Dosing and uses of Incivek (telaprevir)
Adult dosage forms and strengths
tablet
- 375mg
Chronic Hepatitis C
Discontinued; sale and distribution of telaprevir will be discontinued in the United States by October 2014
Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin
Indication is specifically for adults 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
1,125 mg (3 tabs) PO BID (q10-14hr) with food (not low fat)
Administer for 12 weeks in combination with peginterferon alfa and ribavirin (telaprevir must not be used as monotherapy)
Treatment Duration
Duration of treatment depends on HCV-RNA levels
Triple therapy: telaprevir, peginterferon alfa, and ribavirin
Dual therapy: peginterferon alfa and ribavirin
Treatment-naïve and prior relapse patients
- HCV-RNA levels undetectable at weeks 4 and 12: Administer with peginterferon alfa and ribavirin first 12 weeks, then dual therapy an additional 12 weeks
- HCV-RNA levels detectable at weeks 4 and 12 (ie, <1000 IU/mL): Administer with peginterferon alfa and ribavirin first 12 weeks, then dual therapy an additional 36 weeks
Prior partial and null responder patients
- All patients: Administer triple therapy first 12 weeks, then dual therapy an additional 36 weeks
Treatment futility
- Patients with inadequate viral response are unlikely to achieve sustained virologic response, and may develop treatment-emergent resistance substitutions
- Discontinuation of therapy is recommended in all patients with either of the following circumstances:
- HCV-RNA levels >1000 IU/mL at treatment weeks 4 or 12, OR
- HCV-RNA levels detectable at treatment week 24
Renal or Hepatic Impairment
See peginterferon alfa and ribavirin monographs for recommended dose adjustments
Renal impairment
- Mild, moderate, or severe: No dosage adjustment required
- Has not been studied in patients with end-stage renal disease (ESRD) or on hemodialysis
Hepatic impairment
- Moderate-to-severe (Child-Pugh B or C, score 7 or greater): Not recommended
- Decompensated liver disease: Not recommended
Administration
Must be administered in combination with peginterferon alfa and ribavirin
If peginterferon alfa or ribavirin is discontinued for any reason, telaprevir must also be discontinued
To prevent treatment failure, dose must not be reduced or interrupted
Administer with a meal or snack (not low fat)
Pediatric dosage forms and strengths
Safety and efficacy not established
Incivek (telaprevir) adverse (side) effects
>10%
Rash (56%)
Fatigue (56%)
Pruritus (47%)
Nausea (39%)
Anemia (36%)
Diarrhea (26%)
Vomiting (13%)
Hemorrhoids (12%)
Anorectal discomfort (11%)
1-10%
Dysgeusia (10%)
Anal pruritus (6%)
Warnings
Black box warnings
Fatal and nonfatal serious skin reactions (including Stevens Johnson syndrome, drug reaction with eosinophilia and systemic symptoms [DRESS], and toxic epidermal necrolysis [TEN]) reported in patients taking telaprevir in combination with peginterferon alfa and ribavirin
Deaths reported when patients continued to receive this treatment regimen after developing a worsening, or progressive rash and systemic symptoms
If serious skin reactions occur, immediately discontinue all 3 drugs of the treatment regimen (ie, telaprevir, peginterferon alfa, ribavirin)
Patients should be promptly referred for urgent medical care
Also consider stopping any other medications that may be associated with serious skin reactions
Contraindications
Telaprevir inhibits CYP3A; coadministration 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 (ie, narrow therapeutic index drugs that may cause arrhythmia, respiratory depression, sedation)
Telaprevir is a CYP3A substrate; potent CYP3A inducers may significantly reduce telaprevir plasma concentrations and result in reduced efficacy
Hypersensitivity
Also consider contraindications to peginterferon alfa and ribavirin
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
Drugs contraindicated with telaprevir
- Alfuzosin: Potential for hypotension or cardiac arrhythmia
- Rifampin: Significantly reduces telaprevir plasma concentrations
- Carbamazepine, phenobarbital, and phenytoin: Reduces telaprevir plasma concentrations
- Ergot derivatives: Potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia
- Cisapride: Potential for cardiac arrhythmias
- St. John's wort: Reduces telaprevir plasma concentrations
- Lovastatin or simvastatin: Increased risk for myopathy including rhabdomyolysis
- Pimozide: Serious and/or life-threatening cardiac arrhythmias
- Sildenafil or tadalafil: PDE5 inhibitor-associated adverse events (eg, visual abnormalities, hypotension, prolonged erection, syncope)
- PO midazolam or triazolam: Prolonged or increased sedation or respiratory depression
Cautions
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 therapy; use two or more forms of contraception, and have monthly pregnancy tests
Serious skin reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), and Stevens-Johnson Syndrome (SJS); discontinue immediately and do not reintroduce (see Black box warnings)
Anemia: Addition of telaprevir to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared with peginterferon alfa and ribavirin alone; obtain baseline Hgb, white cell differential, and platelet count and monitor at weeks 2, 4, 8, and 12 during treatment and as clinically needed
Use sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment at weeks 4 and 12 as clinically indicated
Not recommended for with moderate-to-severe hepatic impairment (Child-Pugh B or C, score 7 or greater) or with decompensated liver disease
Pregnancy and lactation
Pregnancy category: X
Telaprevir is coadministered with ribavirin; significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant
Lactation: Unknown whether distributed in breast milk; because of the potential for adverse reaction, breastfeeding is not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Incivek (telaprevir)
Mechanism of action
Inhibits HCV NS3/4A protease needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms, which in turn inhibits hepatitis C viral replication
Absorption
Peak plasma time: 4-5 hr
Peak plasma concentration: 3510 ng/mL
AUC: 22,300 (8650) ng•hr/mL
Food: AUC increased by 237% when administered with a standard fat meal (containing 533 kcal and 21 g fat) compared with fasting conditions
Distribution
Protein bound: 59-76% (primarily alpha 1-acid glycoprotein and albumin)
Vd: 252 L (72% interindividual variability)
Metabolism
Extensively metabolized in liver by hydrolysis, oxidation, and reduction
Metabolites: R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the alpha-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites
Metabolized by CYP3A4 is the major CYP isoform; after multiple dosing, nonCYP metabolism is also apparent
Inhibits CYP3A and P-gp
Substrate of CYP3A and P-gp
Elimination
Half-life: 4-4.7 hr (mean); 9-11 hr (at steady state)
Total body clearance: 32.4 L/h
Excretion: feces (82%); exhaled air (9%); urine (1%)
Pharmacogenomics
Among both treatment-naïve and previous treatment failures, subjects of all IL28B genotypes (ie, CT, TT, CC) appeared to have higher SVR rates with telaprevir-containing regimens in clinical trials compared with dual therapy
SVR rates tend to be lower for dual therapy if IL28B CT and TT variants are present compared with IL28B CC
