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INDICATIONS AND USAGE

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 or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers.

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

• Telaprevir must not be administered as monotherapy.
• A high proportion of previous null responders 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.

PEGASYS^® (peginterferon alfa-2a), alone or in combination with COPEGUS^® (ribavirin, USP), is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Efficacy has been demonstrated in subjects with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and in adult subjects with clinically stable HIV disease and CD4 count >100 cells/mm³.

The following points should be considered when initiating therapy with PEGASYS and COPEGUS:

• Use of PEGASYS monotherapy is not recommended for treatment of CHC unless a patient has a contraindication to or significant intolerance to ribavirin. Combination therapy provides substantially better response rates than monotherapy.
• Safety and efficacy have not been demonstrated for treatment longer than 48 weeks.
• The safety and efficacy have not been established in liver or other organ transplant recipients.

IMPORTANT SAFETY INFORMATION

Alpha interferons, including PEGASYS, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy.

Use with ribavirin. Ribavirin, including COPEGUS^®, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. [See COPEGUS Package Insert for additional information and other WARNINGS.]

DOSE REDUCTION for telaprevir

To prevent treatment failure, the dose of telaprevir must not be reduced or interrupted. Refer to the respective prescribing information for dose modification of peginterferon alfa and ribavirin.

DOSE MODIFICATION

If severe adverse reactions or laboratory abnormalities develop during combination PEGASYS/COPEGUS therapy, the dose should be modified until the adverse reactions abate. If intolerance persists after dose adjustment, PEGASYS/COPEGUS therapy should be discontinued. Refer to the full prescribing information for guidelines pertaining to dose modifications and discontinuation of PEGASYS/COPEGUS based on laboratory abnormalities, patients depression status, and cardiac status.

In patients with CrCL less than 30 mL/min, including patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 mcg PEGASYS is recommended. Signs and symptoms of interferon toxicity should be closely monitored. Renal function should be evaluated in all patients on COPEGUS. COPEGUS should be reduced for patients with creatinine clearance <50 mL/min. No data are available for pediatric patients with renal impairment.

DISCONTINUATION OF DOSING

• Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions. Discontinuation of therapy is recommended in all patients with (1) HCV-RNA levels of greater than or equal to 1000 IU/mL at Treatment Week 4 or 12; or (2) confirmed detectable HCV-RNA levels at Treatment Week 24.
• Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log₁₀ reduction from baseline in HCV RNA titer by 12 weeks of therapy or undetectable HCV RNA after 24 weeks of therapy.
• During treatment, patients clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation is observed.
• Patients should be monitored for serious adverse events, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn.
• If peginterferon alfa or ribavirin is discontinued for any reason, telaprevir must also be discontinued.

CONTRAINDICATIONS

Telaprevir in combination with peginterferon alfa and ribavirin is contraindicated:

• in women who are or may become pregnant.
• in men whose female partners are pregnant.

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.
• when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir.
• in combination with: alfuzosin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. Johns wort (Hypericum perforatum), atorvastatin, lovastatin, simvastatin, pimozide, sildenafil (Revatio^®) or tadalafil (Adcirca^®) [for treatment of pulmonary arterial hypertension]^a, orally administered midazolam^a, triazolam

^a

See telaprevir full prescribing information Drug Interactions for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction and for parenterally administered midazolam.

Contraindications to peginterferon alfa and ribavirin also apply to telaprevir combination treatment.

PEGASYS is contraindicated in patients with:

• Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome to alpha interferons, including PEGASYS, or any of its components
• Autoimmune hepatitis
• Hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before treatment
• Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before treatment
• PEGASYS is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications in neonates and infants, which are sometimes fatal.

PEGASYS/COPEGUS combination therapy is additionally contraindicated in:

• Women who are pregnant (PEGASYS: Category C; COPEGUS: Category X)
• Men whose female partners are pregnant
• Patients with known hypersensitivity (urticaria, angioedema, bronchoconstriction, and anaphylaxis) to COPEGUS or to any component of the tablet
• Patients with hemoglobinopathies (e.g., thalassemia major, sicklecell anemia)
• Combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.

WARNINGS AND PRECAUTIONS

Because telaprevir must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy.

Pregnancy: Use with Ribavirin and Peginterferon Alfa

Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking PEGASYS and COPEGUS combination therapy. COPEGUS therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time.

Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.

Female Patients

Hormonal contraceptives may be continued but 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 two effective non-hormonal methods of contraception. Two weeks after completion of telaprevir treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives.

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 (eg, hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (eg, 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 (eg, 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.

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. 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. Treatment of rash with systemic corticosteroids is not recommended.

Anemia

Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of telaprevir to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. Hemoglobin should be monitored prior to and at least every 4 weeks during telaprevir combination treatment. For the management of anemia, ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of telaprevir should be considered. If ribavirin is permanently discontinued for the management of anemia, telaprevir must also be permanently discontinued.

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by COPEGUS. Patients should be assessed for underlying cardiac disease before initiation of COPEGUS therapy. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS.

Drug Interactions

Co-administration of telaprevir combination treatment with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of telaprevir. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions.

Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn:

• Neuropsychiatric reactions (suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction and drug overdose)
• Cardiovascular disorders (hypertension, supraventricular arrhythmias, chest pain and myocardial infarction)
• Bone marrow suppression (severe cytopenias and, rarely, aplastic anemia). Pancytopenia has been reported with concomitant use of azathioprine.
• Autoimmune disorders (including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus)
• Endocrine disorders (hypothyroidism, hyperthyroidism, hyperglycemia, hypoglycemia and diabetes mellitus)
• Ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment)
• Cerebrovascular events (ischemic and hemorrhagic cerebrovascular events)
• Hepatic failure (chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation and death)
• Pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths)
• Infections (bacterial, viral, or fungal), some fatal
• Colitis (ulcerative and hemorrhagic/ischemic colitis), sometimes fatal.
• Pancreatitis, sometimes fatal.
• Hypersensitivity (eg, urticaria, angioedema, bronchoconstriction, and anaphylaxis) and serious skin reactions, including Stevens-Johnson syndrome.
• Impact on growth in pediatric patients (delay in weight and height increases after 48 weeks of therapy)
• Peripheral neuropathy (in combination with telbivudine)

ADVERSE REACTIONS

Serious adverse drug reactions occurred in 3% of subjects who received telaprevir combination treatment compared to none of the subjects treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with telaprevir combination treatment were skin disorders (rash and/or pruritus) and anemia. Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of telaprevir.

The most common adverse drug reactions to telaprevir combination therapy (incidence at least 5% higher with telaprevir than in controls) were rash, pruritus, anemia, nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue, vomiting, and anal pruritus.

Adult Patients:

The most common life-threatening or fatal events induced or aggravated by PEGASYS and COPEGUS include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects.

The most common serious adverse event for PEGASYS with or without COPEGUS was bacterial infection (eg, sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other serious adverse events occurred at a frequency of <1% and included: suicide, suicidal ideation, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (eg, hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

In clinical trials, 98 to 99 percent of subjects experienced one or more adverse events. For hepatitis C subjects, the most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus.

Pediatric Patients:

In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most prevalent adverse events in subjects treated with combination therapy for up to 48 weeks with PEGASYS and COPEGUS were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Most of the adverse events reported in the study were mild or moderate in severity. Severe adverse events were reported in 2 subjects in the PEGASYS plus COPEGUS combination therapy group (hyperglycemia and cholecystectomy). Pediatric subjects treated with PEGASYS plus COPEGUS showed a delay in weight and height increases after 48 weeks of therapy; most had returned to baseline normative growth curve percentiles for weight and height at two years of follow-up.

Please see telaprevir full Prescribing Information for additional important safety information.

Please see PEGASYS full Prescribing Information for boxed WARNINGS and additional important safety information.

PEGASYS^® and COPEGUS^® are registered trademarks of Hoffmann-La Roche Inc. All other brands for listed products are trademarks or registered trademarks (as indicated) of their respective owners and are not trademarks of Genentech, Inc. or Hoffmann-La Roche Inc.