Telaprevir

Pronunciation: tel-A-pre-vir
Class: Antiviral agent

Trade Names

Incivek
- Tablets, oral 375 mg

Pharmacology

Inhibits hepatitis C virus (HCV) NS3/4A serine protease necessary for the proteolytic cleavage of the HCV-encoded polyprotein into mature forms that are essential for viral replication.

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Pharmacokinetics

Absorption

T max is between 4 and 5 h. C max and AUC are approximately 3,510 ng/mL and 22,300 ng•h/mL, respectively. Administration with a standard-fat meal increases AUC 237%; telaprevir should be administered with food (not low fat).

Distribution

Approximately 59% to 76% protein bound. Vd is approximately 252 L.

Metabolism

Extensively metabolized in the liver by hydrolysis, oxidation, and reduction to multiple metabolites; CYP3A4 plays a major role in the metabolism.

Elimination

Mean elimination half-life after 750 mg single dose is 4 to 4.7 h. The effective half-life is 9 to 11 h at steady state. Apparent total Cl is 32.4 L/h. Approximately 82% is recovered in the feces, 9% exhaled in the air, and 1% in urine.

Special Populations

Renal Function Impairment

C max and AUC increased 3% and 21%, respectively, in patients with severe renal impairment.

Hepatic Function Impairment

Steady-state exposure was reduced 15% and 46% in patients with mild and moderate hepatic impairment, respectively, compared with healthy subjects.

Elderly

Age did not have a clinically relevant effect on the exposure to telaprevir.

Children

Pharmacokinetics have not been evaluated.

Gender

No dosage adjustment is necessary based on gender.

Race

Race had no apparent effect on the exposure to telaprevir.

Indications and Usage

Treatment of genotype 1 chronic HCV in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naive or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers.

Contraindications

Women who are or may become pregnant; men whose female partners are pregnant; coadministration with alfuzosin, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin), midazolam oral, pimozide, rifampin, sildenafil ( Revatio ) or tadalafil ( Adcirca ) when used for treatment of pulmonary arterial hypertension (PAH), St. John's wort, and triazolam.

Dosage and Administration

Chronic hepatitis C
Adults

PO 750 mg 3 times daily (7 to 9 h apart) in combination with peginterferon alfa and ribavirin.

Discontinuation of therapy

If HCV RNA level is more than 1,000 units/mL at wk 4 or 12, discontinue triple therapy (peginterferon alfa, ribavirin, and telaprevir); if HCV RNA level is detectable at wk 24, discontinue dual therapy (peginterferon alfa and ribavirin). If peginterferon alfa or ribavirin is discontinued for any reason during therapy, telaprevir must also be discontinued.

Duration of therapy Treatment-naive or prior relapse patients

Administer triple therapy (peginterferon alfa, ribavirin, and telaprevir) for the first 12 wk. In patients with an undetectable HCV RNA level at wk 4 and 12, continue dual therapy (peginterferon alfa and ribavirin) for an additional 12 wk (treatment-naive patients with cirrhosis may benefit from 36 wk of dual therapy); for HCV RNA 1,000 units/mL or less at wk 4 and/or 12, continue dual therapy (peginterferon alfa and ribavirin) for an additional 36 wk.

Prior partial and null responders

Administer triple therapy (peginterferon alfa, ribavirin, and telaprevir) for the first 12 wk and continue dual therapy (peginterferon alfa and ribavirin) for an additional 36 wk.

General Advice

  • Do not administer telaprevir as monotherapy; telaprevir must only be used with peginterferon alfa and ribavirin.
  • Administer with food that contains approximately 20 g of fat (not low fat) within approximately 30 min prior to each dose.
  • To prevent treatment failure, the dose of telaprevir must not be reduced or interrupted.
  • If a dose is missed within 4 h of the time it is usually taken, the dose should be taken as soon as possible. If more than 4 h have passed since the last dose is usually taken, the missed dose should not be taken and the patient should resume the usual schedule.

Storage/Stability

Store between 59° and 86°F. Once the bottle is opened, use within 28 days.

Drug Interactions

Alfuzosin, atorvastatin, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), lovastatin, pimozide, simvastatin, St. John's wort

Plasma concentrations of these agents may be elevated, increasing the risk of serious and/or life-threatening adverse events. Coadministration with telaprevir is contraindicated. Coadministration of telaprevir is contraindicated when sildenafil or tadalafil is used for the treatment of PAH.

Antiarrhythmic agents (eg, amiodarone, bepridil, flecainide, lidocaine [systemic], propafenone, quinidine)

Antiarrhythmic plasma concentrations may be elevated, increasing the risk for serious and/or life-threatening adverse events. Use with caution. Therapeutic concentration monitoring of these agents is recommended.

Anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin)

Telaprevir concentrations may be decreased, carbamazepine concentrations may be elevated, and phenobarbital or phenytoin concentrations may be increased or decreased. Coadminister with caution.

Antidepressants (eg, desipramine, trazodone)

Desipramine and trazodone plasma concentrations may be elevated, increasing the risk of adverse reactions (eg, hypotension, syncope). Use with caution and consider a lower antidepressant dose.

Atazanavir/Ritonavir

Coadministration may result in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure may be increased. Clinical and laboratory monitoring is warranted.

Azole antifungal agents (eg, itraconazole, ketoconazole, posaconazole, voriconazole)

Telaprevir concentrations may be elevated. Itraconazole, ketoconazole, and posaconazole plasma concentrations may be elevated. Voriconazole concentrations may be increased or decreased. When coadministered with telaprevir, high doses of itraconazole or ketoconazole (greater than 200 mg/day) are not recommended. QT interval prolongation and torsades de pointes have been reported. Avoid coadministration of voriconazole.

Benzodiazepines (eg, alprazolam, midazolam, triazolam)

Benzodiazepine concentration may be elevated. Coadministration of oral midazolam and triazolam is contraindicated. Coadministration of midazolam IV with telaprevir should be done in a setting that ensures clinical monitoring and appropriate management in case of respiratory depression and/or prolonged sedation. Midazolam dose reduction should be considered, especially if more than a single midazolam dose is administered.

Bosentan, calcium channel blockers (eg, amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil)

Plasma concentrations of these agents may be increased. Coadminister with caution and close clinical monitoring. A dose reduction for amlodipine should be considered.

Colchicine

Colchicine plasma concentrations may be elevated, increasing the risk of toxicity. Patients with hepatic or renal impairment should not receive colchicine with telaprevir. A reduction in colchicine dosage or an interruption in colchicine treatment is recommended in patients with healthy hepatic or renal function.

Treatment of gout flares with colchicine during treatment with telaprevir

Give colchicine 0.6 mg for 1 dose, followed by colchicine 0.3 mg 1 h later. Not to be repeated before 3 days.

Prophylaxis of gout flares with colchicine during treatment with telaprevir

If the original regimen was colchicine 0.6 mg twice daily, reduce the dosage to colchicine 0.3 mg once daily. If the original regimen was colchicine 0.6 mg once daily, reduce the dosage to colchicine 0.3 mg once every other day.

Treatment of familial Mediterranean fever with colchicine during coadministration of telaprevir

The max daily dose of colchicine is 0.6 mg, which may be given once daily or as colchicine 0.3 mg twice daily.

Corticosteroids, inhaled (eg, budesonide, fluticasone); corticosteroids, systemic (eg, dexamethasone, methylprednisolone, prednisone)

Corticosteroid concentrations may be increased. Coadministration with budesonide, fluticasone, methylprednisolone, and prednisone not recommended. Systemic dexamethasone may decrease telaprevir concentrations, reducing the virologic response. Use dexamethasone with caution or consider alternative therapy.

Darunavir/ritonavir, fosamprenavir/ritonavir

Steady-state exposure to telaprevir and these agents may be reduced. Coadministration of telaprevir and these agents is not recommended.

Digoxin

Digoxin concentrations may be elevated. Start digoxin therapy with the lowest dose. Monitor digoxin serum concentrations for dose titration to obtain the desired clinical effect.

Efavirenz

Steady-state exposure to telaprevir and efavirenz may be reduced, decreasing the virologic response. Clinical and laboratory monitoring is warranted.

Escitalopram

Escitalopram concentrations may be reduced. Monitor the clinical response. Escitalopram dose adjustments may be needed.

Hormonal contraceptives (eg, ethinyl estradiol/norethindrone)

Exposure to ethinyl estradiol may be reduced, decreasing the efficacy. Two effective methods of nonhormonal contraception should be used during treatment with telaprevir. Patients using estrogens as hormone replacement therapy should be monitored for signs of estrogen deficiency.

Immunosuppressive agents (eg, cyclosporine, sirolimus, tacrolimus)

Cyclosporine and tacrolimus plasma concentrations may be markedly increased. Sirolimus concentrations may be increased. Tacrolimus may prolong the QT interval. Immunosuppressant dose reduction and prolongation of the dosing interval to achieve the desired blood levels should be anticipated. Close monitoring of immunosuppressant blood concentrations and frequent assessment of renal function and immunosuppressant-related adverse effects are warranted.

Lopinavir/Ritonavir

Steady-state exposure to telaprevir may be reduced. Coadministration of telaprevir and lopinavir/ritonavir is not recommended.

Macrolide antibiotics (eg, clarithromycin, erythromycin, telithromycin)

Plasma concentrations of telaprevir and macrolide antibiotics may be increased. QT interval prolongation and torsades de pointes have been reported. Coadminister with caution. Clinical monitoring is recommended.

Methadone

Methadone plasma concentrations may be reduced.

PDE5 inhibitors (eg, sildenafil, tadalafil, vardenafil) Treatment of PAH (sildenafil or tadalafil)

The risk for PDE5 inhibitor–associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope, may be increased. Coadministration of telaprevir and sildenafil or tadalafil is contraindicated.

Treatment of erectile dysfunction

During coadministration of telaprevir, do not exceed the following doses:

Sildenafil

25 mg at a single dose in 48 h.

Tadalafil

10 mg at a single dose in 72 h.

Vardenafil

2.5 mg at a single dose in 72 h. Use with caution and monitor for PDE5 inhibitor–associated adverse events. QT interval prolongation has been reported with vardenafil.

Rifamycins (eg, rifabutin, rifampin)

Rifabutin and rifampin may reduce telaprevir plasma concentrations, decreasing the virologic response. Rifabutin concentrations may be increased. Coadministration of rifampin and telaprevir is contraindicated. Coadministration of rifabutin with telaprevir is not recommended.

Salmeterol

Salmeterol concentrations may be elevated. Coadministration is not recommended.

Tenofovir disoproxil fumarate

Tenofovir exposure may be increased. Increased clinical and laboratory monitoring is warranted. Discontinue tenofovir if toxicity develops.

Warfarin

Warfarin concentrations may be altered. Closely monitor INR and adjust the warfarin dose as needed.

Zolpidem

Zolpidem plasma concentrations may be reduced.

Adverse Reactions

The following adverse reactions were reported with peginterferon alfa, ribavirin, and telaprevir combination therapy.

CNS

Fatigue (56%); dysgeusia (10%).

Dermatologic

Rash (56%); pruritus (47%).

GI

Nausea (39%); diarrhea (26%); vomiting (13%); hemorrhoids (12%); anorectal discomfort (11%); anal pruritus (6%).

Hematologic

Anemia (36%).

Lab Tests

Elevated uric acid level (73%); decreased platelets (47%); elevated bilirubin (41%); decreased lymphocytes (15%); decreased ANC (12%); decreased white cell count (8%); decreased hemoglobin.

Precautions

Monitor

Monitor HCV RNA levels at wk 4 and 12, and as clinically indicated. Hematology evaluations (including white cell differential count) are recommended at wk 2, 4, 8, and 12, or as clinically appropriate thereafter. Hemoglobin should be monitored prior to and at least every 4 wk during therapy. Chemistry evaluations (eg, bilirubin, electrolytes, hepatic enzymes, serum creatinine, TSH, uric acid) are recommended as frequently as the hematology evaluations or as clinically indicated.


Pregnancy

Category X (peginterferon, ribavirin, and telaprevir); Category B (telaprevir). Combination therapy may cause fetal harm.

Lactation

Undetermined. Discontinue breast-feeding prior to initiation of treatment.

Children

Safety and efficacy not established.

Elderly

Administer with caution, reflecting greater frequency of decreased hepatic function.

Hepatic Function

Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment, or in patients with decompensated liver disease.

Special Risk Patients

Safety and efficacy not established in patients coinfected with HCV/HIV or HCV/hepatitis B virus, or in solid organ transplant patients.

Anemia

The addition of telaprevir to peginterferon alfa and ribavirin is associated with additional decreases in hemoglobin, compared with treatment with peginterferon alfa and ribavirin alone.

Rash

May occur. A severe rash (eg, a generalized rash, rash with vesicles or bullae or ulcerations other than Stevens-Johnson syndrome) was also reported and may have an eczematous component. Discontinue telaprevir if any rash becomes severe or if systemic symptoms develop and do not restart. Rash should not be treated with systemic corticosteroids; oral antihistamines and/or topical corticosteroids may be used to provide symptomatic relief.

Re-treatment

There are no additional data in re-treating patients who have failed on an HCV NS3/4A protease inhibitor–based treatment nor are there data on repeated courses of telaprevir.

Serious skin reactions

Drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome have been reported and required hospitalization.

Overdosage

Symptoms

Decreased appetite, diarrhea, dysgeusia, headache, nausea, vomiting.

Patient Information

  • Advise patients that extreme care must be taken to avoid pregnancy in women and in female partners of men during treatment, and for 6 mo after completion of all treatment. Counsel women of childbearing potential about use of effective contraception (2 methods) prior to initiating treatment. Advise patients (men and women) to notify their health care provider immediately in the event of a pregnancy.
  • Advise patients that hormonal contraceptives may not be reliable during telaprevir dosing and for up to 2 wk following cessation of telaprevir. During this time, women of childbearing potential should use 2 nonhormonal methods of effective birth control. Examples of nonhormonal methods of contraception include the following: a male condom with spermicidal jelly, female condom with spermicidal jelly (a combination of a male condom and a female condom is not suitable), a diaphragm with spermicidal jelly, a cervical cap with spermicidal jelly, or an intrauterine device (IUD).
  • Inform patients that telaprevir combination treatment may cause rash. The rash can be severe and may be accompanied by fever and skin breakdown. Patients should promptly report any skin changes or itching to their health care provider. Patients should not stop telaprevir because of rash unless instructed by their health care provider.
  • Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions should be taken to prevent transmission of HCV during treatment or in the event of treatment failure.
  • Advise patients that telaprevir must be administered in combination with peginterferon alfa and ribavirin. If peginterferon alfa and/or ribavirin is discontinued for any reason, telaprevir must also be discontinued.
  • Advise patients that the dose of telaprevir must not be reduced or interrupted because it may increase the possibility of treatment failure. Advise patients that the fat content of the meal or snack is critical for the absorption of telaprevir. Food that is taken with telaprevir should be ingested within 30 min prior to each telaprevir dose. Examples of some foods that could be taken with telaprevir include the following: a bagel with cream cheese, ½ cup nuts, 3 tbsp peanut butter, 1 cup ice cream, 2 oz American or cheddar cheese, 2 oz potato chips, or ½ cup trail mix.
  • Inform patients that if a dose of telaprevir is missed within 4 h of the time it is usually taken, to take the prescribed dose of telaprevir with food as soon as possible. If more than 4 h has passed since telaprevir is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

Copyright © 2009 Wolters Kluwer Health.

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