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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
WWW: http://www.janssen-medinfo.co.uk
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: 19/12/2014
SPC INCIVO 375 mg film-coated tablets

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 19/12/2014 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   16-Dec-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



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

 

CCR5 ANTAGONISTS

maraviroc*

maraviroc

AUC12 9.49 (7.94‑11.34)

Cmax 7.81 (5.92‑10.32)

C12 10.17 (8.73‑11.85)

Telaprevir concentrations are not likely to be affected by maraviroc co‑administration (based on historical data and the elimination pathway of telaprevir).

Maraviroc 150 mg twice daily when co‑administered with telaprevir.

 

 

Section 4.8 Undesirable effects

 

Gastrointestinal disorders

very common

nausea, diarrhoea, vomiting, haemorrhoids, proctalgia

common

anal pruritus, rectal haemorrhage, anal fissure

uncommon

proctitis, pancreatitis

Updated on 27/08/2014 and displayed until 19/12/2014
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • 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:   24-Jul-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Section 4.5 - Interaction with other medicinal products and other forms of interaction
 Addition of:

Based on in vitro studies, telaprevir may potentially increase plasma concentrations of medicinal products in which excretion is dependent upon multidrug and toxin extrusion (MATE)‑1 and MATE2‑K (see table 2).

 

ANTIDIABETICS

metformin

↑ metformin

inhibition of MATE‑1 and MATE2‑K

Close monitoring of metformin efficacy and safety is recommended when starting or stopping INCIVO in patients receiving metformin. A dose adjustment of metformin may be necessary.


 Section 5.2 Pharmacokinetics

Addiiton of:

Suppression by telaprevir and VRT‑127394 of CYP enzymes regulated via CAR, PXR and Ah nuclear receptors was observed in vitro in human hepatocytes. Clinical drug‑drug interaction studies with substrates of CYP2B6, CYP2C8, CYP2D6, CYP2C19 and UGT1A1, UGT2B7 and UGT1A3 indicate no clinically relevant impact of the suppression observed in vitro. For other enzymes and transporters (e.g., CYP1A1, CYP1A2, BCRP, OATPs) regulated by the same nuclear receptors, the potential clinical impact is unknown.

 

Transporters

 

No relevant inhibition by telaprevir of the organic cation transporter (OCT) OCT2 was observed in vitro.

 

Telaprevir is a weak in vitro inhibitor of the transporters multidrug and toxin extrusion (MATE) MATE1 and MATE2‑K with an IC50 of 28.3 μM and 32.5 μM, respectively. The clinical implications of this finding are currently unknown.

Updated on 26/06/2014 and displayed until 27/08/2014
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   19-Jun-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



4.4          Special warnings and precautions for use

 

Ribavirin dose reduction is the preferred strategy for managing treatment‑emergent anaemia. For the management of anamia Rrefer to the Summary of Product Characteristics for ribavirin for its dose reduction guidelines information regarding dose reduction and/or discontinuation of ribavirin. If ribavirin is permanently discontinued for the management of anaemia, INCIVO must also be permanently discontinued. If INCIVO is discontinued for anaemia, patients may continue treatment with peginterferon alfa and ribavirin. Ribavirin may be restarted per the dosing modification guidelines for ribavirin. The dose of INCIVO must not be reduced, and INCIVO must not be restarted if discontinued.

 

Updated on 16/04/2014 and displayed until 26/06/2014
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 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   20-Mar-2014
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



SmPC

 

4.2        Posology and method of administration

 

Hepatic impairment

INCIVO is not recommended in patients with moderate to severe hepatic impairment (Child‑Pugh B or C, score ≥ 7) or decompensated liver disease (ascites, portal hypertensive bleeding, encephalopathy, and/or jaundice other than Gilbert’s Syndrome, see section 4.4). Dose modification of INCIVO is not required when administered to hepatitis C patients with mild hepatic impairment (Child‑Pugh A, score 5‑6).

 

 

4.4           Special warnings and precautions for use

 

Use in patients with advanced liver disease

Hypoalbuminaemia and low platelet counts have been identified as predictors of severe complications of liver disease as well as of interferon‑based therapies (e.g., hepatic decompensation, serious bacterial infections). Furthermore, high rates of anaemia have been seen when using INCIVO with peginterferon and ribavirin in patients with these characteristics. INCIVO in combination with peginterferon and ribavirin is not recommended in patients with platelets < 90,000/mm3 and/or albumin < 3.3 g/dl. When INCIVO is used in patients with advanced liver disease very close monitoring and early management of adverse events is recommended.

 

 

These are recommended baseline values for initiation of INCIVO combination treatment:

-                 Haemoglobin: ≥ 12 g/dl (females); ≥ 13 g/dl (males)

-                 Platelet count ≥ 90,000/mm3

-                 Absolute neutrophil counts ≥ 1,500/mm3

-                 Adequately controlled thyroid function (TSH)

-                 Calculated creatinine clearance ≥ 50 ml/min

-                 Potassium ≥ 3.5 mmol/l

-                 Albumin > 3.3 g/dl

 

 

 

Hepatic impairment

INCIVO has not been studied in patients with severe hepatic impairment (Child‑Pugh C, score ≥ 10) or decompensated liver disease (ascites, portal hypertensive bleeding, encephalopathy, and/or jaundice other than Gilbert’s Syndrome) and is not recommended in these populations.

 


section 6.1 sulphate chnages to sulfate 

Updated on 21/01/2014 and displayed until 16/04/2014
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   18-Dec-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Update to Section 4.5

carbamazepine

phenobarbital

phenytoin

↓ telaprevir

↑ carbamazepine

↑ or ↓ phenytoin

↑ or ↓ phenobarbital

induction of CYP3A by anticonvulsants, and inhibition of CYP3A by telaprevir

Co‑administration with these agents is contraindicated.

carbamazepine*

↓ telaprevir

AUC 0.68 (0.58‑0.79)

Cmax 0.79 (0.70‑0.90)

Cmin 0.53 (0.44‑0.65)

↔ carbamazepine

AUC 1.10 (0.99‑1.23)

Cmax 1.09 (0.98‑1.21)

Cmin 1.10 (0.97‑1.24)

induction of CYP3A by carbamazepine, and inhibition of CYP3A by telaprevir

Co‑administration with carbamazepine is contraindicated.

phenytoin*

↓ telaprevir

AUC 0.53 (0.47‑0.60)

Cmax 0.68 (0.60‑0.77)

Cmin 0.32 (0.25‑0.42)

↑ phenytoin

AUC 1.31 (1.15‑1.49)

Cmax 1.27 (1.09‑1.47)

Cmin 1.36 (1.21‑1.53)

induction of CYP3A by phenytoin, and inhibition of CYP3A by telaprevir

Co‑administration with phenytoin is contraindicated.

phenobarbital

↓ telaprevir

↑ or ↓ phenobarbital

induction of CYP3A by phenobarbital, and inhibition of CYP3A by telaprevir

Co‑administration with phenobarbital is contraindicated.

Updated on 24/12/2013 and displayed until 21/01/2014
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:   19-Dec-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

addition of uncommon adverse effect; pre-renal azotemia with or without acute renal failure
Updated on 25/10/2013 and displayed until 24/12/2013
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • 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
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
Updated on 31/05/2013 and displayed until 25/10/2013
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 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
Date of revision of text on the SPC:   27-May-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Section 4.2-addition of twice dailiy dosing schedule

section 4.5 and 4.8-statements referring to twice daily dosing

Section 5.1 and 5.2 : additional clincial trial information BiD dosing
Updated on 24/05/2013 and displayed until 31/05/2013
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:   25-Apr-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Section 4.5

update to information on inhibition of OATP enzymes

Addition interactions added: 


fluvastatin

pitavastatin

pravastatin

rosuvastatin
repaglinide

Updated on 24/04/2013 and displayed until 24/05/2013
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   22-Apr-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Update to Sections 4.4 and 4.8 of SmPC with information on reported Toxic Epidermal Necrolysis (TEN) cases.

Updated on 21/03/2013 and displayed until 24/04/2013
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:   21-Feb-2013
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Section 4.4 Special warnings and precautions for use

Interactions with medicinal products

Telaprevir is a strong inhibitor of the important drug metabolising enzyme CYP3A4. Increased systemic exposures are expected if telaprevir is combined with drugs highly metabolised by this enzyme. Refer to section 4.3 for a listing of medicinal products that are contraindicated for use with INCIVO due to potentially life-threatening adverse events or potential loss of therapeutic effect to INCIVO. Refer to section 4.5 for established and other potentially significant drug-drug interactions

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

 

Telaprevir is a strong inhibitor of CYP3A4. Administration of INCIVO gives rise to increased systemic exposure to medicinal products that are substrates of mainly metabolised by CYP3A or transported by P‑gp. This can give rise to increased risk of adverse effects and may markedly prolong their effects. Please consult the SPC of the concomitant medication for recommendations regarding potent CYP3A4 inhibitors. Information is also included in the table below. It is unknown if telaprevir is a substrate, inducer, or inhibitor of drug transporting proteins other than P‑gp.



ANALGESICS

alfentanil

fentanyl

alfentanil

fentanyl

Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when telaprevir is co‑administered with alfentanil or fentanyl, including oral, buccal, nasal and extended‑release transdermal or transmucosal preparations of fentanyl, especially at initiation of treatment. Dosage adjustment of fentanyl or alfentanil may be necessary. The most marked effects are expected on oral, nasal and buccal/sublingual fentanyl formulations.

Updated on 29/11/2012 and displayed until 21/03/2013
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 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   19-Nov-2012
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



The red text has been added to the SmPC. There are no changes to the Patient Information leaflet.

 

4.4 Special warnings and precautions for use

 

HCV/HIV (human immunodeficiency virus) co‑infection

 

There is limited clinical data from an ongoing study assessing INCIVO in combination with peginterferon alfa and ribavirin was evaluated in 60 HIV‑infected, HCV treatment‑naïve patients who are were either not on HIV antiretroviral therapy or are were being treated with efavirenz or atazanavir/ritonavir in combination with tenofovir disoproxil fumarate and emtricitabine or lamivudine (see sections 4.8 and 5.1). Please refer to section 4.5 for relevant interactions with HIV‑antiviral agents.

 

4.8 Undesirable effects

 

Patients Co‑infected with HIV‑1

The safety profile of INCIVO in HCV/HIV‑1 co‑infected patients (n = 38) either not on antiretroviral therapy or being treated with efavirenz in combination with tenofovir disoproxil fumarate and emtricitabine was similar to the safety profile in mono‑infected HCV patients. Patients receiving atazanavir/ritonavir in the INCIVO combination treatment group and in the peginterferon alfa and ribavirin group experienced a transient increase in indirect bilirubin levels through week 2, returning to near baseline by week 12.

 

 

 

5.1 Pharmacodynamic properties

 

Study 110

Study 110 was a phase II randomised, double‑blind, placebo‑controlled study conducted in patients with chronic genotype 1 HCV/HIV co‑infection who were treatment‑naïve for hepatitis C. Patients were either not on antiretroviral therapy (CD4 count ≥ 500 cells/mm3), or had stable controlled HIV (HIV RNA < 50 copies/ml, CD4 count ≥ 300 cells/mm3) being treated with efavirenz or atazanavir/ritonavir in combination with tenofovir disoproxil fumarate and emtricitabine or lamivudine. Patients were randomised to 12 weeks of INCIVO (750 mg every 8 hours if taken in combination with atazanavir/ritonavir, tenofovir disoproxil fumarate, and emtricitabine or lamivudine OR 1125 mg every 8 hours if taken in combination with efavirenz, tenofovir disoproxil fumarate, and emtricitabine) or placebo. All patients received peginterferon alfa‑2a and ribavirin for 48 weeks. Fifty-five out of 60 patients received ribavirin at a fixed dose of 800 mg/day and the remaining 5 patients received a weight‑based ribavirin dose. At baseline, 3 (8%) subjects had bridging fibrosis and 2 (5%) subjects had cirrhosis in the T12/PR48 arm. In the Pbo/PR arm, 2 (9%) subjects had baseline bridging fibrosis and no subjects had baseline cirrhosis. Table 9 shows the response rates for the T12/PR48 and the Pbo/PR48 arms. The response rate in the Pbo/PR arm was higher than that seen in other clinical studies of peginterferon bitherapy (historical SVR rates < 36%).

 

 

Table 9: Response Rates: Study 110

Treatment Outcome

T12/PR48

% (n/N)

Pbo/PR

% (n/N)

Overall SVR12 ratea

74% (28/38)

45% (10/22)

Subjects on an efavirenz‑based regimen

69% (11/16)

50% (4/8)

Subjects on an atazanavir/ritonavir‑based regimen

80% (12/15)

50% (4/8)

Subjects not receiving antiretroviral therapy

71% (5/7)

33% (2/6)

a       HCV RNA< 25 IU/ml in the week 12 follow‑up window

 

Updated on 09/11/2012 and displayed until 29/11/2012
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   25-Oct-2012
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Section 4.5 addition of;

etravirine*

↓ telaprevir 750 mg q8h

AUC 0.84 (0.71‑0.98)

Cmax 0.90 (0.79‑1.02)

Cmin 0.75 (0.61‑0.92)

↔ etravirine (+ TVR 750 mg q8h)

AUC 0.94 (0.85‑1.04)

Cmax 0.93 (0.84‑1.03)

Cmin 0.97 (0.86‑1.10)

If co‑administered, no dose adjustment is required.

rilpivirine*

↓ telaprevir 750 mg q8h

AUC 0.95 (0.76‑1.18)

Cmax 0.97 (0.79‑1.21)

Cmin 0.89 (0.67‑1.18)

↑ rilpivirine (+ TVR 750 mg q8h)

AUC 1.78 (1.44‑2.20)

Cmax 1.49 (1.20‑1.84)

Cmin 1.93 (1.55‑2.41)

If co‑administered, no dose adjustment is required.


Updated on 30/03/2012 and displayed until 09/11/2012
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   19-Mar-2012
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

Section 2, 4.3, 4.6, 5.1 (ATC code added) + admin changes 5.2, 6.6 (QRD changes)
Section 4.5

raltegravir*

Based on preliminary data, the combination of telaprevir and raltegravir did not result in a clinically significant interaction.

telaprevir

AUC 1.07 (1.001.15)

Cmax 1.07 (0.981.16)

Cmin 1.14 (1.041.26)

raltegravir

AUC 1.31 (1.031.67)

Cmax 1.26 (0.971.62)

Cmin 1.78 (1.262.53)

If co‑administered, no dose adjustment is required.

buprenorphine*

Based on preliminary data, the combination of telaprevir and buprenorphine did not result in a clinically significant interaction

.« buprenorphine

AUC 0.96 (0.84-1.10)

Cmax 0.80 (0.69-0.93)

Cmin 1.06 (0.87-1.30)

No adjustment of the buprenorphine dose is required when co-administered with telaprevir.

Updated on 14/11/2011 and displayed until 30/03/2012
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 not be renewed (A)

Free-text change information supplied by the pharmaceutical company

None provided

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Active Ingredients

 
   Telaprevir