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.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains simeprevir sodium equivalent to 150 mg of simeprevir. Excipientwithknowneffect: each capsule contains 78.4 mg of lactose (as monohydrate). For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Hard capsule (capsule) White gelatin capsule of approximately 22 mm in length, marked with "TMC435 150" in black ink.

CLINICAL PARTICULARS

Posology and method of administration

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

The recommended dosage of OLYSIO is one capsule of 150 mg once daily for 12 weeks, taken with food. OLYSIO must not be administered as monotherapy. 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 table 1. Table 1: Recommended co-administered medicinal product(s) and treatment duration for OLYSIO combination therapy

Treatment-naive and prior relapse patients with cirrhosis who are co-infected with HIV should receive

48 weeks of treatment. Treatment with OLYSIO must be initiated in combination with peginterferon alfa and ribavirin and administered for 12 weeks and then followed by an additional 36 weeks of peginterferon alfa and ribavirin. See Special patient populations - HCV/Human immunodeficiency virus type 1 (HIV-1) co-infection.

Includes treatment-naive patients or patients who failed prior treatment with peginterferon alfa and ribavirin with or without cirrhosis.

OLYSIO with sofosbuvir should only be used in patients who are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment. Ribavirin could be added based on a clinical assessment of

each individual patient (see sections 4.4, 4.8 and 5.1). The recommended treatment duration is 12 weeks. A

longer treatment duration (up to 24 weeks) of OLYSIO with sofosbuvir (with or without ribavirin) could be considered based on an individual basis (see sections 4.4, 4.8 and 5.1).

Refer to table 2 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 during treatment with OLYSIO, peginterferon alfa and ribavirin 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. The HCV RNA thresholds that trigger discontinuation of treatment (i.e., treatment stopping rules) are presented in table 2. Table 2: Treatment stopping rules in patients receiving OLYSIO in combination with peginterferon alfa and ribavirin with inadequate on-treatment virologic response

Re-evaluation of HCV RNA is recommended in case of detectable HCV RNA after previous undetectable HCV RNA to confirm HCV RNA levels prior to discontinuing HCV treatment.

There are no virologic treatment stopping rules that apply to the combination of OLYSIO with sofosbuvir.

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 either medicinal product, refer to the instructions outlined in the respective Summary of Product Characteristics for these medicinal products. If the other medicinal products that are used in combination with OLYSIO for the treatment of CHC are permanently discontinued for any reason, OLYSIO must also be discontinued.

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.

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).

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 use in patients with renal impairment.

No dose adjustment of OLYSIO is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Simeprevir exposure is significantly increased in subjects with severe hepatic impairment (Child-Pugh class C) and no dose recommendation can be given for those patients (see section 5.2). The safety and efficacy of OLYSIO have not been studied in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C); therefore particular caution is recommended when prescribing OLYSIO to HCV infected patients with moderate or severe hepatic impairment. Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with OLYSIO regarding use in patients with decompensated cirrhosis (Child-Pugh class B or C).

Given limited data, the potential risks and benefits of OLYSIO 150 mg should be carefully considered prior to use in East Asian patients (see section 5.2).

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

No dose adjustment of OLYSIO is required in HCV/HIV-1 co-infected patients (see sections 4.8, 5.1 and 5.2). HCV/HIV-1 co-infected patients, irrespective of prior HCV treatment history, should be treated in the same way 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. Methodofadministration OLYSIO must be taken orally once a day with food (see section 5.2). The capsule should be swallowed as a whole.

Contraindications

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

Special warnings and precautions for use

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 mustnot be administered as monotherapy and must be prescribed in combination with other medicinal products for the treatment of CHC. If the other medicinal products that are used in combination with OLYSIO for the treatment of CHC are permanently discontinued, OLYSIO should also be discontinued (see section 4.2). 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).

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. Data are too limited to evaluate whether the presence of Q80K polymorphism in HCV genotype 1a patients reduces the efficacy of simeprevir when OLYSIO is used in combination with other direct acting antivirals against HCV (see section 5.1). Until confirmatory data becomes available, testing for the presence of the Q80K polymorphism should be considered before initiating OLYSIO in combination with sofosbuvir in patients infected with HCV genotype 1a.

Interferon-free regimens with OLYSIO have not been investigated in phase 3 studies (see section 5.1). The optimal regimen and treatment duration have not been established. Interferon-free therapy with OLYSIO should only be used in patients who are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment.

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).

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).

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 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 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.

Simeprevir plasma exposure is significantly increased in subjects with severe hepatic impairment (Child-Pugh class C). The safety and efficacy of OLYSIO have not been studied in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or in decompensated patients; therefore particular caution is recommended when prescribing OLYSIO to these patients (see sections 4.2 and 5.2).

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 baseline, on-treatment and post-treatment laboratory testing requirements including haematology, biochemistry (including hepatic enzymes and bilirubin), and pregnancy testing requirements.

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.

The safety and efficacy of OLYSIO for the treatment of HCV infection in patients co-infected with HBV have not been studied.

The safety and efficacy of OLYSIO have not been studied in organ transplant patients.

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.

Interaction with other medicinal products and other forms of interaction

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 3). 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. Inhibitors of OATP1B1 such as eltrombopag or gemfibrozil may result in mild increases in simeprevir plasma concentrations.

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 3). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir inhibits OATP1B1 and P-gp transporters. Co-administration of OLYSIO with medicinal products that are substrates for OATP1B1 and P-gp transport may result in increased plasma concentrations of such medicinal products (see table 3).

Established and theoretical interactions between simeprevir and selected medicinal products are listed in table 3 (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 3: Interactions and dose recommendation with other medicinal products

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.

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

simeprevir in combination with sofosbuvir have not been established in a phase 3 study.

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.

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

Fertility, pregnancy and lactation

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.

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.

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).

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.

Undesirable effects

Summaryofthesafetyprofile

Use with peginterferon alfa and ribavirin

The overall safety profile of simeprevir in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection who were treatment-naive or who failed prior interferon therapy with or without ribavirin is based on the pooled data from 2 clinical phase 2b studies (studies C205 and C206) and 3 clinical phase 3 studies (studies C208, C216 and HPC3007). The pooled data from the phase 2b and phase 3 studies included 1,486 patients who received simeprevir in combination with peginterferon alfa and ribavirin (of which 924 patients were to receive 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. The safety profile of simeprevir is comparable between patients with HCV genotype 4 infection and genotype 1 infection.

Tabulatedlistofadversereactions

Adverse reactions are reported in table 4. 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 rare (< 1/10,000). Table 4: Adverse reactions of simeprevir in combination with peginterferon alfa and ribavirin reported in adult patients with HCV genotype 1 infection (pooled phase 3 studies C208, C216 and HPC3007; first 12 weeks of treatments; Intent-To-Treat analysis set)

System Organ Class	Frequency category	Simeprevir + peginterferon alfa + ribavirin N=781
Respiratory, thoracic and mediastinal disorders	very common	dyspnoea *
Gastrointestinal disorders	very common common	nausea constipation
Hepatobiliary disorders	common	blood bilirubin increased *
Skin and subcutaneous tissue disorders	very common common	rash , pruritus photosensitivity reaction *

see section below for further details.

Descriptionofselectedadversereactions

Rash and pruritus

During the 12 weeks treatment with simeprevir, rash and pruritus were observed in 21.8% and 21.9% of simeprevir-treated patients, compared to 16.6% and 14.6% in patients treated with placebo, peginterferon alfa and ribavirin, respectively (all grades; pooled phase 3). Most of the rash and pruritus events in simeprevir-treated patients were of mild or moderate severity (grade 1 or grade 2). 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 no patients treated with placebo, peginterferon alfa and ribavirin, respectively.

Blood bilirubin increased

During the 12 weeks treatment with simeprevir, 'blood bilirubin increased' was reported in 7.4% of simeprevir-treated patients, compared to 2.8% in patients treated with placebo, peginterferon alfa and ribavirin (all grades; pooled phase 3). In 2% and 0.3% of the simeprevir-treated patients grade 3 or grade 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). 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.

Photosensitivity reactions

During the 12 weeks treatment with simeprevir, photosensitivity reactions were reported in 4.7% of simeprevir-treated patients compared to 0.8% in patients treated with placebo, peginterferon alfa and ribavirin (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

During the first 12 weeks treatment with simeprevir, dyspnoea was reported in 11.8% of simeprevir-treated patients, compared to 7.6% in patients treated with placebo, peginterferon alfa and ribavirin (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 patients treated with placebo, peginterferon alfa and ribavirin (all grades; pooled phase 3).

Laboratoryabnormalities

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 5. Table 5: Treatment-emergent laboratory abnormalities (WHO worst toxicity grades 1 to 4) observed at a higher incidence in patients treated with simeprevir in combination with peginterferon alfa and ribavirin (pooled phase 3 studies C208, C216 and HPC3007; first 12 weeks of treatments; Intent-To-Treat analysis set)

Laboratory parameter	WHO toxicity range	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%)

ULN = Upper Limit of Normal

Use with sofosbuvir with or without ribavirin

In study HPC2002, assessing simeprevir in combination with sofosbuvir with or without ribavirin, no new safety findings were identified other than those observed with simeprevir in combination with peginterferon alfa and ribavirin; the most common (> 10%) adverse events reported during 12 weeks treatment with simeprevir in combination with sofosbuvir were fatigue (25%), headache (21%), nausea (17%), insomnia (14%) and pruritus (11%). Patients who received ribavirin in combination with simeprevir and sofosbuvir had an increase in frequency (> 10%) of rash (15%) and anaemia (11%) compared with those who did not receive ribavirin (4% and 0%, respectively). Other selected adverse events reported were photosensitivity reactions (7% in patients receiving simeprevir in combination with sofosbuvir versus 6% in patients receiving simeprevir in combination with sofosbuvir and ribavirin) and increased bilirubin (0% versus 9%, respectively).

Otherspecialpopulations

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.

Hepatic impairment

Simeprevir exposure is significantly increased in patients with severe hepatic impairment (see sections 4.2 and 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. A higher incidence of anaemia in patients with advanced fibrosis has been reported.

Reportingofsuspectedadversereactions

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

thenationalreportingsystem

listed in Appendix V.

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, e.g., observing 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).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

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

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-naive 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, genotype 3, and genotype 4 baseline isolates tested were 25 (N=4), 1,014 (N=2), and 0.3 (N=8), 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.

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 6. Table 6: Antiviral activity of simeprevir 200 mg monotherapy (studies C201 and C202)

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.

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 2b and phase 3 clinical studies, 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 7). 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 predominantely 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 7). In patients with HCV genotype 1a with a baseline Q80K amino acid substitution an emerging R155K substitution was observed most frequently at failure. Table 7: Treatment-emergent amino-acid substitutions in pooled phase 2b and phase 3 studies: patients who did not achieve SVR with 150 mg simeprevir in combination with peginterferon alfa and ribavirin (Intent-To-Treat analysis set)

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 genotype 4 infected patients, 20 of 22 (91%) patients who did not achieve SVR had emerging amino acid substitutions at NS3 positions 80, 122, 155 and/or 168 (mainly D168V), similar to the emerging amino acid substitutions observed in genotype 1 infected patients. In study HPC2002 in genotype 1 infected patients treated with simeprevir in combination with sofosbuvir with or without ribavirin, 4 out of 5 patients (80%) with relapse had emerging amino acid substitutions R155K or D168E. No emerging amino acid substitutions associated with sofosbuvir resistance were observed.

The persistence of simeprevir-resistant NS3 amino acid substitutions was assessed following treatment failure. In the pooled analysis of patients receiving 150 mg simeprevir in combination with peginterferon alfa and ribavirin in the phase 2b 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 an ongoing, long-term follow-up study (study HPC3002) in patients who did not achieve SVR with a simeprevir-based regimen in a previous phase 2b study showed that in 70% (16/23) of these patients emerging mutations were no longer detected after a median follow-up of 88 weeks (range 47-147 weeks). The long-term clinical impact of the emergence or persistence of simeprevir-resistance-associated substitutions is unknown.

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 in the phase 2b and phase 3 studies (n=2,007; studies C208, C216, HPC3007, C206), with exception of the substitution Q80K in HCV genotype 1a patients. The observed prevalence of Q80K polymorphism at baseline in the overall study population of the phase 2b and phase 3 studies was 14%, 30% in patients with HCV genotype 1a and 0.5% in patients with HCV genotype 1b. In Europe, the observed prevalence of Q80K polymorphism in genotype 1 overall was 6% (76/1,254), 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 (study HPC3011). In the pooled analysis of the phase 3 studies C208 and C216, and in study HPC3007, 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 compared to HCV genotype 1a patients treated with simeprevir in combination with peginterferon alfa and ribavirin without Q80K (table 8). Table 8: SVR12 rates1 by HCV geno/subtype and presence or absence of baseline Q80K polymorphism in HCV genotype 1 patients treated with simeprevir/placebo in combination with peginterferon alfa and ribavirin (Intent-To-Treat analysis set)

Note: In studies C208, C216, HPC3007 and C206, three HCV genotype 1b infected patients had baseline Q80K polymorphism. All three patients had SVR12.

SVR12/24: sustained virologic response 12/24 weeks after planned end of treatment (EOT).

In the pooled analysis of studies C208 and C216, 69% (58/84) of the HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism at baseline were eligible for a total treatment duration of 24 weeks by meeting the protocol-defined RGT criteria (HCV RNA < 25 IU/ml detectable or undetectable at week 4 and undetectable HCV RNA at week 12); in these patients the SVR12 rate was 78%. Sixty-three percent (53/84) of HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism had undetectable HCV RNA at week 4 (Rapid Virologic Response; RVR); in these patients the SVR12 rate was 79%. Twenty percent (17/84) of HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism had HCV RNA >= 25 IU/ml at week 4; in these patients the SVR12 rate was 12%. In study HPC3007, 80% (24/30) of the HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism at baseline were eligible for a total treatment duration of 24 weeks by meeting the protocol-defined RGT criteria (HCV RNA < 25 IU/ml detectable or undetectable at week 4 and undetectable HCV RNA at week 12); in these patients the SVR12 rate was 58%. Forty-three percent (13/30) of HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism at baseline had undetectable HCV RNA at week 4 (RVR); in these patients the SVR12 rate was 77%. Thirteen percent (4/30) of HCV genotype 1a infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin with Q80K polymorphism had HCV RNA >= 25 IU/ml at week 4; none of these patients achieved a SVR12.

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. 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 inhibitors (S96T, S282T) and non-nucleoside inhibitors (C316N, M414I/L, P495A) remained susceptible to simeprevir in vitro.

The efficacy of simeprevir in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection was evaluated in two phase 3 studies in treatment-naive patients (studies C208 and C216), one phase 3 study in patients who relapsed after prior interferon-based therapy (study HPC3007), one phase 2b study in patients who failed prior therapy with peginterferon and ribavirin (including prior relapsers, partial and null responders) (study C206), and one phase 3 study in patients with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naive or failed previous HCV therapy (study C212). In addition, on-treatment response and preliminary SVR data are available from an ongoing phase 3 study in patients with HCV genotype 4 infection who are treatment-naive or failed previous therapy (study HPC3011). The efficacy of simeprevir as part of an interferon-free regimen with or without ribavirin was evaluated in a phase 2a study in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0-F2, or treatment-naive and prior null responder patients with METAVIR fibrosis score F3-F4 and compensated liver disease (study HPC2002). Prior relapsers were patients who had undetectable HCV RNA at the end of prior interferon-based therapy and detectable HCV RNA during follow-up; prior partial responders were patients with prior on-treatment >= 2 log10 reduction in HCV RNA from baseline at week 12 and detectable HCV RNA at the end of prior therapy with peginterferon and ribavirin; and null responders were patients with prior on-treatment < 2 log10 reduction in HCV RNA from baseline at week 12 during prior therapy with peginterferon and ribavirin. Patients in these studies had compensated liver disease (including cirrhosis), HCV RNA of at least 10,000 IU/ml, and liver histopathology consistent with CHC. In treatment-naive and prior relapser patients, the overall duration of treatment with peginterferon alfa and ribavirin in the phase 3 studies was response-guided. In these patients, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA < 25 IU/ml detectable or undetectable at week 4 AND undetectable HCV RNA at week 12. Plasma HCV RNA levels were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System (25 IU/ml LLOQ and 15 IU/ml limit of detection). Treatment stopping rules for HCV therapy were used to ensure that patients with inadequate on-treatment virologic response discontinued treatment in a timely manner. In the phase 3 study C212, the overall duration of treatment with peginterferon alfa and ribavirin in treatment-naive and prior relapser patients with cirrhosis was not response-guided; these patients received a fixed total duration of 48 weeks with peginterferon alfa and ribavirin with 12 weeks simeprevir. SVR (virologic cure) was defined as undetectable HCV RNA 24 weeks after planned end of treatment in the phase 2b study and was defined as HCV RNA < 25 IU/ml detectable or undetectable 12 weeks after the planned end of treatment in the HPC2002 study and phase 3 studies.

Efficacy in treatment-naive adults with HCV genotype 1 infection Study C208 (QUEST 1) and study C216 (QUEST 2)

The efficacy of simeprevir in treatment-naive patients with HCV genotype 1 infection was demonstrated in two randomised, double-blind, placebo-controlled, 2-arm, multicenter, phase 3 studies (study C208 and study C216). The design of both studies was similar. Patients received 12 weeks of once daily treatment with 150 mg simeprevir or placebo, plus peginterferon alfa-2a (studies C208 and C216) or peginterferon alfa-2b (study C216) and ribavirin, followed by 12 or 36 weeks of therapy with peginterferon alfa and ribavirin in accordance with the on-treatment protocol-defined RGT criteria. Patients in the control groups received 48 weeks of peginterferon alfa-2a or -2b and ribavirin. In the pooled analysis of studies C208 and C216, the 785 enrolled patients had a median age of 47 years (range: 18 to 73 years; with 2% above 65 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) >= 30 kg/m2; 78% had HCV RNA levels > 800,000 IU/ml; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 17% of the overall population and 34% of the patients with genotype 1a had Q80K polymorphism at baseline; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype. 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. The proportion of patients who discontinued all treatment due to an adverse event was 2% in the simeprevir with peginterferon alfa and ribavirin treatment group compared to 1% in the placebo with peginterferon alfa and ribavirin treatment group. Discontinuation of simeprevir or placebo alone due to an adverse event was 1% in both treatments groups. Table 9 shows the response rates in treatment-naive adult patients with HCV genotype 1 infection. Table 9: Treatment outcome in treatment-naive adult patients with HCV genotype 1 infection (pooled data studies C208 and C216; Intent-To-Treat analysis set)

Simeprevir: 150 mg simeprevir for 12 weeks with peginterferon alfa-2a or -2b and ribavirin for 24 or 48 weeks; Placebo: placebo for 12 weeks with peginterferon alfa-2a or -2b and ribavirin for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

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 by meeting the protocol-defined RGT criteria (HCV RNA < 25 IU/ml detectable or undetectable at week 4 and undetectable HCV RNA at week 12); in these patients the SVR12 rate was 88%. Seventy-eight percent (404/521) of simeprevir-treated patients had undetectable HCV RNA at week 4 (RVR); 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 13% (70/521); 67% achieved SVR12. Seven percent (35/521) of simeprevir-treated patients had HCV RNA >= 25 IU/ml at week 4; in these patients the SVR12 rate was 20%. In both C208 and C216 studies, addition of simeprevir to peginterferon alfa and ribavirin did not increase severity of patient-reported fatigue, depressive symptoms or impairments in work and daily activities beyond what was observed in patients treated with peginterferon alfa and ribavirin alone. Additionally, simeprevir-treated patients had significantly reduced time (weeks) with fatigue and impairments in work and daily activity as compared to peginterferon alfa and ribavirin alone. SVR12 rates were statistically significantly higher for the simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype subtype, baseline HCV RNA (less than or equal to 800,000 IU/ml, greater than 800,000 IU/ml), METAVIR fibrosis score, and IL28B genotype. Table 10 shows the SVR rates by METAVIR fibrosis score and IL28B genotype. Table 10: SVR12 rates by METAVIR fibrosis score and IL28B genotype in treatment-naive adult patients with HCV genotype 1 infection (pooled data studies C208 and C216; Intent-To-Treat analysis set)

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 adults with HCV genotype 1 infection who failed previous therapy Study HPC3007 (PROMISE)

This was a randomised, double-blind, placebo-controlled, 2-arm, multicenter, phase 3 study in patients with HCV genotype 1 infection who relapsed after prior interferon-based therapy. Patients received 12 weeks of once daily treatment with 150 mg simeprevir or placebo, plus peginterferon alfa-2a and ribavirin, followed by 12 or 36 weeks of therapy with peginterferon alfa-2a and ribavirin in accordance with the protocol-defined RGT criteria. Patients in the control group received 48 weeks of peginterferon alfa-2a and ribavirin. The 393 enrolled patients in study HPC3007 had a median age of 52 years (range: 20 to 71 years; with 3% above 65 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI >= 30 kg/m2; 84% had HCV RNA levels > 800,000 IU/ml; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 13% of the overall population and 31% of the patients with genotype 1a had Q80K polymorphism at baseline; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype. The prior interferon-based HCV therapy was peginterferon alfa-2a/ribavirin (68%) or peginterferon alfa-2b/ribavirin (27%). The proportion of patients who discontinued all treatment due to an adverse event was 0.4% in the simeprevir with peginterferon alfa and ribavirin treatment group compared to none in the placebo with peginterferon alfa and ribavirin treatment group. None of the patients discontinued simeprevir alone due to an adverse event. Table 11 shows the response rates for the simeprevir and placebo treatment groups in adult patients with HCV genotype 1 infection who relapsed after prior interferon-based therapy. Table 11: Treatment outcome in adult patients with HCV genotype 1 infection who relapsed after prior interferon-based therapy (study HPC3007; Intent-To-Treat analysis set)

Simeprevir: 150 mg simeprevir for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks; Placebo: placebo for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

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 5 simeprevir-treated patients who experienced relapse after

Ninety-three percent (241/260) of the simeprevir-treated patients were eligible for a total treatment duration of 24 weeks by meeting the protocol-defined RGT criteria (HCV RNA < 25 IU/ml detectable or undetectable at week 4 and undetectable HCV RNA at week 12); in these patients the SVR12 rate was 83%. Seventy-seven percent (200/260) of simeprevir-treated patients had undetectable HCV RNA at week 4 (RVR); in these patients the SVR12 rate was 87%. The proportion of simeprevir-treated patients with HCV RNA < 25 IU/ml detectable at week 4 was 18% (47/260); 60% achieved SVR12. Five percent (12/260) of simeprevir-treated patients had HCV RNA >= 25 IU/ml at week 4; in these patients the SVR12 rate was 42%. In study HPC3007, the increases in severity of patient-reported fatigue, depressive symptoms and impairments in work and daily activities were comparable in both treatment groups. The increases lasted longer in patients treated with peginterferon alfa and ribavirin alone. SVR12 rates were statistically significantly higher for the simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype subtype, baseline HCV RNA (less than or equal to 800,000 IU/ml, greater than 800,000 IU/ml), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 12 shows the SVR rates by METAVIR fibrosis score and IL28B genotype. Table 12: SVR12 rates by METAVIR fibrosis score and IL28B genotype in adult patients with HCV genotype 1 infection who relapsed after prior interferon-based therapy (study HPC3007; Intent-To-Treat analysis set)

This was a randomised, double-blind, placebo-controlled, 7-arm, phase 2b study in patients with HCV genotype 1 infection, who failed prior therapy with peginterferon alfa and ribavirin (including prior relapsers, partial responders or null responders). Patients received 12, 24 or 48 weeks of 100 mg or 150 mg simeprevir in combination with 48 weeks of peginterferon alfa-2a and ribavirin, or 48 weeks of placebo in combination with 48 weeks of peginterferon alfa-2a and ribavirin. The 462 enrolled patients in study C206 had a median age of 50 years (range: 20 to 69 years; with 3% above 65 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI >= 30 kg/m2; 86% had HCV RNA levels > 800,000 IU/ml; 63% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 12% of the overall population and 27% of the patients with genotype 1a had Q80K polymorphism at baseline; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 patients). Forty percent of patients were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with peginterferon alfa and ribavirin. One hundred ninety-nine patients received simeprevir 150 mg once daily (pooled analysis) of which 66 patients received simeprevir for 12 weeks, and 66 patients received placebo in combination with peginterferon alfa and ribavirin. The proportion of patients who discontinued all treatment due to an adverse event was 5% in both the 150 mg simeprevir for 12 weeks and the placebo treatment groups; none of the patients discontinued simeprevir or placebo alone. Table 13 shows the response rates for the simeprevir and placebo treatment groups in prior partial responders and null responders. Table 13: Treatment outcome in adult patients with HCV genotype 1 infection who failed prior peginterferon alfa and ribavirin therapy (study C206; prior partial and null responders; Intent-To-Treat analysis set)

150 mg simeprevir: 150 mg simeprevir for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks; pooled 150 mg simeprevir: 150 mg simeprevir for 12, 24 or 48 weeks with peginterferon alfa-2a and ribavirin for 48 weeks; Placebo: placebo with peginterferon alfa-2a and ribavirin for 48 weeks. SVR24: sustained virologic response 24 weeks after planned EOT.

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.

Thirteen percent (9/69) and 26% (13/51) of simeprevir-treated prior partial responders and null responders, respectively, had HCV RNA >= 25 IU/ml at week 4; in these patients, the SVR24 rates were 11% and 8%, respectively (pooled 150 mg simeprevir). In study C206, no treatment related differences in patient reported fatigue severity were observed. Fatigue increased to similar extent and returned to baseline levels after week 48 in all treatment arms. SVR24 rates were higher in the simeprevir-treated patients compared to patients receiving placebo in combination with peginterferon alfa and ribavirin, regardless of HCV geno/subtype, METAVIR fibrosis score and IL28B genotype. Table 14 shows the SVR rates by METAVIR fibrosis scores. Table 14: SVR24 rates by METAVIR fibrosis score in adult patients with HCV genotype 1 infection who failed prior peginterferon alfa and ribavirin therapy (study C206; prior partial and null responders; Intent-To-Treat analysis set)

Pooled 150 mg simeprevir: 150 mg simeprevir for 12, 24 or 48 weeks with peginterferon alfa-2a and ribavirin for 48 weeks; Placebo: placebo for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks. SVR24: sustained virologic response 24 weeks after planned EOT.

Interim data from an ongoing 3-year follow-up study (study HPC3002) in patients who achieved SVR with a simeprevir-based regimen in previous phase 2b studies showed that all patients (n=166) maintained undetectable HCV RNA during a median follow-up time of 16 months.

This is an open label, single arm phase 3 study in HIV-1 patients co-infected with HCV genotype 1 who are treatment-naive or failed prior HCV therapy with peginterferon alfa and ribavirin (including prior relapsers, partial responders or null responders). Non-cirrhotic treatment-naive patients or prior relapsers received 12 weeks of once daily treatment with 150 mg simeprevir plus peginterferon alfa-2a and ribavirin, followed by 12 or 36 weeks of therapy with peginterferon alfa-2a and ribavirin in accordance with the protocol-defined RGT criteria. Prior non-responder patients (partial and null response) and all cirrhotic patients (METAVIR fibrosis score F4) received 36 weeks of peginterferon alfa-2a and ribavirin after the initial 12 weeks of simeprevir in combination with peginterferon alfa-2a and ribavirin. The 106 enrolled patients in study C212 had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI >= 30 kg/m2; 86% had HCV RNA levels > 800,000 IU/ml; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the patients with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment-naive patients, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty-eight percent (n=93) of the patients were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. The median baseline HIV-1 RNA levels and CD4+ cell count in patients not on HAART were 4.18 log10 copies/ml (range: 1.3-4.9 log10 copies/ml) and 677 x 106 cells/l (range: 489-1,076 x 106 cells/l), respectively. The median baseline CD4+ cell count in patients on HAART was 561 x 106 cells/ml (range: 275-1,407 x 106 cells/ml). The proportion of patients who discontinued all treatment due to an adverse event was 5%. The proportion of patients who discontinued simeprevir treatment due to an adverse event was 4%. Table 15 shows the response rates in treatment-naive, prior relapsers, prior partial responders and null responders. Table 15: Treatment outcome in adult patients with HCV genotype 1 infection and HIV-1 co-infection (study C212; treatment-naive patients, prior relapsers, prior partial and null responders; Intent-To-Treat analysis set)

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.

Eighty-nine percent (54/61) of the simeprevir-treated treatment-naive patients and prior relapsers without cirrhosis were eligible for 24 weeks of treatment by meeting the protocol-defined RGT criteria (HCV RNA < 25 IU/ml detectable or undetectable at week 4 and undetectable HCV RNA at week 12); in these patients the SVR12 rate was 87%. Seventy percent (37/53), 93% (14/15), 80% (8/10) and 36% (10/28) of simeprevir-treated treatment-naive patients, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these patients the SVR12 rates were 89%, 93%, 75% and 90%, respectively. Six percent (3/53), 0% (0/15), 20% (2/10) and 25% (7/28) of simeprevir-treated treatment-naive patients, prior relapsers, prior partial responders and prior null responders, respectively, had HCV RNA >= 25 IU/ml at week 4. The SVR12 rates were 0% in treatment-naive patients, prior relapsers and prior null responders and 50% (1/2) in prior partial responders. Table 16 shows the SVR rates by METAVIR fibrosis scores. Table 16: SVR12 rates by METAVIR fibrosis score and IL28B genotype in adult patients with HCV genotype 1 infection and HIV-1 co-infection (study C212; treatment-naive patients, prior relapsers, prior partial and null responders; Intent-To-Treat analysis set)

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.

This is an ongoing open label, single arm phase 3 study in patients with HCV genotype 4 infection who are treatment-naive or failed prior therapy with peginterferon alfa and ribavirin (including prior relapsers, partial responders or null responders). Treatment-naive patients or prior relapsers received once daily treatment with 150 mg simeprevir plus peginterferon alfa-2a and ribavirin for 12 weeks, followed by 12 or 36 weeks of therapy with peginterferon alfa-2a and ribavirin in accordance with the protocol-defined RGT criteria. Prior non-responder patients (partial and null response) received once daily treatment with 150 mg simeprevir plus peginterferon alfa-2a and ribavirin for 12 weeks, followed by 36 weeks of peginterferon alfa-2a and ribavirin. The 107 enrolled patients with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI >= 30 kg/m2; 60% had HCV RNA levels > 800,000 IU/ml; 57% had METAVIR fibrosis score F0, F1, or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; none of the patients had Q80K polymorphism at baseline; 33% (n=35) were treatment-naive HCV patients, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders. At the time of analysis of this ongoing study, 92% of patients (n=98) had completed treatment with simeprevir and 62% of patients (31 treatment-naive patients, 20 prior relapsers, 5 prior partial responders and 10 prior null responders) ended all treatment. Three prior partial responders (30%) and 12 prior null responders (30%) are still on treatment. In the patients evaluable for SVR12, the overall SVR12 rate was 85% (52/61); SVR12 rates were 88% (28/32) in treatment-naive patients, 91% in prior relapsers (19/21), 33% (1/3) in prior partial responders and 80% (4/5) in prior null responders. In the treatment-naive patients or prior relapsers meeting protocol-defined RGT and receiving 24 weeks total treatment, SVR4 and SVR12 rates were 96% (49/51) and 92% (47/51), respectively. Viral breakthrough rates were 24% (11/45), 20% (5/25) and 11% (4/36) in patients with genotype 4a, 4d and 4/other. The clinical relevance of this difference in viral breakthrough rates is unknown.

Efficacy in adults with HCV genotype 1 treated with an interferon-free regimen Study HPC2002 (COSMOS)

This is an open-label, randomised phase 2a study to investigate the efficacy and safety of 12 or 24 weeks of simeprevir (150 mg once daily) in combination with sofosbuvir (400 mg once daily) with or without ribavirin in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0-F2 (Cohort 1), or treatment-naive and prior null responder patients with METAVIR fibrosis score F3-F4 and compensated liver disease (Cohort 2). The 80 enrolled patients without advanced hepatic fibrosis in Cohort 1 had a median age of 56 years (range 27 to 70 years; with 8% above 65 years); 61% were male; 71% were White, 29% Black or African American; 30% had a BMI >= 30 kg/m2; 98% had HCV RNA levels > 800,000 IU/ml; 41% had METAVIR fibrosis score F0 or F1 and 59% had METAVIR fibrosis score F2; 78% had HCV genotype 1a, and the remaining patients had HCV genotype 1b; 39% of the overall population and 50% of the patients with genotype 1a had Q80K polymorphism at baseline; 6% had IL28B CC genotype, 70% IL28B CT genotype, and 24% IL28B TT genotype. All patients were prior null responders to peginterferon alfa and ribavirin. The 87 enrolled patients with advanced hepatic fibrosis in Cohort 2 had a median age of 58 years (range 28 to 70 years; with 3% above 65 years); 67% were male; 91% were White, 9% Black or African American; 44% had a BMI >= 30 kg/m2; 84% had HCV RNA levels > 800,000 IU/ml; 53% had METAVIR fibrosis score F3 and 47% had METAVIR fibrosis score F4 (cirrhosis); 78% had HCV genotype 1a, and 22% HCV genotype 1b; 31% of the overall population and 40% of the patients with genotype 1a had Q80K polymorphism at baseline; 21% had IL28B CC genotype, 56% IL28B CT genotype, and 23% IL28B TT genotype. Fifty four percent of patients were prior null responders to peginterferon alfa and ribavirin and 46% were treatment-naive. In both cohorts, none of the patients from the 12-week treatment groups discontinued treatment due to an adverse event. In the 24-week treatment groups, the proportion of patients who discontinued treatment due to an adverse event was 3% and 2% in Cohort 1 and 2, respectively. Table 17 shows the response rates for prior null responders in Cohort 1 and for treatment-naive and prior null responder patients in Cohort 2. Table 17: Treatment outcome in adult patients with HCV genotype 1 infection who were null responders to prior peginterferon alfa and ribavirin therapy or treatment-naive receiving 12 weeks of simeprevir combination treatment with sofosbuvir with or without ribavirin (study HPC2002; Intent-to-Treat analysis set)

150 mg once daily simeprevir for 12 weeks with 400 mg once daily sofosbuvir with or without ribavirin. SVR12: sustained virologic response 12 weeks after planned EOT.

The overall SVR12 rates in patients receiving 12 weeks of simeprevir in combination with sofosbuvir with or without ribavirin were 95% (39/41) and 93% (38/41) in Cohort 1 and Cohort 2, respectively, and 94% (77/82) across both cohorts. Prior treatment status and ribavirin use did not impact treatment outcome. In Cohort 1, the SVR12 rates in the 24-week treatment groups were 79% (19/24) for the simeprevir with sofosbuvir with ribavirin treatment group and 93% (14/15) in the simeprevir with sofosbuvir without ribavirin treatment group. In Cohort 2, the SVR12 rates in the 24-week treatment groups were 93% (28/30) for the simeprevir with sofosbuvir with ribavirin treatment group and 100% (16/16) in the simeprevir with sofosbuvir without ribavirin treatment group. A total of 6 patients with viral relapse were reported (6/162, 4%): 4 occurred in HCV genotype 1a patients with baseline Q80K polymorphism (3 in Cohort 1 and 1 in Cohort 2) and 2 occurred in HCV genotype 1a patients without Q80K polymorphism. Table 18 shows the SVR12 rates by HCV geno/subtype and Q80K baseline polymorphism. Table 18: SVR12 rates in adult patients with HCV genotype 1 infection who were null responders to prior peginterferon alfa and ribavirin therapy or treatment-naive by geno/subtype and Q80K baseline polymorphism (study HPC2002; Intent-To-Treat analysis set)

150 mg once daily simeprevir for 12 weeks with 400 mg once daily sofosbuvir with or without ribavirin. SVR12: sustained virologic response 12 weeks after planned EOT.

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.

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).

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 peginterferon alfa and ribavirin compared with administration of simeprevir alone.

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.

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

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.

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.

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.

experiments show that simeprevir is a substrate for the drug transporters P-glycoprotein (P-gp), MRP2, OATP1B1, OATP2B1 and OATP1B3. Simeprevir inhibits the uptake transporters OATP1B1 and NTCP and the efflux transporters P-gp/MDR1, MRP2 and BSEP. OATP1B1 and

MRP2 are involved in the transport of bilirubin into and out of hepatocytes. The in vitro inhibitory profile of simeprevir for human BCRP, OATP1B3 and OCT2 has not been studied. 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 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.

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.

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 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 62% higher with a 90% confidence interval of 27% lower to 3.6-fold higher 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 use in patients with renal 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 class B) and 5.2-fold higher in non-HCV infected subjects with severe hepatic impairment (Child-Pugh class C). No dose adjustment of simeprevir is necessary in patients with mild or moderate hepatic impairment; no dose recommendation can be given for patients with severe hepatic impairment (Child-Pugh class C). The safety and efficacy of simeprevir have not been studied in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C), therefore particular caution is recommended in these patients (see section 4.2). Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with simeprevir regarding use in patients with hepatic impairment.

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.

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.

No dose adjustment is necessary based on 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 the phase 3 studies with HCV infected patients treated with 150 mg simeprevir once daily in combination with peginterferon alfa and ribavirin, the range of simeprevir plasma exposure in Asian patients was within the range observed in non-Asian patients. However, the mean simeprevir plasma exposure for these patients (n=14) was 3.4-fold higher than in the pooled phase 3 population. Given limited data, the potential risks and benefits of simeprevir should be carefully considered prior to use in East Asian patients.

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

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

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.

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

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.

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

PHARMACEUTICAL PARTICULARS

List of excipients

Incompatibilities

Shelf life

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.

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.

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.

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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.

Patient population	Treatment	Duration
Treatment-naive and prior relapse patients with HCV genotype 1 or 4 1	OLYSIO + peginterferon alfa + ribavirin 2	24 weeks 3 Treatment with OLYSIO must be initiated in combination with peginterferon alfa and ribavirin and administered for 12 weeks and then followed by an additional 12 weeks of peginterferon alfa and ribavirin.
Prior non-responder patients (including partial and null responders) with HCV genotype 1 or 4 1	OLYSIO + peginterferon alfa + ribavirin 2	48 weeks Treatment with OLYSIO must be initiated in combination with peginterferon alfa and ribavirin and administered for 12 weeks and then followed by an additional 36 weeks of peginterferon alfa and ribavirin.
Patients with HCV genotype 1 or 4, regardless of prior treatment history 4	OLYSIO + sofosbuvir (+/- ribavirin) 5	12 weeks (see sections 4.4, 4.8 and 5.1)

HCV RNA	Action
Treatment week 4: >= 25 IU/ml	Discontinue OLYSIO, peginterferon alfa and ribavirin
Treatment week 12: detectable 1	Discontinue peginterferon alfa and ribavirin (treatment with OLYSIO is complete at week 12)
Treatment week 24: detectable 1	Discontinue peginterferon alfa and ribavirin

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 C m ax 1.12 (1.06-1.19) - caffeine C mi n not studied	No dose adjustment is required.
ANTIARRHYTHMICS
Digoxin 0.25 mg	digoxin AUC 1.39 (1.16-1.67) \| digoxin C m ax 1.31 (1.14-1.51) \| digoxin C mi n 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 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) Mild increases in simeprevir concentrations may occur due to inhibition of CYP3A4 by amiodarone.	Caution is warranted and therapeutic drug monitoring for these antiarrhythmics and/or clinical monitoring (ECG etc.) when orally administered are recommended.
ANTICOAGULANTS
Warfarin 10 mg	S-warfarin AUC 1.04 (1.00-1.07) - S-warfarin C m ax 1.00 (0.94-1.06) - S-warfarin C mi n not studied	No dose adjustment is required. However, it is recommended that the international normalised ratio (INR) be monitored.
ANTICONVULSANTS
Carbamazepine	Not studied. Significant decrease in plasma	It is not recommended to
Oxcarbazepine	concentrations of simeprevir are expected.	co-administer OLYSIO
Phenobarbital		with these anticonvulsants
Phenytoin	(strong CYP3A4 induction)	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 C m ax 1.03 (0.99-1.07) - escitalopram C mi n 1.00 (0.95-1.05) - simeprevir AUC 0.75 (0.68-0.83) simeprevir C m ax 0.80 (0.71-0.89) simeprevir C mi n 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 (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.
Erythromycin 500 mg three times a day	erythromycin AUC 1.90 (1.53-2.36) erythromycin C m ax 1.59 (1.23-2.05) erythromycin C mi n 3.08 (2.54-3.73) simeprevir AUC 7.47 (6.41-8.70) simeprevir C m ax 4.53 (3.91-5.25) simeprevir C mi n 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.
Rifampicin 1 600 mg once daily	rifampicin AUC 1.00 (0.93-1.08) - rifampicin C m ax 0.92 (0.80-1.07) - rifampicin C mi n not studied 25-desacetyl-rifampicin AUC 1.24 (1.13-1.36) 25-desacetyl-rifampicin C ma x 1.08 (0.98-1.19) - 25-desacetyl-rifampicin C mi n not studied simeprevir AUC 0.52 (0.41-0.67) simeprevir C m ax 1.31 (1.03-1.66) simeprevir C mi n 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 C m ax 1.21 (0.93-1.57) \| DXM C mi n not studied dextrorphan AUC 1.09 (1.03-1.15) - dextrorphan C m ax 1.03 (0.93-1.15) - dextrorphan C mi n not studied	No dose adjustment is required.
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
e.g., Aluminium or Magnesium hydroxide, Calcium carbonate	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
H 2 -receptor antagonists
e.g., 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 C m ax 1.14 (0.93-1.39) omeprazole C mi n 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.
HCV PRODUCTS
Antiviral
Sofosbuvir 2 400 mg once daily	sofosbuvir AUC 3.16 (2.25-4.44) sofosbuvir C m ax 1.91 (1.26-2.90) sofosbuvir C mi n not studied GS-331007 AUC 1.09 (0.87-1.37) - GS-331007 C m ax 0.69 (0.52-0.93) GS-331007 C mi n not studied simeprevir AUC 0.94 (0.67-1.33) - simeprevir C m ax 0.96 (0.71-1.30) - simeprevir C mi n not studied	Increase in sofosbuvir exposure observed in the preliminary 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 C m ax 1.03 (0.78-1.36) - raltegravir C mi n 1.14 (0.97-1.36) simeprevir AUC 0.89 (0.81-0.98) - simeprevir C m ax 0.93 (0.85-1.02) - simeprevir C mi n 0.86 (0.75-0.98)	No dose adjustment is required.
Antiretroviral - non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily	efavirenz AUC 0.90 (0.85-0.95) - efavirenz C m ax 0.97 (0.89-1.06) - efavirenz C mi n 0.87 (0.81-0.93) - simeprevir AUC 0.29 (0.26-0.33) simeprevir C m ax 0.49 (0.44-0.54) simeprevir C mi n 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 C m ax 1.04 (0.95-1.13) - rilpivirine C mi n 1.25 (1.16-1.35) simeprevir AUC 1.06 (0.94-1.19) - simeprevir C m ax 1.10 (0.97-1.26) simeprevir C mi n 0.96 (0.83-1.11) -	No dose adjustment is required.
Other NNRTIs	Not studied. Altered plasma concentrations of	It is not recommended to
(Delavirdine,	simeprevir are expected.	co-administer OLYSIO
Etravirine,		with delavirdine, etravirine
Nevirapine)	(CYP3A4 enzyme induction [etravirine or	or nevirapine.
Nevirapine)	nevirapine] or inhibition [delavirdine])	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 C m ax 1.19 (1.10-1.30) tenofovir C mi n 1.24 (1.15-1.33) simeprevir AUC 0.86 (0.76-0.98) simeprevir C m ax 0.85 (0.73-0.99) simeprevir C mi n 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/ritonavir 3 800/100 mg once daily	darunavir AUC 1.18 (1.11-1.25) darunavir C m ax 1.04 (0.99-1.10) - darunavir C mi n 1.31 (1.13-1.52) ritonavir AUC 1.32 (1.25-1.40) ritonavir C m ax 1.23 (1.14-1.32) ritonavir C mi n 1.44 (1.30-1.61) simeprevir AUC 2.59 (2.15-3.11) * simeprevir C m ax 1.79 (1.55-2.06) * simeprevir C mi n 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.
Ritonavir 1 100 mg twice daily	simeprevir AUC 7.18 (5.63-9.15) simeprevir C m ax 4.70 (3.84-5.76) simeprevir C mi n 14.35 (10.29-20.01) (strong CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with ritonavir.
Other ritonavir-boosted or unboosted HIV PIs (e.g., 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 C m ax 3.17 (2.57-3.91) rosuvastatin C mi n not studied (OATP1B1 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 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 C m ax 1.70 (1.42-2.04) atorvastatin C mi n not studied 2-OH-atorvastatin AUC 2.29 (2.08-2.52) 2-OH-atorvastatin C m ax 1.98 (1.70-2.31) 2-OH-atorvastatin C mi n not studied (OATP1B1 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 C m ax 1.46 (1.17-1.82) simvastatin C mi n not studied simvastatin acid AUC 1.88 (1.63-2.17) simvastatin acid C m ax 3.03 (2.49-3.69) simvastatin acid C mi n 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.
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 C m ax 1.18 (1.09-1.27) ethinylestradiol C mi n 1.00 (0.89-1.13) - norethindrone AUC 1.15 (1.08-1.22) - norethindrone C m ax 1.06 (0.99-1.14) - norethindrone C mi n 1.24 (1.13-1.35)	No dose adjustment is required.
IMMUNOSUPPRESSANTS
Ciclosporine 100 mg	ciclosporine AUC 1.19 (1.13-1.26) ciclosporine C m ax 1.16 (1.07-1.26) ciclosporine C mi n not studied Increased simeprevir concentrations may occur due to inhibition of OATP1B1 by ciclosporine.	No dose adjustment is required when co-administered with OLYSIO. Monitoring of blood concentrations of ciclosporine is recommended.
Tacrolimus 2 mg	tacrolimus AUC 0.83 (0.59-1.16) tacrolimus C m ax 0.76 (0.65-0.90) tacrolimus C mi n not studied Increased simprevir concentrations may occur due to inhibition of OATP1B1 by tacrolimus.	No dose adjustment is required when co-administered with OLYSIO. 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
Methadone 4 30-150 mg once daily, individualised dose	R(-) methadone AUC 0.99 (0.91-1.09) - R(-) methadone C m ax 1.03 (0.97-1.09) - R(-) methadone C mi n 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.
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 C m ax 1.31 (1.19-1.45) midazolam C mi n not studied Intravenous: midazolam AUC 1.10 (0.95-1.26) midazolam C m ax 0.78 (0.52-1.17) midazolam C mi n 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.

Genotype	Mean (SE) change in HCV RNA at day 7/8 (log 10 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)

Emerging amino-acid s ubstitutions in NS3	All HCV genotypes N=197 % (n)	Genotype 1a 1 N=116 % (n)	Genotype 1b N=81 % (n)
Any substitution at NS3 position 43, 80, 122, 155, 156, or 168 2	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)
Q80R 3	7.6% (15)	4.3% (5)	12.3% (10)
R155K	45.2% (89)	76.7% (89)	0% (0)
Q80X+D168X 4	8.1% (16)	4.3% (5)	13.6% (11)
R155X+ D168X 4	9.1% (18)	12.9% (15)	3.7% (3)
Q80K 3 , S122A/G/I/T 3 , S122R, R155Q, D168A, D168F 3 , D168H, D168T, I170T 5	Less than 10%	Less than 10%	Less than 10%

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS