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INCIVEK (telaprevir) Tablets 375mg
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use INCIVEK safely and effectively. See full prescribing information for INCIVEK.
INCIVEK™ (telaprevir) Film Coated Tablets, for oral use
Initial U.S. Approval: 2011
WARNING: SERIOUS SKIN REACTIONS
See full prescribing information for complete boxed warning.
Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment [see Warnings and Precautions (5.1)]. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care.
RECENT MAJOR CHANGES
Boxed Warning
Contraindications (4)
Warnings and Precautions (5.1, 5.2)
Warnings and Precautions (5.5)
12/2012
12/2012
12/2012
04/2013
INDICATIONS AND USAGE
INCIVEK is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated, in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C (CHC) in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers. (1)
INCIVEK must not be used as monotherapy and must only be used in combination with peginterferon alfa and ribavirin. (5.6)
A high proportion of previous null responders (particularly those with cirrhosis) did not achieve Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with INCIVEK. (12.4, 14.3)
INCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or other HCV NS3/4A protease inhibitors. (12.4)
DOSAGE AND ADMINISTRATION
750 mg taken 3 times a day (7-9 hours apart) with food (not low fat). (2, 12.3, 17.4)
INCIVEK must be administered with both peginterferon alfa and ribavirin for all patients for 12 weeks, followed by a response-guided regimen of either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on viral response and prior response status. (2)
For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information. (2)
DOSAGE FORMS AND STRENGTHS
375 mg tablets (3)
CONTRAINDICATIONS
All contraindications to peginterferon alfa and ribavirin also apply since INCIVEK must be administered with peginterferon alfa and ribavirin. (4)
Pregnant women and men whose female partners are pregnant: Because ribavirin may cause birth defects and fetal death, telaprevir in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. (4, 5.3, 8.1, 17.2)
Co-administration with drugs that:
are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. (4)
strongly induce CYP3A which may lead to lower exposure and loss of efficacy of INCIVEK. (4)
WARNINGS AND PRECAUTIONS
Serious Skin Reactions/Rash: Fatal and non-fatal serious skin reactions (including SJS, DRESS, and TEN) have been reported. Patients with mild to moderate rash should be monitored for progression. If rash progresses and becomes severe, INCIVEK should be discontinued. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Consider discontinuing other medications known to be associated with serious skin reactions. (5.1)
Anemia: Monitor hemoglobin prior to and at regular intervals during INCIVEK combination treatment. Follow dose modifications for ribavirin; discontinue INCIVEK if required. (5.2)
Pregnancy: Use with Ribavirin and Peginterferon alfa: Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective methods of contraception, and undergo monthly pregnancy tests. (5.3, 8.1, 17.2)
ADVERSE REACTIONS
The most common adverse drug reactions to INCIVEK (incidence at least 5% higher with INCIVEK than in controls) were rash, pruritus, anemia, nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue, vomiting, and anal pruritus. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 877-824-4281 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Co-administration of INCIVEK combination treatment with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of telaprevir. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. (4, 7, 12.3)
USE IN SPECIFIC POPULATIONS
Hepatic Impairment: Safety and efficacy have not been established in patients with Child-Pugh score greater than or equal to 7 (class B and C). (5.7, 8.6)
Co-infection: Safety and efficacy have not been established in HCV/HIV and HCV/HBV co-infected patients. (8.8)
Pediatrics: Safety and efficacy have not been established in pediatric patients. (8.4)
Solid Organ Transplant: Safety and efficacy have not been established in patients undergoing solid organ transplants. (8.9)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 04/2013
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Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SERIOUS SKIN REACTIONS
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C
2 DOSAGE AND ADMINISTRATION
2.1 INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment
2.2 Dose Reduction
2.3 Discontinuation of Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Serious Skin Reactions/Rash
5.2 Anemia
5.3 Pregnancy: Use with Ribavirin and Peginterferon Alfa
5.4 Drug Interactions
5.5 Laboratory Tests
5.6 General
5.7 Hepatic Impairment
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-marketing Experience
7 DRUG INTERACTIONS
7.1 Potential for INCIVEK to Affect Other Drugs
7.2 Potential for Other Drugs to Affect INCIVEK
7.3 Established and Other Potentially Significant Drug Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Co-infection
8.9 Solid Organ Transplantation
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
12.5 Pharmacogenomics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Description of Adult Clinical Trials
14.2 Treatment-Naïve Adults
14.3 Previously Treated Adults
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Serious Skin Reactions/Rash
17.2 Pregnancy
17.3 Hepatitis C Virus Transmission
17.4 Importance of Hydration
17.5 Administration
*
Sections or subsections omitted from the full prescribing information are not listed.
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FULL PRESCRIBING INFORMATION
WARNING: SERIOUS SKIN REACTIONS
Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment [see Warnings and Precautions (5.1)]. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care.
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C
INCIVEK™ (telaprevir), 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 or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers [see Clinical Studies (14.2 and 14.3), including definitions of these terms].
The following points should be considered when initiating treatment with INCIVEK:
-
INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin [see Warnings and Precautions (5.6)].
-
A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with INCIVEK combination treatment [see Microbiology (12.4) and Clinical Studies (14.3)].
-
INCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or other HCV NS3/4A protease inhibitors [see Microbiology (12.4)].
2 DOSAGE AND ADMINISTRATION
2.1 INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment
The recommended dose of INCIVEK tablets is 750 mg (two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food (not low fat) [see Clinical Pharmacology (12.3) and Patient Counseling Information (17.4)].
For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information.
Duration of Treatment
The recommended duration of treatment with INCIVEK is 12 weeks in combination with peginterferon alfa and ribavirin. HCV RNA levels should be monitored at weeks 4 and 12 to determine combination treatment duration and assess for treatment futility (Tables 1 and 2).
Table 1: Recommended Treatment Duration (See also Table 2 for Treatment Futility Rules)
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Treatment-Naïve and Prior Relapse Patients |
|
HCV RNA* |
Triple Therapy |
Dual Therapy |
Total Treatment Duration |
INCIVEK,
peginterferon alfa and ribavirin |
peginterferon alfa and ribavirin |
|
Undetectable (Target Not Detected) at Weeks 4 and 12 |
First 12 weeks |
Additional 12 weeks |
24 weeks |
|
Detectable (1000 IU/mL or less) at Weeks 4 and/or 12 |
First 12 weeks |
Additional 36 weeks |
48 weeks |
|
Prior Partial and Null Responder Patients |
|
|
Triple Therapy |
Dual Therapy |
Total Treatment Duration |
INCIVEK,
peginterferon alfa and ribavirin |
peginterferon alfa and ribavirin |
|
All Patients |
First 12 weeks |
Additional 36 weeks |
48 weeks |
For the purpose of assessing response-guided therapy eligibility at weeks 4 and 12 (see Table 1), an "undetectable" HCV RNA (Target Not Detected) result is required; a confirmed "detectable but below limit of quantification" HCV RNA result should not be considered equivalent to an "undetectable" HCV RNA (Target Not Detected) result [see Laboratory Tests (5.5)].
Treatment-naïve patients with cirrhosis who have undetectable HCV RNA (Target Not Detected) at weeks 4 and 12 of INCIVEK combination treatment may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total) [see Clinical Studies (14.2)].
2.2 Dose Reduction
To prevent treatment failure, the dose of INCIVEK must not be reduced or interrupted. Refer to the respective prescribing information for dose modification of peginterferon alfa and ribavirin [see Warnings and Precautions (5.6)].
2.3 Discontinuation of Dosing
Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions [see Microbiology (12.4)]. Discontinuation of therapy is recommended in all patients with (1) HCV RNA levels of greater than 1000 IU/mL at Treatment Week 4 or 12; or (2) confirmed detectable HCV RNA levels at Treatment Week 24 (see Table 2).
Table 2: Treatment Futility Rules: All Patients
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HCV RNA |
Action |
|
Week 4 or Week 12: Greater than 1000 IU/mL |
Discontinue INCIVEK and peginterferon alfa and ribavirin (INCIVEK treatment complete at 12 weeks) |
|
Week 24: Detectable |
Discontinue peginterferon alfa and ribavirin |
If peginterferon alfa or ribavirin is discontinued for any reason, INCIVEK must also be discontinued.
3 DOSAGE FORMS AND STRENGTHS
Each tablet contains 375 mg of telaprevir. Tablets are available as purple, film-coated, capsule-shaped tablets debossed with the characters "V 375" on one side.
4 CONTRAINDICATIONS
Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.
INCIVEK combination treatment is contraindicated in:
INCIVEK is a strong inhibitor of CYP3A. INCIVEK is contraindicated when combined with drugs 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). INCIVEK is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVEK. Contraindicated drugs are listed below in Table 3 [also see Drug Interactions (7), Table 5 and Clinical Pharmacology (12.3), Tables 6 and 7].
Table 3: Drugs that are Contraindicated with INCIVEK
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Drug Class |
Drugs within Class that are Contraindicated with INCIVEK |
Clinical Comments |
|
|
|
Alpha 1-adrenoreceptor antagonist |
Alfuzosin |
Potential for hypotension or cardiac arrhythmia |
|
Antimycobacterials |
Rifampin |
Rifampin significantly reduces telaprevir plasma concentrations. |
|
Ergot derivatives |
Dihydroergotamine, ergonovine, ergotamine, methylergonovine |
Potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia |
|
GI motility agent |
Cisapride |
Potential for cardiac arrhythmias |
|
Herbal products |
St. John's wort (Hypericum perforatum) |
Plasma concentrations of telaprevir can be reduced by concomitant use of the herbal preparation St. John's wort. |
|
HMG-CoA reductase inhibitors |
Lovastatin, simvastatin |
Potential for myopathy including rhabdomyolysis |
|
Neuroleptic |
Pimozide |
Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias |
|
PDE5 inhibitor |
Sildenafil (Revatio®) or tadalafil (Adcirca®) [for treatment of pulmonary arterial hypertension]* |
Potential for PDE5 inhibitor-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope |
|
Sedatives/hypnotics |
Orally administered midazolam†, triazolam |
Prolonged or increased sedation or respiratory depression |
5 WARNINGS AND PRECAUTIONS
5.1 Serious Skin Reactions/Rash
Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified.
For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care.
In clinical trials, serious skin reactions, including DRESS and SJS were reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all subjects recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).
TEN and Erythema Multiforme (EM) have been observed in post-marketing experience [see also Boxed Warning and Adverse Reactions (6.2)].
Rash events (all grades) developed in 56% of subjects who received INCIVEK combination treatment [see Adverse Reactions (6.1)] and in 34% of subjects who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during INCIVEK combination treatment. Rash events led to discontinuation of INCIVEK alone in 6% of subjects and discontinuation of INCIVEK combination treatment in 1% of subjects. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component.
Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered [see also Boxed Warning]. Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral an |
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