Telaprevir

Class: HCV Protease Inhibitors
VA Class: AM800
Chemical Name: (1S,3aR,6aS) - (2S) - 2 - Cyclohexyl - N - (pyrazinylcarbonyl)glycyl - 3 - methyl - L - valyl - N - [(1S) - 1 - [(cyclopropylamino)oxoacetyl]butyl]octahydro - cyclopenta[c]pyrrole - 1 - carboxamide
Molecular Formula: C₃₆H₅₃N₇O₆
CAS Number: 402957-28-2
Brands: Incivek

Introduction

Antiviral; HCV NS3/4A protease inhibitor.^{1 5 11}

Uses for Telaprevir

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Chronic Hepatitis C Virus (HCV) Infection

Treatment of chronic HCV genotype 1 infection in adults with compensated liver disease (including cirrhosis) who are treatment naive (previously untreated) or were previously treated with interferon-based therapy (including patients with prior null response, partial response, or relapse).^{1 2 3}

Slideshow: 10 Things to Know About Antibiotic Resistance

Used in conjunction with peginterferon alfa (alfa-2a, alfa-2b) and ribavirin;¹ do not use alone.¹

American Association for the Study of Liver Diseases (AASLD) and others recommend an NS3/4A protease inhibitor (i.e., boceprevir, telaprevir) in conjunction with peginterferon alfa and ribavirin as the standard of care for initial treatment of chronic HCV genotype 1 infection in treatment-naive adults.^{119 121} Also recommended for retreatment in adults with virologic relapse or partial response after treatment with other regimens (interferon alfa or peginterferon alfa with or without ribavirin).^{119 121}

Consider that a high proportion of prior null responders (particularly those with cirrhosis) failed to achieve sustained virologic response (SVR) and had treatment-emergent telaprevir resistance-associated mutations during treatment with telaprevir, peginterferon alfa, and ribavirin.¹

Efficacy not established in patients who previously failed therapy with a regimen containing telaprevir or other HCV NS3/4A protease inhibitor.¹

Safety and efficacy not established in patients with chronic HCV and HBV or HIV coinfection or in recipients of liver or other organ transplantations.¹

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.^{96 119 121}

Telaprevir Dosage and Administration

General

• Must be used in conjunction with peginterferon alfa and ribavirin; do not use as monotherapy.¹

• A 12-week regimen of telaprevir, peginterferon alfa, and ribavirin is used initially, followed by a regimen of peginterferon alfa and ribavirin (without telaprevir).¹

• Assess plasma HCV RNA levels at 4 and 12 weeks to determine the appropriate total treatment duration (response-guided therapy) or need to discontinue treatment (treatment futility).¹ (See Laboratory Monitoring under Cautions.)

Administration

Oral Administration

Administer orally 3 times daily (every 7-9) hours within 30 minutes after a meal or snack containing approximately 20 g of fat.¹

If a missed dose is remembered within 4 hours of originally scheduled time, take the dose (with food containing approximately 20 g of fat) as soon as possible and resume regular dosing schedule.¹ If a missed dose is not remembered within 4 hours, skip the dose and resume regular dosing schedule.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Do not reduce telaprevir dosage for any reason.¹ If discontinued because of serious adverse effects (see Dermatologic Effects under Cautions), do not restart.¹ If serious adverse reactions potentially related to peginterferon alfa and/or ribavirin occur, adjust dosage or discontinue peginterferon alfa and ribavirin according to the respective manufacturer’s prescribing information.¹ If peginterferon alfa or ribavirin is discontinued for any reason, telaprevir also must be discontinued.¹

Adults

Treatment of Chronic HCV Infection

Oral

750 mg 3 times daily for 12 weeks in conjunction with peginterferon alfa and ribavirin.¹ After completion of 12 weeks of this 3-drug regimen, all patients who are responding require additional weeks of therapy with peginterferon alfa and ribavirin for a total treatment duration that depends on response (response-guided therapy).¹ (See Table 1.)

To be eligible for response-guided therapy at 4 and 12 weeks, a report of “undetectable” HCV RNA (target not detected) is required; do not consider a result of confirmed “detectable but below the limit of quantification” equivalent to a result of “undetectable” HCV RNA (reported as “target not detected” or “HCV RNA not detected”).¹

Discontinue all 3 drugs (telaprevir, peginterferon alfa, ribavirin) in all patients experiencing treatment futility (i.e., plasma HCV RNA levels >1000 IU/mL at week 4 or 12 or confirmed detectable plasma HCV RNA levels after total treatment duration of 24 weeks).¹

Table 1. Recommended Total Treatment Duration (Response-guided Therapy).1

Patient Type	HCV RNA Levels at Treatment Weeks 4 and 12	Duration of Additional Continued Peginterferon alfa and Ribavirin Therapy following Initial 12 weeks of Concomitant Telaprevir	Total Treatment Duration
Treatment-naive or prior relapse	Undetectable (target not detected) at week 4 and 12	12 weeks	24 weeks
Treatment-naive or prior relapse	Detectable at week 4 and/or 12	36 weeks	48 weeks
Prior partial or null response	All patients	36 weeks	48 weeks

In treatment-naive patients with cirrhosis, consider total treatment duration of 48 weeks (i.e., 12 weeks of telaprevir, peginterferon alfa, and ribavirin, followed by additional 36 weeks of peginterferon alfa and ribavirin) despite undetectable HCV RNA levels (target not detected) at treatment week 4 and 12.¹

Special Populations

Hepatic Impairment

Dosage adjustment not required in patients with mild hepatic impairment (Child-Pugh class A).¹

Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C); appropriate dosages not established.¹

Renal Impairment

Dosage adjustment not required.¹ Not studied in HCV-infected patients with Cl_cr ≤50 mL/minute, including patients with end-stage renal disease or receiving hemodialysis.¹

Cautions for Telaprevir

Contraindications

• Because telaprevir must be used in conjunction with peginterferon alfa and ribavirin, it is contraindicated in women who are or may become pregnant and male partners of pregnant women.¹ Consider contraindications, warnings, and precautions for all 3 drugs.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, ergot alkaloids, lovastatin or simvastatin, oral midazolam or triazolam, pimozide, sildenafil or tadalafil used for treatment of pulmonary arterial hypertension [PAH]).¹ (See Specific Drugs under Interactions.)

• Concomitant use with potent CYP3A inducers that may substantially reduce telaprevir concentrations and efficacy (e.g., rifampin, St. John’s wort [Hypericum perforatum]).¹ (See Specific Drugs under Interactions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Telaprevir must be used in conjunction with peginterferon alfa and ribavirin.¹ Ribavirin may cause birth defects and/or fetal death;¹ peginterferon may have abortifacient effects in humans.^{1 1}

Pregnancy must be avoided in female patients and female partners of male patients receiving ribavirin with or without telaprevir and peginterferon alfa.¹ Obtain a report of a negative pregnancy test for female patients of childbearing potential immediately prior to initiating therapy with telaprevir, peginterferon, and ribavirin and perform monthly pregnancy tests during and for 6 months after ribavirin treatment is completed.¹

Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.¹ Because of pharmacokinetic interactions, systemic hormonal contraceptives may have reduced efficacy in women taking telaprevir (see Specific Drugs under Interactions).¹ Although women may continue to take hormonal contraceptives during telaprevir therapy, they must use 2 additional nonhormonal methods (e.g., intrauterine devices, barrier methods) during and for 2 weeks after telaprevir therapy.¹ Systemic hormonal contraceptives (used according to the manufacturer’s labeling) may be considered 1 of the 2 required effective contraceptive methods beginning 2 weeks after discontinuance of telaprevir.¹

Dermatologic Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Risk of serious skin reactions, including drug rash with eosinophilia and systemic symptoms (DRESS) or Stevens-Johnson syndrome (SJS).^{1 4} DRESS may present as rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis) and may or may not include eosinophilia.¹ SJS may present with fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).¹ Severe rash may have a prominent eczematous component.¹

Rash generally appears during first 4 weeks of telaprevir treatment and improves when telaprevir treatment is completed or discontinued;¹ complete resolution may take weeks.¹

If serious skin reaction occurs, immediately discontinue telaprevir, peginterferon alfa, and ribavirin and promptly refer patient for urgent medical care.¹

If mild to moderate rash occurs, monitor patient for progression of rash or development of systemic symptoms.¹ Discontinue telaprevir if rash becomes severe or if systemic symptoms develop; peginterferon alfa and ribavirin may be continued.¹

Do not reduce telaprevir dosage and do not restart telaprevir if it was discontinued because of rash.¹ If improvement is not observed within 7 days of discontinuing telaprevir, consider sequential or simultaneous interruption or discontinuation of peginterferon alfa and/or ribavirin.¹ If medically indicated, consider earlier interruption or discontinuance of peginterferon alfa and ribavirin.¹

Monitor patient until rash resolves.¹ Use of oral antihistamines and/or topical corticosteroids may provide symptomatic relief of telaprevir-associated rash, but effectiveness of these measures not established.¹ Use of systemic corticosteroids not recommended (see Interactions).¹

Hematologic Effects

Risk of anemia.¹ Concomitant use of telaprevir, peginterferon alfa, and ribavirin is associated with greater decrease in hemoglobin concentrations and higher incidence of anemia than use of peginterferon and ribavirin without telaprevir.¹

Decreased hemoglobin concentrations generally occur during first 4 weeks of treatment with telaprevir, peginterferon alfa, and ribavirin; nadir usually observed at completion of 12-week telaprevir regimen.¹ After telaprevir discontinued, hemoglobin concentrations gradually return to levels generally observed during peginterferon alfa and ribavirin therapy.¹

Assess hemoglobin concentration prior to, at weeks 2, 4, 8, and 12 during telaprevir therapy, and as clinically indicated.¹

If anemia occurs, modify ribavirin dosage according to manufacturer’s labeling.¹ If ribavirin dosage reduction is inadequate, consider discontinuing telaprevir.¹ If ribavirin or peginterferon alfa is discontinued for any reason, telaprevir also must be discontinued; do not reduce telaprevir dosage and do not restart telaprevir if discontinued.¹ Ribavirin may be restarted (without telaprevir) according to manufacturer’s labeling.¹

Drug Interactions

Concomitant use with certain drugs is contraindicated or requires particular caution.¹ (See Specific Drugs under Interactions.)

Laboratory Monitoring

Monitor plasma HCV RNA levels using a sensitive real-time reverse-transcriptase polymerase chain reaction (PCR) assay at 4 and 12 weeks of therapy, and when clinically indicated.¹ Use an assay with a lower limit of HCV RNA quantification of ≤25 IU/mL and a limit of HCV RNA detection of approximately 10–15 IU/mL.¹ When assessing HCV RNA levels for the purposes of response-guided therapy, a result of confirmed “detectable but below limit of quantification” is not considered equivalent to a result of “undetectable” HCV RNA (reported as “target not detected” or “HCV RNA not detected”).¹ (See Dosage.)

Monitor hematology tests (including WBC differential count) and chemistry assessments (i.e., electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, thyroid-stimulating hormone [TSH]) prior to, at weeks 2, 4, 8, and 12 during telaprevir therapy, and when clinically indicated.¹ (See Hematologic Effects under Cautions.)

Specific Populations

Pregnancy

Category B (telaprevir; not indicated for monotherapy).¹

Category X (telaprevir used in conjunction with peginterferon alfa and ribavirin).¹ (See Fetal/Neonatal Morbidity and Mortality and see Contraindications under Cautions.)

Pregnancy registry at 800-593-2214 to monitor pregnancy outcomes of female patients and female partners of male patients exposed to ribavirin.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing prior to initiating treatment.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; use with caution due to greater frequency of decreased hepatic function and of concomitant disease and drug therapy observed in the elderly.¹

Hepatic Impairment

Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score 7 or higher) or in patients with decompensated cirrhosis.¹

Renal Impairment

Not studied in HCV-infected patients with Cl_cr <50 mL/minute, including patients with end-stage renal disease or receiving hemodialysis.¹

Common Adverse Effects

Rash, pruritus, anemia, nausea, diarrhea, hemorrhoids, anorectal discomfort, dysgeusia, fatigue, vomiting, anal pruritus.¹

Interactions for Telaprevir

Metabolized by and inhibits CYP3A.¹ Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1 and does not induce CYP1A, 3A, 2B6, or 2C in vitro.¹

Substrate for and potential inhibitor of P-glycoprotein transport system.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with drugs that are primarily metabolized by CYP3A with possible increased exposure to concomitant drug and subsequent increased or prolonged adverse or therapeutic effects.¹

Potential pharmacokinetic interaction with drugs that are inducers or inhibitors of CYP3A4/5 with possible alteration in telaprevir metabolism and concentrations.¹

Drugs Affecting the P-glycoprotein Transport System

Potential pharmacokinetic interaction with drugs that are substrates for P-glycoprotein transport with possible increased exposure to concomitant drug and subsequent increased or prolonged adverse or therapeutic effects.¹

Potential pharmacokinetic interaction with drugs that are inducers or inhibitors of P-glycoprotein with possible alteration in telaprevir concentrations.¹

Specific Drugs

Drug	Interaction	Comments
Alfuzosin	Possible increased alfuzosin concentrations; potential for serious and/or life-threatening effects (e.g., hypotension, cardiac arrhythmia)1	Concomitant use contraindicated1
Antiarrhythmic agents (amiodarone, flecainide, systemic lidocaine, propafenone, quinidine)	Possible increased antiarrhythmic agent concentrations; potential for serious and/or life-threatening effects1	Use with caution and clinical monitoring1
Anticoagulants, oral (e.g., warfarin)	Possible altered warfarin concentrations1	Monitor INR1
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased telaprevir concentrations and decreased telaprevir efficacy; possible altered anticonvulsant concentrations1	Use with caution; use clinical or laboratory monitoring and titrate anticonvulsant dosage to desired clinical response1
Antifungals, azoles	Ketoconazole: Increased telaprevir concentrations and AUC; increased ketoconazole concentrations1 Itraconazole: Possible increased itraconazole concentrations; possible increased telaprevir concentrations1 Posaconazole: Possible increased posaconazole concentrations; possible increased telaprevir concentrations1 Voriconazole: Possible altered voriconazole concentrations; possible increased telaprevir concentrations1	Consider that QT interval prolongation has been reported with ketoconazole, posaconazole, and voriconazole and that torsades de pointes has been reported with posaconazole and voriconazole1 Ketoconazole: If concomitant use required, do not exceed antifungal dosage of 200 mg daily1 Itraconazole: Use with caution and clinical monitoring; if concomitant use required, do not exceed itraconazole dosage of 200 mg daily1 Posaconazole: Use with caution and clinical monitoring1 Voriconazole: Use with caution and clinical monitoring; only use if benefits justify risks1
Antimycobacterials (rifabutin, rifampin)	Rifabutin: Possible increased rifabutin concentrations; possible decreased telaprevir concentrations and decreased telaprevir efficacy1 Rifampin: Substantially decreased telaprevir concentrations and AUC; possible loss of virologic response1	Rifabutin: Concomitant use not recommended1 Rifampin: Concomitant use contraindicated1
Atazanavir	Ritonavir-boosted atazanavir: Decreased telaprevir concentrations and AUC; increased atazanavir trough concentrations and AUC1 200	Ritonavir-boosted atazanavir: Some experts state dosage adjustments not needed200
Benzodiazepines (alprazolam, midazolam, triazolam)	Midazolam: Increased midazolam concentrations and AUC; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1 Triazolam: Possible increased triazolam concentrations; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1 Alprazolam: Increased alprazolam AUC1	Oral midazolam, triazolam: Concomitant use contraindicated1 IV midazolam: Use with caution; administer IV midazolam in a monitored setting where respiratory depression and/or prolonged sedation can be managed; consider using reduced midazolam dosage, particularly if more than a single dose is given1 Alprazolam: Clinically monitor patient during concomitant use1
Bosentan	Possible increased bosentan concentrations1	Use with caution and clinical monitoring1
Buprenorphine	No clinically important effects on buprenorphine concentrations or AUC1	Dosage adjustments not needed1
Calcium-channel blockers, dihydropyridines (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil)	Amlodipine: Increased amlodipine concentrations and AUC1 Other calcium-channel blockers: Possible increased concentration of calcium channel blocker1	Amlodipine: Use with caution and clinical monitoring; consider reduced amlodipine dosage1 Other calcium-channel blockers: Use with caution and clinical monitoring1
Cisapride	Possible increased cisapride concentrations; potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Colchicine	Possible increased colchicine concentrations and increased risk of colchicine toxicity1	Patients with renal or hepatic impairment: Avoid concomitant use1 Patients without renal or hepatic impairment: Interruption of colchicine treatment or reduction in colchicine dosage recommended1 Colchicine for treatment of gout flares: In those receiving telaprevir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 Colchicine for prophylaxis of gout flares: In those receiving telaprevir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving telaprevir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1
Corticosteroids	Budesonide or fluticasone (nasal spray/oral inhalation): Possible increased concentrations of inhaled corticosteroid; possible reduced serum cortisol concentrations1 Dexamethasone: Possible decreased telaprevir concentrations; possible loss of virologic efficacy1 Methylprednisolone or prednisone: Possible increased corticosteroid concentrations1	Budesonide or fluticasone (nasal spray/oral inhalation): Concomitant use not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 Dexamethasone: Consider alternatives when possible; use concomitantly with caution1 Methylprednisolone or prednisone: Concomitant use not recommended1
Darunavir	Ritonavir-boosted darunavir: Decreased telaprevir and darunavir concentrations and AUCs1 200	Concomitant use not recommended1 200
Digoxin	Increased digoxin concentrations and AUC1	Use lowest initial dosage of digoxin; monitor serum digoxin concentrations and use to guide careful dosage titration1
Efavirenz	Decreased telaprevir concentrations and AUC; no clinically important effect on efavirenz concentrations and AUC1 200	Some experts recommend increasing telaprevir dosage to 1125 mg every 7–9 hours in patients receiving efavirenz and 2 nucleoside reverse transcriptase inhibitors (NRTIs)200
Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Possible increased concentrations of ergot alkaloids; potential for serious and/or life-threatening effects such as ergot toxicity (peripheral vasospasm, ischemia)1	Concomitant use contraindicated1
Escitalopram	Decreased escitalopram concentrations and AUC1	Dosage adjustment of escitalopram may be necessary during concomitant use1
Esomeprazole	Pharmacokinetic interaction not observed1	Dosage adjustments not necessary1
Estrogens/Progestins	Ethinyl estradiol and norethindrone: Decreased ethinyl estradiol concentrations and AUC; no clinically important effect on norethindrone concentrations1	Systemic hormonal contraceptives: Advise women to use 2 alternative methods of contraception (e.g., intrauterine devices, barrier methods) while receiving telaprevir and for 2 weeks after telaprevir (see Fetal/Neonatal Morbidity and Mortality under Cautions)1 Monitor women using estrogens as hormone replacement therapy for signs of estrogen deficiency1
Fosamprenavir	Ritonavir-boosted fosamprenavir: Decreased concentrations and AUCs of telaprevir and amprenavir (active metabolite of fosamprenavir)1 200	Concomitant use not recommended1 200
HMG-CoA reductase inhibitors (statins)	Atorvastatin: Increased atorvastatin concentrations and AUC;1 increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186 Lovastatin or simvastatin: Possible increased statin concentrations and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186	Atorvastatin: Avoid concomitant use1 186 Lovastatin: Concomitant use contraindicated1 186 Simvastatin: Concomitant use contraindicated1 186
Immunosuppressants (cyclosporine, sirolimus, tacrolimus)	Cyclosporine: Increased peak plasma cyclosporine concentrations (approximately 4.6-fold), and cyclosporine AUC (approximately 1.4-fold), and prolonged cyclosporine half-life (approximately fourfold);1 7 clinically important effects on telaprevir pharmacokinetics unlikely7 Sirolimus: Possible increased sirolimus concentrations1 7 Tacrolimus: Increased peak plasma tacrolimus concentrations (approximately 9.3-fold), and tacrolimus AUC (approximately 70-fold), and prolonged tacrolimus half-life (approximately fivefold); clinically important effects on telaprevir pharmacokinetics unlikely1 7	Anticipate need for substantial dosage reduction and prolongation of dosing interval for immunosuppressant agent;1 closely monitor plasma immunosuppressant concentrations and renal function;1 frequently assess for immunosuppressant-associated adverse effects1 Telaprevir not studied in organ transplantation recipients1
Lopinavir/ritonavir	Decreased telaprevir concentrations and AUC; no clinically important effect on lopinavir concentrations and AUC1 200	Concomitant use not recommended1 200
Macrolides (clarithromycin, erythromycin, telithromycin)	Increased concentrations of the macrolide and telaprevir1	Use with caution and clinical monitoring1 QT interval prolongation reported with clarithromycin, erythromycin, and telithromycin; torsades de pointes reported with clarithromycin and erythromycin1
Methadone	Decreased methadone concentrations and AUC1	Initial dosage adjustment not necessary; monitor clinically; methadone dosage adjustment may be needed in some patients1
Peginterferon alfa	Increased telaprevir exposure when administered concomitantly with peginterferon alfa and ribavirin1 No in vitro evidence of antagonistic anti-HCV effects1	Telaprevir must be administered concomitantly with peginterferon alfa and ribavirin1
Pimozide	Possible increased pimozide concentrations; potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Raltegravir	Increased raltegravir concentrations and AUC; no clinically important effect on telaprevir concentrations or AUC1 200	Dosage adjustments not needed1 200
Ribavirin	Increased telaprevir exposure when administered concomitantly with peginterferon alfa and ribavirin1 No in vitro evidence of antagonistic anti-HCV effects1	Telaprevir must be administered concomitantly with peginterferon alfa and ribavirin1
Ritonavir	Low-dose ritonavir (100 mg every 12 hours): Decreased telaprevir concentrations and AUC1	With the exception of ritonavir-boosted atazanavir,200 concomitant use with ritonavir-boosted HIV PIs not recommended1 200
St. John’s wort (Hypericum perforatum)	Possible decreased telaprevir concentrations; possible loss of virologic response1	Concomitant use contraindicated1
Salmeterol	Possible increased salmeterol concentrations and increased risk of salmeterol-associated adverse cardiovascular events (e.g., QT interval prolongation, palpitations, sinus tachycardia)1	Concomitant use not recommended1
Saquinavir	Ritonavir-boosted saquinavir: Possible pharmacokinetic interactions16	Concomitant use not recommended pending further accumulation of data200
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (hypotension, syncope, visual changes, priapism)1	Sildenafil (Revatio) for treatment of PAH: Concomitant use contraindicated1 Sildenafil for treatment of erectile dysfunction: Use reduced sildenafil dosage (do not exceed 25 mg every 48 hours);1 monitor for adverse effects1
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (hypotension, syncope, visual changes, priapism)1	Tadalafil (Adcirca) for treatment of PAH: Concomitant use contraindicated1 Tadalafil for treatment of erectile dysfunction: Use reduced tadalafil dosage (do not exceed 10 mg every 72 hours);1 monitor for adverse effects1
Tenofovir	Increased tenofovir concentrations and AUC; no clinically important effect on telaprevir concentrations and AUC1 200	Increased clinical and laboratory monitoring warranted;1 200 discontinue tenofovir if tenofovir-associated toxicities occur1
Tipranavir	Ritonavir-boosted tipranavir: Possible pharmacokinetic interactions16	Concomitant use not recommended pending further accumulation of data200
Trazodone	Possible increased trazodone concentrations may result in nausea, dizziness, hypotension, and syncope1	Use with caution;1 consider lower trazodone dosage1
Vardenafil	Possible increased vardenafil concentrations 1	Use reduced vardenafil dosage (do not exceed 2.5 mg every 72 hours)1 QT interval prolongation reported with vardenafil; use with caution and monitor clinically 1
Zolpidem	Decreased zolpidem concentrations and AUC1	Monitor clinically and titrate zolpidem dosage to achieve desired clinical response1

Telaprevir Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained approximately 4–5 hours after an oral dose.¹

P-glycoprotein substrate.¹

Most likely absorbed in small intestine; no evidence of absorption in colon.¹

Food

Food increases telaprevir exposure by 117, 237, and 330% when given with a low-fat (249 kcal, 3.6 g fat), standard-fat (533 kcal, 21 g fat), or high-fat meal (928 kcal, 56 g fat), respectively.¹

Special Populations

Steady-state exposure to telaprevir was 15% lower in HCV-negative individuals with mild (Child-Pugh class A) hepatic impairment compared with individuals with normal hepatic function.¹ Steady-state exposure to telaprevir was 46% lower in non-HCV-infected individuals with moderate (Child-Pugh class B) hepatic impairment compared with individuals with normal hepatic function.¹

In previously-treated patients, pharmacokinetic profile similar in those with and without cirrhosis.¹

After a single 750-mg telaprevir dose, the least square mean peak plasma concentration and AUC were 3% and 21% higher in HCV-negative individuals with severe renal impairment (Cl_cr <30 mL/minute) compared with healthy individuals.¹

Population pharmacokinetic analysis indicates age (range 19–70 years), gender, and race do not effect exposure.¹

Distribution

Extent

Preclinical data indicate that first-pass hepatic uptake results in higher telaprevir concentrations in the liver than in plasma.¹¹

Plasma Protein Binding

Approximately 59–76%; primarily α-1-acid glycoprotein and albumin. ¹

Plasma protein binding decreases with increasing telaprevir concentrations.¹

Elimination

Metabolism

Telaprevir interconverts to the R-diastereomer (VRT-127394) which is approximately 30-fold less active than telaprevir.¹

Extensively metabolized in the liver by hydrolysis, oxidation, and reduction; primary metabolites in plasma are the R-diastereomer, pyrazinoic acid, and the product of α-ketoamide reduction (inactive).¹

CYP3A4 is the major CYP isoenzyme responsible for telaprevir metabolism; non-CYP metabolism likely also involved after multiple doses.¹

Elimination Route

Eliminated primarily by liver.¹ Excreted in feces (82%) and exhaled (9%) primarily as metabolites; only 1% eliminated in urine.¹

Half-life

Approximately 9–11 hours at steady state; 4–4.7 hours after single dose.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Keep bottle tightly closed; use within 28 days of opening bottle.¹

Actions and Spectrum

• Direct-acting antiviral (DAA) agent active against HCV.¹

• The α-ketoamide functional group of telaprevir reversibly binds the active serine site of HCV NS3 protease, thereby blocking proteolytic cleavage of NS4A, NS4B, NS5A, and NS5B from the HCV-encoded polyprotein and inhibiting HCV replication in host cells.^{1 6 11}

• Causes biphasic viral decline; rapid first-phase occurs during first few days of treatment, followed by second phase of prolonged viral decline.^{10 12}

• Has in vitro activity against HCV genotypes 1a, 1b, and 2, but is less active against genotypes 3a and 4a.^{1 5}

• Certain amino acid substitutions (mutations) in the HCV NS3 protease domain (V36A/M, T54A/S, R155K/T, A156S/V/T, R155T with D168N, V36A with T54A, B36M/A with R155K/T, T54S/A with A156S/T) have been associated with reduced in vitro susceptibility to telaprevir.^{1 15}

• Majority of HCV isolates from patients in phase 3 clinical studies who did not achieve sustained virologic response (SVR) had treatment-emergent resistance mutations.¹ Clinical impact of prior exposure to HCV protease inhibitors (including telaprevir) is not known.¹

• HCV isolates with treatment-emergent telaprevir resistance mutations with decreased in vitro susceptibility or cross-resistance to other HCV NS3/4A protease inhibitors (e.g., boceprevir) reported.^{1 15} Cross-resistance not expected between telaprevir and interferon, or ribavirin.¹

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Importance of using telaprevir in conjunction with peginterferon and ribavirin; not for monotherapy.¹

• Importance of taking each dose within 30 minutes after eating food that contains approximately 20 grams of fat (e.g., bagel with cream cheese, half-cup nuts, 3 tablespoons peanut butter, 1 cup ice cream, 2 ounces American or cheddar cheese, 2 ounces potato chips, half-cup trail mix).¹

• If a missed dose is remembered within 4 hours of the scheduled time, advise patient to take the missed dose with food and then resume normal dosing schedule.¹ If a missed dose is remembered more than 4 hours after the originally scheduled time, advise patient to skip the missed dose.¹

• Possibility of serious skin reactions.¹ Patients should report any skin changes or symptoms (e.g., rash with or without itching, blisters or skin lesions, mouth sores or ulcers, red or inflamed eyes, facial swelling, fever) to their healthcare provider who will decide whether telaprevir should be discontinued.¹

• Effect of HCV treatment on transmission of HCV unknown; patients should take appropriate precautions to prevent transmission.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise men and women of importance of using effective contraception during and for 6 months after ribavirin therapy.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Telaprevir

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	375 mg	Incivek	Vertex