NAME OF THE MEDICINE INCIVO(r)

Telaprevir The chemical name is (1S, 3aR, 6aS)-2-((S)-2-{(S)-2-Cyclohexyl-2- [(pyrazine-2-carbonyl)-amino] -acetylamino}-3,3-dimethyl-butyryl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid ((S)-1- cyclopropylaminooxalyl-butyl)-amide.

N

H O

N (S)

N

O

N (S)

H

(R)

N

O

(S)

(S)

O

H O H

N (S) N

O

Molecular Formula: C36H53N7O6 CAS: 402957-28-2 MW: 679.9

DESCRIPTION

The active ingredient telaprevir is an inhibitor of the Hepatitis C Virus (HCV) NS3 4A protease, an enzyme that is essential for HCV replication. Telaprevir drug substance is a white to off-white powder with a solubility in water of 0.0047 mg/mL INCIVO is available as yellow, caplet-shaped, film-coated tablets of approximately 20 mm in length, marked with "T375" on one side. The inactive ingredients are hypromellose acetate succinate, sodium lauryl sulfate, calcium hydrogen phosphate anhydrous, croscarmellose sodium, cellulose - microcrystalline, silicon dioxide, sodium stearyl fumarate, polyvinyl alcohol, macrogol 3350, talc - purified, titanium dioxide and iron oxide yellow.

PHARMACOLOGY

Pharmacotherapeutic group: Direct-acting antiviral.

Pharmacodynamics

Mechanism of Action

Telaprevir is a specific inhibitor of the HCV NS3 4A serine protease, which is essential for viral replication.

In vitro

studies

Activity of telaprevir against HCV

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

Resistance

HCV variants associated with on-treatment virologic failure or relapse were evaluated by

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site-directed mutagenesis in the replicon assay (see PHARMACOLOGY - Pharmacodynamics: Clinical Experience). 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 currently no clinical data on re-treating subjects who have failed an HCV NS3-4A protease inhibitor-based therapy, such as telaprevir, nor are there data on repeated courses of telaprevir treatment.

Pharmacokinetics

The pharmacokinetic properties of telaprevir have been evaluated in healthy adult volunteers and in subjects with chronic HCV infection. Telaprevir is to be administered orally with food as 750 mg (two film coated 375 mg tablets) every 8 hours 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.

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). 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

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reduction at the a-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir.

In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major CYP isoform responsible CYP-mediated for telaprevir metabolism. In vitro studies using recombinant aldo-ketoreductases indicated that these and potentially other reductases are also responsible for the reduction of telaprevir. Other proteolytic enzymes are also involved in the hydrolysis of telaprevir. 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 clinical drug-drug interaction studies, induction of metabolic enzymes 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.

Transporters

In vitro

studies demonstrated that telaprevir is an inhibitor of the organic anion transporting polypeptides (OATP) OATP1B1 and OATP2B1.

No relevant inhibition by telaprevir of the organic cation transporter (OCT) OCT2, or the organic anion transporter (OAT) OAT1 was observed in vitro.

Elimination:

Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of total radioactivitiy 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.

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

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Cmax and AUC were 10% and 21% greater, respectively, compared to healthy subjects (see DOSAGE AND ADMINISTRATION). 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 (see DOSAGE AND ADMINISTRATION). 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 dose adjustments are deemed necessary based on gender. Race: Population pharmacokinetic analysis of INCIVO in HCV-infected subjects indicated that race had no apparent effect on the exposure to telaprevir. Elderly: There is limited clinical data on the use of INCIVO in HCV patients aged >= 65 years.

Clinical trials

Clinical virology studies

In Phase 2 and 3 clinical trials of telaprevir, treatment-naive and prior treatment-failure subjects 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. A total of 215 of 1,169 subjects treated with a T12/PR regimen in a Phase 3 clinical trial had on-treatment virologic failure (n = 125) or relapse (n = 90) (see PHARMACOLOGY - Pharmacodynamics: Clinical Experience). Based on population sequencing analyses of HCV in these 215 subjects, 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%) subjects. 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). 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. Subjects with HCV genotype 1a predominately had V36M and R155K single and combination variants, while subjects 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 subjects treated with telaprevir, on-treatment virologic failure was more frequent in subjects with genotype 1a than with genotype 1b and more frequent in prior null responders than in other populations (treatment-naive, prior relapsers, prior partial responders; see PHARMACOLOGY - Pharmacodynamics: Clinical Experience, Efficacy in Previously Treated Adults). Follow-up analysis of INCIVO-treated subjects 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-naive and previously treated subjects from Phase 3 studies 108, 111, and C216 in whom telaprevir-resistant variants had emerged during treatment, 152 (60%) subjects no longer had resistant variants detected by population sequencing (median follow-up of 10 months). Of the

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393 resistant variants detected in the 255 subjects, 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 56 treatment-naive and prior treatment-failure subjects who were treated with a INCIVO regimen in a Phase 2 study and did not achieve SVR, telaprevir-resistant variants were no longer detected in 89% (50/56) of subjects (median follow-up of 25 months). Clonal sequencing analysis of a subset of subjects 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 subjects had returned to pre-treatment levels.

Clinical experience

The efficacy and safety of INCIVO in subjects with genotype 1 chronic hepatitis C were evaluated in three Phase 3 studies: 2 in treatment-naive subjects and 1 in previously treated subjects (relapsers, partial responders, and null responders). Subjects in these studies 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; the peginterferon alfa-2a dose was 180 ug/week, and the ribavirin dose was 1,000 mg/day (subjects weighing < 75 kg) or 1,200 mg/day (subjects weighing >= 75 kg). Plasma HCV RNA values were measured using the COBAS(r) TaqMan(r) 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 below, 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

Efficacy in treatment-naive adults

Study 108 (ADVANCE)

Study 108 was a randomised, double-blind, parallel-group, placebo-controlled, Phase 3 study conducted in treatment-naive subjects. 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. Subjects who had undetectable HCV RNA at weeks 4 and 12 received 24 weeks of peginterferon alfa-2a and ribavirin treatment, and subjects who did not have undetectable HCV RNA 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 subjects had a median age of 49 years (range: 18 to 69); 58% of the subjects 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 1 shows the response rates for the recommended T12/PR and the Pbo/PR48 groups.

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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, geographic region, HCV genotype subtype, baseline HCV RNA (< 800,000, >= 800,000 IU/ml), and extent of liver fibrosis. Table 2 shows SVR rates for subject subgroups.

Study 111 (ILLUMINATE)

Study 111 was a Phase 3, randomised, open label study conducted in treatment-naive subjects. The study was designed to compare SVR rates in subjects with undetectable HCV RNA 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). Subjects with undetectable HCV RNA 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 subjects with undetectable HCV RNA at weeks 4 and 12. The 540 enrolled subjects had a median age of 51 years (range: 19 to 70); 60% of the subjects 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%) subjects had undetectable HCV RNA at weeks 4 and 12. Table 3 shows response rates. In subjects who had undetectable HCV RNA at weeks 4 and 12, there was no

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additional benefit to extending peginterferon alfa-2a and ribavirin treatment to 48 weeks (difference in SVR rates of 2%; 95% confidence interval: -4%, 8%).

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 subjects includes the 322 subjects with undetectable HCV RNA at weeks 4 and 12 and the 218 other

subjects treated in the study (118 who did not have undetectable HCV RNA at week 4 and 12 and 100 who discontinued the study before week 20, when randomisation occurred).

b

On-treatment-virologic failure includes subjects who met a protocol-defined virologic stopping rule or who had detectable HCV RNA at the time of their last dose of study drug and 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.

d

Other includes subjects with detectable HCV RNA at the time of their last study drug but who did not have viral breakthrough, and subjects with a missing SVR assessment.

The SVR rate for Black subjects was 62% (45/73). Table 4 shows SVR rates by extent of liver fibrosis at baseline.

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 subjects includes the 322 subjects with undetectable HCV RNA at weeks 4 and 12 and the 218 other

subjects treated in the study (118 who did not have undetectable HCV RNA at weeks 4 and 12 and 100 who discontinued the study before week 20, when randomisation occurred)

Study 110

Study 110 was a Phase 2 randomised, double-blind, placebo-controlled study conducted in subjects with chronic genotype 1 HCV/HIV co-infection who were treatment-naive for hepatitis C. Subjects 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. Subjects were randomised to 12 weeks of INCIVO (750 mg every 8 hours if taken in combination with atazanavir/ritonavir, tenofovir disoproxil fumarate, and emtricitabine or lamivudine OR 1125 mg every 8 hours if taken in combination with efavirenz, tenofovir disoproxil fumarate, and emtricitabine) or placebo. All subjects received peginterferon alfa-2a and ribavirin for 48 weeks. Fifty-five out of 60 subjects received ribavirin at a fixed dose of 800 mg/day and the remaining 5 subjects received a weight-based ribavirin dose. Table 5 shows the response rates for the T12/PR48 and the Pbo/PR48 arms.

Table 5: Response Rates: Study 110

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Efficacy in previously treated adults

Study C216 (REALIZE)

Study C216 was a randomised, double-blind, placebo-controlled, Phase 3 study conducted in subjects 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 (subjects 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 (subjects 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 two 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). Subjects 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 subjects had a median age of 51 years (range: 21 to 70); 70% of the subjects 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 6 shows the response rates for the recommended simultaneous start (T12/PR48) and the Pbo/PR48 arms.

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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, age, body mass index, HCV genotype subtype, baseline HCV RNA level, and extent of liver fibrosis. Table 7 shows SVR rates by extent of liver fibrosis.

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Study 106 (PROVE 3) and Study 107

Study 106 was a randomised, double-blind, placebo-controlled, Phase 2 study that enrolled subjects 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 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 subjects who were treated in the control group (placebo, peginterferon alfa-2a, and ribavirin) of a Phase 2 study of INCIVO 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 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-naive subjects. All subjects received 12 weeks of INCIVO in combination with the peginterferon alfa/ribavirin standard therapy. Subjects 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 Prescribing Information. At Week 12, INCIVO dosing ended and subjects continued on standard therapy only. The percentage of subjects with SVR in the pooled peginterferon alfa-2a group was 83.8%, in the pooled peginterferon alfa-2b group 81.5% with a 95% confidence interval for the difference of (-10.8, 12.1)

Long-term efficacy data

Study 112 (EXTEND)

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

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.

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CONTRAINDICATIONS

Hypersensitivity to telaprevir or to any of the excipients. TELAPREVIR is a strong inhibitor of CYP3A. Concomitant administration of INCIVO 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 (narrow therapeutic index) is contraindicated. Concomitant administration of INCIVO with active substances that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVO is contraindicated. These active substances include alfuzosin, amiodarone, bepridil, carbamezapine, phenobarbital, phenytoin, flecainide, propafenone, quinidine, flecainide, propafenone, astemizole, terfenadine, cisapride, pimozide, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), rifampicin, St John's wort (Hypericum perforatum), lovastatin, simvastatin, atorvastatin, sildenafil or tadalafil (only when used for treatment of pulmonary arterial hypertension) and orally administered midazolam and triazolam. Concomitant administration of INCIVO with any Class I or III antiarrhythmics is contraindicated. Refer to the Product Information for peginterferon alfa and ribavirin for a list of their contraindications since INCIVO must be used in combination with peginterferon alfa and ribavirin.

PRECAUTIONS

Severe skin reactions and rash

Severe, potentially life-threatening, and fatal skin reactions, including toxic epidermal necrolysis (TEN), have been reported with INCIVO combination treatment (see ADVERSE EFFECTS). 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. 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 receiving peginterferon alfa and ribavirin. In placebo-controlled Phase 2 and 3 trials, 0.4% of patients had Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome). In clinical experience, less than 0.1% of patients had Stevens-Johnson Syndrome. All of these reactions resolved with treatment discontinuation.

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Mild to moderate rashes should be monitored for progression or systemic symptoms. For additional information on mild to moderate rash, see ADVERSE EFFECTS. If a severe rash (defined as involving more than 50% of body surface area) or associated with vesicles , bullae, ulcerations other than SJS) occurs, INCIVO must be discontinued immediately; 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. Patients should be monitored until the rash is resolved. Serious skin reactions including rash with systemic symptoms, progressive severe rash, generalsied bullous eruption, DRESS, SJS/TEN, acute generalised exanthematous pustulosis, and/or erythema multiforme require permanent and immediate disontinuation of TELAPREVIR, peginterferon alfa, and ribavirin. In the case of a serious skin reaction, discontinuation of other medicial products known to be associated with serious skin reactions should be considered. INCIVO must not be restarted if discontinued. Refer also to the Product Information 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. Hemoglobin 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. Hemoglobin values gradually improve after INCIVO dosing completion. Hemoglobin should be monitored at regular intervals prior to and during INCIVO combination treatment (see PRECAUTIONS: Laboratory tests). For the management of anaemia, refer to the Product Information for ribavirin for its dose reduction guidelines. 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.

Drug interactions

Refer to CONTRAINDICATIONS 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 PRECAUTIONS: Interactions with other medicines for established and other potentially significant drug-drug interactions.

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 PHARMACOLOGY: Pharmacodynamics). Exposure at this dose was comparable to the exposure in HCV-infected patients dosed at 750 mg INCIVO every 8 hours plus peginterferon alfa and ribavirin. The potential clinical significance of these findings is uncertain.

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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, vardenafil (see PRECAUTIONS: Interactions with other medicines). INCIVO co-administration with domperidone should be avoided (see PRECAUTIONS: Interactions with other medicines). INCIVO may increase concentrations of the co-administered medicinal product and this may result in an increased risk of their associated cardiac adverse events. In the event that co-administration of such medicinal products with INCIVO is judged strictly necessary, clinical monitoring including ECG assessments is recommended. See CONTRAINDICATIONS for medicinal products with a narrow therapeutic index 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 without a potential for significantly increased plasma concentrations due to CYP3A4 inhibition by telaprevir (e.g. methadone, see PRECAUTIONS: Interactions with other medicines).

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

General

INCIVO must not be administered as monotherapy and must only be prescribed in combination with both peginterferon alfa and ribavirin. The Product Information 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 PHARMACOLOGY - Pharmacodynamics) or on use of repeated courses of INCIVO.

Insufficient virologic response

In patients who have an inadequate viral response, treatment should be discontinued (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

Use of INCIVO in treatment of other HCV genotypes

There is 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.

Use in patients with hepatic impairment

INCIVO has not been studied in patients with severe hepatic impairment (Child-Pugh C, score >= 10) or decompensated liver disease and is not recommended in these populations. INCIVO has not been studied in patients with moderate hepatic impairment (Child-Pugh B, score 7-9). 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 DOSAGE AND ADMINISTRATION and PHARMACOLOGY - Pharmacokinetics).

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

Organ transplant patients

No clinical data are available regarding the treatment of pre-, peri-, or post-transplant patients with INCIVO in combination with peginterferon alfa and ribavirin. Therefore, the use of INCIVO in transplant candidates or patients is not recommended (see also PRECAUTIONS: Interactions with other medicines - Immunosuppressants).

HCV/HIV (human immunodeficiency virus) co-infection

INCIVO in combination with peginterferon alfa and ribavirin was evaluated in 60 HIV-infected, HCV treatment-naive subjects who were either not on antiretroviral therapy or were being treated with efavirenz or atazanavir/ritonavir (ATV/rtv) in combination with tenofovir disoproxil fumarate and emtricitabine or lamivudine (see INTERACTIONS WITH OTHER MEDICINES, ADVERSE EFFECTS and PHARMACOLOGY - Pharmacodynamics).

HCV/HBV (hepatitis B virus) co-infection

There are no data on the use of INCIVO in patients with HCV/HBV co-infection. Therefore, the use of INCIVO in HCV/HBV co-infected patients is not recommended.

Use in 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.

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.

Effects on fertility

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

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 rats, telaprevir caused degenerative changes in testes which were reversible and did not affect fertility.

Use in pregnancy (Category B2) and contraception requirements

INCIVO has shown no teratogenic potential in rats and mice and is not considered a developmental toxicant in these species. 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. As any birth control method can fail, at least 2 reliable forms of effective contraception must be used. Refer also to the Product Information for 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 treatment and for 4 months after all treatment has ended.

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Female patients:

INCIVO combination therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Pregnancy testing should occur monthly during INCIVO combination therapy and for 4 months after all therapy has stopped. Hormonal contraceptives may not be reliable during INCIVO dosing (see PRECAUTIONS: Interactions with other medicines). Therefore, female patients of childbearing potential should use 2 additional methods of effective birth control during INCIVO dosing and for 2 months after the last intake of INCIVO. Examples of non-hormonal methods of contraception include a male condom OR female condom (a combination of a male condom and a female condom is not suitable), a diaphragm with spermicidal jelly, or a cervical cap with spermicidal jelly. As of 2 months after completion of INCIVO treatment, hormonal contraceptives can again be used as one of the 2 required effective methods of birth control; however, specific Product Information recommendations should be respected. Refer also to the Product Information for ribavirin.

Male patients and their female partners:

Male patients and their female partners of childbearing potential must use 2 effective contraceptive methods during treatment and for 7 months after all treatment has ended. Men whose partners are pregnant must be instructed to use a condom to minimise exposure of ribavirin to the partner. Pregnancy testing in non-pregnant female partners is recommended before INCIVO combination therapy, every month during INCIVO combination therapy, and for 7 months after ribavirin therapy has ended. Refer also to the Product Information for ribavirin.

Use in lactation

It is not known whether telaprevir is excreted in human breast 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. Because of the potential for adverse reactions in breastfed infants, breast-feeding must be discontinued prior to initiation of therapy. See also the Product Information for ribavirin.

Laboratory tests

HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated. 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:

• Hemoglobin: >= 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

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

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Chemistry evaluations (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, TSH) are recommended as frequently as the haematology evaluations or as clinically indicated (see ADVERSE EFFECTS). Refer to the Product Information for peginterferon alfa and ribavirin, including pregnancy testing requirements (see PRECAUTIONS: Use in pregnancy and contraception requirements).

Carcinogenicity

Telaprevir has not been tested for its carcinogenic potential.

Genotoxicity

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.

Interactions with other medicines

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

In vitro

studies demonstrated that telaprevir is not a substrate for the organic anion transporter polypeptides (OATPs), OATP1B1 and OATP2B1, but is an inhibitor of these transporters.

Therefore, concomitant administration of TELAPREVIR and OATP substrates (e.g., fluvastatin, pravastatin, rosuvastatin, and repaglinide) should be undertaken with caution.

In vitro

studies evaluating in situ induction potential indicate that telaprevir is not an inducer of CYP1A2, CYP2B6, CYP2C, and CYP3A. However, based on the results of drug-drug interaction clinical studies, induction of metabolic enzymes by telaprevir cannot be excluded.

Interaction studies have only been performed in adults. Associations contraindicated (see also CONTRAINDICATIONS)

CYP3A substrates with a narrow therapeutic index

INCIVO must not be administered concurrently with medicinal products with a narrow therapeutic window that are substrates of cytochrome P450 3A (CYP3A). Co-administration of INCIVO may increase the plasma concentration of these medicinal products, which may lead to serious and/or life-threatening adverse reactions such as cardiac arrhythmia (i.e., amiodarone, astemizole, bepridil, cisapride, flecainide, pimozide, propafenone, quinidine, terfenadine), or peripheral vasospasm or ischemia (i.e., dihydroergotamine, ergonovine, ergotamine, methylergonovine), or myopathy, including rhabdomyolysis (i.e., lovastatin, simvastatin), or prolonged or increased sedation or respiratory depression (i.e., orally administered midazolam, triazolam), or hypotension or cardiac arrhythmia (i.e., alfuzosin, sildenafil, tadalfil for pulmonary arterial hypertension). INCIVO must not be administered concurrently with any Class I or III antiarrhythmics.

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)

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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 should not be combined with INCIVO. Carbamazepine, phenobarbital and phenytoin Co-administration with CYP3A inducers may lead to lower exposure of telaprevir with risk of lower efficacy. Potent CYP3A inducers, such as carbamazepine, phenobarbital and phenytoin, are contraindicated (see CONTRAINDICATIONS).

Other combinations

Table 8 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 events or loss of efficacy. 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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Paediatric population

Interaction studies have only been performed in adults.

Effect on ability to drive or operate machinery

INCIVO has no or negligible influence on the ability to drive and use machines. However, peginterferon alfa, which must be used in combination with INCIVO, may have an effect. Refer also to the Product Information for peginterferon alfa for further information.

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DOSAGE AND ADMINISTRATION

Treatment with INCIVO should be initiated and monitored by a physician experienced in the management of chronic hepatitis C. INCIVO, 750 mg (two 375 mg film-coated tablets) should be taken orally every 8 hours with food (the total daily dose is 6 tablets (2,250 mg)). Patients should be instructed to swallow the tablets whole (e.g., patients should not chew, break or dissolve the tablet). For specific dosage instructions for peginterferon alfa and ribavirin, consult the Product Information for these medicinal products.

Duration of treatment - Treatment-naive 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 HCV RNA 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 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 PHARMACOLOGY - Pharmacodynamics).

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

HCV RNA levels should be monitored at weeks 4 and 12 to determine treatment duration. In Phase 3 studies, the COBAS(r) TaqMan(r) test (version 2.0) was used to determine whether HCV RNA levels were undetectable (see PHARMACOLOGY - Pharmacodynamics). Detectable HCV RNA below the lower limit of assay quantification should not be used as a substitute for "undetectable", for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates. See Table 11 for Guidelines for Discontinuation of INCIVO, Peginterferon Alfa, and Ribavirin Treatment. Treatment-naive patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 of INCIVO combination treatment may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total) (see PHARMACOLOGY - Pharmacodynamics)

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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 11 for Guidelines for Discontinuation of INCIVO, Peginterferon Alfa, and Ribavirin Treatment.

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 11).

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-naive 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 treatment-naive patients with HCV RNA between 100 IU/ml and 1,000 IU/ml at week 12, 2/8 (25%) achieved 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 dosed with peginterferon alfa and ribavirin to prevent treatment failure. The dose of INCIVO must not be reduced to prevent treatment failure.

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If INCIVO treatment is discontinued due to adverse drug reactions or because of insufficient virologic response, INCIVO treatment should not be reinitiated. There is no data on re-treating patients who have failed a course of HCV NS3-4A protease inhibitor-based therapy (see PHARMACOLOGY - Pharmacodynamics) with INCIVO. Refer to the respective Product Information of peginterferon alfa and ribavirin for guidelines on dose modifications, interruptions, discontinuations or resumption of those medicinal products (see PRECAUTIONS). 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). No dose adjustment is recommended for INCIVO in HCV patients with mild, moderate or severe renal impairment (see PRECAUTIONS and PHARMACOLOGY - Pharmacokinetics). Ribavirin is contraindicated, or used with extreme cautions in patients with CrCl < 50 ml/min (see the Product Information for ribavirin).

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 (see PRECAUTIONS). 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 Product Information for peginterferon alfa and ribavirin which are contraindicated in Child-Pugh score >= 6.

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.

OVERDOSAGE

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.

Management of Overdosage

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. 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.

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PRESENTATION AND STORAGE CONDITIONS

375 mg: Yellow, caplet-shaped, film-coated tablets of approximately 20 mm in length, marked with "T375" on one side. Pack size: Bottle pack of 42 tablets. Store below 25oC.

NAME AND ADDRESS

New Zealand Sponsor

Janssen-Cilag (New Zealand) Ltd Auckland, NEW ZEALAND Telephone: 0800 800 806

Date of preparation:

25 October 2013

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