VICTRELIS (boceprevir), Merck's Investigational Medicine, Added to Peginterferon Alfa-2a and Ribavirin Achieved Significantly Higher SVR Rates In Treatment-Failure Patients with Chronic HCV Genotype 1 Compared to Control

Update: Victrelis (boceprevir) Now FDA Approved - May 13, 2011

Results Similar to Regimen using Peginterferon Alfa-2b in HCV RESPOND-2 Study

BERLIN--(BUSINESS WIRE)--Mar 31, 2011 - Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that final results from a Phase III study of VICTRELIS™ (boceprevir), its investigational oral hepatitis C protease inhibitor, added to peginterferon alfa-2a (Pegasys®) and ribavirin therapy demonstrated significantly higher sustained virologic response (SVR)1 rates in adult patients who failed previous treatment for chronic hepatitis C virus (HCV) genotype 1 compared to a control group receiving peginterferon alfa-2a and ribavirin alone, the primary endpoint of the 48-week study. Significantly more patients in the treatment group receiving VICTRELIS achieved SVR, 64 percent (86/134) vs. 21 percent (14/67) for control, p<0.0001; and fewer patients receiving VICTRELIS relapsed after the end of treatment, 12 percent (11/95) vs. 33 percent (7/21) for control. These results were presented for the first time today as part of a late-breaker poster session [Poster #1366] at The International Liver Congress™ / 46th European Association for the Study of the Liver (EASL) annual meeting.

"In this study, the addition of VICTRELIS to peginterferon alfa-2a and ribavirin resulted in approximately a three-fold increase in sustained virologic response in patients who were previous nonresponders or relapsers to standard hepatitis C therapy," said Steven L. Flamm, M.D., professor in medicine-hepatology and surgery, Northwestern University Feinberg School of Medicine, Chicago. "These results are similar to those seen with the 48-week treatment regimen of VICTRELIS added to peginterferon alfa-2b and ribavirin in HCV RESPOND-2, a pivotal Phase III study. Taken together, these studies showed that VICTRELIS combined with either peginterferon alfa-2a or alfa-2b and ribavirin achieved significantly higher SVR rates in chronic HCV genotype 1 patients who failed prior therapy compared to peginterferon and ribavirin alone."

As published in today's edition of The New England Journal of Medicine, in the HCV RESPOND-2 study in patients who failed prior therapy, the addition of VICTRELIS to peginterferon alfa-2b (PEGINTRON®) and ribavirin in a 48-week regimen achieved an SVR rate of 66 percent (107/161) compared to 21 percent for control (17/80), p<0.0001. The relapse rate was 12 percent (14/121) for the group receiving VICTRELIS compared to 32 percent (8/25) for control.

VICTRELIS added to peginterferon alfa-2a and ribavirin

The study of VICTRELIS added to peginterferon alfa-2a and ribavirin (PEG2a/R) presented at EASL was a Phase III, placebo-controlled trial in which 201 adult patients with chronic HCV genotype 1 infection who were either relapsers or nonresponders to prior peginterferon and ribavirin therapy were randomized to one of two 48-week treatment groups in a 1:2 ratio. The control group received a 4-week lead-in of PEG2a/R followed by placebo + PEG2a/R for 44 weeks. The group treated with VICTRELIS received a 4-week lead-in of PEG2a/R followed by the addition of VICTRELIS for 44 weeks. Peginterferon alfa-2a was administered subcutaneously at a dose of 180 mcg once weekly in combination with ribavirin 1,000-1,200 mg/day orally based on patient weight in a divided daily dose. VICTRELIS was administered orally at a dose of 800 mg three times daily. Patients in the study with detectable virus (HCV-RNA) at treatment week 12 were considered treatment failures and discontinued all therapy.

HCV-RNA decline after 4-week lead-in was a stronger predictor of SVR than historical treatment response

In the study, SVR was strongly associated with a patient's response to peginterferon and ribavirin, whether defined by historical classification of response to previous treatment (SVR for prior relapsers was greater than SVR for prior nonresponders), or by a decrease in HCV-RNA at the end of the 4-week lead-in period. The lead-in allowed for an assessment of a patient's current response as compared to their historical response. Patients with good response after the lead-in, defined by a greater than or equal to 1.0-log10 decline in HCV-RNA, achieved an SVR rate of 71 percent (79/112) with VICTRELIS added to PEG2a/R compared to 25 percent (14/57) for PEG2a/R alone. Patients with poor response after the lead-in, defined by a less than 1.0-log10 decline in HCV-RNA, had an SVR rate of 39 percent (7/18) with VICTRELIS added to PEG2a/R compared to 0 percent (0/9) for PEG2a/R alone.

Consistent with results from the HCV RESPOND-2 study, response after the 4-week lead-in phase in this study was a stronger predictor of SVR than historical treatment response.

Tolerability profile

The five most common treatment-emergent adverse events in the study reported for patients receiving VICTRELIS added to PEG2a/R and control, respectively, were: fatigue (50 and 54 percent), anemia (50 and 33 percent), nausea (39 and 27 percent), dysgeusia (39 and 15 percent) and headache (28 and 31 percent). Neutropenia was reported more frequently in patients receiving VICTRELIS compared to control (31 and 18 percent, respectively). Serious adverse events were reported in 13 and 10 percent of patients in the study groups, respectively. Treatment discontinuations due to adverse events over the total course of treatment were 17 percent and 4 percent, respectively. Erythropoietin (EPO) for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 47 and 30 percent of patients in the study groups, respectively.

Merck's global commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. 2011 marks the 10-year anniversary of the introduction of PEGINTRON and ribavirin in combination therapy, a current standard therapy for chronic HCV worldwide. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis care.

About PEGINTRON

PEGINTRON is indicated for use in combination with ribavirin for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease.

The following points should be considered when initiating therapy with PEGINTRON in combination with ribavirin: (1) These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.

PEGINTRON is also indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.

The following points should be considered when initiating therapy with PEGINTRON alone: Combination therapy with ribavirin is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, ribavirin. Combination therapy provides substantially better response rates than monotherapy.

Selected Safety Information on PEGINTRON

 

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

Alpha interferons, including PEGINTRON, 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. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PEGINTRON therapy.

Use with Ribavirin: Ribavirin may cause birth defects and death of the unborn child. 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. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.

 

 

Contraindications

PEGINTRON is contraindicated in patients with known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis to interferon alpha or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment. PEGINTRON/ribavirin combination therapy is additionally contraindicated in women who are pregnant or may become pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), and patients with creatinine clearance less than 50 mL per min.

Pregnancy

Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for six months after completion of therapy. If this drug is used during pregnancy, or if a patient becomes pregnant, the patient should be apprised of the potential hazard to a fetus. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Patients with the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:

 

  • Hemolytic anemia with ribavirin
  • Neuropsychiatric events
  • History of significant or unstable cardiac disease
  • Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication
  • New or worsening ophthalmologic disorders
  • Ischemic and hemorrhagic cerebrovascular events
  • Severe decreases in neutrophil or platelet counts
  • History of autoimmune disorders
  • Pancreatitis and ulcerative or hemorrhagic/ischemic colitis and pancreatitis
  • Pulmonary infiltrates or pulmonary function impairment
  • Child-Pugh score greater than 6 (Class B and C)
  • Increased creatinine levels in patients with renal insufficiency
  • Serious, acute hypersensitivity reactions and cutaneous eruptions
  • Dental/periodontal disorders reported with combination therapy
  • Hypertriglyceridemia may result in pancreatitis (e.g., triglycerides greater than
    1000 mg/dL)
  • Weight loss and growth inhibition reported with combination therapy in pediatric patients.

Life-threatening or fatal neuropsychiatric events, including suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior, sometimes directed towards others, have occurred in patients with and without a previous psychiatric disorder during PEGINTRON treatment and follow-up.

Adverse Events

Serious adverse reactions have occurred in approximately 12 percent of subjects in clinical trials. The most common serious events occurring in subjects treated with PEGINTRON and ribavirin were depression and suicidal ideation, each occurring at a frequency of less than 1 percent. The most common fatal events occurring in subjects treated with PEGINTRON and ribavirin were cardiac arrest, suicidal ideation, and suicide attempt, all occurring in less than 1 percent of subjects.

The incidence of serious adverse reactions was comparable between PEGINTRON monotherapy (about 12 percent) and PEGINTRON/ribavirin combination therapy weight-based (12 percent) or flat-dose (17 percent). In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In a study with PEGINTRON/ribavirin (weight-based) combination therapy in adult patients, anemia with weight-based dosing occurred at an increased rate (29 percent vs. 19 percent); however, the majority of these cases were mild and responded to dose reductions. The incidence of serious adverse reactions reported for the weight-based ribavirin group was 12 percent. There were 31 deaths in clinical trials which occurred during treatment or during follow-up. Of the deaths, 19 were patients on either PEGINTRON or PEGINTRON/ribavirin combination therapy and three occurred during the follow-up period but had been on PEGINTRON/ribavirin combination therapy.

Additional serious adverse reactions seen in clinical trials at a frequency of equal to or less than 1 percent included psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection site necrosis, vasculitis, and phototoxicity.

Greater than 96 percent of all subjects in clinical trials experienced one or more adverse events. Most common adverse reactions (greater than 40 percent) in adult patients receiving either PEGINTRON or PEGINTRON/ribavirin are injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability.

The adverse reaction profile was similar between weight-based and flat-dose PEGINTRON/ribavirin therapies. Weight-based PEGINTRON/ribavirin dosing resulted in increased rates of anemia. Most common adverse reactions with PEGINTRON/ribavirin (weight-based) therapy were psychiatric, which occurred among 68-69 percent of patients and included depression, irritability, and insomnia, each reported by approximately 30-40 percent of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2 percent of all patients during treatment or during follow-up after treatment cessation. Other common reactions included injection site reactions, fatigue/ asthenia, headache, rigors, fever, nausea, myalgia, anxiety/emotional lability/irritability. The severity of some of these systemic symptoms tends to decrease as treatment continues.

Subjects receiving PEGINTRON/ribavirin as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to previous treatment-naïve patients receiving this regimen.

In general, the adverse reaction profile in the pediatric population was similar to that observed in adults. Most common adverse reactions (greater than 25 percent) in pediatric patients receiving PEGINTRON/ribavirin are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, abdominal pain, and vomiting.

Please see full prescribing information at http://www.spfiles.com/pipeg-intron.pdf.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

# # #

Please see attached Prescribing Information, Medication Guide, and Instructions for Use including Boxed Warning for PEGINTRON. The Prescribing Information, Medication Guide, and Instructions for Use are also available at http://www.spfiles.com/pipeg-intron.pdf, http://www.spfiles.com/mgpeg-intron.pdf and http://www.spfiles.com/ifupeg-intron.pdf.

 

 


1 SVR, the protocol specified primary efficacy endpoint of the studies, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.

 

 
PEGINTRON® is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

VICTRELIS is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA

Pegasys® is a trademark of its respective owner and is not a trademark of Merck & Co., Inc., Whitehouse Station, N.J., USA.

 

 
AINF-1003632-0000

 

 
 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

PegIntron safely and effectively. See full prescribing information for PegIntron.

PegIntron (Peginterferon alfa-2b) Injection, Powder for Solution for Subcutaneous Use

Initial U.S. Approval: 2001

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

See full prescribing information for complete boxed warning.

 

  • May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders. (5)

Use with Ribavirin

 

  • Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients. (5.1)
  • Ribavirin is a potential carcinogen. (5.1, 13.1)

RECENT MAJOR CHANGES

Warnings and Precautions, Pulmonary Disorders (5.11) [2/2011]

INDICATIONS AND USAGE

PegIntron is an antiviral indicated for

 

  • Combination therapy with REBETOL (ribavirin):
    Chronic Hepatitis C (CHC) in patients ‰¥3 years with compensated liver disease. (1.1)
    Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (1.1)
  • Monotherapy: CHC in patients (‰¥18 years) with compensated liver disease previously untreated with interferon alpha. (1.1)

DOSAGE AND ADMINISTRATION

 

  • PegIntron is administered by subcutaneous injection.
    PegIntron Dose (Adults)*

 

  PegIntron Dose (Pediatric Patients)   REBETOL Dose* (Adults)

 

  REBETOL Dose (Pediatric Patients)

 

PegIntron/ REBETOL Combination Therapy (2.1)

 

  1.5 mcg/kg/ week

 

  60 mcg/m2/ week

 

  800-1400 mg orally daily with food   15 mg/kg/day orally with food in 2 divided doses

* Refer to Tables 1-7 of the full Prescribing Information.

 

  • Dose reduction is recommended in patients experiencing certain adverse reactions or renal dysfunction. (2.3, 2.5)

DOSAGE FORMS AND STRENGTHS

Single-use vial (with 1.25 mL diluent) and REDIPEN® (3):

 

  • 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, 150 mcg per 0.5 mL.

CONTRAINDICATIONS

 

  • Known hypersensitivity reactions, such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis to interferon alpha or any other product component. (4)
  • Autoimmune hepatitis. (4)
  • Hepatic decompensation (Child-Pugh score >6 [class B and C]) in cirrhotic CHC patients before or during treatment. (4)

Additional contraindications for combination therapy with ribavirin:

 

  • Pregnant women and men whose female partners are pregnant. (4, 8.1)
  • Hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia). (4)
  • Creatinine clearance <50 mL/min. (4)

WARNINGS AND PRECAUTIONS

 

  • Birth defects and fetal death with ribavirin: Patients must have a negative pregnancy test prior to therapy, use at least 2 forms of contraception, and undergo monthly pregnancy tests. (5.1)

Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:

 

  • Hemolytic anemia with ribavirin. (5.1)
  • Neuropsychiatric events. (5.2)
  • History of significant or unstable cardiac disease. (5.3)
  • Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication. (5.4)
  • New or worsening ophthalmologic disorders. (5.5)
  • Ischemic and hemorrhagic cerebrovascular events. (5.6)
  • Severe decreases in neutrophil or platelet counts. (5.7)
  • History of autoimmune disorders. (5.8)
  • Pancreatitis and ulcerative or hemorrhagic/ischemic colitis and pancreatitis. (5.9, 5.10)
  • Pulmonary infiltrates or pulmonary function impairment. (5.11)
  • Child-Pugh score >6 (class B and C). (4, 5.12)
  • Increased creatinine levels in patients with renal insufficiency. (5.13)
  • Serious, acute hypersensitivity reactions and cutaneous eruptions. (5.14)
  • Dental/periodontal disorders reported with combination therapy. (5.16)
  • Hypertriglyceridemia may result in pancreatitis (e.g., triglycerides >1000 mg/dL). (5.17)
  • Weight loss and growth inhibition reported with combination therapy in pediatric patients. (5.18)
  • Peripheral neuropathy when used in combination with telbivudine. (5.19)

ADVERSE REACTIONS

Most common adverse reactions (>40%) in adult patients receiving either

PegIntron or PegIntron/REBETOL are injection site inflammation/

reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability (6.1). Most common adverse reactions (>25%) in pediatric patients receiving PegIntron/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection-site erythema, vomiting (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

 

  • Drug metabolized by CYP450: Caution with drugs metabolized by CYP2C8/9 (e.g., warfarin, phenytoin) or CYP2D6 (e.g., flecainide). (7.1)
  • Methadone: Monitor for increased narcotic effect. (7.2)
  • Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, ribavirin, or both with worsening toxicities. (7.3)
  • Didanosine: Concurrent use with REBETOL is not recommended. (7.3)

USE IN SPECIFIC POPULATIONS

 

  • Ribavirin Pregnancy Registry: 1-800-593-2214 (8.1)
  • Pediatrics: safety and efficacy in pediatrics <3 years old have not been established (8.4)
  • Geriatrics: neuropsychiatric, cardiac, pulmonary, GI, and systemic (flu-like) adverse reactions may be more severe (8.5)
  • Organ transplant: safety and efficacy have not been studied (8.6)
  • HIV or HBV co-infection: safety and efficacy have not been established (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 02/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING – RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C

2 DOSAGE AND ADMINISTRATION

2.1 PegIntron/REBETOL Combination Therapy

2.2 PegIntron Monotherapy

2.3 Dose Reduction

2.4 Discontinuation of Dosing

2.5 Renal Function

2.6 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Use with Ribavirin

5.2 Neuropsychiatric Events

5.3 Cardiovascular Events

5.4 Endocrine Disorders

5.5 Ophthalmologic Disorders

5.6 Cerebrovascular Disorders

5.7 Bone Marrow Toxicity

5.8 Autoimmune Disorders

5.9 Pancreatitis

5.10 Colitis

5.11 Pulmonary Disorders

5.12 Hepatic Failure

5.13 Patients with Renal Insufficiency

5.14 Hypersensitivity

5.15 Laboratory Tests

5.16 Dental and Periodontal Disorders

5.17 Triglycerides

5.18 Impact on Growth- Pediatric Use

5.19 Peripheral Neuropathy

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Metabolized by Cytochrome P-450

7.2 Methadone

7.3 Use with Ribavirin (Nucleoside Analogues)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Organ Transplant Recipients

8.7 HIV or HBV Co-infection

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C in Adults

14.2 Chronic Hepatitis C in Pediatrics

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Pregnancy

17.2 HCV Transmission

17.3 Laboratory Evaluations, Hydration, “Flu-like” Symptoms

17.4 Instructions for Use

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

Alpha interferons, including PegIntron, 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. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PegIntron therapy [see Warnings and Precautions (5) and Adverse Reactions (6.1)].

Use with Ribavirin

Ribavirin may cause birth defects and death of the unborn child. 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 REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. [See REBETOL package insert]

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C

Combination therapy:

PegIntron® in combination with REBETOL® (ribavirin) is indicated for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease.

The following points should be considered when initiating therapy with PegIntron in combination with REBETOL:

 

  • These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
  • Patients with the following characteristics are less likely to benefit from retreatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection [see Clinical Studies (14)].
  • No safety and efficacy data are available for treatment of longer than 1 year.

Monotherapy (for patients who are intolerant to ribavirin):

PegIntron (peginterferon alfa-2b) is indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.

The following point should be considered when initiating therapy with PegIntron alone:

 

  • Combination therapy with REBETOL is preferred over PegIntron monotherapy unless there are contraindications to or significant intolerance of REBETOL.

Combination therapy provides substantially better response rates than monotherapy [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2. 1 PegIntron/REBETOL Combination Therapy

REBETOL should be taken with food. REBETOL should not be used in patients with creatinine clearance <50 mL/min.

Adults

The recommended dose of PegIntron is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg of REBETOL orally based on patient body weight. The volume of PegIntron to be injected depends on the strength of PegIntron and patient's body weight (see Table 1).

Duration of Treatment – Interferon Alpha-naïve Patients

The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks.

Duration of Treatment – Re-treatment with PegIntron/REBETOL of Prior Treatment Failures

The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies (14.1)].

TABLE 1

Recommended PegIntron Combination Therapy Dosing (Adults)

 

Body weight
kg (lbs)
  PegIntron REDIPEN® or Vial Strength to Use   Amount of PegIntron (mcg) to Administer Volume (mL)* of PegIntron to Administer   REBETOL Daily Dose   REBETOL Number of Capsules
<40 (<88)

 

  50 mcg per 0.5 mL   50 0.5   800 mg/day   2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

 

40 – 50 (88 – 111)

 

  80 mcg per 0.5 mL   64 0.4   800 mg/day   2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

 

51 – 60 (112 – 133)

 

    80 0.5   800 mg/day   2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

 

61 – 65 (134 – 144)

 

  120 mcg per 0.5 mL   96 0.4   800 mg/day   2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

 

66 – 75 (145 – 166)

 

    96 0.4   1000 mg/day   2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

 

76 – 80 (167 – 177)

 

    120 0.5   1000 mg/day   2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

 

81 – 85 (178 – 187)

 

      1200 mg/day   3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

 

86 – 105 (188 – 231)

 

  150 mcg per 0.5 mL   150 0.5   1200 mg/day   3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

 

>105 (>231)

 

  **   ** **   1400 mg/day   3 x 200 mg capsules A.M. 4 x 200 mg capsules P.M.

 

* When reconstituted as directed.

** For patients weighing >105 kg (>231 pounds), the PegIntron dose of 1.5 mcg/kg/week should be calculated based on the individual patient weight. Two vials of PegIntron may be necessary to provide the dose.

Pediatric Patients

Dosing for pediatric patients is determined by body surface area for PegIntron and by body weight for REBETOL. The recommended dose of PegIntron is 60mcg/m2/week subcutaneously in combination with 15 mg/kg/day of REBETOL orally in 2 divided doses (see Table 2) for pediatric patients ages 3 to 17 years. Patients who reach their 18th birthday while receiving PegIntron/REBETOL, should remain on the pediatric dosing regimen. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

TABLE 2

Recommended REBETOL* Dosing in Combination Therapy (Pediatrics)

 

Body weight
kg (lbs)
  REBETOL Daily Dose   REBETOL Number of Capsules
<47 (<103)

 

  15 mg/kg/day   Use REBETOL Oral Solution**
47 – 59

(103-131)

 

  800 mg/day   2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

 

60 – 73 (132-162)

 

  1000 mg/day   2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

 

>73 (>162)

 

  1200 mg/day   3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

 

*REBETOL to be used in combination with PegIntron 60 mcg/m2 weekly.

** REBETOL Oral Solution may be used for any patient regardless of body weight.

2.2 PegIntron Monotherapy

The recommended dose of PegIntron regimen is 1 mcg/kg/week subcutaneously for 1 year administered on the same day of the week. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable after 24 weeks of therapy. The volume of PegIntron to be injected depends on patient weight (see Table 3).

TABLE 3

Recommended PegIntron Monotherapy Dosing

 

Body weight

kg (lbs)

 

    PegIntron REDIPEN or Vial Strength to Use     Amount of
PegIntron (mcg) to Administer
    Volume (mL)* of PegIntron to Administer
‰¤45

(‰¤100)

 

    50 mcg per 0.5 mL     40     0.4
46 – 56 (101 – 124)

 

        50     0.5
57 – 72 (125 – 159)

 

    80 mcg per 0.5 mL     64     0.4
73 – 88 (160 – 195)

 

        80     0.5
89 – 106 (196 – 234)

 

    120 mcg per 0.5 mL     96     0.4
107 – 136 (235 – 300)

 

        120     0.5
137 – 160 (301 – 353)

 

    150 mcg per 0.5 mL     150     0.5
* When reconstituted as directed.

2.3 Dose Reduction

If a serious adverse reaction develops during the course of treatment [see Warnings and Precautions (5)] discontinue or modify the dosage of PegIntron and REBETOL until the adverse event abates or decreases in severity. If persistent or recurrent serious adverse events develop despite adequate dosage adjustment, discontinue treatment. For guidelines for dose modifications and discontinuation based on depression or laboratory parameters, see Tables 4 and 5. Dose reduction of PegIntron in adult patients on PegIntron/REBETOL combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Dose reduction in patients on PegIntron monotherapy is accomplished by reducing the original starting dose of 1 mcg/kg/week to 0.5 mcg/kg/week. Dose reduction of PegIntron in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 6 or 7.

In the adult combination therapy Study 2, dose reductions occurred in 42% of subjects receiving PegIntron 1.5 mcg/kg plus REBETOL 800 mg daily, including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events [see Adverse Reactions (6.1)].

Dose reduction in pediatric patients is accomplished by modifying the recommended dose in a 2-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Tables 4 and 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving PegIntron 60 mcg/m2 weekly plus REBETOL 15 mg/kg daily.

TABLE 4

Guidelines for Modification or Discontinuation of PegIntron or PegIntron/REBETOL and for Scheduling Visits for Patients with Depression

 

Depression Severity*

 

    Initial Management (4-8 weeks)     Depression Status
 

Posted: March 2011

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