Incivo

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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

1. NAME OF THE MEDICINAL PRODUCT

INCIVO 375 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 375 mg of telaprevir.

Excipient: 2.3 mg of sodium per film-coated tablet.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.
Yellow caplet shaped tablets of approximately 20 mm in length, marked with “T375” on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

INCIVO, in combination with peginterferon alfa and ribavirin, is indicated for the treatment of 
genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis):
- who are treatment-naïve;
- who have previously been treated with interferon alfa (pegylated or non-pegylated) alone or in 

combination with ribavirin, including relapsers, partial responders and null responders (see 
sections 4.4 and 5.1).

4.2 Posology and method of administration

Treatment with INCIVO should be initiated and monitored by a physician experienced in the 
management of chronic hepatitis C.

Posology
INCIVO, 1,125 mg (three 375 mg film-coated tablets) should be taken orally twice daily (b.i.d.) with 
food. Alternatively, 750 mg (two 375 mg tablets) can be taken orally every 8 hours (q8h) with food. 
The total daily dose is 6 tablets (2,250 mg). Taking INCIVO without food or without regard to the 
dosing interval may result in decreased plasma concentrations of telaprevir which could reduce the 
therapeutic effect of INCIVO.

INCIVO should be administered in conjunction with ribavirin and either peginterferon alfa-2a or -2b. 
Please consult sections 4.4 and 5.1 regarding the selection of peginterferon alfa-2a or -2b. For specific 
dosage instructions for peginterferon alfa and ribavirin, the Summary of Product Characteristics for 
these medicinal products should be consulted.

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Duration of treatment – Treatment-naïve adults and prior treatment relapsers
Treatment with INCIVO must be initiated in combination with peginterferon alfa and ribavirin and 
administered for 12 weeks (see figure 1).
- Patients with undetectable hepatitis C virus ribonucleic acid (HCV RNA) (target not detected) 

at weeks 4 and 12 receive an additional 12 weeks of peginterferon alfa and ribavirin alone for a 
total treatment duration of 24 weeks.

- Patients with detectable HCV RNA at either weeks 4 or 12 receive an additional 36 weeks of 
peginterferon alfa and ribavirin alone for a total treatment duration of 48 weeks.

- For all patients with cirrhosis irrespective of undetectable HCV RNA (target not detected) at 
weeks 4 or 12, an additional 36 weeks of peginterferon alfa and ribavirin alone for a total 
treatment duration of 48 weeks is recommended (see section 5.1).

Figure 1: Duration of treatment for treatment-naïve patients and prior treatment 
relapsers

HCV RNA levels should be monitored at weeks 4 and 12 to determine treatment duration. In Phase 3 
studies, a sensitive real-time PCR assay with a limit of quantification of 25 IU/ml and a limit of 
detection of 10-15 IU/ml was used to determine whether HCV RNA levels were undetectable (target 
not detected) (see section 5.1). Detectable HCV RNA below the lower limit of assay quantification 
should not be used as a substitute for “undetectable” (target not detected), for making decisions on 
treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates. See 
table 1 for Guidelines for Discontinuation of INCIVO, Peginterferon Alfa, and Ribavirin Treatment.

Duration of treatment – Previously treated adults with prior partial or prior null response
Treatment with INCIVO must be initiated in combination with peginterferon alfa and ribavirin and 
administered for 12 weeks, followed by peginterferon alfa and ribavirin therapy alone (without 
INCIVO) for a total treatment duration of 48 weeks (see figure 2).

Figure 2: Duration of treatment for previously treated patients with prior partial or prior 
null response

HCV RNA levels should be monitored at weeks 4 and 12. See table 1 for Guidelines for 
Discontinuation of INCIVO, Peginterferon Alfa, and Ribavirin Treatment.

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All patients
Since it is highly unlikely that patients with inadequate viral responses will achieve a sustained 
virologic response (SVR), it is recommended that patients with HCV RNA > 1,000 IU/ml at week 4 or
week 12 discontinue therapy (refer to table 1).

Table 1: Guidelines for discontinuation of INCIVO, Peginterferon Alfa, and Ribavirin 
treatment
Medicinal products HCV RNA > 1,000 IU/ml at 

week 4 of treatmenta
HCV RNA > 1,000 IU/ml at 

week 12 of treatmenta

INCIVO Permanently discontinue INCIVO treatment completed
Peginterferon alfa and 
Ribavirin

Permanently discontinue

a
treatment with INCIVO, peginterferon alfa, and ribavirin. These guidelines may not perform similarly when a lead-in 
treatment with peginterferon alfa and ribavirin has been used prior to starting INCIVO therapy (see section 5.1).

In the Phase 3 studies, none of the patients with HCV RNA > 1,000 IU/ml at either week 4 or week 12 
achieved SVR with continued peginterferon alfa and ribavirin treatment. In treatment-naïve patients in 
the Phase 3 studies, 4/16 (25%) patients with HCV RNA levels between 100 IU/ml and 1,000 IU/ml at
week 4 achieved SVR. In patients with HCV RNA between 100 IU/ml and 1,000 IU/ml at week 12, 
2/8 (25%) achieved an SVR.

In prior null responders, consideration should be given to conduct an additional HCV RNA test 
between weeks 4 and 12. If the HCV RNA concentration is > 1,000 IU/ml, INCIVO, peginterferon 
alfa, and ribavirin should be discontinued.

For patients receiving a total of 48 weeks of treatment, peginterferon alfa and ribavirin should be 
discontinued if HCV RNA is detectable at week 24 or week 36.

INCIVO must be taken with peginterferon alfa and ribavirin to prevent treatment failure.

To prevent treatment failure, the dose of INCIVO must not be reduced or interrupted.

If INCIVO treatment is discontinued due to adverse drug reactions or because of insufficient virologic
response, INCIVO treatment should not be reinitiated.

Refer to the respective Summary of Product Characteristics of peginterferon alfa and ribavirin for 
guidelines on dose modifications, interruptions, discontinuations or resumption of those medicinal 
products (see section 4.4).

When administered twice daily (b.i.d.), in case a dose of INCIVO is missed within 6 hours of the time 
it is usually taken, patients should be instructed to take the prescribed dose of INCIVO with food as 
soon as possible. If the missed dose is noticed more than 6 hours after the time INCIVO should be
taken, the missed dose should be skipped and the patient should resume the normal dosing schedule.

When administered every 8 hours (q8h), in case a dose of INCIVO is missed within 4 hours of the 
time it is usually taken, patients should be instructed to take the prescribed dose of INCIVO with food 
as soon as possible. If the missed dose is noticed more than 4 hours after the time INCIVO should be
taken, the missed dose should be skipped and the patient should resume the normal dosing schedule.

Special populations
Renal impairment
There are no clinical data on the use of INCIVO in HCV patients with moderate or severe renal 
impairment (CrCl ≤ 50 ml/min) (see section 4.4). In HCV-negative patients with severe renal 
impairment, no clinically relevant change in telaprevir exposure was observed (see section 5.2).
Therefore, no dose adjustment is recommended for INCIVO in HCV patients with renal impairment.

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There are no clinical data on the use of INCIVO in patients on haemodialysis.

Refer also to the Summary of Product Characteristics for ribavirin for patients with CrCl < 50 ml/min.

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).

Refer also to the Summary of Product Characteristics for peginterferon alfa and ribavirin which are 
contraindicated in Child-Pugh score ≥ 6.

HCV/Human immunodeficiency virus type (HIV)-1 co-infection
HCV/HIV-1 co-infected patients should be treated in the same way as HCV mono-infected patients.
Drug interactions need to be carefully taken into account, see sections 4.4 and 4.5. Patients on an 
efavirenz-based regimen must receive INCIVO 1,125 mg every 8 hours. For outcomes obtained in 
HIV co-infected patients, see section 5.1.

Liver transplant patients without cirrhosis
Treatment with INCIVO must be initiated in combination with peginterferon alfa and ribavirin and 
administered for 12 weeks with an additional 36 weeks of peginterferon alfa and ribavirin alone for a 
total treatment duration of 48 weeks. No dose adjustment of INCIVO is required in stable liver 
transplant patients (see sections 4.8 and 5.1). A lower ribavirin dose (600 mg/day) at initiation of 
INCIVO treatment is recommended (see section 5.1). At the initiation and discontinuation of INCIVO 
treatment, doses of co-administered tacrolimus or cyclosporine A need to be markedly adjusted (see 
sections 4.4 and 4.5, Immunosuppressants).

Elderly
There are limited clinical data on the use of INCIVO in HCV patients aged ≥ 65 years.

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

Method of administration
Patients should be instructed to swallow the tablets whole (e.g. patients should not chew, break or 
dissolve the tablet).

4.3 Contraindications

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

Concomitant administration with active substances that are highly dependent on CYP3A for clearance 
and for which elevated plasma concentrations are associated with serious and/or life-threatening 
events. These active substances include alfuzosin, amiodarone, bepridil, quinidine, astemizole,
terfenadine, cisapride, pimozide, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, 
methylergonovine), lovastatin, simvastatin, atorvastatin, sildenafil or tadalafil (only when used for 
treatment of pulmonary arterial hypertension), quetiapine and orally administered midazolam or
triazolam (see section 4.5).

Concomitant administration with Class Ia or III antiarrhythmics, except for intravenous lidocaine (see 
section 4.5).

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Concomitant administration of INCIVO with active substances that strongly induce CYP3A e.g. 
rifampicin, St John's wort (Hypericum perforatum), carbamazepine, phenytoin and phenobarbital and 
thus may lead to lower exposure and loss of efficacy of INCIVO.

Refer to the Summary of Product Characteristics for peginterferon alfa and ribavirin for a list of their 
contraindications since INCIVO must be used in combination with peginterferon alfa and ribavirin.

4.4 Special warnings and precautions for use

Severe rash
Severe, potentially life-threatening and fatal skin reactions have been reported with INCIVO 
combination treatment. Toxic epidermal necrolysis (TEN) including fatal outcome has been observed 
in post-marketing experience (see section 4.8). Fatal cases have been reported in patients with 
progressive rash and systemic symptoms who continued to receive INCIVO combination treatment 
after a serious skin reaction was identified.

In placebo-controlled Phase 2 and 3 trials, severe rash (primarily eczematous, pruritic and involving 
more than 50% body surface area) was reported in 4.8% of patients who received INCIVO 
combination treatment compared to 0.4% receiving peginterferon alfa and ribavirin. Available data 
suggest that peginterferon alfa, and perhaps also ribavirin, may contribute to the frequency and 
severity of rash associated with INCIVO combination treatment.

5.8% of patients discontinued INCIVO alone due to rash events and 2.6% of patients discontinued 
INCIVO combination treatment for rash events compared to none of those receiving peginterferon 
alfa and ribavirin.

In placebo-controlled Phase 2 and 3 trials, 0.4% of patients had suspected Drug Rash with 
Eosinophilia and Systemic Symptoms (DRESS). In INCIVO clinical experience, less than 0.1% of 
patients had Stevens-Johnson Syndrome (SJS). All of these reactions resolved with treatment 
discontinuation.

DRESS presents as a rash with eosinophilia associated with one or more of the following features: 
fever, lymphadenopathy, facial oedema, and internal organ involvement (hepatic, renal, pulmonary). It 
may appear at any time after start of treatment, although the majority of cases appeared between six 
and ten weeks after the start of treatment with INCIVO.

Prescribers should ensure that patients are fully informed about the risk of severe rashes, and to 
consult with their prescriber immediately if they develop a new rash or worsening of an existing rash.
All rashes should be monitored for progression and until the rash is resolved. The rash may take 
several weeks to resolve. Other medicinal products associated with severe cutaneous reactions should 
be used with caution during administration of INCIVO combination treatment to avoid potential 
confusion as to which medicinal product could be contributing to a severe cutaneous reaction. In the 
case of a serious skin reaction, discontinuation of other medicinal products known to be associated 
with serious skin reactions should be considered.

For additional information on mild to moderate rash, see section 4.8.

The recommendations for monitoring of cutaneous reactions, and for discontinuation of INCIVO, 
ribavirin and peginterferon alfa are summarised in the table below:

Extent and features of Cutaneous 
Reactions

Recommendations for Monitoring of Cutaneous 
Reactions and Discontinuation of INCIVO, 
Ribavirin and Peginterferon alfa for Severe Rash

Mild rash: localised skin eruption and/or a 
skin eruption with a limited distribution (up 
to several isolated sites on the body)

Monitor for progression or systemic symptoms until 
the rash is resolved.

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Moderate rash: Diffuse rash ≤ 50% of body 
surface area

Monitor for progression or systemic symptoms until 
the rash is resolved. Consider consultation with a 
specialist in dermatology.

For moderate rash that progresses, permanent 
discontinuation of INCIVO should be considered. If 
the rash does not improve
within 7 days following INCIVO discontinuation, 
ribavirin should be interrupted. Interruption of 
ribavirin may be required sooner if the rash worsens 
despite discontinuation of telaprevir. Peginterferon 
alfa may be continued unless interruption is 
medically indicated.

For moderate rash that progresses to severe (≥ 50% 
body surface area), permanently discontinue 
INCIVO (see below).

Severe rash: Extent of rash > 50% of body 
surface area or associated with vesicles, 
bullae, ulcerations other than SJS

Permanently discontinue INCIVO immediately.
Consultation with a specialist in dermatology is 
recommended.
Monitor for progression or systemic symptoms until 
the rash is resolved.

Peginterferon alfa and ribavirin may be continued. If 
improvement is not observed within 7 days of 
INCIVO discontinuation, sequential or simultaneous 
interruption or discontinuation of ribavirin and/or 
peginterferon alfa should be considered. If medically
indicated, earlier interruption or discontinuation of 
peginterferon alfa and ribavirin may be needed.

Serious skin reactions including rash with 
systemic symptoms, progressive severe rash, 
suspicion or diagnosis of generalised 
bullous eruption, DRESS, SJS/TEN, acute 
generalized exanthematous pustulosis, 
erythema multiforme

Permanent and immediate discontinuation of 
INCIVO, peginterferon alfa, and ribavirin. Consult 
with a specialist in dermatology.

If discontinued due to a skin reaction, INCIVO must not be restarted. Refer also to the Summary of 
Product Characteristics for peginterferon alfa and ribavirin for severe skin reactions associated with 
these products.

Anaemia
In placebo-controlled Phase 2 and 3 clinical trials, the overall incidence and severity of anaemia 
increased with INCIVO combination treatment compared to peginterferon alfa and ribavirin alone. 
Haemoglobin values of < 10 g/dl were observed in 34% of patients who received INCIVO 
combination treatment and in 14% of patients who received peginterferon alfa and ribavirin. 
Haemoglobin values of < 8.5 g/dl were observed in 8% of INCIVO combination treatment compared 
to 2% of patients receiving peginterferon alfa and ribavirin. A decrease in haemoglobin levels occurs 
during the first 4 weeks of treatment, with lowest values reached at the end of INCIVO dosing. 
Haemoglobin values gradually improve after completion of INCIVO dosing.

Haemoglobin should be monitored at regular intervals prior to and during INCIVO combination 
treatment (see section 4.4, Laboratory tests).

Ribavirin dose reduction is the preferred strategy for managing treatment-emergent anaemia. Refer to 
the Summary of Product Characteristics for ribavirin for information regarding dose reduction and/or 

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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.

Pregnancy and contraception requirements
Because INCIVO must be used in combination with peginterferon alfa and ribavirin, the
contraindications and warnings applicable to those medicinal products are applicable to combination 
therapy.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species 
exposed to ribavirin, therefore, extreme care must be taken to avoid pregnancy in female patients and 
in female partners of male patients.

Female patients of childbearing potential and their male partners as well as male patients and their 
female partners must use 2 effective contraceptive methods during INCIVO treatment and afterwards
as recommended in the Summary of Product Characteristics for ribavirin, and as described below.

Hormonal contraceptives may be continued but may not be reliable during INCIVO dosing and for up 
to two months following cessation of INCIVO (see section 4.5). During this time, female patients of 
childbearing potential should use two effective non-hormonal methods of contraception. Two months 
after completion of INCIVO treatment, hormonal contraceptives are again appropriate as one of the 
two required effective methods of birth control.

For additional information, see sections 4.5 and 4.6.

Cardiovascular
Results of a study conducted in healthy volunteers demonstrated a modest effect of telaprevir at a 
dose of 1,875 mg every 8 hours on the QTcF interval with a placebo-adjusted maximum mean 
increase of 8.0 msec (90% CI: 5.1-10.9) (see section 5.1). Exposure at this dose was comparable to 
the exposure in HCV-infected patients receiving a dose of 750 mg INCIVO every 8 hours plus 
peginterferon alfa and ribavirin. The potential clinical significance of these findings is uncertain.

INCIVO should be used with caution with Class Ic antiarrhythmics propafenone and flecainide, 
including appropriate clinical and ECG monitoring.

Caution is recommended when prescribing INCIVO concurrently with medicinal products known to 
induce QT prolongation and which are CYP3A substrates such as erythromycin, clarithromycin, 
telithromycin, posaconazole, voriconazole, ketoconazole, tacrolimus, salmeterol (see section 4.5).
INCIVO co-administration with domperidone should be avoided (see section 4.5). INCIVO may 
increase concentrations of the co-administered medicinal product and this may result in an increased 
risk of their associated cardiac adverse reactions. In the event that co-administration of such medicinal
products with INCIVO is judged strictly necessary, clinical monitoring including ECG assessments is 
recommended. See also section 4.3 for medicinal products which are contraindicated with INCIVO.

Use of INCIVO should be avoided in patients with congenital QT prolongation, or a family history of 
congenital QT prolongation or sudden death. In the event that treatment with INCIVO in such patients
is judged strictly necessary, patients should be closely monitored, including ECG assessments.

Use INCIVO with caution in patients with:
- a history of acquired QT prolongation;
- clinically relevant bradycardia (persistent heart rate < 50 bpm);
- a history of heart failure with reduced left-ventricular ejection fraction;
- a requirement for medicinal products known to prolong the QT interval but the metabolism of 

which is not mainly CYP3A4 dependent (e.g. methadone, see section 4.5).

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Such patients should be closely monitored, including ECG assessments.

Electrolyte disturbances (e.g., hypokalaemia, hypomagnesaemia and hypocalcaemia) should be 
monitored and corrected, if necessary, prior to initiation and during INCIVO therapy.

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.

Laboratory tests
HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated (see also 
guidelines for discontinuation of INCIVO, section 4.2).

The following laboratory evaluations (complete blood count with white blood cell differential counts, 
electrolytes, serum creatinine, liver function tests, TSH, uric acid) must be conducted in all patients 
prior to initiating INCIVO combination treatment.

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

Haematology evaluations (including white cell differential count) are recommended at weeks 2, 4, 8 
and 12 and as clinically appropriate.

Chemistry evaluations (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, TSH) are 
recommended as frequently as the haematology evaluations or as clinically indicated (see section 4.8).

Refer to the Summary of Product Characteristics for peginterferon alfa and ribavirin, including 
pregnancy testing requirements (see section 4.6).

The use of INCIVO in combination with peginterferon alfa-2b
The Phase 3 studies were all conducted with peginterferon alfa-2a in combination with INCIVO and 
ribavirin. There is no data using INCIVO in combination with peginterferon alfa-2b in 
treatment-experienced patients and limited data in treatment-naïve patients. Naïve patients treated 
with either peginterferon alfa-2a/ribavirin (n = 80) or peginterferon alfa-2b/ribavirin (n = 81) in 
combination with INCIVO, in an open label study, had comparable SVR rates. However, patients 
treated with peginterferon alfa-2b experienced more frequent viral breakthrough, and were less likely 
to meet the criteria for shortened total treatment duration (see section 5.1).

General
INCIVO must not be administered as monotherapy and must only be prescribed in combination with 
both peginterferon alfa and ribavirin. The Summary of Product Characteristics for peginterferon alfa 
and ribavirin must therefore be consulted before starting therapy with INCIVO.

There are no clinical data on re-treating patients who have failed an HCV NS3-4A protease 
inhibitor-based therapy (see section 5.1).

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Insufficient virologic response
In patients who have an inadequate viral response, treatment should be discontinued (see sections 4.2 
and 4.4, Laboratory tests).

Use of INCIVO in treatment of other HCV genotypes
There are not sufficient clinical data to support the treatment of patients with HCV genotypes other 
than genotype 1. Therefore, the use of INCIVO in patients with non-genotype-1 HCV is not 
recommended.

Renal impairment
The safety and efficacy have not been established in patients with moderate or severe renal 
impairment (CrCl < 50 ml/min) or in patients on haemodialysis. Refer to section 4.4, Laboratory tests.
Refer also to the Summary of Product Characteristics for ribavirin for patients with CrCL < 50 ml/min 
(see also section 4.2 and 5.2).

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.

INCIVO has not been studied in HCV-infected patients with moderate hepatic impairment 
(Child-Pugh B, score 7-9). In HCV negative patients with moderate hepatic impairment, reduced 
exposure to telaprevir was observed. The appropriate dose of INCIVO in hepatitis C-infected patients 
with moderate hepatic impairment has not been determined. Therefore, INCIVO is not recommended 
in these patients (see sections 4.2 and 5.2).

Refer to the Summary of Product Characteristics for peginterferon alfa and ribavirin which must be 
co-administered with INCIVO.

Organ transplant patients
INCIVO in combination with peginterferon alfa and ribavirin was evaluated in 74 HCV-1 infected, 
post-liver transplant patients without cirrhosis receiving either tacrolimus or cyclosporine A. At the 
initiation of INCIVO treatment, doses of co-administered tacrolimus or cyclosporine A need to be 
markedly reduced, including a prolongation in the dosing interval for tacrolimus, in order to maintain 
therapeutic plasma concentrations of the immunosuppressant. Upon completion of INCIVO, doses of 
tacrolimus or cyclosporine A need to be increased, and the dosing interval for tacrolimus will need to 
be reduced. Some patients may require higher doses of tacrolimus or cyclosporine A than at the 
initiation of treatment. These changes should be based on frequent monitoring of tacrolimus or 
cyclosporine A plasma concentrations during INCIVO treatment. For information on the use of 
INCIVO in combination with peginterferon alfa and ribavirin in treatment-naïve and 
treatment-experienced HCV-1 infected patients who were liver transplant recipients and were on a 
stable regimen of the immunosuppressants tacrolimus or cyclosporine A, see sections 4.2, 
4.5, Immunosuppressants, 4.8, and 5.1.

No clinical data are available regarding the treatment of pre- or peri-liver or other transplant patients 
with INCIVO in combination with peginterferon alfa and ribavirin.

HCV/HIV co-infection
Interactions between telaprevir and HIV antiretroviral agents are frequent, and the recommendations 
in table 2, section 4.5, should be carefully followed.

Among HIV regimens that can be used (not limited to those below) the following should be taken into 
account:

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Atazanavir/ritonavir: this combination is associated with a high frequency of 
hyperbilirubinaemia/icterus. In Study HPC3008 (see sections 4.8 and 5.1), transient grade 3 
(2.5 to ≤5 X ULN) and grade 4 (>5 X ULN) bilirubin increases during INCIVO treatment were seen 
in 39% and in 22% of the 59 patients on atazanavir/ritonavir, respectively.

Efavirenz: with this combination the telaprevir dose must be increased to 1,125 mg three times per 
day (q8h).

HCV/HBV (hepatitis B virus) co-infection
There are no data on the use of INCIVO in patients with HCV/HBV co-infection.

Paediatric population
INCIVO is not recommended for use in children and adolescents younger than 18 years of age 
because the safety and efficacy has not been established in this population.

Thyroid disease
Increase in thyroid stimulating hormone (TSH) may occur during INCIVO combination treatment, 
which may indicate worsening or recurrence of pre-existing or previous hypothyroidism, or new-onset 
hypothyroidism (see section 4.8). TSH levels should be determined before and during the course of 
INCIVO combination treatment and treated as clinically appropriate, including potential adjustment 
of thyroid replacement therapy in patients with pre-existing hypothyroidism (see section 4.4, 
Laboratory tests).

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.

Important information about some of the ingredients of INCIVO
This medicinal product contains 2.3 mg sodium per tablet, which should be taken into consideration 
by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Telaprevir is partly metabolised in the liver by CYP3A and is a P-glycoprotein (P-gp) substrate. Other 
enzymes are also involved in the metabolism (see section 5.2). Co-administration of INCIVO and 
medicinal products that induce CYP3A and/or P-gp may markedly decrease telaprevir plasma 
concentrations. Co-administration of INCIVO and medicinal products that inhibit CYP3A and/or P-gp 
may increase telaprevir plasma concentrations.

INCIVO is a strong, time-dependent inhibitor of CYP3A4 and also markedly inhibits P-gp. The time 
dependency indicates that inhibition of CYP3A4 may be intensified during the first 2 weeks of 
treatment. After ending treatment, approximately one week may be needed for the inhibition to 
completely disappear. Administration of INCIVO may increase systemic exposure to medicinal 
products that are substrates of CYP3A or P-gp, which could increase or prolong their therapeutic 
effect and adverse reactions. Based on the results of drug-drug interaction clinical studies (e.g., 
escitalopram, zolpidem, ethinylestradiol), induction of metabolic enzymes by telaprevir cannot be 
excluded.

Telaprevir inhibits organic anion transporter polypeptides (OATPs) OATP1B1 and OATP2B1. 
Concomitant administration of INCIVO and drugs transported by these transporters such as 
fluvastatin, pravastatin, rosuvastatin, pitavastatin, bosentan and repaglinide should be undertaken with 
caution (see table 2). Simvastatin is contraindicated due to the predicted marked increase in exposure 
caused by multiple mechanisms.

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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).

Interaction studies have only been performed in adults.

Contraindications of concomitant use (see section 4.3)
INCIVO must not be administered concurrently with active substances that are highly dependent on 
CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or 
life-threatening events such as cardiac arrhythmia (i.e., amiodarone, astemizole, bepridil, cisapride, 
pimozide, quinidine, terfenadine), or peripheral vasospasm or ischemia (i.e., dihydroergotamine, 
ergonovine, ergotamine, methylergonovine), or myopathy, including rhabdomyolysis (i.e., lovastatin, 
simvastatin, atorvastatin), or prolonged or increased sedation or respiratory depression (i.e., 
quetiapine, orally administered midazolam or triazolam), or hypotension or cardiac arrhythmia (i.e., 
alfuzosin and sildenafil for pulmonary arterial hypertension).

INCIVO must not be administered concurrently with Class Ia or III antiarrhythmics, except for 
intravenous lidocaine.

INCIVO should be used with caution with Class Ic antiarrhythmics propafenone and flecainide,
including appropriate clinical and ECG monitoring (see section 4.4).

Rifampicin
Rifampicin reduces the telaprevir plasma AUC by approximately 92%. Therefore, INCIVO must not 
be co-administered with rifampicin.

St John’s wort (Hypericum perforatum)
Plasma concentrations of telaprevir can be reduced by concomitant use of the herbal preparation 
St John’s wort (Hypericum perforatum). Therefore, herbal preparations containing St John’s wort 
must not be combined with INCIVO.

Carbamazepine, phenytoin and phenobarbital
Co-administration with inducers may lead to lower exposure of telaprevir with risk of lower efficacy. 
Potent CYP3A inducers, such as carbamazepine, phenytoin and phenobarbital, are contraindicated 
(see section 4.3).

Mild and moderate CYP3A inducers
Mild and moderate CYP3A inducers should be avoided, particularly in patients who are prior 
non-responders (partial or null responders for peginterferon alfa/ribavirin), unless specific dose 
recommendations are given (refer to table 2).

Other combinations
Table 2 provides dosing recommendations as a result of drug interactions with INCIVO. These 
recommendations are based on either drug interaction studies (indicated with *) or predicted 
interactions due to the expected magnitude of interaction and potential for serious adverse reactions or 
loss of efficacy. Most drug-drug interaction studies have been performed with a telaprevir dose of 
750 mg every 8 hours (q8h). Given that the 1,125 mg b.i.d. regimen results in the same daily dose 
with similar drug exposures of telaprevir, the relative drug interactions are expected to be similar.

The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) for each pharmacokinetic 
parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), 
below (↓) or above (↑) the 80-125% range.

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Table 2: INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL 
PRODUCTS

Medicinal products by 
therapeutic areas

Effect on concentration of 
INCIVO or concomitant 
medicinal product and 
possible mechanism

Clinical comment

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.

ANTIARRHYTHMICS
lidocaine
(intravenous)

↑ lidocaine
inhibition of CYP3A

Caution is warranted and clinical monitoring is 
recommended when intravenous lidocaine is 
administered for the treatment of acute 
ventricular arrhythmia.

digoxin* ↑ digoxin
AUC 1.85 (1.70-2.00)
Cmax 1.50 (1.36-1.65)
effect on P-gp transport in 
the gut

The lowest dose of digoxin should be initially 
prescribed. The serum digoxin concentrations 
should be monitored and used for titration of 
digoxin dose to obtain the desired clinical 
effect.

ANTIBACTERIALS
clarithromycin
erythromycin
telithromycin
troleandomycin

↑ telaprevir
↑ antibacterials
inhibition of CYP3A

Caution is warranted and clinical monitoring is 
recommended when co-administered with 
INCIVO.
QT interval prolongation and Torsade de 
Pointes have been reported with clarithromycin 
and erythromycin. QT interval prolongation 
has been reported with telithromycin (see 
section 4.4).

ANTICOAGULANTS
warfarin ↑ or ↓ warfarin

modulation of metabolic 
enzymes

It is recommended that the international 
normalised ratio (INR) be monitored when 
warfarin is co-administered with telaprevir.

dabigatran  dabigatran
 telaprevir
effect on P-gp transport in 
the gut

Caution is warranted, laboratory and clinical 
monitoring is recommended.

ANTICONVULSANTS
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.

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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.

ANTIDEPRESSANTS
escitalopram* ↔ telaprevir

↓ escitalopram
AUC 0.65 (0.60-0.70)
Cmax 0.70 (0.65-0.76)
Cmin 0.58 (0.52-0.64)
mechanism unknown

Clinical relevance unknown.
Doses may need to be increased when 
combined with telaprevir. 

trazodone ↑ trazodone
inhibition of CYP3A

Concomitant use may lead to adverse events 
such as nausea, dizziness, hypotension and 
syncope. If trazodone is used with telaprevir, 
the combination should be used with caution 
and a lower dose of trazodone should be 
considered.

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.

ANTIEMETICS
domperidone ↑ domperidone

inhibition of CYP3A
Co-administration of domperidone with 
INCIVO should be avoided (see section 4.4).

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ANTIFUNGALS
ketoconazole*
itraconazole
posaconazole
voriconazole

↑ ketoconazole (200 mg)
AUC 2.25 (1.93-2.61)
Cmax 1.75 (1.51-2.03)

↑ ketoconazole (400 mg)
AUC 1.46 (1.35-1.58)
Cmax 1.23 (1.14-1.33)

↑ telaprevir (with 
ketoconazole 400 mg)
AUC 1.62 (1.45-1.81)
Cmax 1.24 (1.10-1.41)

↑ itraconazole
↑ posaconazole
↑ or ↓ voriconazole

Inhibition of CYP3A.
Due to multiple enzymes 
involved with voriconazole 
metabolism, it is difficult to 
predict the interaction with 
telaprevir.

When co-administration is required, high doses 
of itraconazole (> 200 mg/day) or 
ketoconazole (> 200 mg/day) are not 
recommended. Caution is warranted and 
clinical monitoring is recommended for 
itraconazole, posaconazole, and voriconazole.
QT interval prolongation and Torsade de 
Pointes have been reported with voriconazole 
and posaconazole. QT interval prolongation 
has been reported with ketoconazole (see 
section 4.4).
Voriconazole should not be administered to 
patients receiving telaprevir unless an 
assessment of the benefit/risk ratio justifies its 
use.

ANTI-GOUT
colchicine ↑ colchicine

inhibition of CYP3A
Patients with renal or hepatic impairment 
should not be given colchicine with INCIVO, 
due to the risk of colchicine toxicity.
In patients with normal renal and hepatic 
function, an interruption of colchicine 
treatment is recommended, or only a limited 
colchicine treatment course at a reduced 
colchicine dose should be used.

ANTIMYCOBACTERIALS
rifabutin ↓ telaprevir

↑ rifabutin
induction of CYP3A by 
rifabutin, inhibition of 
CYP3A by telaprevir

Telaprevir may be less effective due to 
decreased concentrations. The concomitant use 
of rifabutin and telaprevir is not recommended.

rifampicin* ↓ telaprevir
AUC 0.08 (0.07-0.11)
Cmax 0.14 (0.11-0.18)
↑ rifampicin
induction of CYP3A by 
rifampicin, inhibition of 
CYP3A by telaprevir

Co-administration of rifampicin with telaprevir 
is contraindicated.

ANTIPSYCHOTICS
quetiapine Due to CYP3A inhibition 

by telaprevir, 
concentrations of 
quetiapine are expected to 
increase.

Concomitant administration of INCIVO and 
quetiapine is contraindicated as it may increase 
quetiapine-related toxicity. Increased plasma 
concentrations of quetiapine may lead to coma.

BENZODIAZEPINES
alprazolam* ↑ alprazolam

AUC 1.35 (1.23-1.49)
Cmax 0.97 (0.92-1.03)

Clinical relevance unknown.
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parenterally administered 
midazolam*

oral midazolam*

oral triazolam

↑ midazolam (intravenous)
AUC 3.40 (3.04-3.79)
Cmax 1.02 (0.80-1.31)

↑ midazolam (p.o.)
AUC 8.96 (7.75-10.35)
Cmax 2.86 (2.52-3.25)

↑ triazolam

inhibition of CYP3A

Co-administration should be done in a setting 
which ensures clinical monitoring and 
appropriate medical management in case of 
respiratory depression and/or prolonged 
sedation.
Dose reduction for parenterally administered 
midazolam should be considered, especially if 
more than a single dose of midazolam is 
administered.

Co-administration of oral midazolam or 
triazolam with telaprevir is contraindicated.

zolpidem 
(non-benzodiazepine 
sedative)*

↓ zolpidem
AUC 0.53 (0.45-0.64)
Cmax 0.58 (0.52-0.66)
mechanism unknown

Clinical relevance unknown.
Increased dose of zolpidem may be required to 
maintain efficacy.

CALCIUM CHANNEL BLOCKERS
amlodipine* ↑ amlodipine

AUC 2.79 (2.58-3.01)
Cmax 1.27 (1.21-1.33)
inhibition of CYP3A

Caution should be used and dose reduction for 
amlodipine should be considered. Clinical 
monitoring is recommended.

diltiazem
felodipine
nicardipine
nifedipine
nisoldipine
verapamil

↑ calcium channel blockers
inhibition of CYP3A and/or 
effect on P-gp transport in 
the gut

Caution is warranted and clinical monitoring of 
patients is recommended.

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.

CORTICOSTEROIDS
Systemic
dexamethasone

↓ telaprevir
induction of CYP3A

Concomitant use may result in loss of 
therapeutic effect of telaprevir. Therefore this 
combination should be used with caution or 
alternatives should be considered.

inhaled/nasal
fluticasone
budesonide

↑ fluticasone
↑ budesonide
inhibition of CYP3A

Co-administration of fluticasone or budesonide 
and telaprevir is not recommended unless the 
potential benefit to the patient outweighs the 
risk of systemic corticosteroid side effects.

ENDOTHELIN RECEPTOR ANTAGONIST
bosentan ↑ bosentan

↓ telaprevir
induction of CYP3A by 
bosentan, inhibition of 
CYP3A and organic anion 
transporter polypeptides 
(OATPs) by telaprevir

Caution is warranted and clinical monitoring is 
recommended.Me

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HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs)
atazanavir/ritonavir* ↓ telaprevir

AUC 0.80 (0.76-0.85)
Cmax 0.79 (0.74-0.84)
Cmin 0.85 (0.75-0.98)
↑ atazanavir
AUC 1.17 (0.97-1.43)
Cmax 0.85 (0.73-0.98)
Cmin 1.85 (1.40-2.44)
inhibition of CYP3A by 
telaprevir

Hyperbilirubinaemia is frequent with this 
combination. Clinical and laboratory 
monitoring for hyperbilirubinaemia is 
recommended (see section 4.4 and 4.8).

darunavir/ritonavir* ↓ telaprevir
AUC 0.65 (0.61-0.69)
Cmax 0.64 (0.61-0.67)
Cmin 0.68 (0.63-0.74)
↓ darunavir
AUC 0.60 (0.57-0.63)
Cmax 0.60 (0.56-0.64)
Cmin 0.58 (0.52-0.63)
mechanism unknown

It is not recommended to co-administer 
darunavir/ritonavir and telaprevir (see 
section 4.4).

fosamprenavir/ritonavir* ↓ telaprevir
AUC 0.68 (0.63-0.72)
Cmax 0.67 (0.63-0.71)
Cmin 0.70 (0.64-0.77)
↓ amprenavir
AUC 0.53 (0.49-0.58)
Cmax 0.65 (0.59-0.70)
Cmin 0.44 (0.40-0.50)
mechanism unknown

It is not recommended to co-administer 
fosamprenavir/ritonavir and telaprevir (see 
section 4.4).

lopinavir/ritonavir*  telaprevir
AUC 0.46 (0.41-0.52)
Cmax 0.47 (0.41-0.52)
Cmin 0.48 (0.40-0.56)
↔ lopinavir
AUC 1.06 (0.96-1.17)
Cmax 0.96 (0.87-1.05)
Cmin 1.14 (0.96-1.36)
mechanism unknown

It is not recommended to co-administer 
lopinavir/ritonavir and telaprevir (see 
section 4.4).

HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
efavirenz* ↓ telaprevir 1,125 mg every 

8 hours (relative to 750 mg
every 8 hours)
AUC 0.82 (0.73-0.92)
Cmax 0.86 (0.76-0.97)
Cmin 0.75 (0.66-0.86)
↓ efavirenz (+ TVR 
1,125 mg every 8 hours)
AUC 0.82 (0.74-0.90)
Cmax 0.76 (0.68-0.85)
Cmin 0.90 (0.81-1.01)
induction of CYP3A by 
efavirenz.

If co-administered, telaprevir 1,125 mg q8h 
should be used (see section 4.4).

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tenofovir disoproxil 
fumarate*

↔ telaprevir
AUC 1.00 (0.94-1.07)
Cmax 1.01 (0.96-1.05)
Cmin 1.03 (0.93-1.14)
↑ tenofovir
AUC 1.30 (1.22-1.39)
Cmax 1.30 (1.16-1.45)
Cmin 1.41 (1.29-1.54)
effect on P-gp transport in 
the gut

Increased clinical and laboratory monitoring 
are warranted (see section 4.4).

abacavir
zidovudine

Not studied. An effect of telaprevir on 
UDP-glucuronyltransferases cannot be ruled 
out and may affect the plasma concentrations 
of abacavir or zidovudine.

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.

INTEGRASE INHIBITORS
raltegravir* ↔ telaprevir

AUC 1.07 (1.00-1.15)
Cmax 1.07 (0.98-1.16)
Cmin 1.14 (1.04-1.26)
↑ raltegravir
AUC 1.31 (1.03-1.67)
Cmax 1.26 (0.97-1.62)
Cmin 1.78 (1.26-2.53)

If co-administered, no dose adjustment is 
required.

HMG-CoA REDUCTASE INHIBITORS
atorvastatin* ↑ atorvastatin

AUC 7.88 (6.82-9.07)
Cmax 10.6 (8.74-12.85)
inhibition of CYP3A and 
OATPs by telaprevir

Co-administration of atorvastatin and 
telaprevir is contraindicated (see section 4.3).

fluvastatin
pitavastatin
pravastatin
rosuvastatin

↑ statin
inhibition of CYP3A and 
OATPs by telaprevir

Caution is warranted and clinical monitoring is 
recommended.

Refer to section 4.3 for HMG-CoA reductase 
inhibitors that are contraindicated with 
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HORMONAL CONTRACEPTIVES/OESTROGEN
ethinylestradiol*
norethindrone*

↓ ethinylestradiol
AUC 0.72 (0.69-0.75)
Cmax 0.74 (0.68-0.80)
Cmin 0.67 (0.63-0.71)
↔ norethindrone
AUC 0.89 (0.86-0.93)
Cmax 0.85 (0.81-0.89)
Cmin 0.94 (0.87-1.00)
mechanism unknown

Additional methods of non-hormonal 
contraception should be used when hormonal 
contraceptives are co-administered with 
telaprevir.
Patients using oestrogens as hormone 
replacement therapy should be clinically 
monitored for signs of oestrogen deficiency.
Refer to sections 4.4 and 4.6.

IMMUNOSUPPRESSANTS
cyclosporine*
tacrolimus*
sirolimus

↑ cyclosporine
AUC 4.64 (3.90-5.51)
Cmax 1.32 (1.08-1.60)
↑ tacrolimus
AUC 70.3 (52.9-93.4)**
Cmax 9.35 (6.73-13.0)**
↑ sirolimus

↑ telaprevir

**calculated based on data 
obtained with a reduced 
dose

inhibition of CYP3A, 
inhibition of transport 
proteins

Marked immunosuppressant dose reductions 
with or without prolongation of the dosing 
intervals will be required. Close monitoring of 
immunosuppressant blood levels, renal 
function and immunosuppressant related side 
effects are recommended when 
co-administered with telaprevir. Tacrolimus 
may prolong the QT interval (see section 4.4).

INHALED BETA AGONIST
salmeterol ↑ salmeterol

inhibition of CYP3A
Concurrent administration of salmeterol and 
telaprevir is not recommended. The 
combination may result in increased risk of 
cardiovascular adverse events associated with 
salmeterol, including QT prolongation, 
palpitations, and sinus tachycardia (see 
section 4.4).

INSULIN SECRETAGOGUES
repaglinide ↑ repaglinide

inhibition of OATPs by 
telaprevir

Caution is warranted and clinical monitoring is 
recommended.

NARCOTIC ANALGESIC
methadone* ↓ R-methadone

AUC 0.71 (0.66-0.76)
Cmax 0.71 (0.66-0.76)
Cmin 0.69 (0.64-0.75)

No effect on unbound 
R-methadone 
concentrations.

Displacement of methadone 
from plasma proteins.

No adjustment of methadone dose is required 
when initiating co-administration of telaprevir. 
However, clinical monitoring is recommended 
as the dose of methadone during maintenance 
therapy may need to be adjusted in some 
patients.
QT interval prolongation and Torsade de 
Pointes have been reported with methadone 
(see section 4.4). ECG should be monitored at 
baseline and regularly during telaprevir 
treatment.

buprenorphine*  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.

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PDE-5 INHIBITORS
sildenafil
tadalafil
vardenafil

↑ PDE-5 inhibitors
inhibition of CYP3A

It is not recommended to co-administer 
sildenafil or vardenafil and telaprevir. 
Tadalafil for treatment of erectile dysfunction 
can be used with caution at a single dose not 
exceeding 10 mg dose in 72 hours and with 
increased monitoring for tadalafil associated 
adverse events.
Co-administration of sildenafil or tadalafil and 
telaprevir in the treatment of pulmonary 
arterial hypertension is contraindicated (see 
section 4.3).

PROTON PUMP INHIBITORS
esomeprazole* ↔ telaprevir

AUC 0.98 (0.91-1.05)
Cmax 0.95 (0.86-1.06)

Proton pump inhibitors can be used without 
dose modification.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no data from the use of INCIVO in pregnant women. Animal studies are insufficient with 
respect to human reproductive toxicity (see section 5.3). INCIVO is not recommended during 
pregnancy and in women of childbearing potential not using contraception.

Contraception in males and females
Because INCIVO must be used in combination with peginterferon alfa and ribavirin, the 
contraindications and warnings applicable to those medicinal products are applicable to combination 
therapy.

Due to the combined treatment with peginterferon alfa and ribavirin, female patients of childbearing 
potential and their male partners as well as male patients and their female partners must use 
2 effective contraceptive methods during INCIVO treatment. Following completion of INCIVO 
therapy contraceptive recommendations should be followed as in the Summary of Product 
Characteristics for ribavirin, and as described below.

Hormonal contraceptives may be continued but may not be reliable during INCIVO dosing and for up 
to two months following cessation of INCIVO (see section 4.5). During this time, female patients of 
childbearing potential should use two effective non-hormonal methods of contraception. Two months 
after completion of INCIVO treatment, hormonal contraceptives are again appropriate as one of the 
two required effective methods of birth control.

Refer to the Summary of Product Characteristics for ribavirin and peginterferon alpha for additional 
information.

Breast-feeding
Telaprevir and its major metabolite are excreted in rat milk (see section 5.3). It is not known whether 
telaprevir is excreted in human breast milk. Because of the potential for adverse reactions in breastfed
infants, due to the combined treatment of INCIVO with peginterferon alfa and ribavirin, 
breast-feeding must be discontinued prior to initiation of therapy. See also the Summary of Product 
Characteristics for ribavirin.

Fertility
INCIVO had no effects on fertility or fecundity when evaluated in rats.

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4.7 Effects on ability to drive and use machines

INCIVO has no or negligible influence on the ability to drive and use machines. No studies on the 
effects of INCIVO on the ability to drive and use machines have been performed. Syncope and 
retinopathy have been reported in some patients taking INCIVO and should be considered when 
assessing a patient’s ability to drive or operate machines. Refer also to the Summary of Product 
Characteristics for peginterferon alfa and ribavirin for further information.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of INCIVO is based on Phase 2 and 3 clinical trial data (both controlled and 
uncontrolled) containing 3,441 patients who received INCIVO combination treatment and on 
spontaneous postmarketing reports.

INCIVO must be administered with peginterferon alfa and ribavirin. Refer to their respective 
Summary of Product Characteristics for their associated adverse reactions.

The incidence of adverse drug reactions (ADRs) of at least moderate intensity (≥ Grade 2) was higher 
in the INCIVO group than in the placebo group.

During the INCIVO/placebo treatment phase, the most frequently reported ADRs of at least Grade 2 
in severity in the INCIVO group (incidence ≥ 5.0%) were anaemia, rash, pruritus, nausea, and 
diarrhoea.
During the INCIVO/placebo treatment phase, the most frequently reported ADRs of at least Grade 3 
in the INCIVO group (incidence ≥ 1.0%) were anaemia, rash, thrombocytopenia, lymphopenia, 
pruritus, and nausea.

Tabulated summary of adverse reactions
ADRs to INCIVO are presented in table 3.

ADRs are listed by system organ class (SOC) and frequency: very common (≥ 1/10), common 
(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000). Within each 
frequency grouping, ADRs are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions to INCIVO (taken in combination with peginterferon alfa 
and ribavirin) in HCV-infected patients in clinical trialsa and post-marketing

System Organ Class (SOC) Frequency 
category

Adverse Drug Reactions
INCIVO, peginterferon alfa, and 
ribavirin combination therapy

Infections and infestations common oral candidiasis
Blood and lymphatic system 
disorders

very common anaemia
common thrombocytopeniab, lymphopeniab

Endocrine disorders common hypothyroidism
Metabolism and nutrition 
disorders

common hyperuricaemiab, hypokalaemiab

uncommon gout
Nervous system disorders common dysgeusia, syncope
Eye disorders uncommon retinopathy
Gastrointestinal disorders very common nausea, diarrhoea, vomiting, haemorrhoids, 

proctalgia
common anal pruritus, rectal haemorrhage, anal 

fissure
uncommon proctitis, pancreatitis

Hepatobiliary disorders common hyperbilirubinaemiab

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Skin and subcutaneous tissue 
disorders

very common pruritus, rash
common eczema, swelling face, exfoliative rash
uncommon drug rash with eosinophilia and systemic 

symptoms (DRESS), urticaria
rare SJS, TEN, erythema multiforme

Renal and urinary disorders uncommon blood creatinine increasedb, pre-renal 
azotemia with or without acute renal 
failure

General disorders and 
administration site conditions

common oedema peripheral, product taste abnormal

a
the placebo-controlled Phase 2 and Phase 3 Studies (pooled data) included 1,346 HCV-infected patients

b
incidence rates are based on adverse event reporting rates (additionally, see Laboratory abnormalities below)

In the analysis of an additional study, Study C211, the safety profile of combination therapy with 
INCIVO 1,125 mg twice daily was similar to the safety profile for patients receiving combination 
therapy with INCIVO 750 mg every 8 hours. No new safety findings were identified.

Laboratory abnormalities
Selected laboratory abnormalities of at least moderate intensity (≥ Grade 2) that represent a worsening 
from baseline and are considered ADRs observed in HCV-infected patients treated with INCIVO 
combination treatment from the pooled data from the placebo-controlled Phase 2 and Phase 3 trials 
are presented in the table below:

Table 4: Selected laboratory abnormalities (DAIDSa Grade ≥ 2) that represent a worsening 
from baseline and are considered adverse drug reactions in HCV-infected patients treated 
with INCIVO combination treatment from the pooled data from the placebo-controlled 
Phase 2 and Phase 3 trials

Grade 2 Grade 3 Grade 4
Increaseb

uric acid 17.9%
(10.1-12.0 mg/dl)

4.6%
(12.1-15.0 mg/dl)

1.1%
(> 15.0 mg/dl)

bilirubin 13.6%
(1.6-2.5 x ULN)

3.6%
(2.6-5.0 x ULN)

0.3%
(> 5.0 x ULN)

total cholesterol 15.4%
(6.20–

7.77 mmol/l
240 - 300 mg/dl)

2.0%
(> 7.77 mmol/l
> 300 mg/dl)

NA

low-density 
lipoprotein

6.9%
(4.13–

4.90 mmol/l
160–190 mg/dl)

2.5%
(≥ 4.91 mmol/l
≥ 191 mg/dl)

NA

creatinine 0.9%
(1.4–1.8 x ULN)

0.2%
(1.9-3.4 x ULN)

0%
(> 3.4 x ULN)

Decreaseb

haemoglobin 27.0%
(9.0-9.9 g/dl

or any decrease 
3.5-4.4 g/dl)

51.1%
(7.0-8.9 g/dl

or any decrease 
≥ 4.5 g/dl)

1.1%
(< 7.0 g/dl)

platelet count 24.4%
(50,000–

99,999/mm3)

2.8%
(25,000–

49,999/mm3)

0.2%
(< 25,000/mm3)

absolute 
lymphocyte count

13.1%
(500-599/mm3)

11.8%
(350-499/mm3)

4.8%
(< 350/mm3)

potassium 1.6%
(2.5–2.9 mEq/l)

0%
(2.0-2.4 mEq/l)

0%
(< 2.0 mEq/l)

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NA = not applicable
a

The Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events (DAIDS, version 1.0, 
December 2004) was used in the pooled laboratory datasets.

b
The incidence was calculated by the number of patients for each parameter.

Most laboratory values return to levels observed with peginterferon alfa and ribavirin by week 24, 
except platelet counts, which remain at levels lower than observed with peginterferon alfa and 
ribavirin until week 48 (see section 4.4).

Increases in serum uric acid occur very commonly during treatment with INCIVO in combination 
with peginterferon alfa and ribavirin. After the end of INCIVO treatment, uric acid values typically 
decrease over the following 8 weeks and are comparable to those observed in patients receiving 
peginterferon alfa and ribavirin alone.

Description of selected adverse reactions
Rash
Severe, potentially life-threatening and fatal skin reactions have been reported with INCIVO 
combination treatment, including DRESS, SJS, and TEN (see section 4.4). In placebo-controlled 
Phase 2 and 3 trials, the overall incidence and severity of rash increased when INCIVO was 
co-administered with peginterferon alfa and ribavirin. During INCIVO treatment, rash events (all 
grades) were reported in 55% of patients who received INCIVO combination treatment and in 33% of 
patients who received peginterferon alfa and ribavirin.

More than 90% of rashes were of mild or moderate severity. The rash reported during INCIVO 
combination treatment was assessed as a typically pruritic, eczematous rash, and involved less than 
30% of body surface area. Half the rashes started during the first 4 weeks, but rash can occur at any 
time during INCIVO combination treatment. Discontinuation of INCIVO combination treatment is not 
required for mild and moderate rash.

See section 4.4 for recommendations for monitoring of rash and discontinuation of INCIVO, ribavirin, 
and peginterferon alfa. Patients experiencing mild to moderate rash should be monitored for signs of 
progression; however, progression was infrequent (less than 10%). In clinical trials, the majority of 
patients were administered antihistamines and topical corticosteroids. Improvement of rash occurs 
after INCIVO dosing completion or discontinuation; however, rashes may take several weeks to 
resolve.

Anaemia
In placebo-controlled Phase 2 and 3 trials, anaemia (all grades) was reported in 32.1% of patients who 
received INCIVO combination treatment and in 14.8% of patients who received peginterferon alfa 
and ribavirin. Ribavirin dose reductions were used for management of anaemia. 21.6% of patients 
receiving INCIVO combination treatment required ribavirin dose reduction for anaemia compared to 
9.4% of patients receiving peginterferon alfa and ribavirin alone. Erythropoisis-stimulating agents 
(ESAs) were generally not permitted and used in only 1% of patients in the Phase 2 and 3 clinical 
trials. In the placebo-controlled Phase 2 and 3 trials, transfusions were reported during the 
INCIVO/placebo treatment phase in 2.5% of patients receiving INCIVO combination treatment and 
0.7% in patients receiving peginterferon alfa and ribavirin alone. Transfusion rates over the whole 
study period were 4.6% and 1.6%, respectively. In placebo-controlled Phase 2 and 3 trials, 1.9% of 
patients discontinued INCIVO alone due to anaemia, and 0.9% of patients discontinued INCIVO 
combination treatment due to anaemia compared to 0.5% receiving peginterferon alfa and ribavirin
(see section 4.4).

Anorectal signs and symptoms
In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, 
and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved 
after completion of INCIVO dosing.

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Patients Co-infected with HIV-1
The overall safety profile of INCIVO in HCV/HIV-1 co-infected patients (either not on antiretroviral 
therapy or on antiretroviral therapy) was similar to the safety profile in mono-infected HCV patients, 
except for patients receiving atazanavir/ritonavir who frequently experienced a transient increase in 
indirect bilirubin levels (including grades 3 to 4) through week 2, returning to near baseline by 
week 12 (see section 4.4).

Liver transplant patients without cirrhosis
The overall safety profile of INCIVO in treatment- naïve and treatment-experienced HCV-1 infected 
patients who were liver transplant recipients on a stable regimen of the immunosuppressants 
tacrolimus or cyclosporine A was generally similar to the safety profile of INCIVO in patients without 
a history of liver transplantation, although anaemia was reported more frequently (55.4% versus 
32.1% in the Phase 2-3 safety pooling) during the INCIVO treatment phase. To manage anaemia, at 
initiation of INCIVO treatment a lower starting dose of ribavirin (600 mg/day) was used; during the 
overall treatment phase the ribavirin dose was further reduced in 36.5% of patients, 41.9% received 
ESAs and 21.6% received blood transfusions (see sections 4.4 and 4.5, Immunosuppressants).

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

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

4.9 Overdose

The highest documented INCIVO dose administered is 1,875 mg every 8 hours for 4 days in healthy 
volunteers. In that study, the following common adverse events were reported more frequently with 
the 1,875 mg every 8 hours regimen compared to the 750 mg every 8 hours regimen: nausea, 
headache, diarrhoea, decreased appetite, dysgeusia and vomiting.

No specific antidote is available for overdose with INCIVO. Treatment of overdose with INCIVO
consists of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient. If indicated, elimination of unabsorbed active substance may be achieved 
by emesis or gastric lavage. Gastric lavage should only be performed if this can be done within one 
hour after ingestion. Administration of activated charcoal may also be used to aid in the removal of 
unabsorbed active substance.

It is not known whether telaprevir is dialyzable by peritoneal or haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AE11.

Mechanism of action
Telaprevir is an inhibitor of the HCV NS3•4A serine protease, which is essential for viral replication.

In vitro studies
Activity of telaprevir against HCV

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25

In an HCV subtype 1b replicon assay, the telaprevir IC50 value against wild-type HCV was 0.354 µM 
similar to a subtype 1a infectious virus assay IC50 of 0.28 µM.

Resistance
HCV variants associated with on-treatment virologic failure or relapse were evaluated by site-directed 
mutagenesis in the replicon assay. Variants V36A/M, T54A/S, R155K/T, and A156S conferred lower 
levels of in vitro resistance to telaprevir (3- to 25-fold increase in telaprevir IC50), and the A156V/T 
and V36M+R155K variants conferred higher levels of in vitro resistance to telaprevir (> 25-fold 
increase in telaprevir IC50). Replicon variants generated from patient-derived sequences showed 
similar results.

The in vitro replication capacity of telaprevir-resistant variants was lower than that of wild-type virus.

Cross-resistance
Telaprevir-resistant variants were tested for cross-resistance against representative protease inhibitors
in the HCV replicon system. Replicons with single substitutions at position 155 or 156 and double 
variants with substitutions at residues 36 and 155 showed cross-resistance to all protease inhibitors 
tested with a wide range of sensitivities. All telaprevir-resistant variants studied remained fully 
sensitive to interferon-alfa, ribavirin, and representative HCV nucleoside and non-nucleoside 
polymerase inhibitors in the replicon system. There are no clinical data on re-treating patients who 
have failed an HCV NS3-4A protease inhibitor-based therapy, such as telaprevir, nor are there data on 
repeated courses of telaprevir treatment.

Clinical virology studies
In Phase 2 and 3 clinical trials of telaprevir, treatment-naïve and prior treatment-failure patients with 
predominant telaprevir-resistant variants at baseline (pre-treatment) were rare (V36M, T54A and 
R155K < 1% and T54S 2.7%). Predominant baseline resistance to telaprevir does not preclude 
successful treatment with telaprevir, peginterferon alfa, and ribavirin. The impact of predominant 
telaprevir-resistant variants at baseline is likely greatest in patients with a poor interferon response, 
such as prior null responders.

A total of 215 of 1,169 patients treated with a T12/PR regimen in a Phase 3 clinical trial had 
on-treatment virologic failure (n = 125) or relapse (n = 90). Based on population sequencing analyses 
of HCV in these 215 patients, the emergence of telaprevir-resistant HCV variants was detected in 
105 (84%) virologic failures and in 55 (61%) relapsers, and wild-type virus was detected in 15 (12%) 
virologic failures and in 24 (27%) relapsers. HCV sequencing data were not available for 16 (7%) 
patients. Sequence analyses of the telaprevir-resistant variants identified substitutions at 4 positions in 
the NS3-4A protease region, consistent with the mechanism of action for telaprevir (V36A/M, 
T54A/S, R155K/T, and A156S/T/V). In the C211 Phase 3 clinical trial, there was no difference in the 
type of emerging variants between patients receiving telaprevir 1,125 mg twice daily (b.i.d.) and 
patients receiving telaprevir 750 mg every 8 hours (q8h). Similar proportions of patients in both 
treatment groups had telaprevir-resistant variants at the time of failure. On-treatment virologic failure 
during telaprevir treatment was predominantly associated with higher-level resistant variants, and 
relapse was predominantly associated with lower-level resistant variants or wild-type virus.

Patients with HCV genotype 1a predominately had V36M and R155K single and combination 
variants, while patients with HCV genotype 1b predominately had V36A, T54A/S, and A156S/T/V 
variants. This difference is likely due to the higher genetic barrier for the V36M and R155K 
substitutions for genotype 1b than genotype 1a. Among patients treated with telaprevir, on-treatment 
virologic failure was more frequent in patients with genotype 1a than with genotype 1b and more 
frequent in prior null responders than in other populations (treatment-naïve, prior relapsers, prior 
partial responders; see section 5.1, Clinical Experience, Efficacy in Previously Treated Adults).

The resistance profile observed in Study HPC3008 in HCV/HIV-1 co-infected patients was similar to 
the resistance profile in mono-infected HCV patients.

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The resistance profile observed in Study HPC3006 in treatment-naïve and treatment-experienced 
HCV-1 infected liver transplant recipients who were on a stable regimen of the immunosuppressants 
tacrolimus or cyclosporine A was similar to the resistance profile in HCV-infected patients without a 
liver transplant.

Follow-up analysis of INCIVO-treated patients who did not achieve an SVR showed that the 
population of wild-type virus increased and the population of telaprevir-resistant variants became
undetectable over time after the end of telaprevir treatment. Of a combined 255 treatment-naïve and 
previously treated patients from Phase 3 studies 108, 111, and C216 in whom telaprevir-resistant 
variants had emerged during treatment, 152 (60%) patients no longer had resistant variants detected 
by population sequencing (median follow-up of 10 months). Of the 393 resistant variants detected in 
the 255 patients, 68% of NS3-36, 84% of NS3-54, 59% of NS3-155, 86% of NS3-156, and 52% of 
NS3-36M+NS3-155K variants were no longer detected.

In a follow-up study of 98 treatment-naïve and prior treatment-failure patients who were treated with 
a INCIVO regimen in a Phase 2 or Phase 3study and did not achieve SVR, telaprevir-resistant variants 
were no longer detected in 85% (83/98) of patients (median follow-up of 27.5 months). Clonal 
sequencing analysis of a subset of patients who had wild-type HCV by population sequencing (n=20), 
comparing the frequency of resistant variants before the start of telaprevir treatment and at follow-up, 
showed that the HCV variant population in all patients had returned to pre-treatment levels. The 
median time for telaprevir-resistant variants to become undetectable by population sequencing was 
longer for variants NS3-36 (6 months), NS3-155 (9 months) and NS3-36M+NS3-155K (12 months) 
predominantly observed in patients with genotype 1a than for variants NS3-54 (2 months) and 
NS3-156 (3 months) predominantly observed in patients with genotype 1b.

Clinical efficacy and safety
The efficacy and safety of INCIVO in patients with genotype 1 chronic hepatitis C were evaluated in 
four Phase 3 studies: 3 in treatment-naïve patients and 1 in previously treated patients (relapsers, 
partial responders, and null responders). Patients in these studies, 108, 111 and C216, had 
compensated liver disease, detectable HCV RNA, and liver histopathology consistent with chronic 
hepatitis C. Unless otherwise indicated, INCIVO was administered at a dosage of 750 mg every 
8 hours (q8h); the peginterferon alfa-2a dose was 180 µg/week, and the ribavirin dose was 
1,000 mg/day (patients weighing < 75 kg) or 1,200 mg/day (patients weighing ≥ 75 kg). Plasma 
HCV RNA values were measured using the COBAS® TaqMan® HCV test (version 2.0), for use with 
the High Pure System. The assay had a lower limit of quantification of 25 IU/ml.

In the description of Phase 3 study outcomes for Studies 108, 111, and C216, SVR, considered 
virologic cure, was defined based on the HCV RNA assessment in the study week 72 visit window, 
using the last measurement in the window. In the case of missing data within the week 72 window, the 
last HCV RNA data point from week 12 of follow-up onwards was used. In addition, the limit of 
quantification of 25 IU/ml was used to determine SVR.

In the description of the Phase 3 study outcomes for Study C211, HPC3008 and HPC3006, SVR12, 
considered virologic cure, was defined based on HCV RNA below the limit of quantification 
(25 IU/ml) using the last measurement in the visit window 12 weeks after the planned end of 
treatment.

Efficacy in treatment-naïve adults
Study C211
Study C211 was a randomised, open-label, Phase 3 study conducted in treatment-naïve patients who 
were randomised to one of two treatment groups: INCIVO 750 mg every 8 hours [T12(q8h)/PR] or 
INCIVO 1,125 mg twice daily [T12(b.i.d.)/PR] in combination with peginterferon alfa-2a and 
ribavirin. The primary objective was to demonstrate the noninferiority of T12(b.i.d.)/PR over 
T12(q8h)/PR. All patients received 12 weeks of treatment with INCIVO in combination with 
peginterferon alfa-2a and ribavirin. At week 12, INCIVO dosing ended and patients continued on 
peginterferon alfa-2a and ribavirin treatment. The total treatment duration was determined based on 

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the patients’ individual on-treatment viral response. If a patient achieved undetectable HCV RNA 
(target not detected) at week 4, the total treatment duration was 24 weeks. Otherwise, the total 
treatment duration was 48 weeks.

The 740 enrolled patients had a median age of 51 years (range: 18 to 70); 60% of the patients were 
male; 21% had a body mass index ≥ 30 kg/m2; 5% were Black; 2% were Asian; 85% had baseline 
HCV RNA levels ≥ 800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had HCV 
genotype 1a; and 43% had HCV genotype 1b.

The SVR12 rate for the T12(b.i.d.)/PR group was 74% (274/369) compared to 73% (270/371) in the 
T12(q8h)/PR group with 95% confidence interval of the difference: -4.9%, 12.0%. The lower limit of 
the 95% CI (-4.9%) was greater than the pre-determined noninferiority margin of -11% and therefore 
the non inferiority of T12(b.i.d.)/PR over T12(q8h)/PR was demonstrated. Table 5 shows the response 
rates for the T12(b.i.d.)/PR group and the T12(q8h)/PR group.

Table 5: Response rates: Study C211

Treatment outcome

T12(b.i.d.)/PR
N = 369
% (n/N)

T12(q8h)/PR
N = 371
% (n/N)

SVR12 74% (274/369) 73% (270/371)
Undetectable HCV RNA (target not detected) 
at week 4a

69% (256/369) 67% (250/371)

Undetectable HCV RNA (target not detected) 
at weeks 4 and 12

66% (244/369) 63% (234/371)

SVR in patients with undetectable HCV RNA 
(target not detected) at weeks 4 and 12

89% (218/244) 89% (209/234)

SVR in patients who did not have undetectable 
HCV RNA (target not detected) at weeks 4 
and 12

45% (56/125) 45% (61/137)

Patients without SVR 26% (95/369) 27% (101/371)
On-treatment virologic failureb 10% (38/369) 10% (36/371)
Relapsec 8% (23/300) 6% (19/293)
Otherd 9% (34/369) 12% (46/371)
T12(b.i.d.)/PR: INCIVO 1,125 mg twice daily for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks; 
T12(q8h)/PR: INCIVO 750 mg every 8 hours for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks
a

Patients with planned total treatment duration of 24 weeks.
b

On-treatment-virologic failure includes patients who met a protocol-defined virologic stopping rule and/or had viral 
breakthrough.

c
Relapse was defined as having less than 25 IU/ml at the planned end of treatment followed by HCV RNA ≥ 25 IU/ml 
at the last observation within the SVR follow-up visit window. The denominator when calculating the relapse rate 
represents the number of patients with end-of-treatment response (HCV RNA < 25 IU/ml).

d
Other includes patients with detectable HCV RNA at the planned end of treatment but who did not have viral 
breakthrough, and patients with a missing SVR assessment during planned follow-up.

Table 6 shows SVR rates by IL28B genotype and the stage of liver fibrosis at baseline.

Table 6: SVR rates for patient subgroups: Study C211
Subgroup T12(b.i.d.)/PR

N = 369
% (n/N)

T12(q8h)/PR
N = 371
% (n/N)

IL28B genotype
CC 92% (97/105) 87% (92/106)
CT 67% (139/206) 68% (141/208)
TT 66% (38/58) 65% (37/57)

Baseline liver fibrosis
No fibrosis or minimal fibrosis 80% (138/172) 79% (140/177)

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Portal fibrosis 79% (75/95) 80% (68/85)
Bridging fibrosis 67% (32/48) 64% (38/59)
Cirrhosis 54% (29/54) 49% (24/49)

T12(b.i.d.)/PR: INCIVO 1,125 mg twice daily for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks;
T12(q8h)/PR: INCIVO 750 mg every 8 hours for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks 

Study 108 (ADVANCE)
Study 108 was a randomised, double-blind, parallel-group, placebo-controlled, Phase 3 study 
conducted in treatment-naïve patients. INCIVO was given for the first 8 weeks of treatment (T8/PR 
regimen) or the first 12 weeks of treatment (T12/PR regimen) in combination with peginterferon 
alfa-2a and ribavirin for either 24 or 48 weeks. Patients who had undetectable HCV RNA (target not 
detected) at weeks 4 and 12 received 24 weeks of peginterferon alfa-2a and ribavirin treatment, and 
patients who did not have undetectable HCV RNA (target not detected) at week 4 and week 12 
received 48 weeks of peginterferon alfa-2a and ribavirin treatment. The control regimen (Pbo/PR) had 
a fixed treatment duration of 48 weeks, with telaprevir-matching placebo for the first 12 weeks and 
peginterferon alfa-2a and ribavirin for 48 weeks.

The 1,088 enrolled patients had a median age of 49 years (range: 18 to 69); 58% of the patients were 
male; 23% had a body mass index ≥ 30 kg/m2; 9% were Black; 11% were Hispanic or Latino; 77% 
had baseline HCV RNA levels ≥ 800,000 IU/ml; 15% had bridging fibrosis; 6% had cirrhosis; 59% 
had HCV genotype 1a; and 40% had HCV genotype 1b.

The SVR rate for the T8/PR group was 72% (261/364) (P < 0.0001 compared to Pbo/PR48 group). 
Table 7 shows the response rates for the recommended T12/PR and the Pbo/PR48 groups.

Table 7: Response rates: Study 108

Treatment outcome

T12/PR
N = 363
n/N (%)

Pbo/PR48
N = 361
n/N (%)

SVRa
79% (285/363)
(74%, 83%)b

46% (166/361)
(41%, 51%)b

Undetectable HCV RNA (target not detected) at 
weeks 4 and 12 (eRVR) 58% (212/363) 8% (29/361)

SVR in eRVR patients 92% (195/212) 93% (27/29)

No eRVR 42% (151/363) 92% (332/361)
SVR in no eRVR patients 60% (90/151) 42% (139/332)

HCV RNA < 25 IU/ml at End of Treatment 82% (299/363) 62% (225/361)

Relapse 4% (13/299) 26% (58/225)

T12/PR: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks;
Pbo/PR: placebo for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks
a

P < 0.0001; T12/PR compared to Pbo/PR48. The difference in SVR rates (95% confidence interval) between the 
T12/PR and Pbo/PR groups was 33 (26, 39).

b
95% confidence interval

SVR rates were higher (absolute difference of at least 28%) for the T12/PR group than for the 
Pbo/PR48 group across subgroups by sex, age, race, ethnicity, body mass index, HCV genotype 
subtype, baseline HCV RNA (< 800,000, ≥ 800,000 IU/ml), and extent of liver fibrosis. Table 8 
shows SVR rates for patient subgroups.

Table 8: SVR rates for patient subgroups: Study 108
Subgroup T12/PR Pbo/PR
Men 78% (166/214) 46% (97/211)
45 to ≤ 65 years of age 73% (157/214) 39% (85/216)
Black 62% (16/26) 29% (8/28)
Hispanic Latino 77% (27/35) 39% (15/38)

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BMI ≥ 30 kg/m2 73% (56/77) 44% (38/87)
Baseline HCV RNA ≥ 800,000 IU/ml 77% (215/281) 39% (109/279)
HCV genotype 1a 75% (162/217) 43% (90/210)
HCV genotype 1b 84% (119/142) 51% (76/149)
Baseline liver fibrosis

No fibrosis, minimal fibrosis, or portal 
fibrosis

82% (237/290) 49% (140/288)

Bridging fibrosis 63% (33/52) 35% (18/52)
Cirrhosis 71% (15/21) 38% (8/21)

T12/PR: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 24 or 48 weeks;
Pbo/PR: placebo for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks

Study 111 (ILLUMINATE)
Study 111 was a Phase 3, randomised, open label study conducted in treatment-naïve patients. The 
study was designed to compare SVR rates in patients with undetectable HCV RNA ( target not 
detected) at weeks 4 and 12 who were treated with INCIVO for 12 weeks in combination with 
peginterferon alfa-2a and ribavirin for either 24 weeks (T12/PR24 regimen) or 48 weeks 
(T12/PR48 regimen). Patients with undetectable HCV RNA ( target not detected) at weeks 4 and 12 
were randomised at week 20 to receive either 24 weeks or 48 weeks of peginterferon alfa-2a and 
ribavirin treatment. The primary assessment was an evaluation of non-inferiority, using a margin of 
-10.5% of the 24-week regimen compared to the 48-week regimen in patients with undetectable 
HCV RNA (target not detected) at weeks 4 and 12.

The 540 enrolled patients had a median age of 51 years (range: 19 to 70); 60% of the patients were 
male; 32% had a body mass index ≥ 30 kg/m2; 14% were Black; 10% were Hispanic or Latino; 82% 
had baseline HCV RNA levels > 800,000 IU/ml; 16% had bridging fibrosis; 11% had cirrhosis; 72% 
had HCV genotype 1a; and 27% had HCV genotype 1b.

A total of 352 (65%) patients had undetectable HCV RNA (target not detected) at weeks 4 and 12. 
Table 9 shows response rates. In patients who had undetectable HCV RNA (target not detected) at 
weeks 4 and 12, there was no additional benefit to extending peginterferon alfa-2a and ribavirin 
treatment to 48 weeks (difference in SVR rates of 2%; 95% confidence interval: -4%, 8%).

Table 9: Response rates: Study 111
Patients with undetectable 

HCV RNA (target not detected) at 
weeks 4 and 12

T12/PR
All Patientsa

N=540
Treatment outcome

T12/PR24
N = 162

T12/PR48
N = 160

SVR 92% (149/162)
(87%, 96%)b

90% (144/160)
(84%, 94%)b

74% (398/540)
(70%, 77%)b

HCV RNA < 25 IU/ml at End of 
Treatment

98% (159/162) 93% (149/160) 79% (424/540)

Relapse 6% (10/159) 1% (2/149) 4% (19/424)

T12/PR24: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 24 weeks;
T12/PR48: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks
a

All patients includes the 322 patients with undetectable HCV RNA (target not detected) at weeks 4 and 12 and the 
218 other patients treated in the study (118 who did not have undetectable HCV RNA (target not detected) at week 4 
and 12 and 100 who discontinued the study before week 20, when randomisation occurred).

b
95% confidence interval

The SVR rate for Black patients was 62% (45/73). Table 10 shows SVR rates by extent of liver 
fibrosis at baseline.

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Table 10: SVR rates by extent of liver fibrosis at baseline: Study 111

Subgroup

Patients with undetectable 
HCV RNA (target not detected) at 

weeks 4 and 12
T12/PR

All Patientsa

T12/PR24 T12/PR48
No fibrosis, minimal fibrosis, or 
portal fibrosis

96% (119/124) 91% (115/127) 77% (302/391)

Bridging fibrosis 95% (19/20) 86% (18/21) 74% (65/88)
Cirrhosis 61% (11/18) 92% (11/12) 51% (31/61)

T12/PR24: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 24 weeks;
T12/PR48: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks
a

All patients includes the 322 patients with undetectable HCV RNA (target not detected) at weeks 4 and 12 and the 
218 other patients treated in the study (118 who did not have undetectable HCV RNA (target not detected) at weeks 4 
and 12 and 100 who discontinued the study before week 20, when randomisation occurred)

Efficacy in previously treated adults
Study C216 (REALIZE)
Study C216 was a randomised, double-blind, placebo-controlled, Phase 3 study conducted in patients
who did not achieve SVR with prior treatment with peginterferon alfa-2a and ribavirin or 
peginterferon alfa-2b and ribavirin. The study enrolled prior relapsers (patients with HCV RNA 
undetectable at end of treatment with a pegylated interferon-based regimen, but HCV RNA detectable 
within 24 weeks of treatment follow-up) and prior non-responders (patients who did not have 
undetectable HCV RNA levels during or at the end of a prior course of at least 12 weeks of 
treatment). The non-responder-population was comprised of 2 subgroups: prior partial responders 
(greater than or equal to 2 log10 reduction in HCV RNA at week 12, but not achieving HCV RNA 
undetectable at end of treatment with a peginterferon and ribavirin) and prior null responders (less 
than 2 log10 reduction in HCV RNA at week 12 of prior treatment with peginterferon and ribavirin).

Patients were randomised in a 2:2:1 ratio to one of three treatment groups: simultaneous start 
(T12/PR48): INCIVO from day 1 through week 12; delayed start (T12(DS)/PR48): INCIVO from 
week 5 through week 16; Pbo/PR48: placebo through week 16. All treatment regimens had a 48-week 
duration of peginterferon alfa-2a and ribavirin treatment.

The 662 enrolled patients had a median age of 51 years (range: 21 to 70); 70% of the patients were 
male; 26% had a body mass index ≥ 30 kg/m2; 5% were Black; 11% were Hispanic or Latino; 89% 
had baseline HCV RNA levels > 800,000 IU/ml; 22% had bridging fibrosis; 26% had cirrhosis; 54% 
had HCV genotype 1a; and 46% had HCV genotype 1b.

SVR rates for the T12(DS)/PR group were 88% (124/141) for prior relapsers, 56% (27/48) for prior 
partial responders, and 33% (25/75) for prior null responders. Table 11 shows the response rates for 
the recommended simultaneous start (T12/PR48) and the Pbo/PR48 arms.

Table 11: Response rates: Study C216

Treatment outcome
T12/PR48
% (n/N)

Pbo/PR48
% (n/N)

SVR
Prior relapsersa 84% (122/145)

(77%, 90%)b
22% (15/68)
(13%, 34%)b

Prior partial respondersa 61% (30/49)
(46%, 75%)b

15% (4/27)
(4%, 34%)b

Prior null respondersa 31% (22/72)
(20%, 43%)b

5% (2/37)
(1%, 18%)b

HCV RNA < 25 IU/ml at End of 
Treatment
Prior relapsers 87% (126/145) 63% (43/68)

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Prior partial responders 73% (36/49) 15% (4/27)
Prior null responders 39% (28/72) 11% (4/37)

Relapse
Prior relapsers 3% (4/126) 63% (27/43)
Prior partial responders 17% (6/36) 0% (0/4)
Prior null responders 21% (6/28) 50% (2/4)

T12/PR48: INCIVO for 12 weeks followed by placebo for 4 weeks, in combination with peginterferon alfa-2a and 
ribavirin for 48 weeks;
Pbo/PR48: placebo for 16 weeks in combination with peginterferon alfa-2a and ribavirin for 48 weeks
a

P < 0.001, T12/PR compared to Pbo/PR48. The difference in SVR rates (95% confidence interval) between the 
T12/PR and Pbo/PR groups were 63 (51, 74) for prior relapsers, 46 (27, 66) for prior partial responders, and 26 (13, 
39) for prior null responders.

b
95% confidence interval

For all populations in the study (prior relapsers, prior partial responders, and prior null responders), 
SVR rates were higher for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, 
age, race, ethnicity, body mass index, HCV genotype subtype, baseline HCV RNA level, and extent of 
liver fibrosis. Table 12 shows SVR rates by extent of liver fibrosis.

Table 12: SVR rates by extent of liver fibrosis at baseline: Study C216
Extent of liver fibrosis T12/PR Pbo/PR48
Prior relapsers

No or minimal fibrosis or portal fibrosis 84% (68/81) 32% (12/38)
Bridging fibrosis 86% (31/36) 13% (2/15)
Cirrhosis 82% (23/28) 7% (1/15)

Prior partial responders
No or minimal fibrosis or portal fibrosis 79% (19/24) 18% (3/17)
Bridging fibrosis 71% (5/7) 0 (0/5)
Cirrhosis 33% (6/18) 20% (1/5)

Prior null responders
No or minimal fibrosis or portal fibrosis 31% (9/29) 6% (1/18)
Bridging fibrosis 47% (8/17) 0 (0/9)
Cirrhosis 19% (5/26) 10% (1/10)

T12/PR48: INCIVO for 12 weeks followed by placebo for 4 weeks, in combination with peginterferon alfa-2a and 
ribavirin for 48 weeks;
Pbo/PR48: placebo for 16 weeks in combination with peginterferon alfa-2a and ribavirin for 48 weeks

Table 13 shows the SVR rates by week 4 response (< 1 log10 or ≥ 1 log10 reduction in HCV RNA) for 
prior partial responders and for prior null responders in the T12(DS)/PR group.

Table 13: SVR rates by week 4 response (< 1 log10 or ≥ 1 log10 reduction) in the T12(DS)/PR48 
group: Study C216

Prior Treatment Response

T12(DS)/PR
% (n/N)a

< 1 log10 reduction in HCV 
RNA at week 4

≥ 1 log10 reduction in HCV 
RNA at week 4

Prior partial responders 56% (10/18) 63% (17/27)
Prior null responders 15% (6/41) 54% (15/28)
a

only includes data on patients who had week 4 HCV RNA available

Study 106 and Study 107
Study 106 was a randomised, double-blind, placebo-controlled, Phase 2 study that enrolled patients 
who had failed prior treatment with peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and 
ribavirin. Among prior relapsers in the T12/PR24 treatment group who had undetectable HCV RNA 

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(target not detected) at weeks 4 and 12 of treatment, the SVR rate was 89% (25/28) and the relapse 
rate was 7%.

Study 107 was an open label, rollover study for patients who were treated in the control group 
(placebo, peginterferon alfa-2a, and ribavirin) of a Phase 2 study of telaprevir and who did not 
achieve SVR in the Phase 2 study. Among prior relapsers in the T12/PR24 treatment group who had 
undetectable HCV RNA (target not detected) at week 4 and 12 of treatment, the SVR rate was 100% 
(24/24).

Use of peginterferon alfa 2a or 2b
Two types of peginterferon alfa (2a and 2b) were studied in the Phase 2a open label, randomised 
study C208 in treatment-naïve patients.
All patients received 12 weeks of INCIVO in combination with the peginterferon alfa/ribavirin 
standard therapy. Patients were randomised to 1 of 4 treatment groups:
- INCIVO 750 mg every 8 hours with peginterferon alfa-2a 180 g/week and ribavirin 

1,000 or 1,200 mg/day
- INCIVO 750 mg every 8 hours with peginterferon alfa-2b 1.5 g/kg/week and ribavirin 

800 or 1,200 mg/day
- INCIVO 1,125 mg every 12 hours with peginterferon alfa-2a 180 g/week and ribavirin 

1,000 or 1,200 mg/day
- INCIVO 1,125 mg every 12 hours with peginterferon alfa-2b 1.5 g/kg/week and ribavirin 

800 or 1,200 mg/day
Peginterferon alfa-2a/peginterferon alfa-2b and ribavirin were used according to their relevant 
Summary of Product Characteristics. At week 12, INCIVO dosing ended and patients continued on 
standard therapy only. 73.8% (59/80) of patients in the pooled peginterferon alfa-2a group met the 
criteria (undetectable HCV RNA (target not detected) at week 4 through week 20) for the shortened 
24 week peginterferon/ribavirin treatment duration versus 61.7% (50/81) of patients in the pooled 
peginterferon alfa-2b group.

Table 14: Pooled response rates: Study C208

Treatment outcome

T12P(2a)R48
N = 80

(%) n/N

T12P(2b)R48
N = 81

(%) n/N
SVRa 83.8 (67/80) 81.5 (66/81)

Viral breakthrough 5 (4/80) 12.3 (10/81)

Relapse 8.1 (6/74b) 4.2 (3/71b)
T12/P(2a)R48: INCIVO for 12 weeks in combination with peginterferon alfa-2a and ribavirin for 24 or 48 weeks
T12/P(2b)R48: INCIVO for 12 weeks in combination with peginterferon alfa-2b and ribavirin for 24 or 48 weeks
a

95% confidence interval for the difference was (-10.8, 12.1)
b

Denominator was the number of patients with undetectable HCV RNA (target not detected) at end of treatment

Long-term efficacy data
Study 112 (EXTEND)
A 3-year follow-up study of patients who achieved SVR with an INCIVO-based regimen showed that 
> 99% (122/123) of patients maintained their SVR status through the available follow-up period 
(median duration of 22 months).

Efficacy in adults with HCV/HIV-1 co-infection
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 

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combination with atazanavir/ritonavir, tenofovir disoproxil fumarate, and emtricitabine or lamivudine 
OR 1,125 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%) patients had bridging fibrosis 
and 2 (5%) patients had cirrhosis in the T12/PR48 arm. In the Pbo/PR arm, 2 (9%) patients had 
baseline bridging fibrosis and no patients had baseline cirrhosis. Table 15 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 15: Response Rates: Study 110

Treatment Outcome
T12/PR48
% (n/N)

Pbo/PR
% (n/N)

Overall SVR12 ratea 74% (28/38) 45% (10/22)
Patients on an efavirenz-based regimen 69% (11/16) 50% (4/8)
Patients on an atazanavir/ritonavir-based 
regimen

80% (12/15) 50% (4/8)

Patients not receiving antiretroviral 
therapy

71% (5/7) 33% (2/6)

T12/PR48: INCIVO for 12 weeks with peginterferon alfa-2a and ribavirin for 48 weeks; Pbo/PR: placebo for 12 weeks 
with peginterferon alfa-2a and ribavirin for 48 weeks
a

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

Study HPC3008
Study HPC3008 was an open-label, Phase 3b study conducted in patients with chronic genotype 1 
HCV/HIV-1 co-infection who were treatment-naïve for hepatitis C or who did not achieve SVR with
prior treatment with peginterferon alfa (2a or 2b) and ribavirin (including prior relapsers, prior partial 
responders and prior null responders). Patients were required to have an HIV-1 RNA < 50 copies/ml 
and CD4 count > 300 cells/mm3 at screening. Patients received INCIVO at a dosage of 750 mg every 
8 hours, except for patients on an efavirenz-based regimen who received INCIVO at a dosage of 
1,125 mg every 8 hours. Treatment-naive patients or prior relapsers who were non-cirrhotic and 
achieved extended rapid virologic response (eRVR) received 12 weeks of treatment with INCIVO 
plus peginterferon alfa-2a and ribavirin followed by 12 weeks of treatment with peginterferon alfa-2a 
and ribavirin (total treatment duration of 24 weeks). Treatment-naive patients and prior relapsers who 
did not achieve eRVR, prior partial responders, prior null responders, and all cirrhotic patients 
received 12 weeks of treatment with INCIVO plus peginterferon alfa-2a and ribavirin followed by 
36 weeks of treatment with peginterferon alfa-2a and ribavirin (total treatment duration of 48 weeks). 
All patients received ribavirin at a fixed dose of 800 mg/day. Antiretroviral therapy regimens included 
efavirenz, atazanavir/ritonavir, raltegravir, etravirine, or darunavir/ritonavir in combination with 
tenofovir or abacavir and either lamivudine or emtricitabine.

The primary objective of the study was to assess the antiviral efficacy of INCIVO, peginterferon 
alfa-2a, and ribavirin in HCV/HIV-1 co-infected patients as measured by SVR12.

The 162 enrolled patients had a median age of 46 years (range: 20 to 67 years); 78.4% of the patients 
were male; 6.8% had a body mass index ≥ 30 kg/m2; 4.3% were Black; 1.9% were Asian; 87.0% had 
baseline HCV RNA levels ≥ 800,000 IU/ml; 17.3% had bridging fibrosis; 13.0% had cirrhosis; 65.6% 
had HCV genotype 1a; 33.8% had HCV genotype 1b; 39.5% (n = 64) were HCV treatment-naïve;
17.9% (n = 29) were prior relapsers; 11.1% (n = 18) were prior partial responders; 31.5% (n = 51) 
were prior null responders. Median (range) CD4 cell count at baseline was 
651 (277 to 1,551 cells/mm3).

Table 16 shows the response rates in treatment-naïve patients and in treatment-experienced patients 
by subgroup (treatment-naïve, prior relapsers and prior non-responders).

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Table 16: Treatment outcome in adult patients with genotype 1 HCV infection and HIV-1 
co-infection in Study HPC3008)

Treatment-Experienced Patients by Subgroup
Treatment Outcome Treatment-Naïve 

Patients
N = 64

% (n/N)

Prior Relapsers
N = 29

% (n/N)

Prior 
Non-respondersa

N = 69
% (n/N)

SVR12 64.1% (41/64) 62.1% (18/29) 49.3% (34/69)
Undetectable HCV RNA 
(target not detected) at 
weeks 4 and 12

57.8% (37/64) 48.3% (14/29) 42.0% (29/69)

SVR in patients with 
undetectable HCV RNA 
(target not detected) at 
weeks 4 and 12

83.8% (31/37) 92.9% (13/14) 89.7% (26/29)

SVR in patients who did 
not have undetectable 
HCV RNA (target not 
detected) at weeks 4 
and 12

37.0% (10/27) 33.3% (5/15) 20.0% (8/40)

SVR rates for patients with or without cirrhosis
Patients without cirrhosis 65.5% (38/58) 61.5% (16/26) 52.6% (30/57)
Patients with cirrhosis 50.0% (3/6) 66.7% (2/3) 33.3% (4/12)
Outcome for patients without SVR12
On-treatment virologic 
failureb

21.9% (14/64) 3.4% (1/29) 37.7% (26/69)

Relapsec 8.9% (4/45) 5.3% (1/19) 8.1% (3/37)
Otherd 7.8% (5/64) 31.0% (9/29) 8.7% (6/69)
a

Prior non-responders includes prior partial responders and prior null responders.
b

On-treatment virologic failure was defined as meeting a virologic stopping rule and/or having viral breakthrough.
c

Relapse was defined as having HCV RNA ≥ 25 IU/ml during the follow-up period after previous HCV RNA 
< 25 IU/ml at planned end of treatment and not achieving SVR12.

d
Other includes patients with detectable HCV RNA at their actual end of treatment but who did not have viral 
breakthrough, and patients with a missing HCV RNA assessment during planned follow-up.

Liver transplant recipients
Study HPC3006 was an open-label, Phase 3b study in treatment- naïve and treatment-experienced 
chronic genotype 1 HCV- infected patients who were first time liver transplant recipients and were on 
a stable regimen of the immunosuppressants tacrolimus or cyclosporine A. No patients had cirrhosis 
of the liver graft. Patients received INCIVO at a dosage of 750 mg every 8 hours. All patients started 
with a dose of 600 mg/day of ribavirin and 180 µg/week of peginterferon alfa-2a. All patients 
received 12 weeks of treatment with INCIVO plus peginterferon alfa-2a and ribavirin followed by 
36 weeks of treatment with peginterferon alfa-2a and ribavirin (total treatment duration of 48 weeks).

The primary objective of the study was to assess the antiviral efficacy of INCIVO, peginterferon 
alfa-2a, and ribavirin in HCV-infected liver transplant recipients as measured by SVR12.

The 74 enrolled patients had a median age of 56 years (range: 43 to 68 years); 91.9% of the patients 
were male; 24.3% had a body mass index ≥ 30 kg/m2; 1.4% were Black; 95.9% had baseline HCV 
RNA levels ≥ 800,000 IU/ml; 10.8% had bridging fibrosis; none had cirrhosis; 38.9% had HCV 
genotype 1a; 58.3% had HCV genotype 1b; 2.8% had HCV genotype 1d; 21.6% had IL28B 
genotype CC; 54.1% had IL28B genotype CT; 24.3% had IL28B genotype TT; 28.4% (n = 21) were 
HCV treatment- naïve; 71.6% (n = 53) were treatment-experienced [14.9% (n = 11) were prior 
relapsers; 40.5% (n = 30) were prior non-responders; 16.2% (n = 12) could not be classified]; median 
time since liver transplantation was 2.5 years (range: 0.6 to 9.5 years); 67.6% (n = 50) received 
tacrolimus; 32.4% (n = 24) received cyclosporine A.

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Table 17 shows the overall response rates in treatment- naïve and treatment-experienced chronic 
genotype 1 HCV- infected liver transplant recipients and by subgroup (patients receiving tacrolimus 
or cyclosporine A).

Table 17: Treatment outcome in genotype 1 HCV-infected liver transplant recipients 
(Study HPC3006)
Treatment outcome Patients receiving 

tacrolimus
N = 50

% (n/N)

Patients receiving 
cyclosporine A

N = 24
% (n/N)

All patients
N = 74

% (n/N)

SVR12 66% (33/50) 83% (20/24) 72% (53/74)
Outcome for patients without SVR12
All patients

On-treatment virologic 
failurea

12% (6/50) 8% (2/24) 11% (8/74)

Relapseb 11% (4/37) 0 7% (4/56)
Otherc 14% (7/50) 8% (2/24) 12% (9/74)

a
On-treatment virologic failure was defined as meeting a virologic stopping rule or having viral breakthrough. Note 
that the virologic stopping rules taken into account in this treatment outcome analysis are actual stopping rules, i.e., 
those derived from disposition and exposure data, as opposed to mathematical stopping rules, i.e., derived from the 
HCV RNA data.

b
Relapse was defined as having detectable plasma HCV RNA from planned end of treatment onwards after previous 
HCV RNA < 25 IU/ml at planned end of HCV treatment, and not achieving SVR12. The denominator is the number 
of patients with HCV RNA < 25 IU/ml at planned end of treatment or a missing HCV RNA assessment at planned end 
of treatment and HCV RNA < 25 IU/ml during follow-up from planned end of treatment onwards.

c
Other includes patients with detectable HCV RNA at their actual end of treatment but who did not meet the definition 
of on-treatment virologic failure, and patients with a missing HCV RNA assessment during planned follow-up.

Clinical Studies Examining QT Interval
In two double-blind, randomised, placebo- and active-controlled studies conducted to evaluate the 
effect on the QT interval, telaprevir monotherapy at a dose of 750 mg every 8 hours was not 
associated with a clinically relevant effect on QTcF interval. In one of those studies, a telaprevir 
1,875 mg every 8 hours regimen was evaluated and the placebo-adjusted maximum mean increase in 
QTcF was 8.0 msec (90% CI: 5.1-10.9). Plasma concentrations with the telaprevir 1,875 mg every 
8 hours dose used in this trial were comparable to those observed in studies in HCV-infected patients 
who received telaprevir 750 mg every 8 hours in combination with peginterferon alfa-2a and ribavirin.

Paediatric population
No clinical studies have been performed in paediatric patients.

The European Medicines Agency has deferred the obligation to submit the results of studies with 
INCIVO in one or more subsets of the paediatric population in chronic hepatitis C (see section 4.2 for 
information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of telaprevir have been evaluated in healthy adult volunteers and in 
subjects with chronic HCV infection. Telaprevir can be administered orally with food as 375 mg
tablets, 1,125 mg twice daily (b.i.d.) for 12 weeks, in combination with peginterferon alfa and 
ribavirin. Alternatively, telaprevir can be administered orally with food as 375 mg tablets, 750 mg
every 8 hours (q8h) for 12 weeks, in combination with peginterferon alfa and ribavirin. Exposure to 
telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after 
administration of telaprevir alone.

Telaprevir exposure is comparable during co-administration with either peginterferon alfa-2a and 
ribavirin or peginterferon alfa-2b and ribavirin.

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Absorption
Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for 
absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are 
generally achieved after 4 – 5 hours. In vitro studies performed with human Caco-2 cells indicated 
that telaprevir is a substrate of P-glycoprotein (P-gp).

Telaprevir exposure was similar regardless of whether the total daily dose of 2,250 mg was 
administered as 750 mg every 8 hours (q8h) or 1,125 mg twice daily (b.i.d.). Based upon population 
pharmacokinetic modelling of telaprevir steady-state exposures, the Geometric Mean Least Square 
Ratios (90% CI) of 1,125 mg twice daily (b.i.d.) versus 750 mg every 8 hours (q8h) were 1.08 (1.02; 
1.13) for AUC24,ss, 0.878 (0.827; 0.930) for Ctrough,ss, and 1.18 (1.12;1.24) for Cmax,ss.

The exposure to telaprevir was increased by 20% when taken following a high-fat caloric meal (56 g 
fat, 928 kcal) compared to an intake following a standard normal caloric meal (21 g fat, 533 kcal). 
When compared to administration following a standard normal caloric meal, exposure (AUC)
decreased by 73% when telaprevir was taken on an empty stomach, by 26% following a low-calorie 
high-protein meal (9 g fat, 260 kcal), and by 39% following a low-calorie low-fat meal (3.6 g fat, 
249 kcal). Therefore, telaprevir should be taken with food.

Distribution
Telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to 
alpha 1-acid glycoprotein and albumin.

After oral administration, the typical apparent volume of distribution (Vd) was estimated to be 252 l, 
with an inter-individual variability of 72.2%.

Biotransformation
Telaprevir is extensively metabolised in the liver, involving hydrolysis, oxidation, and reduction. 
Multiple metabolites were detected in faeces, plasma, and urine. After repeated oral administration, 
R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent 
reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant 
metabolites of telaprevir.

CYP3A4 is partly responsible for the metabolism of telaprevir. Other enzymes are also involved in the 
metabolism such as aldo-ketoreductases and other proteolytic enzymes. Studies using recombinant
human CYP supersomes showed that telaprevir was a CYP3A4 inhibitor, and a time- and 
concentration-dependent inhibition of CYP3A4 by telaprevir was observed in human liver 
microsomes. No relevant inhibition by telaprevir of CYP1A2, CYP2A6, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6, and CYP2E1 isozymes was observed in vitro. No relevant induction 
by telaprevir of CYP1A2, CYP2B6, CYP2C, and CYP3A isozymes was observed in vitro. Based on 
the results of drug-drug clinical interaction studies (e.g., escitalopram, zolpidem, ethinylestradiol), 
induction of metabolic enzymes by telaprevir cannot be excluded.

In vitro studies demonstrated that telaprevir is not an inhibitor of UGT1A9 or UGT2B7. In vitro
studies with recombinant UGT1A3 suggested that telaprevir may inhibit this enzyme. The clinical 
relevance of this is uncertain as administration of telaprevir with a single dose of buprenorphine, a
partial UGT1A3 substrate, to healthy adult subjects did not result in increases in buprenorphine 
exposures. No relevant inhibition by telaprevir of alcohol dehydrogenase was observed in vitro. 
However, sufficiently high concentrations were not tested for intestinal inhibition to be excluded.

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 

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(e.g., CYP1A1, CYP1A2, BCRP, OATPs) regulated by the same nuclear receptors, the potential 
clinical impact is unknown.

Transporters
In vitro studies demonstrated that telaprevir is an inhibitor of OATP1B1 and OATP2B1.

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.

Elimination
Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of 
total radioactivity was recovered in faeces, urine and expired air within 96 hours post-dose. The 
median recovery of the administered radioactive dose was approximately 82% in the faeces, 9% in 
exhaled air and 1% in urine. The contribution of unchanged 14C – telaprevir and VRT-127394 towards 
total radioactivity recovered in faeces was 31.8% and 18.7%, respectively.

After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 l/h with an 
inter-individual variability of 27.2%. The mean elimination half-life after single-dose oral 
administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady-state, the 
effective half-life is about 9-11 hours.

Linearity/non-linearity
The exposure (AUC) to telaprevir increased slightly greater than proportionally to the dose after 
single-dose administration of 375 up to 1,875 mg with food, possibly due to saturation of metabolic 
pathways or efflux transporters.

An increase in dose from 750 mg every 8 hours to 1,875 mg every 8 hours in a multiple-dose study 
resulted in a less than proportional increase (i.e., about 40%) in telaprevir exposure.

Special populations
Paediatric population
Data in the paediatric population are currently not available.

Renal impairment
The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750 mg to 
HCV-negative subjects with severe renal impairment (CrCl < 30 ml/min). The mean telaprevir Cmax
and AUC were 10% and 21% greater, respectively, compared to healthy subjects (see section 4.2).

Hepatic impairment
Telaprevir is primarily metabolised in the liver. Steady-state exposure to telaprevir was 15% lower in 
subjects with mild hepatic impairment (Child-Pugh Class A, score 5-6) compared to healthy subjects. 
Steady-state exposure to telaprevir was 46% lower in subjects with moderate hepatic impairment 
(Child-Pugh Class B, score 7-9) compared to healthy subjects. Effect on unbound telaprevir 
concentrations is unknown (see sections 4.2 and 4.4).

Gender
The effect of subject gender on telaprevir pharmacokinetics was evaluated using population 
pharmacokinetics of data from Phase 2 and 3 studies of INCIVO. No relevant effect of gender was 
identified.

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Race
Population pharmacokinetic analysis of INCIVO in HCV-infected subjects indicated that the exposure 
to telaprevir was similar in Blacks/African-Americans and Caucasians.

Elderly
There is limited pharmacokinetic data on the use of INCIVO in HCV patients aged ≥ 65 years and no 
data in subjects > 70 years of age.

5.3 Preclinical safety data

Animal toxicology and/or pharmacology
In rats and dogs, telaprevir was associated with a reversible reduction of red blood cell parameters 
accompanied by a regenerative response. In both rats and dogs, AST/ALT elevations were observed in 
most studies, of which the increase in ALT in rats was not normalised after recovery. 
Histopathological findings in the liver were similar in both rat and dog studies, of which not all were 
fully resolved after recovery. In rats (but not in dogs), telaprevir caused degenerative changes in testes 
which were reversible and did not affect fertility. In general, exposure levels in relation to human 
values were low in animal pharmacology and toxicology studies.

Carcinogenesis and mutagenesis
Telaprevir has not been tested for its carcinogenic potential. Neither telaprevir nor its major 
metabolite caused damage to DNA when tested in the standard battery of mutagenesis assays, in the 
presence and absence of metabolic activation.

Impairment of fertility
Telaprevir had no effects on fertility or fecundity when evaluated in rats.

Embryo-fœtal development
Telaprevir readily crosses the placenta in both rat and mouse giving a foetal: maternal exposure of 
19 - 50%. Telaprevir did not have any teratogenic potential in rat or mouse. In a fertility and early 
embryonic development study in rats, an increase in non-viable conceptuses was observed. Dosing of 
the animals did not result in any exposure-margin when compared to human exposure.

Excretion into milk
When administered to lactating rats, levels of telaprevir and its major metabolite were higher in milk 
compared to those observed in plasma. Rat offspring exposed to telaprevir in utero showed normal 
body weight at birth. However, when fed via milk from telaprevir-treated dams, body weight gain of 
rat pups was lower than normal (likely due to taste aversion). After weaning, rat pup body weight gain 
returned to normal.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
hypromellose acetate succinate
calcium hydrogen phosphate (anhydrous)
microcrystalline cellulose
silica colloidal anhydrous
sodium lauryl sulphate
croscarmellose sodium
sodium stearyl fumarate

Tablet film-coat
polyvinyl alcohol

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macrogol
talc
titanium dioxide (E171)
iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not 
remove the desiccant.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle containing 42 film-coated tablets and fitted with 
polypropylene (PP) child resistant closure and induction seal liner. Desiccant (one pouch or two 
pouches) is added.

INCIVO is available in packs containing 1 bottle (total of 42 film-coated tablets) or 4 bottles (total of 
168 film-coated tablets).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/11/720/001 4-bottle pack
EU/1/11/720/002 1-bottle pack

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 September 2011

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10. DATE OF REVISION OF THE TEXT

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

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41

ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

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

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Janssen-Cilag S.p.A.
Via C. Janssen
IT-04100 Borgo San Michele
Latina, Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

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

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 
for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-
portal.

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

 Risk Management Plan (RMP)

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

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

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

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time.

 Additional risk minimisation measures

The Marketing Authorisation Holder shall agree to the format and content of the healthcare 
professional educational pack with the National Competent Authority prior to launch in the Member 
State.
The Marketing Authorisation Holder shall ensure that all physicians who are expected to prescribe or 
use INCIVO are provided with a healthcare professional educational pack containing the following:
 The Summary of Product Characteristics
 The Patient Information Leaflet
 The Physician Leaflet

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The Physician Leaflet should contain the following key elements:
 Rash and Severe Cutaneous Adverse Reactions safety data from Phases 2 and 3
 Incidence of rash and severe cutaneous reactions
 Grading and management of rash and severe cutaneous reactions, particularly with respect to 

criteria for the continuation or discontinuation of telaprevir and the other treatment 
components.

 Pictures of rash according to different grades

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (1-bottle pack)

1. NAME OF THE MEDICINAL PRODUCT

INCIVO 375 mg film-coated tablets
telaprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 375 mg of telaprevir.

3. LIST OF EXCIPIENTS

Contains sodium.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

42 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Swallow the tablets whole.

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER

EU/1/11/720/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

incivo 375 mg

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL (1-bottle pack)

1. NAME OF THE MEDICINAL PRODUCT

INCIVO 375 mg film-coated tablets
telaprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 375 mg of telaprevir.

3. LIST OF EXCIPIENTS

Contains sodium.

4. PHARMACEUTICAL FORM AND CONTENTS

42 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Swallow the tablets whole.

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Do not remove the desiccant.

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER

EU/1/11/720/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (4-bottle pack)

1. NAME OF THE MEDICINAL PRODUCT

INCIVO 375 mg film-coated tablets
telaprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 375 mg of telaprevir.

3. LIST OF EXCIPIENTS

Contains sodium.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

168 film-coated tablets (4 bottles containing 42 tablets each)
The bottles are not to be distributed individually.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Swallow the tablets whole.

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER

EU/1/11/720/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

incivo 375 mg

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL (4-bottle pack)

1. NAME OF THE MEDICINAL PRODUCT

INCIVO 375 mg film-coated tablets
telaprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 375 mg of telaprevir.

3. LIST OF EXCIPIENTS

Contains sodium.

4. PHARMACEUTICAL FORM AND CONTENTS

42 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Swallow the tablets whole.

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Do not remove the desiccant.

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER

EU/1/11/720/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

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B. PACKAGE LEAFLET

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Package leaflet: Information for the user

INCIVO 375 mg film-coated tablets
telaprevir

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

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

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

effects not listed in this leaflet. See section 4.

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

1. What INCIVO is and what it is used for

INCIVO acts against the virus that causes hepatitis C infection and is used to treat chronic hepatitis C 
infection in adult patients (aged 18–65 years) in combination with peginterferon alfa and ribavirin. 
INCIVO contains a substance called telaprevir and belongs to a group of medicines called ‘NS3-4A 
protease inhibitors’. The NS3-4A protease inhibitor reduces the amount of hepatitis C virus in your 
body. INCIVO must not be taken alone and must be taken in combination with peginterferon alfa and 
ribavirin to be sure your treatment works. INCIVO can be used for patients with chronic hepatitis C 
infection who have never been treated before or can be used in patients with chronic hepatitis C 
infection who have been treated previously with an interferon-based regimen.

2. What you need to know before you take INCIVO

Do not take INCIVO if you are allergic to telaprevir or any of the other ingredients of this medicine
(listed in section 6).

See the package leaflets for peginterferon alfa and ribavirin for a list of their contraindications (e.g. 
pregnancy precautions for men and women) since INCIVO must be used in combination with 
peginterferon alfa and ribavirin. Ask your doctor if you are unsure about any contraindications 
mentioned in the package leaflets.

Do not use INCIVO in combination with any of the following medicines as they may increase the 
risk of severe side effects, and/or affect the way INCIVO or the other medicine works:

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Medicine (name of the active substance) Purpose of the medicine
alfuzosin to treat symptoms of an enlarged prostate 

(alpha-1-adrenoreceptor antagonists)

amiodarone, bepridil, quinidine, other Class Ia
or III antiarrhythmics

to treat certain heart disorders such as irregular 
heart beat (antiarrhythmics)

astemizole, terfenadine to treat allergy symptoms (antihistamines)

rifampicin to treat some infections like tuberculosis 
(antimycobacterial)

dihydroergotamine, ergonovine, ergotamine, 
methylergonovine

to treat migraine and headaches (ergot 
derivatives)

cisapride to treat some stomach conditions 
(gastrointestinal motility agents)

St John’s wort (Hypericum perforatum) an herbal product to relieve anxiety

atorvastatin, lovastatin, simvastatin to lower cholesterol levels (HMG CoA 
reductase inhibitors)

pimozide to treat psychiatric conditions (neuroleptics)

sildenafil, tadalafil Sildenafil or tadalafil must not be used to treat a 
heart and lung disorder called pulmonary 
arterial hypertension. There are other uses for 
sildenafil and tadalafil. Please see section ‘Other
medicines and INCIVO’.

quetiapine to treat schizophrenia, bipolar disorder and 
major depressive disorder

midazolam (taken by mouth), triazolam (taken 
by mouth)

to help you sleep and/or relieve anxiety 
(sedatives/hypnotics)

carbamazepine, phenobarbital, phenytoin to treat epileptic seizures (anticonvulsants)

If you are taking any of the above, ask your doctor about switching to another medicine.

Warnings and precautions
Talk to your doctor or pharmacist before taking INCIVO.

INCIVO must be taken in combination with peginterferon alfa and ribavirin. It is therefore very 
important that you read the package leaflets that are provided with these medicines, too. If you have 
any questions about your medicines, please ask your doctor or pharmacist.

Make sure that you check the following points and tell your doctor treating your hepatitis C virus 
(HCV) if any of these apply to you.

- Skin rash
Patients taking INCIVO may develop a skin rash. There may be itching with the rash. Usually 
the rash is mild or moderate, but the rash may be, or may become, severe and/or 
life-threatening. You should contact your doctor immediately if you develop a rash or have a 

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rash that gets worse. INCIVO must not be restarted if discontinued by your doctor. You must 
carefully read the information under Rash in section 4 Possible Side Effects.

- Anaemia (decrease in your red blood cells)
Tell your doctor if you experience tiredness, weakness, shortness of breath, light-headedness, 
and/or the feeling of the heart racing. These may be symptoms of anaemia.

- Heart problems
Tell your doctor if you have heart failure, irregular heartbeat, slow heart rate, an abnormality 
shown in your heart tracing (ECG) called ’long QT syndrome’, or a family history of a heart 
condition called ’congenital QT syndrome’.
Your doctor may request additional monitoring during your INCIVO treatment.

- Liver problems
Tell your doctor if you have had other problems with your liver such as liver failure. Signs 
might be yellowing of the skin or eyes (jaundice), swelling of the stomach (ascites) or legs due 
to fluid, and bleeding from swollen veins (varices) in the gullet (oesophagus). Your doctor may 
evaluate how severe your liver disease is before deciding if you can take INCIVO.

- Infections
Tell your doctor if you have an hepatitis B infection so that your doctor can decide if INCIVO 
is right for you.

- Organ transplant
Tell your doctor if you have had or are going to have a liver or other organ transplant as 
INCIVO might not be right for you in this situation.

Blood tests
Your doctor will do blood tests before starting treatment and regularly during your treatment:
- to see how much virus is in your blood and to determine if you have the type of virus 

(genotype 1) that can be treated with INCIVO. Decisions related to your treatment may be 
made based on the results of these tests. Your doctor will monitor your early response to 
treatment and how much virus is in your blood. If your treatment is not working, your doctor 
may stop your medicines. If your doctor stops INCIVO, it should not be restarted.

- to check if you have anaemia (decrease in your red blood cells).
- to check for changes in some values of your blood cells or chemistry. These can be seen in the 

results from blood tests. Your doctor will explain these to you. Examples are: blood count 
levels, thyroid (a gland in your neck that controls your metabolism) levels, liver and kidney 
tests.

INCIVO has only been used in a limited number of patients of 65 years or older. If you belong to this 
age group, please discuss the use of INCIVO with your doctor.

Children and adolescents
INCIVO is not for use in children or adolescents, because it has not been sufficiently studied in 
patients under 18 years of age.

Other medicines and INCIVO
INCIVO may affect other medicines or other medicines may affect INCIVO. Tell your doctor or 
pharmacist if you are taking, have recently taken or might take any other medicines.

Tell your doctor if you take any of the following medicines:

Medicine (name of the active substance) Purpose of the medicine
flecainide, propafenone to treat certain heart disorders such as irregular 

heart beat (antiarrhythmics)

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alfentanil, fentanyl to treat pain (analgesics) or used during surgery 
to induce sleep

digoxin, intravenous lidocaine to treat certain heart disorders such as abnormal 
heart beat (antiarrhythmics)

clarithromycin, erythromycin, telithromycin, 
troleandomycin

to treat bacterial infections (antibacterials)

warfarin, dabigatran to prevent blood clots (anticoagulants)
escitalopram, trazodone to treat mood disorders (antidepressants)
metformin to treat diabetes (antidiabetics)
domperidone to treat vomiting and nausea (antiemetics)
itraconazole, ketoconazole, posaconazole, 
voriconazole

to treat fungal infections (antifungals)

colchicine to treat inflammatory arthritis (anti-gout agents)
rifabutin to treat certain infections (antimycobacterials)
alprazolam, midazolam through injection to help you sleep and/or relieve anxiety 

(benzodiazepines)
zolpidem to help you sleep and/or relieve anxiety 

(non-benzodiazepine sedatives)
amlodipine, diltiazem, felodipine, nicardipine, 
nifedipine, nisoldipine, verapamil

to decrease blood pressure (calcium channel 
blockers)

maraviroc to treat HIV infections (CCR5 antagonist)
budesonide, inhaled/nasal fluticasone, 
dexamethasone if taken by mouth or through 
injection

to treat asthma or to treat inflammatory and 
autoimmune conditions (corticosteroids)

bosentan to treat a heart and lung disorder called 
pulmonary arterial hypertension (endothelin 
receptor antagonist)

atazanavir/ritonavir, darunavir/ritonavir, 
fosamprenavir/ritonavir, lopinavir/ritonavir

to treat HIV infections (HIV-protease inhibitors)

abacavir, efavirenz, tenofovir disoproxil 
fumarate, zidovudine

to treat HIV infections (reverse transcriptase 
inhibitors)

fluvastatin, pitavastatin, pravastatin, 
rosuvastatin

to lower cholesterol levels (HMG CoA 
reductase inhibitors)

all types of hormonal contraceptives (‘the pill’) hormonal contraceptives 
oestrogen-based medicines hormone replacement therapy
cyclosporine, sirolimus, tacrolimus to lower your immune system

(immunosuppressants), medicines used in some 
rheumatic diseases or to avoid problems with
organ transplants

salmeterol to improve breathing for asthma (inhaled beta 
agonists)

repaglinide to treat type II diabetes (blood glucose lowering 
medicine)

methadone for the treatment of opioid (narcotic) 
dependence

sildenafil, tadalafil, vardenafil to treat erectile dysfunction or to treat a heart 
and lung disorder called pulmonary arterial 
hypertension (PDE-5 inhibitors)

INCIVO with food and drink
INCIVO must always be taken together with food. The food is important to get the right levels of 
medicine in your body.

Pregnancy and breast-feeding
If you are pregnant, you must not take INCIVO. INCIVO must be used in combination with 

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peginterferon alfa and ribavirin. Ribavirin can damage your unborn baby. It is therefore absolutely 
essential that you take all precautions not to get pregnant during this therapy.

If you or your female partner become pregnant during INCIVO treatment or the months that follow, 
you must contact your doctor immediately (see section ’Pregnancy precautions for men and women’ 
below).

If you are breast-feeding, you must stop breast-feeding before starting to take INCIVO. It is not 
known whether telaprevir, the active ingredient in INCIVO, is found in human breast milk.

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy precautions for men and women
Since INCIVO must be used in combination with ribavirin and ribavirin can be very damaging to an 
unborn baby, both female and male patients must take special precautions in order to prevent 
pregnancy. Any birth control method can fail, and, therefore, you and your partner must use at least 
two effective birth control methods during INCIVO therapy and afterwards. Following the end of 
the INCIVO treatment, please see the ribavirin package leaflet regarding continued contraception 
requirements.

Female patients of childbearing age and their male partners
A hormonal contraceptive (‘the pill’) may not be reliable during the treatment with INCIVO. 
Therefore, you and your partner must use two other birth control methods during the time you are 
taking INCIVO and for 2 months after stopping this medicine.

You must read the package leaflets for peginterferon alfa and ribavirin for additional information.

Driving and using machines
Some patients may experience fainting or problems with vision during INCIVO treatment. Do not 
drive or operate machines if you feel faint or have problems with your vision while taking INCIVO.
See also the package leaflets for peginterferon alfa and ribavirin.

INCIVO contains sodium
This medicine contains 2.3 mg sodium per tablet, which should be taken into consideration by patients
on a controlled sodium diet. Tell your doctor if you have to take care of your salt intake and follow a 
low sodium diet.

3. How to take INCIVO

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.

Instructions for proper use
Your doctor will decide on the appropriate dose regimen for you.
The recommended dose regimen is:
- 3 tablets of INCIVO twice daily (morning and evening) with food. The total dose is 6 tablets 

per day,
or

- 2 tablets of INCIVO every 8 hours with food. The total dose is 6 tablets per day.

If you have both hepatitis C virus infection and human immunodeficiency virus infection, and are 
taking efavirenz, the recommended dose regimen is 3 tablets of INCIVO every 8 hours with food.

You must always take INCIVO with food as this is important to get the right levels of medicine in 
your body. You must not reduce your dose of INCIVO. Swallow the tablets whole. Do not chew, 

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break, or dissolve the tablets before you swallow them. Tell your health care provider if you have 
problems swallowing whole tablets.

Since INCIVO treatment always needs to be used together with peginterferon alfa and ribavirin, 
please also check the package leaflets for the dosage instructions of these medicines. If you need help, 
ask your doctor or pharmacist.

Take INCIVO with peginterferon alfa and ribavirin for 12 weeks. The total duration of treatment of 
peginterferon alfa and ribavirin varies from 24 to 48 weeks depending on treatment response and 
whether you have been treated before. Your doctor will measure blood levels of your virus at weeks 4 
and 12 to determine your treatment duration. The recommended total duration of treatment for 
patients who have received a liver transplant is 48 weeks. Please check with your doctor and follow 
the recommended duration of treatment.

If your doctor stops INCIVO because of side effects or because your treatment is not working, 
INCIVO should not be restarted.

Removing the child resistant cap

The plastic bottle comes with a child resistant cap and should be opened as 
follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more INCIVO than you should
Contact your doctor or pharmacist immediately to ask for advice.
In case of overdose you may experience nausea, headache, diarrhoea, decreased appetite, abnormal 
taste and vomiting.

If you forget to take INCIVO
If you are taking INCIVO twice daily (morning and evening)
If you notice the missed dose within 6 hours, you must take three tablets immediately. Always take 
the tablets with food. If you notice the missed dose after 6 hours, then skip the intake and take the 
next doses as usual. Do not take a double dose to make up for a forgotten dose.

If you are taking INCIVO every 8 hours
If you notice the missed dose within 4 hours, you must take two tablets immediately. Always take the 
tablets with food. If you notice the missed dose after 4 hours, then skip the intake and take the next 
doses as usual. Do not take a double dose to make up for a forgotten dose.

If you stop using INCIVO
Unless your doctor tells you to stop, continue taking INCIVO in order to ensure that your medicine 
continues to work against the virus. INCIVO must not be restarted if discontinued by your doctor.

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

4. Possible side effects

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

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Rash
Patients taking INCIVO frequently get an itchy skin rash. Usually the rash is mild or moderate, but the 
rash may be, or may become, severe and/or life-threatening. Rarely patients may have other symptoms 
with the rash that may be a sign of a severe skin reaction.

Contact your doctor immediately if you get a skin rash.

Also contact your doctor immediately:
- if your rash worsens, OR
- if you develop other symptoms with a rash such as:

- fever
- tiredness
- swelling of the face
- swelling of lymph glands, OR

- if you have a wide-spread rash with peeling skin which may be accompanied by fever, flu-like 
symptoms, painful skin blisters, and blisters in the mouth, eyes, and/or genitals.

Your doctor should check your rash to determine how to manage it. Your doctor may stop your 
treatment. INCIVO must not be restarted if discontinued by your doctor.

Contact your doctor immediately also if you develop any of the following symptoms:
- tiredness, weakness, shortness of breath, light-headedness, and/or feeling of heart racing. These 

may be symptoms of anaemia (decrease in your red blood cells);
- fainting;
- painful inflammation of the joints most commonly in the foot (gout);
- problems with your eyesight;
- bleeding from the anus;
- swelling of the face.

The frequency rate of the side effects associated with INCIVO is given below.

Very common side effects (affects more than 1 in 10 people):
- low red blood cell count (anaemia);
- nausea, diarrhoea, vomiting;
- swollen veins in the rectum or anus (haemorrhoids), pain in the anus or rectum;
- skin rash and itching of the skin.

Common side effects (affects less than 1 in 10 people):
- fungal infection in the mouth;
- low blood platelet count, decrease in lymphocytes (a type of white blood cell), decrease in 

thyroid gland activity, increase in uric acid in your blood, decrease in potassium in your blood, 
increase in bilirubin in your blood;

- change in taste;
- fainting;
- itching around or near the anus, bleeding around or near the anus or rectum, a small tear in the 

skin that lines the anus that may cause pain and/or bleeding during bowel movements;
- red, cracked, dry, scaly skin (eczema), rash with red, cracked, dry, scaly skin (exfoliative rash);
- swelling of the face, swelling of the arms and/or legs (oedema);
- abnormal product taste.

Uncommon side effects (affects less than 1 in 100 people):
- increase in creatinine in your blood;
- painful inflammation of the joints most commonly in the foot (gout);
- damage to back of the eye (retina);
- inflammation of the anus and rectum;
- inflamed pancreas

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- severe rash, which may be accompanied by fever, fatigue, swelling of the face or lymph glands, 
increase of eosinophils (type of white blood cells), effects on liver, kidney or lung (a reaction 
called DRESS);

- hives (urticaria)
- dehydration. Signs and symptoms of dehydration include increased thirst, dry mouth, decreased 

urine frequency or volume, and dark coloured urine. It is important to stay hydrated with fluids 
during INCIVO combination treatment.

Rare side effects (affects less than 1 in 1,000 people):
- a wide-spread severe rash with peeling skin which may be accompanied by fever, flu-like 

symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome).

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

See also the package leaflets for peginterferon alfa and ribavirin for side effects reported for these 
products.

5. How to store INCIVO

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month.

INCIVO tablets should be stored in the original bottle. Keep the bottle tightly closed in order to 
protect from moisture. Each bottle contains one pouch or two pouches of desiccant to keep the tablets 
dry. Do not remove this desiccant from the bottle. Do not eat the desiccant.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What INCIVO contains
The active substance is telaprevir. Each tablet of INCIVO contains 375 mg of telaprevir.
The other ingredients are:

Tablet core
hypromellose acetate succinate, calcium hydrogen phosphate (anhydrous), microcrystalline
cellulose, silica colloidal anhydrous, sodium lauryl sulphate, croscarmellose sodium, sodium 
stearyl fumarate

Tablet film-coat
polyvinyl alcohol, macrogol, talc, titanium dioxide (E171), iron oxide yellow (E172)

What INCIVO looks like and contents of the pack
Film-coated tablet. Yellow caplet-shaped tablets of approximately 20 mm in length, marked with 
‘T375’ on one side.
INCIVO is available in packs containing one bottle or 4 bottles per carton. Each bottle contains one
pouch or two pouches to keep the tablets dry (desiccant).
Not all pack-sizes may be marketed.

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


63

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

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

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

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

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

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

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

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

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

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

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

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

Nederland
Janssen-Cilag B.V.
Dr. Paul Janssenweg 150
NL-5026 RH Tilburg
Tel: +31 13 583 73 73

Eesti
Janssen-Cilag Polska Sp. z o.o. Eesti filiaal
Lõõtsa 2
EE-11415 Tallinn
Tel: +372 617 7410

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

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64

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

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

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

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

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

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

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

România
Johnson & Johnson România SRL
Str. Tipografilor nr. 11-15
Clădirea S-Park, Corp A2, Etaj 5
013714 Bucureşti, ROMÂNIA
Tel: +40 21 207 1800

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

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

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

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

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

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

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

Sverige
Janssen-Cilag AB
Box 7073
SE-192 07 Sollentuna
Tel: +46 8 626 50 00

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65

Latvija
Janssen-Cilag Polska Sp. z o.o. filiāle Latvijā
Mūkusalas iela 101
Rīga, LV-1004
Tel: +371 678 93561

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

This leaflet was last revised in {MM/YYYY}.

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu/.

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

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