Medication Guide App

Generic Name: 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

Introduction

Antiviral; HCV NS3/4A protease inhibitor (PI).1 5 11

Uses for Incivek

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 those with prior null response, partial response, or relapse).1 2 3 17

Slideshow: Harvoni, Sovaldi, Olysio and the Evolving Treatment of HCV

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

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 PI.1

Safety and efficacy not established in chronic HCV patients with 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.119 Information from the American Association for the Study of Liver Diseases (AASLD), IDSA, and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including current recommendations for initial treatment, is available at .119

Incivek 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

Ensure that patient is well hydrated during telaprevir, peginterferon alfa, and ribavirin therapy.1

If a missed telaprevir 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 missed dose is not remembered within 4 hours, skip the dose and resume regular dosing schedule.1

Dosage

Do not reduce telaprevir dosage for any reason.1 If discontinued because of serious adverse effects (see Dermatologic Reactions 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 Clcr ≤50 mL/minute, including patients with end-stage renal disease or receiving hemodialysis.1

Cautions for Incivek

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

Warnings

Dermatologic Reactions

Risk of serious (sometimes fatal) skin reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).1 4 14 21 Fatalities reported in some patients with progressive rash and systemic symptoms who continued to receive telaprevir combination regimen after serious skin reaction identified.1 14

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 is a common adverse reaction associated with telaprevir;1 generally appears during first 4 weeks of treatment, but can occur at any time.1 21 Skin reactions frequently present as pruritic, eczematous dermatitis with spongiotic pattern as predominant histologic finding.21

Genetic or demographic risk factors for telaprevir-associated dermatitis or more severe dermatologic reactions (e.g., DRESS, SJS) not clearly identified to date.21

If serious skin reaction occurs, including progressive severe rash or rash with systemic symptoms (e.g., fever, nausea, diarrhea, mouth sores/ulcerations, facial edema, red or inflamed eyes, liver inflamation), immediately discontinue telaprevir, peginterferon alfa, and ribavirin and promptly refer patient for urgent medical care.1 14 Consider discontinuing other drugs that may be associated with serious dermatologic reactions.1 14

If mild to moderate rash occurs, monitor patient for progression of rash or development of systemic symptoms.1 Discontinue telaprevir if rash progresses or becomes severe or if systemic symptoms develop; peginterferon alfa and ribavirin may be continued.1 If improvement not observed within 7 days of discontinuing telaprevir, consider sequential or simultaneous interruption or discontinuance of peginterferon alfa and/or ribavirin.1 Consider earlier interruption or discontinuance of peginterferon alfa and ribavirin if medically indicated.1 Monitor patient until rash resolves.1

Do not reduce telaprevir dosage and do not restart telaprevir if it was discontinued because of rash.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 21 Use of systemic corticosteroids not recommended (see Interactions).1

Other Warnings and Precautions

Hematologic Effects

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

Decreased hemoglobin generally occurs during first 4 weeks of treatment with telaprevir, peginterferon alfa, and ribavirin; nadir usually observed at completion of 12-week telaprevir regimen.1 Hemoglobin ≤10 g/dL occurs earlier and more frequently with a combination regimen containing telaprevir than a regimen of peginterferon alfa and ribavirin.1 Anemia requiring ribavirin dosage reduction, blood transfusion, and/or administration of an erythropoiesis-stimulating agent has occurred as soon as 10 days after initiation a telaprevir-containing regimen.1 Following telaprevir discontinuance, hemoglobin gradually returns to levels generally observed during peginterferon alfa and ribavirin therapy.1

Assess hemoglobin prior to, at least at weeks 2, 4, 8, and 12 during telaprevir therapy, and as clinically indicated.1 Consider earlier and more frequent monitoring in some patients.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

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 alfa, 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

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 and Administration.)

Monitor hematology tests (including hemoglobin, WBC differential, and platelet 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 Clcr <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 Incivek

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

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

Inhibits organic anion transport polypeptides (OATP) 1B1 and 2B1; not a substrate for OATP1B1 or OATP2B1.1

Not a substrate for breast cancer resistance protein (BCRP) or multidrug resistance protein (MRP) 2; does not inhibit BCRP, MRP2, organic anion transporter (OAT) 1, or organic cation transporter (OCT) 2.1

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 adverse 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 or Affected by P-glycoprotein Transport

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

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

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

Potential pharmacokinetic interaction with drugs that are substrates for OATP1B1 or 2B1 with possible increased exposure to the concomitant drug and increased risk of adverse effects.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 24 200

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 18

Dosage adjustments not needed1 18

Calcium-channel blockers, dihydropyridines (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil)

Amlodipine: Increased amlodipine concentrations and AUC1 22

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 24 200

Concomitant use not recommended1 200

Digoxin

Increased digoxin concentrations and AUC1 19

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 24 200

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

Elvitegravir/cobicistat/emtricitabine/tenofovir

Concomitant use not recommended pending further accumulation of data200

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 20

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 20

Monitor women using estrogens as hormone replacement therapy for signs of estrogen deficiency1

Etravirine

Clinically important interaction not observed24

Fosamprenavir

Ritonavir-boosted fosamprenavir: Decreased concentrations and AUCs of telaprevir and amprenavir (active metabolite of fosamprenavir)1 24 200

Concomitant use not recommended1 200

HMG-CoA reductase inhibitors (statins)

Atorvastatin: Substantially increased atorvastatin concentrations and AUC;1 22 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

Fluvastatin, pitavastatin, pravastatin, rosuvastatin: Possible increased statin concentrations1

Atorvastatin: Avoid concomitant use1 186

Lovastatin: Concomitant use contraindicated1 186

Simvastatin: Concomitant use contraindicated1 186

Fluvastatin, pitavastatin, pravastatin, rosuvastatin: Use with caution; clinical monitoring recommended1

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 25

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 24 200

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 23

Initial dosage adjustment not necessary; monitor clinically; methadone dosage adjustment may be needed in some patients1 23

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

Repaglinide

Possible increased repaglinide concentrations1

Use with caution; clinical monitoring recommended1

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

Rilpivirine

Increased rilpivirine concentrations; no effect on telaprevir concentrations24

Dosage adjustment not warranted24

Ritonavir

Low-dose ritonavir (100 mg every 12 hours): Decreased telaprevir concentrations and AUC1 24

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

Incivek 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 (Clcr <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 (i.e., aldo-ketoreductases and other reductases, proteolytic hydrolysis) may also be 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 PIs (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 PIs (e.g., boceprevir) reported.1 15 Cross-resistance not expected between telaprevir and interferon, or ribavirin.1

Advice to Patients

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

  • Importance of taking each telaprevir 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 telaprevir 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 missed dose is remembered more than 4 hours after the originally scheduled time, advise patient to skip the missed dose.1

  • Possibility of serious, potentially fatal, skin reactions that may require hospitalization.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 health-care provider who will decide whether telaprevir should be discontinued.1 (See Dermatologic Reactions under Cautions.)

  • Importance of maintaining adequate hydration during treatment; inform patient of signs and symptoms of dehydration.1 Importance of contacting health-care provider in the event of poor fluid intake or severe vomiting and/or diarrhea.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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 4, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Vertex Pharmaceuticals Incorporated. Incivek (telaprevir) film-coated tablets prescribing information. Cambridge, MA; 2013 Apr.

2. Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011; 364:2405-16. [PubMed 21696307]

3. Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011; 364:2417-28. [PubMed 21696308]

4. Montaudié H, Passeron T, Cardot-Leccia N et al. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology. 2010; 221:303-5. [PubMed 20798484]

5. Smith LS, Nelson M, Naik S et al. Telaprevir: An NS3/4A Protease Inhibitor for the Treatment of Chronic Hepatitis C. Ann Pharmacother. 2011; 45:639-48. [PubMed 21558488]

6. Gentile I, Carleo MA, Borgia F et al. The efficacy and safety of telaprevir - a new protease inhibitor against hepatitis C virus. Expert Opin Investig Drugs. 2010; 19:151-9. [PubMed 20001560]

7. Garg V, van Heeswijk R, Eun Lee J et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology. 2011; 54:20-7. [PubMed 21618566]

8. Sarrazin C, Kieffer TL, Bartels D et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007; 132:1767-77. [PubMed 17484874]

9. Vicenti I, Rosi A, Saladini F et al. Naturally occurring hepatitis C virus (HCV) NS3/4A protease inhibitor resistance-related mutations in HCV genotype 1-infected subjects in Italy. J Antimicrob Chemother. 2012; 67:984-7. [PubMed 22258932]

10. Guedj J, Perelson AS. Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: Implications for treatment duration. Hepatology. 2011; 53:1801-8. [PubMed 21384401]

11. Perni RB, Almquist SJ, Byrn RA et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006; 50:899-909. [PubMed 16495249]

12. Forestier N, Reesink HW, Weegink CJ et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology. 2007; 46:640-8. [PubMed 17879366]

13. De Francesco R, Carfí A. Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Adv Drug Deliv Rev. 2007; 59:1242-62. [PubMed 17869377]

14. Food and Drug Administration. FDA drug safety communication: Serious skin reactions after combination treatment with the hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin. 2012 Dec 19. From FDA website.

15. Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology. 2010; 138:447-62. [PubMed 20006612]

16. Seden K, Back D, Khoo S. New directly acting antivirals for hepatitis C: potential for interaction with antiretrovirals. J Antimicrob Chemother. 2010; 65:1079-85. [PubMed 20335191]

17. Sherman KE, Flamm SL, Afdhal NH et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011; 365:1014-24. [PubMed 21916639]

18. Luo X, Trevejo J, van Heeswijk RP et al. Effect of telaprevir on the pharmacokinetics of buprenorphine in volunteers on stable buprenorphine/naloxone maintenance therapy. Antimicrob Agents Chemother. 2012; 56:3641-7. [PubMed 22564847]

19. Garg V, Chandorkar G, Farmer HF et al. Effect of telaprevir on the pharmacokinetics of midazolam and digoxin. J Clin Pharmacol. 2012; 52:1566-73. [PubMed 22162542]

20. Garg V, van Heeswijk R, Yang Y et al. The pharmacokinetic interaction between an oral contraceptive containing ethinyl estradiol and norethindrone and the HCV protease inhibitor telaprevir. J Clin Pharmacol. 2012; 52:1574-83. [PubMed 22039291]

21. Roujeau JC, Mockenhaupt M, Tahan SR et al. Telaprevir-related dermatitis. JAMA Dermatol. 2013; 149:152-8. [PubMed 23560295]

22. Lee JE, van Heeswijk R, Alves K et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother. 2011; 55:4569-74. [PubMed 21825288]

23. van Heeswijk R, Verboven P, Vandevoorde A et al. Pharmacokinetic interaction between telaprevir and methadone. Antimicrob Agents Chemother. 2013; 57:2304-9. [PubMed 23478952]

24. van Heeswijk RP, Beumont M, Kauffman RS et al. Review of drug interactions with telaprevir and antiretrovirals. Antivir Ther. 2013; :. [PubMed 23344266]

25. O'Leary JG, McKenna GJ, Klintmalm GB et al. Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients. Liver Transpl. 2013; 19:463-5. [PubMed 23408534]

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website.

186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (February 12, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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