Olysio - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

4   CLINICAL PARTICULARS

4. CLINICALPARTICULARS4.1 Therapeutic indications

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

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

4.2 Posology and method of administration

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

Posology

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

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

Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with OLYSIO.

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

Table 1:   Recommended treatment duration for OLYSIO combination therapy with

sofosbuvir with or without ribavirin in patients with HCV genotype 1 or 4

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

The daily dose of ribavirin is weight based (< 75 kg = 1,000 mg and > 75 kg = 1,200 mg) and administered oi^’ly in

two divided doses with food; also refer to the Summary of Product Characteristics of ribavirin.

Table 2:   Recommended treatment duration for OLYSIO combination therapy with

peginterferon alfa and ribavirin1 in HCV genotype 1 or 4

1

2

3

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

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

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

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

Treatment discontinuation in patients with inadequate on-treatment virologic response

OLYSIO in combination with sofosbuvir

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

OLYSIO in combination with peginterferon alfa and ribavrin

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

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

Table 3:   Treatment stopping rules in patients receiving OLYSIO in combination with

peginterferon alfa and ribavirin with inadequate on-treatment virologic response

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

Dosage adjustment or interruption of OLYSIO treatment

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

Dosage adjustment or interruption of medicinal products used in combination with OLYSIO for the treatment of CHC

If adverse reactions, potentially related to the medicinal products that are used in combination with OLYSIO for the treatment of CHC, require dosage adjustment or interruption of the medicinal product(s), refer to the instructions outlined in the respective Summary of Product Characteristics for these medicinal products.

If other medicinal products used in combination with OLYSIO for the treatment of CHC are permanently discontinued for any reason, OLYSIO must also be discontinued. When ribavirin is added to the combination of OLYSIO and sofosbuvir, and ribavirin needs to be discontinued, treatment of OLYSIO with sofosbuvir without ribavirin can be continued (see section 5.1).

Missed dose

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

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

Special population s

Elderly (over 65 years of age)

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

Renal impairment

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

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

4.3 Contraindications

4.4 Special

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

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

Hepatic decompensation and hepatic failure

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

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

Hepatic impairment

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

Severe bradycardia and heart block

Cases of bradycardia have been observed when OLYSIO is used in combination with sofosbuvir and concomitant amiodarone. The mechanism is not established.

Cases are potentially life threatening, therefore amiodarone should only be used in patients on OLYSIO combination treatment with sofosbuvir when other alternative antiarrhythmic treatments ar not tolerated or are contraindicated.

Should concomitant use of amiodarone be considered necessary, it is recommended that patients are closely monitored when initiating OLYSIO combination treatment with sofosbuvir. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting.

Due to the long elimination half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on OLYSIO combination treatment with sofosbuvir.

All patients receiving OLYSIO combination treatment with sofosbuvir in combination with amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.

Pre-treatment testing for NS3 Q80K polymorphism in p atients infected with HCV genotype 1a OLYSIO in combination with sofosbuvir

In HCV genotype 1a infected patients with cirrhosis, testing for the presence of the NS3 Q80K polymorphism may be considered prior to initiation of therapy with OLYSIO in combination with sofosbuvir (see section 5.1).

In HCV genotype 1a infected patients without cirrhosis, simeprevir efficacy in combination with sofosbuvir at the recommended 12-week treatment duration was not impacted by the presence of the NS3 Q80K polymorphism (see section 5.1).

OLYSIO in combination with peginterferon alfa and ribavirin

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

Co-a dministration with other direct acting antivirals against HCV

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

OLYSIO in combination with peginterferon alfa-2b

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

Pregnancy and contraception

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

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

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

Photosensitivity

Photosensitivity reactions have been observed with OLYSIO combination treatment (see section

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

Rash

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

Laboratory testing during treatment with OLYSIO, peginterferon alfa and ribavirin

HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated (see also guidelines for treatment duration and stopping rules; section 4.2). Use of a sensitive quantitative HCV RNA assay for monitoring HCV RNA levels during treatment is recommended.

Refer to the Summary of Product Characteristics of peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing requirements including haematology, biochemistry (including hepatic enzymes and bilirubin), and pregnancy testing requirements.

Interactions with medicinal produ is

Co-administration of OLYSIO with substances that moderately or strongly induce or inhibit cytochrome P450 3A (CYP3A4) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively.

Please refer to section 4.5 for information on interactions with medicinal products.

Hepatitis B vir us (HBV) co-infection

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

Organ transplant patients

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

Excipient of OLYSIO capsules

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

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products that affect simeprevir exposure

The primary enzyme involved in the biotransformation of simeprevir is CYP3A4 (see section 5.2) and clinically relevant effects of other medicinal products on simeprevir pharmacokinetics via CYP3A4 may occur. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A4 may significantly increase the plasma exposure of simeprevir, while co-administration with moderate or strong inducers of CYP3A4 may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see table 4). Therefore, co-administration of OLYSIO with substances that moderately or strongly inhibit or induce CYP3A4 is not recommended.

Hepatic uptake of simeprevir is mediated by OATP1B1/3. Inhibitors of OATP1B1/3 such as eltrombopag or gemfibrozil may result in increases in simeprevir plasma concentrations.

Medicinal products that are affected by the use of simeprevir

Simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Co-administration of OLYSIO with medicinal products that are primarily metabolised by CYP3A4 may result in increased plasma concentrations of such medicinal products (see table 4). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo.

Simeprevir inhibits OATP1B1/3, P-gp and BCRP transporters. Co-administration of OLYSIO with medicinal products that are substrates for OATP1B1/3, P-gp and BCRP transport may result in increased plasma concentrations of such medicinal products (see table 4).

Patients treated with vitamin K antagonists

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

Interaction table

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

Table 4:   Interactions and dose recommendation with other medicinal products

HCV PRODUCTS

Antiviral

4.6 Fertility, pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8

4.9 Overdose      

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

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

Antiviral activity in vitro

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

Antiviral activity in vivo

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

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

Resistance

Resistance in cell culture

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

Resistance in clinical studies

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

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

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

Table 10:  Treatment-emergent amino-acid substitutions in pooled phase 2 and phase 3

studies: patients who did not achieve SVR with 150 mg simeprevir in combination with peginterferon alfa and ribavirin

1

2

3

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

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

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

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

5Two patients had emerging single substitution I170T.

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

In study HPC3011 in HCV genotype 4 infected patients, 28 of 32 (88%) patients who did not achieve

SVR had emerging amino acid substitutions at NS3 positions 80, 122, 155, 156 and/or 168 (mainly substitutions at position 168; 24 out of 32 [75%] patients), similar to the emerging amino acid substitutions observed in genotype 1 infected patients.

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

Persistence of resistance-associated substitutions

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

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

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

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

Effect of baseline HCV polymorphisms on treatment response

Analyses were conducted to explore the association between naturally-occurring ba amino acid substitutions (polymorphisms) and treatment outcome.

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

The Q80K polymorphism was not observed in patieith genotype 4 infection.

The presence of Q80K at baseline was associat treated with simeprevir in combination with peginterferon alfa and ribavirin (tables 19, 21, 22).

Cross-resistance

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

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

Clinical efficacy and safety

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

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

Simeprevir in combination with sofosbuvir

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

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

design

SMV = simeprevir.

1

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

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

To prior treatment with peginterferon alfa and ribavirin.

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

Efficacy in patients with HCV genotype 1

OPTIMIST-1 and OPTIMIST-2

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

Demographics and baseline characteristics (studies HPC3017 and HPC3018)

Ta

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

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

Table 13:  Treatment outcome in HCV genotype 1 infected patients receiving 12 weeks

simeprevir + sofosbuvir (studies HPC3017 and HPC3018)

Superior versus historical control rate (historical SVR rates of approved combination treatments of direct acting

antivirals with peginterferon alfa and ribavirin).

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

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

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

COSMOS

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

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

Table 14 shows the response rates for patients without cirrhosis (METAVIR scores F0–3) receiving 12 weeks of simeprevir +sofosbuvir with or without ribavirin; extending treatment to 24 weeks did not

increase response rates in comparison with 12 weeks treatment. Ribavirin use and prior treatment status (treatment-naive and prior null responders) did not impact treatment outcome. The overall SVR12 rate was similar in patients receiving simeprevir + sofosbuvir with or without ribavirin. The response rates for patients with cirrhosis (METAVIR score F4) receiving 12 or 24 weeks of simeprev + sofosbuvir are shown in table 15.

Table 14:  Treatment outcome in HCV genotype 1 infected patients without cirrhosi

receiving 12 weeks simeprevir + sofosbuvir, with or without ribavirin (study HPC2002)

95% (41/43)

Table 15:  Treatment outcome in HCV genotype 1 infected patients with cirrhosis receiving

12 or 24 weeks simeprevir + sofosbuvir, with or without ribavirin

1The one patient with on-treatment failure discontinued treatment early due to an adverse event.

2

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

Efficacy in adults with HCV genotype 4

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

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

6.35 log10 IU/ml; 18% had cirrhosis; 25% had HCV genotype 4a, and 73% HCV genotype 4d; 85% had non-CC IL28B alleles (CT or TT); 33% were treatment-naïve, and 68% were treatment-experienced.

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

Table 16:  Treatment outcome in HCV genotype 4 infected patients receiving 12 weeks

simeprevir + sofosbuvir (studies HPC2014 and HPC3021)

Simeprevir in combination with peginterferon alfa and ribavirin

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

Table 17:  Studies conducted with simeprevir + peginterferon alfa + ribavirin: population and

summary of study design

1

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

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

Relapsers after prior interferon-based therapy.

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

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

Table 18:  Studies conducted with simeprevir + peginterferon alfa + ribavirin: dem

and baseline characteristics

1 HCV/HIV-1 co-infected patients.

2

Treatment-experienced to prior treatment with peginterferon and ribavirin.

Efficacy in treatment-naive patients with HCVgenotype 1 infection

In studies C208 (QUEST-1) and C216 (QUEST-2), treatment-naive patients received simeprevir (150 mg once daily) + peginterferon alfa + ribavirin for 12 weeks, followed by 12 or 36 additional weeks of peginterferon alfa + ribavirin (see tables 17 and 18). In study C208, all patients received peginterferon alfa-2a; in study C216, 69% of the patients received peginterferon alfa-2a and 31% received peginterferon alfa-2b.

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

  
  

  4 simeprevir-treated patients who exper

  
  

Table 19:  Treatment outcome in treatment-naive HCV genotype 1 infected patients (pooled

data studies C208 and C216)

ator of patients with undetectable HCV RNA at actual EOT. Includes lapse after SVR12.

1p < 0.001.

2

Viral relapse rates are calculated with a

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

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

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

Efficacy in treatment-experienced patients with HCV genotype 1 infection

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

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

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

Table 20:  Treatment outcome in treatment-experienced 1HCV genotype 1 infected patients

(studies HPC3007 and C206)

1

2

3

4

Treatment-experienced to prior treatment with peginterferon and ribavirin.

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

p < 0.001.

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

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

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

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

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

Efficacy in patients with HCV genotype 1 and HIV-1 co-infection

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

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

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

(study C212)

1p < 0.001 compared to historical control of peginterferon alfa and ribavirin.

2Viral relapse rates are calculated with a denominator of patients with undetectable HCV RNA at actual EOT and with at least one follow-up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12, who was considered to have an HCV re-infection (based on phylogenetic analyses).

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

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

Efficacy in patients with HCV genotype 4 infection

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

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

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

  Treatment outcome	Treatment-naïve patients N = 35 % (n/N)	Prior relapsers N = 22 % (n/N)	Prior partial responders N = 10 % (n/N)	Prior null responders N*=3o % (n N)
  SVR12	83% (29/35)	86% (19/22)	60% (6/10)	^40% (16/40)

  
  
  
  

5.2 Pharmacokinetic properties

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

Absorption

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

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

Effect of food on absorption

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

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

Distribution

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

Biotransformation

Simeprevir is metabolised in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system.

Involvement of CYP2C8 and CYP2C19 cannot be excluded. Moderate or strong inhibitors of

CYP3A4 significantly increase the plasma exposure of simeprevir, and moderate or strong inducers of

CYP3A4 significantly reduce plasma exposure of simeprevir. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

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

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

Elimination

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

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

Linearity/non-linearity

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

Special populations

Elderly (above 65 years of age)

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

Renal impairment

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

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

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

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

Hepatic impairment

Simeprevir is primarily metabolised by the liver.

Plasma exposure of simeprevir in HCV infected patients was about 2-to 3-fold higher compared to that observed in healthy subjects.

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

and efficacy of simeprevir have not been established in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh B or C). OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) (see sections 4.2 and 4.4).

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

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

Body weight

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

Race

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

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

No dose adjustment is necessary based on race.

Patients co-infected with HIV-1

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

Paediatric population

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

5.3 Preclinical safety data

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

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

There were no adverse effects of sime nervous system) in animal studies.

Carcinogenicity and mutagenicity

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

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.

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

Environmental Risk Assessment (ERA)

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

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content

Sodium lauryl sulfate

Magnesium stearate

Colloidal anhydrous silica

Croscarmellose sodium

Lactose monohydrate

Capsule shell

Gelatin

Titanium dioxide (E171)

Black printing ink

Shellac (E904)

Iron oxide black (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

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

Pack sizes of 7 or 28 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/924/001 (7 capsules)

EU/1/14/924/002 (28 capsules)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 May 2014