FDA Notifications

HCV virus protease inhibitor is approved

On May 23, 2011, the Food and Drug Administration approved telaprevir (Incivek®), an hepatitis C virus (HCV) protease inhibitor. Telaprevir is the second direct acting antiviral drug against the hepatitis C virus to be approved.

Telaprevir, in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve (patients who have not received interferon-based drug therapy for their infection) or who have previously been treated with interferon-based treatment and not responded adequately, including prior null responders, partial responders, and relapsers.

The current standard of care for patients with hepatitis C infection is peginterferon alfa and ribavirin taken for 48 weeks. Less than 50 percent of patients respond to this therapy.

The following points should be considered when initiating treatment with telaprevir:

• Telaprevir must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin.

• A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with telaprevir combination treatment.

• Telaprevir efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes telaprevir or other HCV NS3/4A protease inhibitors.

DOSAGE AND ADMINISTRATION:

Telaprevir/Peginterferon Alfa/Ribavirin Combination Treatment:

The recommended dose of telaprevir tablets is 750 mg (two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food (not low fat).

For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information.

Duration of Treatment:

The recommended duration of treatment with telaprevir is 12 weeks in combination with peginterferon alfa and ribavirin. HCV-RNA levels should be monitored at weeks 4 and 12 to determine combination treatment duration and assess for treatment futility.

CONTRAINDICATIONS :

Telaprevir combination treatment is contraindicated in:

• Pregnant women and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.

• Telaprevir is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index).

• Telaprevir is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir.

• The contraindicated medications include the following:

— Alfuzosin

— Rifampin

— Dihydroergotamine

— Ergonovine, ergotamine, methylergonovine

— Cisapride

— St John's Wort (Hypericum perforatum)

— Atorvastatin, lovastatin, simvastatin

— Pimozide

— Sildenafil (Revatio®) or tadalafil (Adcirca®) [for treatment of pulmonary arterial hypertension].

WARNINGS AND PRECAUTIONS:

The Warnings and Precautions for telaprevir include drug interactions and the following:

• Pregnancy (Use with Ribavirin and Peginterferon Alfa): Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy and have monthly pregnancy test and for six months after treatment ends. Hormonal contraceptives may not be reliable during telaprevir dosing and for up to two weeks following cessation of telaprevir. During this time, female patients of childbearing potential should use 2 non-hormonal methods of effective birth control. Examples of non-hormonal methods of contraception include a male condom with spermicidal jelly or 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).

• Serious Skin Reactions: Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS) were reported in less than 1% of subjects who received telaprevir combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all patients recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).

If a serious skin reaction occurs, all components of telaprevir combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care.

• Rash: Rash developed in 56% of subjects who received telaprevir combination treatment. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received telaprevir combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component.

Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, telaprevir should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of telaprevir discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. Telaprevir must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended.