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Janssen-Cilag Ltd

50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG, UK
Telephone: +44 1494 567 567
Fax: +44 1494 567 568
Medical Information Direct Line: +353 1 800 709 122
Medical Information e-mail: medinfo@janssen-cilag.co.uk
Customer Care direct line: +353 1 620 2300
Medical Information Facsimile: +44 (0) 1494 567 445
Summary of Product Characteristics last updated on medicines.ie: 2/12/2018
SPC OLYSIO 150mg hard capsules

When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 2/12/2018 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   08-Feb-2018
Legal Category:   Product subject to medical prescription which may be renewed (B)

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4.4     Special warnings and precautions for use

 

 

Addition of:

 

Photosensitivity

Photosensitivity reactions, some resulting in hospitalisation, have been observed with OLYSIO combination treatment (see section 4.8). Patients should be warnedinformed of the risk of photosensitivity reactions and on the importance of applying appropriate sun protective measures, such as wearing protective clothing and using sunscreen, during treatment with OLYSIO. Patients should limitExcess exposure to sun as much as possible and avoid 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.

 

 

4.8     Undesirable effects

 

Photosensitivity reactions

Photosensitivity reactions, some resulting in hospitalisation, have been reported in the post-marketing setting with OLYSIO combination treatment.

 

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

 

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

 

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

 

Updated on 8/18/2017 and displayed until 2/12/2018
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   20-Jul-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



5.1     Pharmacodynamic properties



Data from an 3‑yearongoing, long‑term follow‑up study (study HPC3002) in patients who did not achieve SVR with a simeprevir‑based regimen in combination with peginterferon alfa and ribavirin in a previous phase 2 or phase 3 study showed that in 7086% (16/2337/43) of these patients the emerging mutations at time of failure in the previous study were no longer detected after a median follow‑up of 88 180 weeks (range 47‑147 230 weeks) (study HPC3002).

Updated on 3/1/2017 and displayed until 8/18/2017
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   23-Feb-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.4     Special warnings and precautions for use

 

 

 

Hepatitis B virus (HBV) co‑infection

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

 

 

4.5     Interaction with other medicinal products and other forms of interaction

HCV PRODUCTS

Ledipasvir2

390 mg once daily

ledipasvir AUC 1.75 (1.56‑1.96)1.92 (1.77‑2.07)

ledipasvir Cmax 1.64 (1.45‑1.86)1.81 (1.69‑2.94)

ledipasvir Cmin 1.74 (1.55‑1.97) not studied

simeprevir AUC 3.05 (2.43‑3.84)2.69 (2.44‑2.96)

simeprevir Cmax 2.34 (1.95‑2.81)2.61 (2.34‑2.86)

simeprevir Cmin 4.69 (3.40‑6.47) not studied

Concentrations of ledipasvir and simeprevir are increased when simeprevir is co‑administered with ledipasvir. Co‑administration is not recommended. It is not recommended to co‑administer OLYSIO with a ledipasvir‑containing medicinal product.

 

 

IMMUNOSUPPRESSANTS

Ciclosporin

100 mg

 

patient individualised dose4

ciclosporin AUC 1.19 (1.13‑1.26) ↑

ciclosporin Cmax 1.16 (1.07‑1.26) ↑

ciclosporin Cmin not studied

simeprevir AUC 5.68 (3.58‑9.00)5.81 (3.56‑9.48)56

simeprevir Cmax 4.74 (3.12‑7.18) ↑56

simeprevir Cmin not studied5

 

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

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

Tacrolimus

2 mg

 

patient individualised dose45

tacrolimus AUC 0.83 (0.59‑1.16) ↓

tacrolimus Cmax 0.76 (0.65‑0.90) ↓

tacrolimus Cmin not studied

simeprevir AUC 1.90 (1.37‑2.63) 1.85 (1.18‑2.91)67

simeprevir Cmax 1.85 (1.40‑2.46)1.79 (1.22‑2.62)67

simeprevir Cmin not studied67

 

(OATP1B1 inhibition by tacrolimus)

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

 

Updated on 12/14/2016 and displayed until 3/1/2017
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   09-Dec-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

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Section 4.5 Interaction with other medicinal products and other forms of interaction

 

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.

 

ANTICOAGULANTS

Warfarin and other vitamin K antagonists

10 mg

warfarin 10 mg:

S-warfarin AUC 1.04 (1.00-1.07) ↔

S-warfarin Cmax 1.00 (0.94-1.06) ↔

S-warfarin Cmin not studied

While no change in the pharmacokinetics of warfarin is expected, close monitoring of INR is recommended with all vitamin K antagonists. This is due to potential liver function changes during treatment with OLYSIO. No dose adjustment is required. However, it is recommended that the international normalised ratio (INR) be monitored.

 

Updated on 10/25/2016 and displayed until 12/14/2016
Reasons for adding or updating:
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   19-Oct-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

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6.3     Shelf life

 

23 years

Updated on 8/24/2016 and displayed until 10/25/2016
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   18-Aug-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

 

Section 4.8

 

Hepatic impairment

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

A higher incidence of anaemia in patients with advanced fibrosis receiving simeprevir in combination with peginterferon alfa and ribavirin has been reported.

Updated on 7/5/2016 and displayed until 8/24/2016
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   30-Jun-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.2

Dosage information updates and chnaged to tabular information.

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. When ribavirin has beenis added to the combination of OLYSIO and sofosbuvir, and ribavirin needs to be discontinued, consideration can be given to continue treatment of OLYSIO with sofosbuvir alone without ribavirin can be continued (see section 5.1).

 

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




Section 4.4

Use of simeprevir Pre-treatment testing for NS3 Q80K polymorphism in patients infected with HCV genotype 1a

OLYSIO in combination with sofosbuvir

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

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

 

OLYSIO in combination with peginterferon alfa and ribavirin

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

 

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 therapy

The optimal regimen and treatment duration for interferon‑free regimens have not yet been established.


Section 4,8
New trial date added, major update to Dection 4.8

Section 5.1

new data added ,combination of simepravir and sofosbuvir

 

 

 

 

Updated on 2/25/2016 and displayed until 7/5/2016
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   28-Jan-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.2     Posology and method of administration

 

 

Hepatic 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 isOLYSIO is not recommended when prescribing OLYSIO to HCV infected for patients with moderate or severe hepatic impairment (Child‑Pugh class B or C) (see sections 4.4 and 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 decompensated cirrhosis (Child‑Pugh class B or C).

 

 

4.4     Special warnings and precautions for use

 

Hepatic impairment

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

 

 

Hepatic impairment

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).

 

5.2     Pharmacokinetic properties

 

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 established in HCV infected patients with moderate or severe hepatic impairment (Child‑Pugh class B or C)., therefore particular caution is recommended in these patientsOLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child‑Pugh class B or C) (see sections 4.2 and 4.4).

Updated on 8/25/2015 and displayed until 2/25/2016
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   20-Aug-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



The main changes relate to:

·         Change to delete recommendations for East Asian patients

·         Addition of information on Hepatic decompensation/failure

·         Addition of Severe bradycardia/heart block with amiodarone

Updated on 7/28/2015 and displayed until 8/25/2015
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   25-Jun-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.2     Posology and method of administration

 

 

Patient population

Treatment

Duration

Treatment‑naïve, prior relapse1 and prior non‑responder2 patients (including partial and null responders) with HCV genotype 1 or 4, with or without cirrhosis, with or without HIV co‑infection

OLYSIO + sofosbuvir

(+/- ribavirin)3

12 weeks4 (see sections 4.4, 4.8 and 5.1)

 

 

3.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

 

Interferon‑free therapy

Interferon‑free regimens with OLYSIO have not been investigated in phase 3 studies (see section 5.1). The optimal regimen and treatment duration for interferon‑free regimens have not yet 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.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Ledipasvir

30 mg once daily

ledipasvir AUC 1.92 (1.772.07)

ledipasvir Cmax 1.81 (1.692.94)

ledipasvir Cmin not studied

simeprevir AUC 2.69 (2.442.96)

simeprevir Cmax 2.61 (2.342.86)

simeprevir Cmin not studied

Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration is not recommended.

 

 

Dolutegravir

Not studied. No clinically relevant drugdrug interaction is expected.

No dose adjustment is required.

 

 

 

 

Updated on 3/27/2015 and displayed until 7/28/2015
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   26-Feb-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.2 Posology and method of administration

Table 2: Treatment stopping rules in patients receiving OLYSIO in combination with peginterferon alfa and ribavirin with inadequate on‑treatment virologic response

HCV RNA

Action

Treatment week 4: ≥ 25 IU/ml

Discontinue OLYSIO, peginterferon alfa and ribavirin

Treatment week 12: ≥ 25 IU/mldetectable1

Discontinue peginterferon alfa and ribavirin (treatment with OLYSIO is complete at week 12)

Treatment week 24: ≥ 25 IU/mldetectable1

Discontinue peginterferon alfa and ribavirin

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

Updated on 2/19/2015 and displayed until 3/27/2015
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   22-Jan-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section  4.2 Posology and method of administration

 

Table 1: Recommended co‑administered medicinal product(s) and treatment duration for OLYSIO combination therapy

 

 

Table 1: Recommended co‑administered medicinal product(s) and treatment duration for OLYSIO combination therapy

Patient population

Treatment

Duration

Treatment‑naïve and prior relapse1 patients with HCV genotype 1 or 41

OLYSIO + peginterferon alfa + ribavirin2

24 weeks3

 

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.

with or without cirrhosis, who are not coinfected with HIV

 

without cirrhosis, who are co‑infected with HIV

OLYSIO + peginterferon alfa + ribavirin2

24 weeks3

 

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.

with cirrhosis, who are co‑infected with HIV

OLYSIO + peginterferon alfa + ribavirin2

48 weeks3

 

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.

Prior non‑responder4 patients (including partial and null responders) with HCV genotype 1 or 41, with or without cirrhosis, with or without HIV co‑infection

OLYSIO + peginterferon alfa + ribavirin2

48 weeks3

 

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.

Treatment‑naïve, prior relapse1 and prior non‑responder4 patients (including partial and null responders) with HCV genotype 1 or 4, with or without cirrhosis, with or without HIV co‑infection Patients with HCV genotype 1 or 4, regardless of prior treatment history4

OLYSIO + sofosbuvir

(+/- ribavirin)5

12 weeks6 (see sections 4.4, 4.8 and 5.1)

1     Includes patients with or without cirrhosis and those co‑infected with human immunodeficiency virus (HIV). Relapse or non‑response following prior treatment with interferon (pegylated or non‑pegylated), with or without ribavirin (see section 5.1).

2     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).

3     Treatment‑naïve 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.Recommended duration of treatment provided that patient does not meet a stopping rule (see table 2).

4     Non‑response following prior treatment with interferon (pegylated or non‑pegylated), with or without ribavirin (see section 5.1).Includes treatment‑naive patients or patients who failed prior treatment with peginterferon alfa and ribavirin with or without cirrhosis.

5     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).

6     No stopping rules apply to the combination of OLYSIO with sofosbuvir.

 

 

Use with sofosbuvir

 

……….. When ribavirin has been added to the combination of OLYSIO and sofosbuvir, and ribavirin needs to be discontinued, consideration can be given to continue treatment of OLYSIO with sofosbuvir alone (see section 5.1).

 

4.4     Special warnings and precautions for use

 

 

 

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).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Minor changes

 

 

4.8     Undesirable effects

 

Other selected adverse events of interest (grouped term) reported during 12 weeks treatment with simeprevir were rash (11% in patients receiving simeprevir in combination with sofosbuvir without ribavirin versus 20% in patients receiving simeprevir in combination with sofosbuvir and ribavirin), anemia (0% versus 13%, respectively), photosensitivity reactions (7% versus 6%, respectively) and increased bilirubin (0% versus 9%, respectively).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).

 

 

5.1     Pharmacodynamic properties

 

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‑naïve 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‑naïve 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‑naïve 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.The proportion of patients who discontinued simeprevir due to an adverse event was 1%. Table 17 shows the response rates in treatment‑naïve, prior relapsers, prior partial responders and prior null responders.

 

Table 17: Treatment outcome in adult patients with HCV genotype 4 infection (Study HPC3011; final analysis; Intent‑To‑Treat analysis set)

Treatment outcome1

Treatment‑naïve patients

N=35

% (n/N)

Prior relapsers

N=22

% (n/N)

Prior partial responders

N=10

% (n/N)

Prior null responders

N=40

% (n/N)

SVR12

83% (29/35)

86% (19/22)

60% (6/10)

40% (16/40)

Outcome for patients without SVR12

On‑treatment failure2

9% (3/35)

9% (2/22)

20% (2/10)

45% (18/40)

Viral relapse3

9% (3/35)

5% (1/22)

20% (2/10)

15% (6/40)

Missing SVR124

0% (0/35)

0% (0/22)

0% (0/10)

0% (0/40)

1    150 mg simeprevir for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks.

2    On‑treatment failure was defined as the proportion of patients with confirmed detectable HCV RNA at EOT (including but not limited to patients who met the protocol‑specified treatment stopping rules and/or experienced viral breakthrough).

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

4    Patients with missing data at the SVR assessment time point.

 

Eightynine percent (51/57) of the simeprevir‑treated treatment‑naïve patients and prior relapsers were eligible for a total treatment duration of 24 weeks by meeting the protocol‑defined RGT criteria; in these patients the SVR12 rate was 94%.

 

Eighty percent (28/35), 82% (18/22), 40% (4/10) and 48% (19/40) of simeprevir‑treated treatment‑naïve patients, prior relapsers, prior partial responders and prior null responders, respectively, had undetectable HCV RNA at week 4 (RVR). In these patients the SVR12 rates were 96%, 94%, 100% and 68%, respectively.

 

Eleven percent (4/35), 5% (1/22), 10% (1/10) and 23% (9/40) of simeprevir‑treated treatment‑naïve patients, prior relapsers, prior partial responders and prior null responders, respectively, had HCV RNA ≥ 25 IU/ml at week 4; none achieved SVR12.

 

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

 

Table 18 shows the SVR rates by METAVIR fibrosis scores and IL28B genotype.

 

Table 18: SVR12 rates by METAVIR fibrosis score and IL28B genotype in adult patients with HCV genotype 4 infection (Study HPC3011; final analysis; Intent‑To‑Treat analysis set)

Subgroup

Treatment‑naïve patients

% (n/N)

Prior relapsers

% (n/N)

Prior partial responders

% (n/N)

Prior null responders

% (n/N)

METAVIR fibrosis score

F0‑2

85% (22/26)

91% (10/11)

100% (5/5)

47% (8/17)

F3‑4

78% (7/9)

82% (9/11)

20% (1/5)

35% (7/20)

F4

50% (1/2)

78% (7/9)

20% (1/5)

36% (5/14)

IL28B genotype

CC

100% (7/7)

100% (1/1)

-

-

CT

82% (14/17)

82% (14/17)

60% (3/5)

41% (9/22)

TT

80% (8/10)

100% (4/4)

60% (3/5)

39% (7/18)

 

 

The overall SVR12 rate was 93% (26/28) in patients receiving 12 weeks treatment of simeprevir in combination with sofosbuvir without ribavirin when pooling both cohorts.

 

 

5.2     Pharmacokinetic properties

 

 Minor changes

Updated on 1/23/2015 and displayed until 2/19/2015
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   18-Dec-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

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Section 4.4 Special warnings and precautions for use

 

Organ transplant patients

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

Co‑administration of OLYSIO with ciclosporin is not recommended as this leads to significantly higher exposure of simeprevir based on interim data from an ongoing phase 2 study in HCV infected post‑liver transplant patients (see section 4.5).

 

 

4.5          Interaction with other medicinal products and other forms of interaction

 

 

Daclatasvir

60 mg once daily

daclatasvir AUC 1.96 (1.842.10) ­

daclatasvir Cmax 1.50 (1.391.62) ­

daclatasvir Cmin 2.68 (2.422.98) ­

simeprevir AUC 1.44 (1.321.56) ­

simeprevir Cmax 1.39 (1.271.52) ­

simeprevir Cmin 1.49 (1.33‑1.67) ­

No dose adjustment of daclatasvir or OLYSIO is required.

 

Ciclosporin

100 mg

 

patient individualised dose4

ciclosporin AUC 1.19 (1.13‑1.26) ­

ciclosporin Cmax 1.16 (1.07‑1.26) ­

ciclosporin Cmin not studied

simeprevir AUC 5.81 (3.56‑9.48) ­5

simeprevir Cmax 4.74 (3.12‑7.18) ­5

simeprevir Cmin not studied5

 

Increased simeprevir concentrations may occur due to inhibition of (OATP1B1, P‑gp and CYP3A inhibition by ciclosporin)

 

No dose adjustment is required when co‑administered with OLYSIO. Monitoring of blood concentrations of ciclosporine is recommended.

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

Tacrolimus

2 mg

 

patient individualised dose4

tacrolimus AUC 0.83 (0.59‑1.16) ¯

tacrolimus Cmax 0.76 (0.65‑0.90) ¯

tacrolimus Cmin not studied

simeprevir AUC 1.85 (1.18‑2.91) ­6

simeprevir Cmax 1.79 (1.22‑2.62) ­6

simeprevir Cmin not studied6

 

Increased simeprevir concentrations may occur due to inhibition of (OATP1B1 inhibition by tacrolimus)

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

 

 

Updated on 5/19/2014 and displayed until 1/23/2015
Reasons for adding or updating:
  • New SPC for new product
Date of revision of text on the SPC:  
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

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Active Ingredients

 
   Simeprevir sodium