapse (25%; 5/20). All patients with or 
without cirrhosis receiving 12 weeks of simeprevir + sofosbuvir achieved SVR12 (table 16).

Table 16: Treatment outcome in HCV genotype 4 infected patients receiving 12 weeks 
simeprevir + sofosbuvir (studies HPC2014 and HPC3021)

Treatment outcome Study HPC2014
N = 43

% (n/N)

Study HPC3021
N = 40

% (n/N)
SVR12 100% (43/43) 100% (40/40)

without cirrhosis
with cirrhosis

100% (20/20)
100% (23/23)

100% (33/33)
100% (7/7)

Simeprevir in combination with peginterferon alfa and ribavirin
The efficacy of simeprevir in combination with peginterferon alfa and ribavirin was evaluated in 
patients with HCV genotype 1 or 4 infection, with or without HIV-1 co-infection, who were 
treatment-naïve or treatment-experienced (following prior interferon-based therapy) (tables 17 and 
18).

Table 17: Studies conducted with simeprevir + peginterferon alfa + ribavirin: population and 
summary of study design

Study1 Population Number 
of patients 
enrolled

Summary of study design

C208 - C216
(QUEST-1 and 
QUEST-2; 
Phase 3)

Genotype 1, treatment-naïve 
patients, with compensated 
cirrhosis or without cirrhosis

785 12 weeks SMV + peg-IFN-alfa + 
RBV, followed by 12 or 36 weeks 
peg-IFN-alfa + RBV3;
control group: 48 weeks placebo + 
peg-IFN-alfa + RBVHPC3007

(PROMISE; 
Phase 3)

Genotype 1, prior relapsers2, 
with compensated cirrhosis or 
without cirrhosis

393

C206
(ASPIRE; 
Phase 2)

Genotype 1, 
treatment-experienced4

patients, with compensated 
cirrhosis or without cirrhosis

462 12, 24 or 48 weeks SMV in 
combination with 48 weeks 
peg-IFN-alfa + RBV;
control group: 48 weeks placebo + 
peg-IFN-alfa + RBV

C212
(Phase 3)

Genotype 1, treatment-naïve 
or treatment-experienced4, 
HCV/HIV-1 co-infected 
patients, with compensated 
cirrhosis or without cirrhosis

106 treatment-naïve patients or prior 
relapsers without cirrhosis: 12 weeks 
SMV + peg-IFN-alfa + RBV, 
followed by 12 or 36 weeks 
peg-IFN-alfa + RBV3;
prior non-responder patients (partial 
and null responders) without 
cirrhosis and all treatment-naïve and 
treatment-experienced patients with 
cirrhosis: 12 weeks SMV + 
peg-IFN-alfa + RBV, followed by 
36 weeks peg-IFN-alfa + RBV

HPC3011
(RESTORE; 
Phase 3)

Genotype 4, treatment-naïve 
or treatment-experienced4

patients, with compensated 
cirrhosis or without cirrhosis

107 treatment-naïve patients or prior 
relapsers: 12 weeks SMV + 
peg-IFN-alfa + RBV, followed by 12 
or 36 weeks peg-IFN-alfa + RBV3;
prior non-responder patients (partial 

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and null responders): 12 weeks SMV 
+ peg-IFN-alfa + RBV, followed by 
36 weeks peg-IFN-alfa + RBV

peg-IFN-alfa = peginterferon alfa; RBV = ribavirin (body-weight based twice daily ribavirin dosing, according to the 
Summary of Product Characteristics of ribavirin); SMV = simeprevir.
1

Double-blind, randomised, placebo-controlled, except for studies C212 and HPC3011 which were open-label, single 
arm.

2
Relapsers after prior interferon-based therapy.

3
Overall treatment duration with peg-IFN-alfa and RBV was response-guided. The planned total duration of HCV 
treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy criteria were met: 
HCV RNA < 25 IU/ml detectable or undetectable at week 4 AND undetectable HCV RNA at week 12. Treatment 
stopping rules for HCV therapy were used to ensure that patients with inadequate on-treatment virologic response 
discontinued treatment in a timely manner.

4
Includes relapsers, partial and null responders to prior treatment with peginterferon and ribavirin.

Table 18: Studies conducted with simeprevir + peginterferon alfa + ribavirin: demographics 
and baseline characteristics

Pooled C208 
and C216
N = 785

HPC3007

N = 393

C206

N = 462

C2121

N = 106

HPC3011

N = 107
Age (years)

median (range)
% above 65 yrs

47 (18-73)
2%

52 (20-71)
3%

50 (20-69)
3%

48 (27-67)
2%

49 (27-69)
5%

Male gender 56% 66% 67% 85% 79%
Race

White
Black/African American
Asian

91%
7%
1%

94%
3%
2%

93%
5%
2%

82%
14%
1%

72%
28%

-
Hispanic 17% 7% - 6% 7%
BMI ≥ 30 kg/m2 23% 26% 25% 12% 14%
Baseline HCV RNA levels 
> 800,000 IU/ml

78% 84% 86% 86% 60%

METAVIR fibrosis score
F0-2
F3
F4

74%
16%
10%

69%
15%
15%

63%
19%
18%

67%
19%
13%

57%
14%
29%

IL28B genotype
CC
CT
TT

29%
56%
15%

24%
64%
12%

18%
65%
18%

27%
56%
17%

8%
58%
35%

HCV geno/subtype and presence of baseline Q80K polymorphism in HCV genotype 1a
HCV genotype 1a

with Q80K
HCV genotype 1b
HCV genotype 4a - 4d

48%
34%
51%

-

42%
31%
58%

-

41%
27%
58%

-

82%
34%
17%

-

-
-
-

42% - 24%
Prior treatment history

treatment-naïve
treatment-experienced2

prior relapser
prior partial responder
prior null responder

100%
-

-

100%
-
-

-

40%
35%
25%

50%

14%
9%

26%

33%

21%
9%

37%
1

HCV/HIV-1 co-infected patients.
2

Treatment-experienced to prior treatment with peginterferon and ribavirin.

Efficacy in treatment-naïve patients with HCV genotype 1 infection
In studies C208 (QUEST-1) and C216 (QUEST-2), treatment-naïve patients received simeprevir 
(150 mg once daily) + peginterferon alfa + ribavirin for 12 weeks, followed by 12 or 36 additional 

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weeks of peginterferon alfa + ribavirin (see tables 17 and 18). In study C208, all patients received 
peginterferon alfa-2a; in study C216, 69% of the patients received peginterferon alfa-2a and 31% 
received peginterferon alfa-2b.

Table 19 shows the response rates in HCV genotype 1 infected treatment-naïve patients.

Table 19: Treatment outcome in treatment-naïve HCV genotype 1 infected patients (pooled 
data studies C208 and C216)

Treatment Outcome simeprevir + peginterferon + 
ribavirin
N = 521
% (n/N)

placebo + peginterferon + 
ribavirin
N = 264
% (n/N)

Overall SVR12 80% (419/521)1 50% (132/264)

Outcome for patients without SVR12
On-treatment failure 8% (42/521) 33% (87/264)
Viral relapse2 11% (51/470) 23% (39/172)

SVR12 rates for selected subgroups
METAVIR fibrosis score

F0-2 84% (317/378) 55% (106/192)
F3-4 68% (89/130) 36% (26/72)
F4 60% (29/48) 34% (11/32)

IL28B genotype
CC 95% (144/152) 80% (63/79)
CT 78% (228/292) 41% (61/147)
TT 61% (47/77) 21% (8/38)

HCV geno/subtype and presence of Q80K polymorphism in HCV genotype 1a
Genotype 1a 75% (191/254) 47% (62/131)

with Q80K 58% (49/84) 52% (23/44)
without Q80K 84% (138/165) 43% (36/83)

Genotype 1b 85% (228/267) 53% (70/133)
1

p < 0.001.
2

Viral relapse rates are calculated with a denominator of patients with undetectable HCV RNA at actual EOT. Includes 
4 simeprevir-treated patients who experienced relapse after SVR12.

Eighty-eight percent (459/521) of the simeprevir-treated patients were eligible for a total treatment 
duration of 24 weeks; in these patients the SVR12 rate was 88%. Seventy-nine percent (404/509) of 
simeprevir-treated patients had undetectable HCV RNA at week 4; in these patients the SVR12 rate 
was 90%. The proportion of simeprevir-treated patients with HCV RNA < 25 IU/ml detectable at 
week 4 was 14% (70/509); 67% achieved SVR12.

In the pooled analysis of studies C208 and C216, 69% (58/84) of the simeprevir-treated HCV 
genotype 1a infected patients with Q80K polymorphism at baseline were eligible for a total treatment 
duration of 24 weeks; in these patients the SVR12 rate was 78%. Sixty-five percent (53/81) of the 
simeprevir-treated HCV genotype 1a infected patients with Q80K polymorphism had undetectable 
HCV RNA at week 4; in these patients the SVR12 rate was 79%.

SVR12 rates were statistically significantly higher for patients receiving simeprevir with peginterferon 
alfa-2a or peginterferon alfa-2b and ribavirin (88% and 78%, respectively) compared to patients 
receiving placebo with peginterferon alfa-2a or peginterferon alfa-2b and ribavirin (62% and 42%, 
respectively) (study C216).

Efficacy in treatment-experienced patients with HCV genotype 1 infection
In study HPC3007 (PROMISE), patients who relapsed after prior IFN-based therapy received 
simeprevir (150 mg once daily) + peginterferon alfa-2a + ribavirin for 12 weeks, followed by 12 or 
36 additional weeks of peginterferon alfa-2a + ribavirin (see tables 17 and 18).

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In study C206 (ASPIRE), patients who failed prior peg-IFN/RBV therapy received 12, 24 or 48 weeks 
simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks of peginterferon alfa-2a + 
ribavirin (see tables 17 and 18).

Table 20 shows the response rates in treatment-experienced patients with HCV genotype 1 infection. 
Table 21 shows the SVR rates for selected subgroups for study HPC3007.

Table 20: Treatment outcome in treatment-experienced1 HCV genotype 1 infected patients 
(studies HPC3007 and C206)

Treatment Outcome Study HPC3007 Study C206
simeprevir

% (n/N)
placebo
% (n/N)

150 mg 
simeprevir
12 weeks
% (n/N)

placebo
% (n/N)

SVR2

Prior relapsers 79% (206/260)3 37% (49/133) 77% (20/26) 37% (10/27)
Prior partial responders - - 65% (15/23) 9% (2/23)
Prior null responders - - 53% (9/17) 19% (3/16)

Outcome for patients without SVR
On-treatment failure

Prior relapsers 3% (8/260) 27% (36/133) 8% (2/26) 22% (6/27)
Prior partial responders - - 22% (5/23) 78% (18/23)
Prior null responders - - 35% (6/17) 75% (12/16)

Viral relapse4

Prior relapsers 19% (46/249) 48% (45/93) 13% (3/23) 47% (9/19)
Prior partial responders - - 6% (1/17) 50% (2/4)
Prior null responders - - 18% (2/11) 25% (1/4)

1
Treatment-experienced to prior treatment with peginterferon and ribavirin.

2
SVR: SVR12 for study HPC3007 and SVR24 for study C206.

3
p < 0.001.

4
Viral relapse rates are calculated with a denominator of patients with undetectable HCV RNA at EOT and with at least 
one follow-up HCV RNA assessment. Study HPC3007: includes 5 simeprevir-treated patients who experienced relapse 
after SVR12.

Table 21: SVR12 rates for selected subgroups (study HPC3007)

Subgroup simeprevir + peginterferon + 
ribavirin
% (n/N)

placebo + peginterferon + 
ribavirin
% (n/N)

METAVIR fibrosis score
F0-2 82% (137/167) 41% (40/98)
F3-4 73% (61/83) 24% (8/34)
F4 74% (29/39) 26% (5/19)

IL28B genotype
CC 89% (55/62) 53% (18/34)
CT 78% (131/167) 34% (28/83)
TT 65% (20/31) 19% (3/16)

HCV geno/subtype and presence of Q80K polymorphism in HCV genotype 1a
Genotype 1a 70% (78/111) 28% (15/54)

with Q80K 47% (14/30) 30% (6/20)
without Q80K 79% (62/79) 26% (9/34)

Genotype 1b 86% (128/149) 43% (34/79)

In study HPC3007, 93% (241/260) of the simeprevir-treated patients were eligible for a total treatment 
duration of 24 weeks; in these patients the SVR12 rate was 83%. Seventy-seven percent (200/259) of 
simeprevir-treated patients had undetectable HCV RNA at week 4; in these patients the SVR12 rate 

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was 87%. The proportion of simeprevir-treated patients with HCV RNA < 25 IU/ml detectable at 
week 4 was 18% (47/259); 60% achieved SVR12.

In study HPC3007, 80% (24/30) of the simeprevir-treated HCV genotype 1a infected patients with 
Q80K polymorphism at baseline were eligible for a total treatment duration of 24 weeks; in these 
patients the SVR12 rate was 58%. Forty-five percent (13/29) of the simeprevir-treated HCV 
genotype 1a infected patients with Q80K polymorphism had undetectable HCV RNA at week 4; in 
these patients the SVR12 rate was 77%.

Efficacy in patients with HCV genotype 1 and HIV-1 co-infection
In study C212, patients with HIV-1 co-infection who were treatment-naïve or failed prior 
peg-IFN/RBV therapy received simeprevir (150 mg once daily) + peginterferon alfa-2a + ribavirin for 
12 weeks, followed by 12 or 36 additional weeks of peginterferon alfa-2a + ribavirin (see tables 17
and 18). Eighty-eight percent (n = 93) of the patients were on HIV therapy, most commonly with 2 
NRTIs + raltegravir. The median baseline CD4+ cell count in patients on highly active antiretroviral 
therapy (HAART) was 561 x 106 cells/ml (range: 275-1,407 x 106 cells/ml).

Table 22 shows the response rates in HCV genotype 1 infected patients with HIV-1 co-infection.

Table 22: Treatment outcome in HCV genotype 1 infected patients with HIV-1 co-infection 
(study C212)

Treatment outcome Treatment-naïve 
patients
N = 53

% (n/N)

Prior 
relapsers

N = 15
% (n/N)

Prior partial 
responders

N = 10
% (n/N)

Prior null 
responders

N = 28
% (n/N)

SVR12 79% (42/53)1 87% (13/15) 70% (7/10) 57% (16/28)1

Outcome for patients without SVR12
On-treatment failure 9% (5/53) 0% (0/15) 20% (2/10) 39% (11/28)
Viral relapse2 10% (5/48) 13% (2/15) 0% (0/7) 12% (2/17)

SVR12 rates for selected subgroups
METAVIR fibrosis score

F0-2 89% (24/27) 78% (7/9) 50% (1/2) 57% (4/7)
F3-4 57% (4/7) 100% (2/2) 67% (2/3) 60% (6/10)
F4 100% (2/2) 100% (1/1) 100% (1/1) 60% (3/5)

IL28B genotype
CC 100% (15/15) 100% (7/7) 100% (1/1) 80% (4/5)
CT 70% (19/27) 100% (6/6) 71% (5/7) 53% (10/19)
TT 80% (8/10) 0% (0/2) 50% (1/2) 50% (2/4)

HCV geno/subtype and presence of Q80K polymorphism in HCV genotype 1a
Genotype 1a 77% (33/43) 83% (10/12) 67% (6/9) 54% (13/24)

with Q80K 86% (12/14) 33% (1/3) 100% (1/1) 50% (6/12)
without Q80K 72% (21/29) 100% (9/9) 63% (5/8) 58% (7/12)

Genotype 1b 90% (9/10) 100% (3/3) 100% (1/1) 75% (3/4)
1

p < 0.001 compared to historical control of peginterferon alfa and ribavirin.
2

Viral relapse rates are calculated with a denominator of patients with undetectable HCV RNA at actual EOT and with at 
least one follow-up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12, 
who was considered to have an HCV re-infection (based on phylogenetic analyses).

Eighty-nine percent (54/61) of the simeprevir-treated treatment-naïve patients and prior relapsers
without cirrhosis were eligible for 24 weeks of treatment; in these patients the SVR12 rate was 87%.
Seventy-one percent (37/52), 93% (14/15), 80% (8/10) and 36% (10/28) of simeprevir-treated 
treatment-naïve patients, prior relapsers, prior partial responders and prior null responders had 
undetectable HCV RNA at week 4. In these patients the SVR12 rates were 89%, 93%, 75% and 90%, 
respectively.

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Two patients had HIV virologic failure defined as confirmed HIV-1 RNA ≥ 200 copies/ml after 
previous < 50 copies/ml; these failures occurred 36 and 48 weeks after end of simeprevir treatment.

Efficacy in patients with HCV genotype 4 infection
In study HPC3011 (RESTORE), patients who were treatment-naïve or failed prior peg-IFN/RBV 
therapy received simeprevir (150 mg once daily) + peginterferon alfa-2a + ribavirin for 12 weeks, 
followed by 12 or 36 additional weeks of peginterferon alfa-2a + ribavirin (see tables 17 and 18).

Table 23 shows the response rates in HCV genotype 4 infected patients.

Table 23: Treatment outcome in HCV genotype 4 infected patients (study HPC3011)

Treatment outcome Treatment-naïve 
patients
N = 35

% (n/N)

Prior 
relapsers

N = 22
% (n/N)

Prior partial 
responders

N = 10
% (n/N)

Prior null 
responders

N = 40
% (n/N)

SVR12 83% (29/35) 86% (19/22) 60% (6/10) 40% (16/40)

Outcome for patients without SVR12
On-treatment failure 9% (3/35) 9% (2/22) 20% (2/10) 45% (18/40)
Viral relapse1 9% (3/35) 5% (1/22) 20% (2/10) 15% (6/40)

SVR12 rates for selected subgroups
METAVIR fibrosis score

F0-2 85% (22/26) 91% (10/11) 100% (5/5) 47% (8/17)
F3-4 78% (7/9) 82% (9/11) 20% (1/5) 35% (7/20)
F4 50% (1/2) 78% (7/9) 20% (1/5) 36% (5/14)

IL28B genotype
CC 100% (7/7) 100% (1/1) - -
CT 82% (14/17) 82% (14/17) 60% (3/5) 41% (9/22)
TT 80% (8/10) 100% (4/4) 60% (3/5) 39% (7/18)

1
Viral relapse rates are calculated with a denominator of patients with undetectable (or unconfirmed detectable) 
HCV RNA at actual EOT.

Eighty-nine percent (51/57) of the simeprevir-treated treatment-naïve patients and prior relapsers were 
eligible for a total treatment duration of 24 weeks; in these patients the SVR12 rate was 94%. Eighty 
percent (28/35), 90% (18/20), 40% (4/10) and 49% (19/39) of simeprevir-treated treatment-naïve 
patients, prior relapsers, prior partial responders and prior null responders, respectively, had 
undetectable HCV RNA at week 4. In these patients the SVR12 rates were 96%, 94%, 100% and 68%, 
respectively.

Viral breakthrough rates were 24% (11/45), 20% (5/25) and 11% (4/36) in patients with genotype 4a, 
4d and 4/other, respectively. The clinical relevance of this difference in viral breakthrough rates is 
unknown.

Clinical study examining QT interval
The effect of simeprevir 150 mg once daily and 350 mg once daily for 7 days on the QT interval was 
evaluated in a randomised, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg once 
daily), 4-way cross-over study in 60 healthy subjects. No meaningful changes in QTc interval were 
observed with either the recommended dose of 150 mg once daily or the supratherapeutic dose of 
350 mg once daily.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
simeprevir in one or more subsets of the paediatric population from 3 years to less than 18 years of age 
in the treatment of chronic viral hepatitis C (see section 4.2 for information on paediatric use).

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5.2 Pharmacokinetic properties

The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in 
adult HCV infected patients. Plasma exposure of simeprevir (AUC) in HCV infected patients was 
about 2- to 3-fold higher compared to that observed in healthy subjects. Plasma Cmax and AUC of 
simeprevir were similar during co-administration of simeprevir with peginterferon alfa and ribavirin 
compared with administration of simeprevir alone.

Absorption
The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir in 
fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 
6 hours post dose.

In vitro experiments with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.

Effect of food on absorption
Compared to intake without food, administration of simeprevir with food to healthy subjects increased 
the AUC by 61% after a high-fat, high-caloric (928 kcal) and 69% after a normal caloric (533 kcal) 
breakfast, and delayed the absorption by 1 hour and 1.5 hours, respectively.

Simeprevir must be taken with food (see section 4.2). The type of food does not affect exposure to 
simeprevir.

Distribution
Simeprevir is extensively bound to plasma proteins ( 99.9%), primarily to albumin and, to a lesser 
extent, alfa-1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with 
renal or hepatic impairment.

Biotransformation
Simeprevir is metabolised in the liver. In vitro experiments with human liver microsomes indicated 
that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system.
Involvement of CYP2C8 and CYP2C19 cannot be excluded. Moderate or strong inhibitors of 
CYP3A4 significantly increase the plasma exposure of simeprevir, and moderate or strong inducers of 
CYP3A4 significantly reduce plasma exposure of simeprevir. Simeprevir does not induce CYP1A2 or
CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

In vitro experiments show that simeprevir is a substrate for the drug transporters P-glycoprotein 
(P-gp), MRP2, OATP1B1/3 and OATP2B1. Simeprevir inhibits the uptake transporters OATP1B1/3
and NTCP and the efflux transporters P-gp/MDR1, MRP2, BCRP and BSEP. OATP1B1/3 and MRP2 
are involved in the transport of bilirubin into and out of hepatocytes. Simeprevir does not inhibit 
OCT2 in vitro.

Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, the majority of 
the radioactivity in plasma (up to 98%) was accounted for by unchanged drug and a small part of the 
radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites 
identified in faeces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both 
and by O-demethylation followed by oxidation.

Elimination
Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its 
elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on 
average 91% of the total radioactivity was recovered in faeces. Less than 1% of the administered dose 
was recovered in urine. Unchanged simeprevir in faeces accounted for on average 31% of the 
administered dose.

The terminal elimination half-life of simeprevir was 10 to 13 hours in healthy subjects and 41 hours in 
HCV infected patients receiving 200 mg simeprevir.

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Linearity/non-linearity
Plasma Cmax and the area under the plasma concentration time curve (AUC) increased more than dose 
proportional after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring 
following repeated dosing. Steady-state was reached after 7 days of once daily dosing.

Special populations
Elderly (above 65 years of age)
There is limited data on the use of simeprevir in patients older than 65 years. Age (18-73 years) had no 
clinically meaningful effect on the pharmacokinetics of simeprevir based on a population 
pharmacokinetic analysis (n = 21, age above 65 years) of HCV infected patients treated with 
simeprevir. No dose adjustment of simeprevir is required in elderly patients (see section 4.2).

Renal impairment
Renal elimination of simeprevir is negligible. Therefore, it is not expected that renal impairment will 
have a clinically relevant effect on the exposure to simeprevir.

Compared to healthy subjects with normal renal function (classified using the Modification of Diet in 
Renal Disease [MDRD] eGFR formula; eGFR ≥ 80 ml/min), the mean steady-state AUC of simeprevir 
was 1.62-fold higher (90% confidence interval: 0.73-3.6) in subjects with severe renal impairment 
(eGFR below 30 ml/min). As exposure may be increased in HCV infected patients with severe renal 
impairment, caution is recommended when prescribing simeprevir to these patients (see section 4.2).

As simeprevir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by 
dialysis.

Refer to the respective Summary of Product Characteristics of the medicinal products used in 
combination with simeprevir regarding their use in patients with renal impairment.

Hepatic impairment
Simeprevir is primarily metabolised by the liver.
Plasma exposure of simeprevir in HCV infected patients was about 2- to 3-fold higher compared to 
that observed in healthy subjects.

Compared to healthy subjects with normal hepatic function, the mean steady-state AUC of simeprevir 
was 2.4-fold higher in non-HCV infected subjects with moderate hepatic impairment (Child-Pugh B) 
and 5.2-fold higher in non-HCV infected subjects with severe hepatic impairment (Child-Pugh C).

No dose adjustment of simeprevir is necessary in patients with mild hepatic impairment. The safety 
and efficacy of simeprevir have not been established in HCV infected patients with moderate or severe 
hepatic impairment (Child-Pugh B or C). OLYSIO is not recommended in patients with moderate or 
severe hepatic impairment (Child-Pugh B or C) (see sections 4.2 and 4.4).

Refer to the respective Summary of Product Characteristics of the medicinal products used in 
combination with simeprevir regarding their use in patients with hepatic impairment.

Gender
No dose adjustment is necessary based on gender. Gender had no clinically relevant effect on the 
pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV infected 
patients treated with simeprevir in combination with peginterferon alfa and ribavirin.

Body weight
No dose adjustment is necessary based on body weight or body mass index. These characteristics have 
no clinically relevant effect on the pharmacokinetics of simeprevir based on a population 
pharmacokinetic analysis of HCV infected patients treated with simeprevir in combination with 
peginterferon alfa and ribavirin.

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Race
Population pharmacokinetic estimates of exposure of simeprevir were comparable between Caucasian 
and Black/African American HCV infected patients treated with simeprevir in combination with 
peginterferon alfa and ribavirin.

In a phase 3 study conducted in China and South-Korea, the mean plasma exposure of simeprevir in 
Asian HCV infected patients was 2.1-fold higher compared to non-Asian HCV infected patients in a 
pooled phase 3 population from global studies.

No dose adjustment is necessary based on race.

Patients co-infected with HIV-1
Pharmacokinetic parameters of simeprevir were comparable between patients with HCV genotype 1
infection with or without HIV-1 co-infection.

Paediatric population
The pharmacokinetics of simeprevir in children aged below 18 years have not been investigated.

5.3 Preclinical safety data

In rodents, simeprevir elicited toxic effects in the liver, pancreas and gastrointestinal systems. Dosing 
of animals resulted in similar (dogs) or lower (rats) exposures than those observed in humans at the 
recommended dose of 150 mg once daily. In dogs, simeprevir was associated with a reversible 
multifocal hepatocellular necrosis with associated increases in ALT, AST, alkaline phosphatase and/or 
bilirubin. This effect was observed at higher systemic exposures (11-fold) than those in humans at the 
recommended dose of 150 mg once daily.

Simeprevir in vitro was very mildly irritating to the eyes. In vitro, simeprevir induced a phototoxic 
response on BALB/c 3T3 fibroblasts after UVA exposure, in the absence and presence of protein 
supplements. Simeprevir was not irritating to rabbit skin, and is not likely to cause skin sensitisation.

There were no adverse effects of simeprevir on vital functions (cardiac, respiratory and central 
nervous system) in animal studies.

Carcinogenicity and mutagenicity
Simeprevir was not genotoxic in a series of in vitro and in vivo tests. Carcinogenicity studies with 
simeprevir have not been conducted.

Reproductive toxicology
Studies carried out in rats did not reveal significant findings on fertility, embryo-fetal development or 
pre- and post-natal development at any of the tested doses (corresponding to a systemic exposure in 
rats similar or lower than that observed in humans at the recommended dose of 150 mg once daily). 
Supernumerary ribs and delayed ossification were reported in mice at 4-fold higher exposures than 
those observed in humans at the recommended dose of 150 mg once daily.

In pregnant rats, simeprevir concentrations in placenta, fetal liver and foetus were lower compared to 
those observed in blood. When administered to lactating rats, simeprevir was detected in plasma of 
suckling rats likely due to excretion of simeprevir via milk.

Environmental Risk Assessment (ERA)
Simeprevir is classified as a PBT (persistent, bioaccumulative and toxic) substance (see section 6.6).

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6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Sodium lauryl sulfate
Magnesium stearate
Colloidal anhydrous silica
Croscarmellose sodium
Lactose monohydrate

Capsule shell
Gelatin
Titanium dioxide (E171)

Black printing ink
Shellac (E904)
Iron oxide black (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from light.
This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Opaque polyvinylchloride/polyethylene/polyvinylidenechloride (PVC/PE/PVDC) aluminium 
push-through blister strips of 7 capsules.

Pack sizes of 7 or 28 capsules.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal 
product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/924/001 (7 capsules)

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EU/1/14/924/002 (28 capsules)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 May 2014

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

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40

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Janssen-Cilag SpA
Via C. Janssen
Borgo San Michele
04100 Latina
Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

 Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the below measures:

Description Due date
In order to evaluate the recurrence of hepatocellular carcinoma associated with 
OLYSIO, the MAH shall conduct and submit the results of a prospective safety 
study using data deriving from a cohort of a well-defined group of patients, based 
on an agreed protocol. The final study report shall be submitted by:

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

OLYSIO 150 mg hard capsules
simeprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains simeprevir sodium equivalent to 150 mg simeprevir.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate

4. PHARMACEUTICAL FORM AND CONTENTS

7 hard capsules
28 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

Press edge of pocket

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

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9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Disposal: Read the package leaflet.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/924/001 (7 capsules)
EU/1/14/924/002 (28 capsules)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

olysio 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

OLYSIO 150 mg capsules
simeprevir

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Mon
Tue
Wed
Thu
Fri
Sat
Sun

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B. PACKAGE LEAFLET

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Package leaflet: Information for the patient

OLYSIO 150 mg hard capsules
simeprevir

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What OLYSIO is and what it is used for
2. What you need to know before you take OLYSIO
3. How to take OLYSIO
4. Possible side effects
5. How to store OLYSIO
6. Contents of the pack and other information

1. What OLYSIO is and what it is used for

What OLYSIO is
- OLYSIO contains the active substance ‘simeprevir’. It acts against the virus that causes 

hepatitis C infection, called ‘hepatitis C virus’ (HCV).
- OLYSIO must not be used by itself. OLYSIO must always be used as part of a course of 

treatment with other medicines for treating chronic hepatitis C infection. It is therefore 
important that you also read the package leaflets that are provided with these other medicines 
before you start taking OLYSIO. If you have any further questions about any of these 
medicines, ask your doctor or pharmacist.

What OLYSIO is used for
OLYSIO is used with other medicines to treat chronic (long-term) hepatitis C infection in adults.

How OLYSIO works
OLYSIO helps to fight against hepatitis C infection by preventing HCV from multiplying. When used 
together with other medicines to treat chronic hepatitis C infection, OLYSIO helps to clear HCV from
your body.

2. What you need to know before you take OLYSIO

Do not take OLYSIO if you are allergic to simeprevir or any of the other ingredients of this medicine
(listed in section 6). Do not take OLYSIO if this applies to you. If you are not sure, talk to your doctor 
or pharmacist before taking OLYSIO.

Warnings and precautions
Talk to your doctor or pharmacist about all your medical conditions before taking OLYSIO in 
particular if:
- you have hepatitis C that is not ‘genotype 1’ or ‘genotype 4’;

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- you have ever taken any medicines to treat hepatitis C;
- you have any other liver problems in addition to hepatitis C;
- you have a current or previous infection with the hepatitis B virus, since your doctor may want 

to monitor you more closely;
- you have had or are going to have an organ transplant.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
OLYSIO.

When taking OLYSIO combination treatment, tell your doctor if you have the following symptoms as 
they may be a sign of worsening liver problems:
- notice yellowing of your skin or eyes
- your urine is darker than normal
- notice swelling of your stomach area.
This is particularly significant if these are accompanied by either of the following symptoms:
- feel sick (nauseous), are sick (vomit) or lose your appetite
- confusion.

OLYSIO combination treatment with sofosbuvir may result in slowing of the heart rate (pulse) along 
with other symptoms when taken with amiodarone, a medicine used to treat irregular heart beat.
Tell your doctor if any of the following applies:
- you currently take, or have taken in the last few months, the medicine amiodarone (your doctor 

may consider alternative treatments if you have taken this medicine)
- you take other medicines to treat irregular heart beat or high blood pressure.
Tell your doctor immediately if you are taking OLYSIO with sofosbuvir and any medicines for heart 
problems, and during treatment you experience:
- shortness of breath
- light-headedness
- palpitations
- fainting.

Sensitivity to sunlight
You may be more sensitive to sunlight (photosensitivity) when taking OLYSIO (see section 4 for 
information about side effects).
During your treatment with OLYSIO, use appropriate sun protection (such as a sun hat, sunglasses and 
sunscreen). Especially avoid intense or prolonged exposure to sunlight (including tanning devices).
If you develop a photosensitivity reaction during treatment, contact your doctor immediately.

Rash
You may experience a rash during treatment with OLYSIO. Rash may become severe.
If you develop a rash during treatment, contact your doctor immediately.

Blood tests
Your doctor will test your blood before you start your treatment and regularly during your treatment. 
These blood tests help your doctor to
- check if the treatment is working for you
- check your liver function.

Children and adolescents
OLYSIO must not be used in children and adolescents (under 18 years of age) because it has not been 
studied in this age group.

Other medicines and OLYSIO
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because OLYSIO and other medicines may interact with each other.

In particular tell your doctor or pharmacist if you take any of the following medicines:

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- digoxin, disopyramide, flecainide, mexiletine, propafenone or quinidine (when taken by mouth) 
or amiodarone to treat irregular heart beat

- clarithromycin, erythromycin (when taken by mouth or given by injection) or telithromycin to 
treat bacterial infections

- warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your 
doctor may need to increase the frequency of your blood tests to check how well your blood can 
clot.

- carbamazepine, oxcarbazepine, phenobarbital or phenytoin to prevent seizures
- astemizole or terfenadine to treat allergies
- itraconazole, fluconazole, ketoconazole, posaconazole or voriconazole (when taken by mouth or 

given by injection) to treat fungal infections
- rifabutin, rifampicin or rifapentine to treat infections like tuberculosis
- amlodipine, bepridil, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine or verapamil 

(when taken by mouth) to decrease blood pressure
- dexamethasone (when given by injection or taken by mouth) to treat asthma or inflammation 

and auto-immune diseases
- cisapride to treat stomach problems
- milk thistle (a herbal medicine) for liver problems
- St John’s wort (Hypericum perforatum, a herbal medicine) for anxiety or depression
- ledipasvir to treat hepatitis C infection
- cobicistat to increase levels of some medicines used to treat HIV infection
- atazanavir, darunavir, delavirdine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, 

nelfinavir, nevirapine, ritonavir, saquinavir or tipranavir to treat HIV infection
- atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin to lower cholesterol 

levels
- ciclosporin, sirolimus or tacrolimus to lower immune response or prevent organ transplant 

failures
- sildenafil or tadalafil to treat ‘pulmonary arterial hypertension’
- midazolam or triazolam (when taken by mouth) to help you sleep or for anxiety

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking
OLYSIO.

In addition, tell your doctor if you take any medicines used to treat irregular heart beat or high blood 
pressure.

Pregnancy, contraception and breast-feeding
Pregnancy
If you are pregnant, think you might be pregnant or are planning to become pregnant, ask your doctor 
or pharmacist for advice before taking this medicine.
Pregnant women should not take OLYSIO unless specifically directed by the doctor.
When OLYSIO is used with ribavirin, please read the package leaflet for ribavirin for information 
regarding pregnancy. Ribavirin can affect your unborn baby.
- If you are a woman, you must not become pregnant during treatment and for several 

months afterwards.
- If you are a man, your female partner must not become pregnant during your treatment and 

for several months afterwards.
If pregnancy occurs during this period, you must contact your doctor straight away.

Contraception
Women must use an effective method of contraception during treatment with OLYSIO.
When OLYSIO is used with ribavirin, read the package leaflet for ribavirin for information regarding 
contraception requirements. You and your partner must use an effective method of contraception 
during treatment and for several months afterwards.

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Breast-feeding
Talk to your doctor if you are breast-feeding before taking OLYSIO. This is important because it is 
not known whether simeprevir can pass into breast milk. The doctor will advise you to stop 
breast-feeding or to stop taking OLYSIO while breast-feeding.

Driving and using machines
Combination treatment of OLYSIO with other medicines used for treating your chronic hepatitis C 
infection may affect your ability to drive and use machines. Do not drive or use machines if you feel 
faint or have problems with your vision. Read the package leaflets for these other medicines for 
information regarding driving and using machines.

OLYSIO contains lactose
OLYSIO contains lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, talk to your doctor before taking this medicine.

3. How to take OLYSIO

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.
You must take OLYSIO as part of a course of treatment with other medicines for treating your chronic 
hepatitis C infection. A course of OLYSIO lasts for either 12 or 24 weeks but you may need to take 
the other medicines for longer, according to your doctor’s instructions. Read the package leaflets for 
these medicines for their dosage and directions on ‘how to take’ them.

How to take
- The recommended dose of OLYSIO is one capsule (150 milligrams) once a day.
- The days of the week are printed on the blister strip - this will help you remember to take your 

capsule.
- Try to take OLYSIO at the same time each day.
- Always take OLYSIO with food. The type of food is not important.
- Take this medicine by mouth.
- Swallow the capsule whole.

How to remove capsule
Press either edge of the pocket to 
push the capsule through the foil, as 
shown.
Do not press the capsule from the 
center of the pocket. This can 
damage or break open the capsule.

If the capsule shell has been broken or opened, some medicine may be lost and you should take a new 
capsule. If the capsule shell is indented or bent - without being broken or opened - the capsule can still 
be used.

If you take more OLYSIO than you should
If you take more OLYSIO than you should, talk to your doctor or pharmacist immediately.

If you forget to take OLYSIO
- If it is more than 12 hours until your next dose, take the missed dose as soon as possible with 

food. Then continue taking OLYSIO at the usual scheduled time.
- If it is less than 12 hours until your next dose, skip the missed dose. Then take the next dose of 

OLYSIO at the usual scheduled time.
- Do not take a double dose to make up for a forgotten dose.
If you are not sure what to do, contact your doctor or pharmacist.

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Do not stop taking OLYSIO
Do not stop taking OLYSIO unless your doctor tells you to. If you do, your medicine may not work 
properly.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, OLYSIO can cause side effects, although not everybody gets them.

The following side effects may happen with OLYSIO when used in combination with sofosbuvir:
Common: may affect up to 1 in 10 people:
- itching of the skin
- skin rash*
- constipation
- being sensitive to sunlight (photosensitivity)
- increased ‘bilirubin’ levels in your blood (bilirubin is a pigment made by the liver).
* Skin rash may affect more than 1 in 10 people (very common) when OLYSIO is used in 

combination with sofosbuvir for 24 weeks.

The following side effects may happen with OLYSIO when used in combination with peginterferon 
alfa and ribavirin:
Very common: may affect more than 1 in 10 people:
- feeling sick (nausea)
- itching of the skin
- skin rash
- being short of breath.
Common: may affect up to 1 in 10 people:
- increased ‘bilirubin’ levels in your blood (bilirubin is a pigment made by the liver)*
- being sensitive to sunlight (photosensitivity)
- constipation.
* In a clinical study in Asian patients from China and South-Korea, increased blood ‘bilirubin’ 

levels were reported in more than 1 in 10 people (very common).

Read the package leaflets for the other medicines used for treating your hepatitis C infection for side 
effects reported with these medicines.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store OLYSIO

- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and blister 

packaging after EXP. The expiry date refers to the last day of that month.
- This medicine does not require any special temperature storage conditions.
- Store in the original package in order to protect from light.
- This medicine may pose a risk to the environment. Do not throw away any medicines via 

wastewater or household waste. Ask your pharmacist how to throw away medicines you no 
longer use. These measures will help protect the environment.

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53

6. Contents of the pack and other information

What OLYSIO contains
- The active substance is simeprevir. Each capsule contains simeprevir sodium equivalent to 

150 milligrams of simeprevir.
- The other ingredients are sodium lauryl sulfate, magnesium stearate, colloidal anhydrous silica, 

croscarmellose sodium, lactose monohydrate, gelatin, titanium dioxide (E171), iron oxide black 
(E172) and shellac (E904).

What OLYSIO looks like and contents of the pack
The hard capsules are white, with ‘TMC435 150’ printed in black ink.
OLYSIO is supplied in push-through blister strips of 7 capsules. The days of the week are printed on 
the blister strip.
OLYSIO is available in packs containing 7 capsules (1 blister) or 28 capsules (4 blisters).
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Antwerpseweg 15-17
B-2340 Beerse
Tel/Tél: +32 14 64 94 11

Lietuva
UAB "JOHNSON & JOHNSON"
Geležinio Vilko g. 18A
LT-08104 Vilnius
Tel: +370 5 278 68 88

България
„Джонсън & Джонсън България” ЕООД
ж.к. Младост 4
Бизнес Парк София, сграда 4
София 1766
Тел.: +359 2 489 94 00

Luxembourg/Luxemburg
Janssen-Cilag NV
Antwerpseweg 15-17
B-2340 Beerse
Belgique/Belgien
Tél/Tel: +32 14 64 94 11

Česká republika
Janssen-Cilag s.r.o.
Karla Engliše 3201/06
CZ-150 00 Praha 5 - Smíchov
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Nagyenyed u. 8-14
H-Budapest, 1123
Tel.: +36 1 884 2858

Danmark
Janssen-Cilag A/S
Bregnerødvej 133
DK-3460 Birkerød
Tlf: ++45 45 94 82 82

Malta
AM MANGION LTD.
Mangion Building, Triq Ġdida fi Triq Valletta
MT-Ħal-Luqa LQA 6000
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Johnson & Johnson Platz 1
D-41470 Neuss
Tel: +49 2137 955-955

Nederland
Janssen-Cilag B.V.
Graaf Engelbertlaan 75
NL-4837 DS Breda
Tel: +31 76 711 1111

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Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Lõõtsa 2
EE-11415 Tallinn
Tel: +372 617 7410

Norge
Janssen-Cilag AS
Postboks 144
NO-1325-Lysaker
Tlf: +47 24 12 65 00

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Λεωφόρος Ειρήνης 56
GR-151 21 Πεύκη, Αθήνα
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Vorgartenstraße 206B
A-1020 Wien
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Paseo de las Doce Estrellas, 5-7
E-28042 Madrid
Tel: +34 91 722 81 00

Polska
Janssen-Cilag Polska Sp. z o.o.
ul. Iłżecka 24
PL-02-135 Warszawa
Tel.: +48 22 237 60 00

France
Janssen-Cilag
1, rue Camille Desmoulins, TSA 91003
F-92787 Issy Les Moulineaux, Cedex 9
Tél: 0 800 25 50 75 / +33 1 55 00 40 03

Portugal
Janssen-Cilag Farmacêutica, Lda.
Estrada Consiglieri Pedroso, 69 A
Queluz de Baixo
PT-2734-503 Barcarena
Tel: +351 21 43 68 835

Hrvatska
Johnson & Johnson S.E. d.o.o.
Oreškovićeva 6h
10010 Zagreb
Tel: +385 1 6610 700

România
Johnson & Johnson România SRL
Str. Tipografilor nr. 11-15
Clădirea S-Park, Corp B3-B4, Etaj 3
013714 Bucureşti, ROMÂNIA
Tel: +40 21 207 1800

Ireland
Janssen-Cilag Ltd.
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG
United Kingdom
Tel: +44 1 494 567 444

Slovenija
Johnson & Johnson d.o.o.
Šmartinska cesta 53
SI-1000 Ljubljana
Tel: +386 1 401 18 30

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Hörgatúni 2
IS-210 Garðabær
Sími: +354 535 7000

Slovenská republika
Johnson & Johnson s.r.o.
CBC III, Karadžičova 12
SK-821 08 Bratislava
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Via M.Buonarroti, 23
I-20093 Cologno Monzese MI
Tel: +39 02 2510 1

Suomi/Finland
Janssen-Cilag Oy
Vaisalantie/Vaisalavägen 2
FI-02130 Espoo/Esbo
Puh/Tel: +358 207 531 300

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Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ,
Λεωφόρος Γιάννου Κρανιδιώτη 226
Λατσιά
CY-2234 Λευκωσία
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Box 4042
SE-16904 Solna
Tel: +46 8 626 50 00

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Mūkusalas iela 101
Rīga, LV-1004
Tel: +371 678 93561

United Kingdom
Janssen-Cilag Ltd.
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG - UK
Tel: +44 1 494 567 444

This leaflet was last revised in {month YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

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http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET