INCIVO 375 mg film-coated tablets
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.
Film-coated tablet.
Yellow caplet shaped tablets of approximately 20 mm in length, marked with “T375” on one side.
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).
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.
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.
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).
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Table 1: Guidelines for discontinuation of INCIVO, Peginterferon Alfa, and Ribavirin treatment
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Medicinal products
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HCV RNA > 1,000 IU/ml at week 4 of treatmenta
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HCV RNA > 1,000 IU/ml at week 12 of treatmenta
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INCIVO
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Permanently discontinue
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INCIVO treatment completed
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Peginterferon alfa and Ribavirin
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Permanently discontinue
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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.
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)
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).
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.
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:
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Extent and features of Cutaneous Reactions
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Recommendations for Monitoring of Cutaneous Reactions and Discontinuation of INCIVO, Ribavirin and Peginterferon alfa for Severe Rash
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Mild rash: localised skin eruption and/or a skin eruption with a limited distribution (up to several isolated sites on the body)
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Monitor for progression or systemic symptoms until the rash is resolved.
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Moderate rash: Diffuse rash ≤ 50% of body surface area
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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).
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Severe rash: Extent of rash > 50% of body surface area or associated with vesicles, bullae, ulcerations other than SJS
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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.
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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
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Permanent and immediate discontinuation of INCIVO, peginterferon alfa, and ribavirin. Consult with a specialist in dermatology.
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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 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).
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 eva luations (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 eva luations (including white cell differential count) are recommended at weeks 2, 4, 8 and 12 and as clinically appropriate.
Chemistry eva luations (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, TSH) are recommended as frequently as the haematology eva luations 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).
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 eva luated 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:
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.
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.
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
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Medicinal products by therapeutic areas
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Effect on concentration of INCIVO or concomitant medicinal product and possible mechanism
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Clinical comment
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ANALGESICS
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alfentanil
fentanyl
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↑ 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.
|
|
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
|
|
|
