Merck's Investigational Medicine Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure and Treatment-Naï

Oct 30, 2010 9:20am

BOSTON--(BUSINESS WIRE)-- Merck reported today that final results from two pivotal Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, demonstrated significantly higher sustained virologic response (SVR)¹ rates in adult patients who previously failed treatment (treatment-failure; HCV RESPOND-2) and in adult patients who were new to treatment (treatment-naïve; HCV SPRINT-2) for chronic hepatitis C virus (HCV) genotype 1 compared to control, the primary objective of the studies. The results for the primary endpoints of these studies, which were first reported in a news release in August 2010², and a broad range of further data analyses from these studies are being presented in oral and poster presentations at the 61^st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).^3,4,5

"We are excited by the results of these pivotal studies," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "In these studies, boceprevir substantially increased success rates compared to standard therapy, both for patients who received 48 weeks of treatment and for patients treated with the response-guided therapy approach, many of whom were able to be treated for 28 to 36 weeks," he added. "Based on these data, Merck has initiated the submission of a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration (FDA) on a rolling basis, and we expect to complete regulatory submissions in the U.S. and E.U. in 2010."

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir administered in combination with PEGINTRON^® (peginterferon alfa-2b) and REBETOL^® (ribavirin, USP) (Peg/riba) to assess whether the addition of boceprevir could improve SVR rates and potentially shorten overall treatment duration compared to the use of Peg/riba alone for 48 weeks, which is the current standard duration of therapy. In each study, patients were randomized to three groups:

Response-guided therapy (RGT), in which total treatment duration was based on certain early response criteria. Treatment-failure patients with undetectable virus (HCV-RNA) at week 8 were eligible to stop all treatment at 36 weeks. Treatment-naïve patients with undetectable virus
(HCV-RNA) during weeks 8 through 24 were eligible to stop all treatment at 28 weeks.
48 weeks of treatment, in which patients received a 4-week Peg/riba lead-in followed by the addition of boceprevir for 44 weeks.
Control, in which patients received Peg/riba for 48 weeks.

In both studies, all patients were treated with a 4-week lead-in of PEGINTRON (1.5 mcg/kg/week) and an investigational dose of REBETOL (600-1,400 mg/day), followed by the addition of boceprevir (800 mg three times a day).

In primary results, addition of boceprevir significantly increased SVR rates compared to control

HCV RESPOND-2, which was conducted at U.S. and international sites, included 403 adult patients who had failed prior therapy, including patients who relapsed or were non-responders to prior treatment with peginterferon and ribavirin. HCV SPRINT-2 was conducted in 1,097 treatment-naïve adult patients at U.S. and international sites who were enrolled in two separate cohorts, one with 938 non-African-American/non-Black patients and the other with 159 African-American/Black patients.

As previously reported, the primary results of these two studies were as follows: In treatment-failure patients in HCV RESPOND-2, boceprevir increased SVR rates to 59 percent for the RGT arm (95/162) and 66 percent for the 48-week treatment arm (107/161) compared to 21 percent for control (17/80). In treatment-naïve patients in HCV SPRINT-2, boceprevir increased SVR rates to 63 percent for the RGT arm (233/368) and 66 percent for the 48-week treatment arm (242/366), compared to 38 percent for control (137/363). (All primary endpoints achieved statistical significance of p<0.0001 based on intent-to-treat analyses.)

Researchers present new analyses on boceprevir response-guided therapy

In secondary analyses presented for the first time at AASLD, researchers reported that nearly half of all patients in the boceprevir RGT arms met early response criteria and received a shorter total duration of therapy:

In the RGT arm of the treatment-failure study, 46 percent (74/162) of patients met the early response criteria and were eligible to stop all treatment at 36 weeks, which is 12 weeks shorter than current standard therapy. In these patients, the SVR rate was 86 percent (64/74).
In the RGT arm of the treatment-naïve study, 44 percent of patients (162/368) met the early response criteria and were eligible to stop all treatment at 28 weeks, which is 20 weeks shorter than current standard therapy. In these patients, the SVR rates were 97 percent (143/147) in non-African-American/non-Black treatment-naïve patients and 87 percent (13/15) in African-American/Black treatment-naïve patients.

For the corresponding patients in the boceprevir 48-week treatment arms of these studies, the SVR rates were 88 percent (74/84) in treatment-failure patients, 96 percent (137/142) in non-African-American/non-Black treatment-naïve patients and 95 percent (18/19) in African-American/Black treatment-naïve patients.

Patients in the boceprevir RGT arms of these studies who did not meet the early response criteria and were treated for up to 48 weeks also achieved substantially higher SVR rates compared to control. In these patients, the SVR rates were 40 percent (29/72) in treatment-failure patients, 74 percent (52/70) in non-African-American/non-Black treatment-naïve patients and 58 percent (7/12) in African-American/Black treatment-naïve patients.

"In the study of patients who failed prior treatment, boceprevir combination therapy helped the majority of patients achieve sustained virologic response, the goal of treatment," said Bruce Bacon, M.D., professor of Internal Medicine, Saint Louis University School of Medicine and co-principal investigator of HCV RESPOND-2. "This is the only study to evaluate a strategy for shorter treatment in these difficult-to-treat patients. We observed that many patients in the boceprevir response-guided therapy arm were able to have their treatment duration reduced by three months compared to current standard duration of treatment."

"In these studies, boceprevir response-guided therapy provided physicians flexibility in the management of their patients' HCV therapy, which enabled them to adapt treatment duration based on individual patient response," said Fred Poordad, M.D., chief of hepatology in the division of gastroenterology at Cedars-Sinai Medical Center, associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles (UCLA), and co-principal investigator of the HCV SPRINT-2 study. "These studies were designed with a four-week lead-in strategy that was intended to help physicians identify their patients' responsiveness to interferon prior to the addition of a protease inhibitor, which provided an early indication of the likelihood of treatment success."

Tolerability profile in treatment-failure patients

The five most common treatment-related adverse events in the HCV RESPOND-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (54, 57, and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39 and 38 percent), chills (35, 30 and 30 percent) and influenza-like illness (23, 23 and 25 percent). Anemia was reported in 43, 46 and 20 percent of patients in the study arms, respectively. Serious adverse events were reported in 10, 14 and 5 percent of patients in the study arms, respectively.

Treatment discontinuations due to adverse events over the total course of all treatment were 8 percent and 12 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 3 percent for control. Treatment discontinuations due to anemia were 0 percent and 3 percent for the boceprevir arms, respectively, compared to 0 percent for control. Erythropoietin (EPO) for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 41 and 46 percent of patients in the boceprevir RGT and 48-week treatment arms, respectively, compared to 21 percent for control.

Tolerability profile in treatment-naïve patients

The five most common treatment-related adverse events in the HCV SPRINT-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (52, 57 and 59 percent), headache (45, 43 and 42 percent), nausea (46, 42 and 40 percent), anemia (49, 49 and 29 percent) and dysgeusia (bad taste) (37, 43 and 18 percent). Serious adverse events were reported in 11, 12 and 9 percent of patients in the study arms, respectively.

Treatment discontinuations due to adverse events over the total course of all treatment were 12 percent and 16 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 16 percent for control. Treatment discontinuations due to anemia were 2 percent for each of the boceprevir treatment arms compared to 1 percent for control. EPO for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 43 percent of patients in each of the boceprevir treatment arms compared to 24 percent for control.

The HCV RESPOND-2 and HCV SPRINT-2 studies each employed futility or "stopping" rules, whereby patients in any treatment arm who had detectable virus at week 12 in the HCV RESPOND-2 study or at week 24 in the HCV SPRINT-2 study were considered treatment failures and discontinued all treatment. These stopping rules allowed for patients in the studies who did not respond to treatment to have their therapy stopped early, thereby avoiding unnecessary treatment.

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. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to viral hepatitis care.

About PEGINTRON

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

The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (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 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.

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 REBETOL 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/REBETOL 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

REBETOL 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 REBETOL 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 REBETOL 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/REBETOL 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/REBETOL (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 REBETOL 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/REBETOL combination therapy and three occurred during the follow-up period but had been on PEGINTRON/REBETOL 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/REBETOL 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/REBETOL therapies. Weight-based PEGINTRON/REBETOL dosing resulted in increased rates of anemia. Most common adverse reactions with PEGINTRON/REBETOL (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/REBETOL 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/REBETOL 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 and at http://www.spfiles.com/pirebetol.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 2009 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 and Medication Guides, including Boxed Warnings, for PEGINTRON and REBETOL. The full Prescribing Information and Medication Guides are also available at http://www.spfiles.com/pipeg-intron.pdf and http://www.spfiles.com/pirebetol.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.

² Merck news release: In Pivotal Phase III Studies, Merck's Investigational Medicine Boceprevir Helped Majority of Patients with Chronic Hepatitis C Genotype 1 Infection Achieve Sustained Virologic Response, the Primary Endpoint of the Studies. Available at: http://www.merck.com/newsroom/news-release-archive/home.html. Aug. 4, 2010.

³ B.R. Bacon et al. HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin. Abstract 216.

⁴ F. Poordad et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. Abstract LB-4.

⁵ J. Bronowicki et al. Response-Guided Therapy (RGT) with Boceprevir (BOC) + Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1 Was Similar to a 48-Wk Fixed-Duration Regimen with BOC + P/R in SPRINT-2. Abstract LB-15.

PEGINTRON^®and REBETOL^®are registered trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

F- 33538820T

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, Endocrine Disorders (5.4)				[1/2010]
Warnings and Precautions, Ophthalmologic Disorders (5.5)				[8/2009]
Warnings and Precautions, Pulmonary Disorders (5.11)				[8/2009]
Warnings and Precautions, Peripheral Neuropathy (5.19)				[8/2009]

----------------------------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 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.

Revised: 1/2010

_______________________________________________________________________________________________________________________________________

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 Coinfection

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 Medication Guide

17.2 Pregnancy

17.3 HCV Transmission

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

*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 mcg per 0.5 mL	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)		120	0.5	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 mcg per 0.5 mL	50	0.5
57 – 72 (125 – 159)	80 mcg per 0.5 mL	64	0.4
73 – 88 (160 – 195)	80 mcg per 0.5 mL	80	0.5
89 – 106 (196 – 234)	120 mcg per 0.5 mL	96	0.4
107 – 136 (235 – 300)	120 mcg per 0.5 mL	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
Depression Severity^*	Dose Modification	Visit Schedule	Remains Stable	Improves	Worsens
Mild	No change	Evaluate once weekly by visit or phone.	Continue weekly visit schedule.	Resume normal visit schedule.	See moderate or severe depression
Moderate	Adults: Adjust Dose* Pediatrics: Decrease dose to 40 mcg/m²/week, then to 20 mcg/m²/week, if needed	Evaluate once weekly (office visit at least every other week).	Consider psychiatric consultation. Continue reduced dosing.	If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced dosing or return to normal dose.	See severe depression
Severe	Discontinue PegIntron/REBETOL permanently.	Obtain immediate psychiatric consultation.	Psychiatric therapy as necessary
^* See DSM-IV for definitions. For patients on PegIntron/REBETOL combination therapy: 1^st dose reduction of PegIntron is to 1 mcg/kg/week, 2^nd dose reduction (if needed) of PegIntron is to 0.5 mcg/kg/week. For patients on PegIntron monotherapy: decrease PegIntron dose to 0.5 mcg/kg/week.

TABLE 5. Guidelines for Dose Modification and Discontinuation of PegIntron or PegIntron/REBETOL Based on Laboratory Parameters in Adults and Pediatrics
Laboratory Values	PegIntron		REBETOL
	Adults	Pediatrics	Adults	Pediatrics
Hgb < 10g/dL	For patients with cardiac disease, reduce by 50%*	See footnote*	Adjust Dose**	1^st reduction to 12mg/kg/day 2^nd reduction to 8mg/kg/day
WBC < 1.5 x 10⁹/L Neutrophils < 0.75 x 10⁹/L Platelets < 50 x 10⁹/L (Adults) < 70 x 10⁹/L (Pediatrics)	Adjust Dose***	1^st reduction to 40mcg/m²/week 2^nd reduction to 20mcg/m²/week	No Dose Change	No Dose Change
Hgb < 8.5g/dL WBC < 1 x 10⁹/L Neutrophils < 0.5 x 10⁹/L Platelets <25 x 10⁹/L (Adults) < 50 x 10⁹/L (Pediatrics) Creatinine > 2 mg/dL (Pediatrics)	Permanently Discontinue	Permanently Discontinue	Permanently Discontinue	Permanently Discontinue

* For adult patients with a history of stable cardiac disease receiving PegIntron in combination with ribavirin, the PegIntron dose should be reduced by half and the ribavirin dose by 200 mg/day if a >2 g/dL decrease in hemoglobin is observed during any 4-week period. Both PegIntron and ribavirin should be permanently discontinued if patients have hemoglobin levels <12 g/dL after this ribavirin dose reduction. Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease ≥2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing.

** 1^st dose reduction of REBETOL is by 200 mg/day, except in patients receiving the 1400 mg dose it is by 400 mg/day; 2^nd dose reduction of REBETOL (if needed) is by an additional 200 mg/day.

*** For patients on PegIntron/REBETOL combination therapy: 1^st dose reduction of PegIntron is to 1 mcg/kg/week, 2^nd dose reduction (if needed) of PegIntron is to 0.5 mcg/kg/week. For patients on PegIntron monotherapy: decrease PegIntron dose to 0.5 mcg/kg/week.

TABLE 6 Reduced PegIntron Dose (0.5 mcg/kg) for (1 mcg/kg) Monotherapy in Adults
Body weight kg(lbs)	PegIntron REDIPEN/Vial Strength to Use	Amount of PegIntron (mcg) to Administer	Volume (mL) of PegIntron to Administer**
≤45 (≤100)	50 mcg per 0.5 mL*	20	0.2
46 – 56 (101 – 124)	50 mcg per 0.5 mL*	25	0.25
57 – 72 (125 – 159)	50 mcg per 0.5 mL	30	0.3
73 – 88 (160 – 195)	50 mcg per 0.5 mL	40	0.4
89 – 106 (196 – 234)	50 mcg per 0.5 mL	50	0.5
107 – 136 (235 – 300)	80 mcg per 0.5 mL	64	0.4
≥137 (≥301)	80 mcg per 0.5 mL	80	0.5
* Must use vial. Minimum delivery for REDIPEN 0.3 mL.
** When reconstituted as directed.

TABLE 7 Two-Step Dose Reduction of PegIntron in Combination Therapy in Adults
First Dose Reduction to PegIntron 1 mcg/kg				Second Dose Reduction to PegIntron 0.5 mcg/kg
Body weight kg(lbs)	PegIntron REDIPEN/Vial Strength to Use	Amount of PegIntron (mcg) to Administer	Volume (mL) of PegIntron to Administer**	Body weight kg(lbs)	PegIntron REDIPEN/Vial Strength to Use	Amount of PegIntron (mcg) to Administer	Volume (mL) of PegIntron to Administer**
<40 (<88)	50 mcg per 0.5 mL	35	0.35	<40 (<88)	50 mcg per 0.5 mL*	20	0.2
40 – 50 (88 – 111)		45	0.45	40 – 50 (88 – 111)	50 mcg per 0.5 mL*	25	0.25
51 – 60 (112 – 133)		50	0.5	51 – 60 (112 – 133)	50 mcg per 0.5 mL	30	0.3
61 – 75 (134 – 166)	80 mcg per 0.5 mL	64	0.4	61 – 75 (134 –166)		35	0.35
76 – 85 (167 – 187)	80 mcg per 0.5 mL	80	0.5	76 – 85 (167 – 187)		45	0.45
86-104 (188-230)	120 mcg per 0.5 mL	96	0.4	86-104 (188-230)		50	0.5
105-125 (231-275)	120 mcg per 0.5 mL	108	0.45	105-125 (231-275)	80 mcg per 0.5 mL	64	0.4
>125 (>275)	150 mcg per 0.5 mL	135	0.45	>125 (>275)	80 mcg per 0.5 mL	72	0.45
* Must use vial. Minimum delivery for REDIPEN 0.3 mL
** When reconstituted as directed

2.4 Discontinuation of Dosing

Adults

It is recommended that HCV genotype 1 interferon-alfa-naïve patients receiving PegIntron, alone or in combination with ribavirin, be discontinued from therapy if there is not 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. Regardless of genotype, previously treated patients who have detectable HCV-RNA at Week 12 or 24, are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Pediatrics (3-17 years of age)

It is recommended that patients receiving PegIntron/REBETOL combination (excluding those with HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped <2 log₁₀ compared to pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.

2.5 Renal Function

In patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), the PegIntron dose should be reduced by 25%. Patients with severe renal dysfunction (creatinine clearance 10-29 mL/min), including those on hemodialysis, should have the PegIntron dose reduced by 50%. If renal function decreases during treatment, PegIntron therapy should be discontinued. When PegIntron is administered in combination with REBETOL, subjects with impaired renal function or those over the age of 50 should be more carefully monitored with respect to the development of anemia. PegIntron/REBETOL should not be used in patients with creatinine clearance <50 mL/min.

2.6 Preparation and Administration

PegIntron REDIPEN

PegIntron REDIPEN consists of a dual-chamber glass cartridge with sterile, lyophilized peginterferon alfa-2b in the active chamber and Sterile Water for Injection USP in the diluent chamber. The PegIntron in the glass cartridge should appear as a white to off-white tablet-shaped solid that is whole or in pieces, or powder.

To reconstitute the lyophilized peginterferon alfa-2b in the REDIPEN:

Hold the REDIPEN upright (dose button down) and press the 2 halves of the pen together until there is an audible click.
Gently invert the pen to mix the solution. DO NOT SHAKE. The reconstituted solution has a concentration of either 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, or 150 mcg per 0.5 mL for a single subcutaneous injection.
Visually inspect the solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear and colorless. Do not use the solution if it is discolored or not clear, or if particulates are present.

Keeping the pen upright, attach the supplied needle and select the appropriate PegIntron dose by pulling back on the dosing button until the dark bands are visible and turning the button until the dark band is aligned with the correct dose. The prepared PegIntron solution is to be injected subcutaneously.

The PegIntron REDIPEN is a single-use pen and does not contain a preservative. The reconstituted solution should be used immediately and cannot be stored for more than 24 hours at 2^°-8^° C [see How Supplied/Storage and Handling (16)]. DO NOT REUSE THE REDIPEN. The sterility of any remaining product can no longer be guaranteed. DISCARD THE UNUSED PORTION. Pooling of unused portions of some medications has been linked to bacterial contamination and morbidity.

PegIntron Vials

Two BD® Safety-Lok^® syringes are provided in the package; one syringe is for the reconstitution steps and one for the patient injection. There is a plastic safety sleeve to be pulled over the needle after use. The syringe locks with an audible click when the green stripe on the safety sleeve covers the red stripe on the needle. Instructions for the preparation and administration of PegIntron Powder for Injection are provided below.

Reconstitute the PegIntron lyophilized product with only 0.7 mL of the 1.25 mL of supplied diluent (Sterile Water for Injection USP). The diluent vial is for single use only. The remaining diluent should be discarded. No other medications should be added to solutions containing PegIntron, and
PegIntron should not be reconstituted with other diluents.
Swirl gently to hasten complete dissolution of the powder. The reconstituted solution should be clear and colorless.
Visually inspect the solution for particulate matter and discoloration prior to administration. The solution should not be used if discolored or cloudy, or if particulates are present.
The appropriate PegIntron dose should be withdrawn and injected subcutaneously. PegIntron vials are for single use only and do not contain a preservative.

The reconstituted solution should be used immediately and cannot be stored for more than 24 hours at 2°-8° C [see How Supplied/Storage and Handling (16)]. DO NOT REUSE THE VIAL. The sterility of any remaining product can no longer be guaranteed. DISCARD THE UNUSED PORTION. Pooling of unused portions of some medications has been linked to bacterial contamination and morbidity.

3 DOSAGE FORMS AND STRENGTHS

Single-use vial: 1.25 mL diluent vial: 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, 150 mcg per 0.5 mL.
Single-use REDIPEN: 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, 150 mcg per 0.5 mL.

4 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
hepatic decompensation (Child-Pugh score >6 [class B and C]) in cirrhotic CHC patients before or during treatment

PegIntron /REBETOL combination therapy is additionally contraindicated in:

women who are pregnant. REBETOL may cause fetal harm when administered to a pregnant woman. REBETOL is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
men whose female partners are pregnant
patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
patients with creatinine clearance <50 mL/min

5 WARNINGS AND PRECAUTIONS

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 be withdrawn from therapy.

5.1 Use with Ribavirin

Pregnancy

REBETOL may cause birth defects and death of the unborn child. REBETOL 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 2 forms of contraception and have monthly pregnancy tests [see BOXED WARNING, Contraindications (4), Patient Counseling Information (17), and REBETOL package insert].

Anemia

Ribavirin caused hemolytic anemia in 10% of PegIntron/REBETOL-treated subjects within 1 to 4 weeks of initiation of therapy. Complete blood counts should be obtained pretreatment and at Week 2 and Week 4 of therapy or more frequently if clinically indicated. Anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of REBETOL may be necessary [see Dosage and Administration (2.3) and REBETOL package insert].

5.2 Neuropsychiatric Events

Life-threatening or fatal neuropsychiatric events, including suicide, 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. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with interferon alpha. PegIntron should be used with extreme caution in patients with a history of psychiatric disorders. Patients should be advised to report immediately any symptoms of depression or suicidal ideation to their prescribing physicians. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with PegIntron be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, PegIntron should be stopped immediately and psychiatric intervention instituted [see Dosage and Administration (2.3)]. Cases of encephalopathy have been observed in some patients, usually elderly, treated at higher doses of PegIntron.

5.3 Cardiovascular Events

Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with PegIntron. PegIntron should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require PegIntron therapy should be closely monitored [see Warnings and Precautions (5.15)]. Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron /REBETOL combination therapy [see REBETOL package insert].

5.4 Endocrine Disorders

PegIntron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with PegIntron. Diabetes mellitus, including cases of new onset Type 1 diabetes, has been observed in patients treated with alpha interferons, including PegIntron. Patients with these conditions who cannot be effectively treated by medication should not begin PegIntron therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue PegIntron therapy.

5.5 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 may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Peginterferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

5.6 Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PegIntron. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made, and a causal relationship between interferon alfa-based therapies and these events is difficult to establish.

5.7 Bone Marrow Toxicity

PegIntron suppresses bone marrow function, sometimes resulting in severe cytopenias. PegIntron should be discontinued in patients who develop severe decreases in neutrophil or platelet counts [see Dosage and Administration (2.3)]. Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia.

5.8 Autoimmune Disorders

Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis) have been observed in patients receiving PegIntron.

PegIntron should be used with caution in patients with autoimmune disorders.

5.9 Pancreatitis

Fatal and nonfatal pancreatitis have been observed in patients treated with alpha interferon. PegIntron therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.

5.10 Colitis

Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. PegIntron treatment should be discontinued immediately in patients who develop these signs and symptoms. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferons.

5.11 Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure or patient deaths, may be induced or aggravated by PegIntron or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PegIntron combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.

5.12 Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PegIntron. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and alpha interferons with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients’ clinical status and hepatic function should be closely monitored, and PegIntron treatment should be immediately discontinued if decompensation (Child-Pugh score >6) is observed [see Contraindications (4)].

5.13 Patients with Renal Insufficiency

Increases in serum creatinine levels have been observed in patients with renal insufficiency receiving interferon alpha products, including PegIntron. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and PegIntron dosing should be adjusted accordingly or discontinued [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)]. PegIntron monotherapy should be used with caution in patients with creatinine clearance <50 mL/min; the potential risks should be weighed against the potential benefits in these patients. Combination therapy with REBETOL must not be used in patients with creatinine clearance <50 mL/min [see REBETOL Package Insert].

5.14 Hypersensitivity

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) and cutaneous eruptions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

5.15 Laboratory Tests

PegIntron alone or in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. Transient elevations in ALT (2- to 5-fold above baseline) were observed in 10% of subjects treated with PegIntron, and were not associated with deterioration of other liver functions. Triglyceride levels are frequently elevated in patients receiving alpha interferon therapy including PegIntron and should be periodically monitored.

Patients on PegIntron or PegIntron/REBETOL combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial CBC (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at Weeks 2, 4, 8, and 12, and then at 6-week intervals or more frequently if abnormalities developed. In pediatric subjects, the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment Week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see Dosage and Administration (2)].

Patients who have pre-existing cardiac abnormalities should have electrocardiograms done before treatment with PegIntron/REBETOL.

5.16 Dental and Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving PegIntron/REBETOL combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of REBETOL and PegIntron. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, patients should be advised to rinse out their mouth thoroughly afterwards.

5.17 Triglycerides

Elevated triglyceride levels have been observed in patients treated with interferon alpha, including PegIntron therapy. Hypertriglyceridemia may result in pancreatitis [see Warnings and Precautions (5.9)]. Elevated triglyceride levels should be managed as clinically appropriate. Discontinuation of PegIntron therapy should be considered for patients with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting, and persistently elevated triglycerides (e.g., triglycerides >1000 mg/dL).

5.18 Impact on Growth-Pediatric Use

Data on the effects of PegIntron plus REBETOL on growth come from an open-label study in subjects 3 through 17 years of age, and weight and height changes are compared to US normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lags behind that predicted by normative population data for the entire length of treatment. After about 6 months post-treatment (follow-up Week 24), subjects had weight gain rebounds and regained their weight to 53^rd percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57^th percentile). After about 6 months post-treatment, height gain stabilized and subjects treated with PegIntron plus REBETOL had an average height percentile of 44^th percentile, which was less than the average of the normative population and less than their average baseline height (51^st percentile). Severely inhibited growth velocity (< 3^rd percentile) was observed in 70% of the subjects while on treatment. Of the subjects experiencing severely inhibited growth, 20% had continued inhibited growth velocity (< 3^rd percentile) after 6 months of follow-up.

Among the boys studied, the age groups of 3 to 11 years old and 12 to 17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months post-treatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3 to 11 years old and treated for 48 weeks had the largest average drop in height and weight percentiles (13 percentiles and 7 percentiles, respectively), whereas girls 12 to 17 years old continued along their average baseline height and weight percentiles after 6 months post-treatment.

5.19 Peripheral Neuropathy

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated.

6 ADVERSE REACTIONS

Clinical trials with PegIntron alone or in combination with REBETOL have been conducted in over 6900 subjects from 3 to 75 years of age.

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without REBETOL [see BOXED WARNING, Warnings and Precautions (5)]. The most common serious events occurring in subjects treated with PegIntron and REBETOL were depression and suicidal ideation [see Warnings and Precautions (5.2)], each occurring at a frequency of less than 1%. The most common fatal events occurring in subjects treated with PegIntron and REBETOL were cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions (5.2, 5.5)], all occurring in less than 1% of subjects.

Greater than 96% of all subjects in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions in adult subjects receiving either PegIntron or PegIntron/REBETOL were injection-site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and emotional lability/irritability. The most common adverse events in pediatric subjects, ages 3 and older, were pyrexia, headache, vomiting, neutropenia, fatigue, anorexia, injection-site erythema, and abdominal pain.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults

Study 1 compared PegIntron monotherapy with INTRON® A monotherapy. Study 2 compared combination therapy of PegIntron/REBETOL with combination therapy with INTRON A/REBETOL. In these studies, nearly all study subjects in clinical trials experienced one or more adverse reactions. Study 3 compared a PegIntron/weight-based REBETOL combination to a PegIntron/flat dose REBETOL regimen. Study 4 compared 2 PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving Pegasys^® (180 mcg/week)/Copegus^® (1000-1200 mg/day).

Adverse reactions that occurred in Studies 1 and 2 at >5% incidence are provided in Table 8 by treatment group. Due to potential differences in ascertainment procedures, adverse reaction rate comparisons across studies should not be made. Table 9 summarizes the treatment-related/treatment emergent adverse reactions in Study 4 that occurred at a ≥10% incidence.

TABLE 8 Adverse Reactions Occurring in > 5% of Subjects
	Percentage of Subjects Reporting Adverse Reactions*
	Study 1		Study 2
Adverse Reactions	PegIntron 1 mcg/kg (n=297)	INTRON A 3 MIU (n=303)	PegIntron 1.5 mcg/kg/ REBETOL (n=511)	INTRON A/ REBETOL (n=505)
Application Site
Injection Site Inflammation/Reaction	47	20	75	49
Autonomic Nervous System
Dry Mouth	6	7	12	8
Increased Sweating	6	7	11	7
Flushing	6	3	4	3
Body as a Whole
Fatigue/Asthenia	52	54	66	63
Headache	56	52	62	58
Rigors	23	19	48	41
Fever	22	12	46	33
Weight Loss	11	13	29	20
Right Upper Quadrant Pain	8	8	12	6
Chest Pain	6	4	8	7
Malaise	7	6	4	6
Central/Peripheral Nervous System
Dizziness	12	10	21	17
Endocrine
Hypothyroidism	5	3	5	4
Gastrointestinal
Nausea	26	20	43	33
Anorexia	20	17	32	27
Diarrhea	18	16	22	17
Vomiting	7	6	14	12
Abdominal Pain	15	11	13	13
Dyspepsia	6	7	9	8
Constipation	1	3	5	5
Hematologic Disorders
Neutropenia	6	2	26	14
Anemia	0	0	12	17
Leukopenia	<1	0	6	5
Thrombocytopenia	7	<1	5	2
Liver and Biliary System
Hepatomegaly	6	5	4	4
Musculoskeletal
Myalgia	54	53	56	50
Arthralgia	23	27	34	28
Musculoskeletal Pain	28	22	21	19
Psychiatric
Insomnia	23	23	40	41
Depression	29	25	31	34
Anxiety/Emotional Lability/Irritability	28	34	47	47
Concentration Impaired	10	8	17	21
Agitation	2	2	8	5
Nervousness	4	3	6	6
Reproductive, Female
Menstrual Disorder	4	3	7	6
Resistance Mechanism
Viral Infection	11	10	12	12
Fungal Infection	<1	3	6	1
Respiratory System
Dyspnea	4	2	26	24
Coughing	8	5	23	16
Pharyngitis	10	7	12	13
Rhinitis	2	2	8	6
Sinusitis	7	7	6	5
Skin and Appendages
Alopecia	22	22	36	32
Pruritus	12	8	29	28
Rash	6	7	24	23
Skin Dry	11	9	24	23
Special Senses, Other
Taste Perversion	<1	2	9	4
Vision Disorders
Vision Blurred	2	3	5	6
Conjunctivitis	4	2	4	5

*Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category.


TABLE 9 Summary of Treatment-related/Treatment-emergent Adverse Reactions (≥10% Incidence) By Descending Frequency
	Percentage of Patients Reporting Treatment-Related/Treatment- emergent Adverse Reactions
	Study 4
Adverse Reactions	PegIntron 1.5 mcg/kg with REBETOL (n=1019)	PegIntron 1 mcg/kg with REBETOL (n=1016)	Pegasys 180 mcg with Copegus (n=1035)
Fatigue	67	68	64
Headache	50	47	41
Nausea	40	35	34
Chills	39	36	23
Insomnia	38	37	41
Anemia	35	30	34
Pyrexia	35	32	21
Injection Site Reactions	34	35	23
Anorexia	29	25	21
Rash	29	25	34
Myalgia	27	26	22
Neutropenia	26	19	31
Irritability	25	25	25
Depression	25	19	20
Alopecia	23	20	17
Dyspnea	21	20	22
Arthralgia	21	22	22
Pruritus	18	15	19
Influenza-like Illness	16	15	15
Dizziness	16	14	13
Diarrhea	15	16	14
Cough	15	16	17
Weight Decreased	13	10	10
Vomiting	12	10	9
Unspecified Pain	12	13	9
Dry Skin	11	11	12
Anxiety	11	11	10
Abdominal Pain	10	10	10
Leukopenia	9	7	10

The adverse reaction profile in Study 3, which compared PegIntron/weight-based REBETOL combination to a PegIntron/flat-dose REBETOL regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat-dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions.

The incidence of serious adverse reactions was comparable in all studies. In the PEG monotherapy trial (Study 1) the incidence of serious adverse reactions was similar (about 12%) in all treatment groups. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/REBETOL groups compared to 14% in the INTRON A/REBETOL group. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and with the flat-dose REBETOL regimen.

There have been 31 subject deaths which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PegIntron/REBETOL combination therapy, and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of which were probable suicides, and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received PegIntron/REBETOL combination therapy, 5 in the PegIntron 1.5 mcg/REBETOL arm (N=1019) and 1 in the PegIntron 1 mcg/REBETOL arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides which occurred during the off-treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/REBETOL combination therapy.

In Studies 1 and 2, 10% to 14% of subjects receiving PegIntron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based REBETOL and 14% of subjects receiving PegIntron and flat-dose REBETOL discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In Study 4, 13% of subjects in the PegIntron 1.5 mcg/REBETOL arm, 10% in the PegIntron 1 mcg/REBETOL arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PegIntron (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PegIntron 1.5 mcg/kg > PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all 3 groups, 33% to 35%. The most common reasons for dose modifications were neutropenia (18%) or anemia (9%). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with WBD compared to flat dosing (29% and 23%, respectively). 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, compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring a second dose reduction to 90 mcg/week with Pegasys.

In the PegIntron/REBETOL combination trials the most common adverse reactions were psychiatric which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see Warnings and Precautions (5.2)]. In Study 4, psychiatric adverse reactions occurred in 58 % of subjects in the PegIntron 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm.

PegIntron induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection-site pain was infrequent (2-3%) in all groups. In Study 3 there was a 23% to 24% incidence overall for injection-site reactions or inflammation.

In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing adverse reactions by body class in the PegIntron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10% to 15% of subjects, weight loss, fatigue, and headache had not resolved.

Individual serious adverse reactions in Study 2 occurred at a frequency ≤1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, 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.

Subjects receiving PegIntron/REBETOL as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naïve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%), and vomiting (27%). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection-site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment; 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations.

Dose modifications were required in 25% of subjects, most commonly for anemia, neutropenia, and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction.

Adverse reactions that occurred with a ≥10% incidence in the pediatric trial subjects are provided in Table 10.

TABLE 10 Percentage of Pediatric Subjects With Treatment-emergent/Treatment-related Adverse Reactions (in at Least 10% of All Subjects)

System Organ Class Preferred Term		All Subjects n=107
Blood and Lymphatic System Disorders
Neutropenia		33%
Anemia		11%
Leukopenia		10%
Gastrointestinal Disorders
Abdominal Pain		21%
Abdominal Pain Upper		12%
Vomiting		27%
Nausea		18%
General Disorders and Administration Site Conditions
Pyrexia		80%
Fatigue		30%
Injection-site Erythema		29%
Chills		21%
Asthenia		15%
Irritability		14%
Investigations
Weight Decreased		19%
Metabolism and Nutrition Disorders
Anorexia		29%
Decreased Appetite		22%
Musculoskeletal and Connective Tissue Disorders
Arthralgia		17%
Myalgia		17%
Nervous System Disorders
Headache		62%
Dizziness		14%
Skin and Subcutaneous Tissue Disorders
Alopecia		17%

Laboratory Values

Adults

Changes in selected laboratory values during treatment with PegIntron alone or in combination with REBETOL treatment are described below. Decreases in hemoglobin, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.3) and Warnings and Precautions (5.1, 5.7)].

Hemoglobin. Hemoglobin levels decreased to <11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in hemoglobin levels <11 g/dL. Reductions in hemoglobin to <9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the PegIntron/REBETOL and INTRON A/REBETOL groups. In Study 4, patients receiving PegIntron (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to <10 g/dL (28%) and to <8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects, respectively. Hemoglobin levels become stable by treatment Weeks 4 to 6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the PegIntron monotherapy trial, hemoglobin decreases were generally mild, and dose modifications were rarely necessary [see Dosage and Administration (2.3)].

Neutrophils. Decreases in neutrophil counts were observed in a majority of subjects treated with PegIntron alone (70%) or as combination therapy with REBETOL in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (<0.5 x 10⁹/L) occurred in 1% of subjects treated with PegIntron monotherapy, 2% of subjects treated with INTRON A/REBETOL, and in approximately 4% of subjects treated with PegIntron/REBETOL in Study 2. Two percent of subjects receiving PegIntron monotherapy and 18% of subjects receiving PegIntron/REBETOL in Study 2 required modification of interferon dosage. Few subjects (<1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pretreatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.3)].

Platelets. Platelet counts decreased to <100,000/mm³ in approximately 20% of subjects treated with PegIntron alone or with REBETOL and in 6% of subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (<50,000/mm³) occur in <4% of subjects. Patients may require discontinuation or dose modification as a result of platelet decreases [see Dosage and Administration (2.3)]. In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Triglycerides. Elevated triglyceride levels have been observed in patients treated with interferon alphas, including PegIntron [see Warnings and Precautions (5.17)].

Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or PegIntron (with or without REBETOL) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new-onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period, 7% of subjects still had abnormal TSH values [see Warnings and Precautions (5.4)].

Bilirubin and Uric Acid.In Study 2, 10% to 14% of subjects developed hyperbilirubinemia and 33% to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.

Pediatric Subjects

Decreases in hemoglobin, white blood cells, platelets, and neutrophils may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.3)]. Changes in selected laboratory values during treatment of 107 pediatric subjects with PegIntron/REBETOL combination therapy are described in Table 11. Most of the changes in laboratory values in this study were mild or moderate.


		TABLE 11: Selected Hematological Abnormalities During Treatment Phase with PegIntron Plus REBETOL in Previously Untreated Pediatric Subjects
		Laboratory Parameter^*		All Subjects (n=107)
		Hemoglobin (g/dL)
		9.5 – <11.0		30%
		8.0 – <9.5		2%
		WBC (x10⁹/L)
		2.0 – 2.9		39%
		1.5 – <2.0		3%
		Platelets (x10⁹/L)
		70 - 100		1%
		50 - <70		-
		25 – <50		1%
		Neutrophils (x10⁹/L)
		1.0 – 1.5		35%
		0.75 – <1.0		26%
		0.5 – <0.75		13%
		<0.5		3%
		Total Bilirubin
		1.26 - 2.59 xN^†		7%
		Evidence of Hepatic Failure		-
		* The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included.
		^† N=Upper limit of normal

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Approximately 2% of subjects receiving PegIntron (32/1759) or INTRON A (11/728) with or without REBETOL developed low-titer (≤160) neutralizing antibodies to PegIntron or INTRON A. The clinical and pathological significance of the appearance of serum-neutralizing antibodies is unknown. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PegIntron with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PegIntron therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders

pure red cell aplasia, thrombotic thrombocytopenic purpura

Cardiac Disorders

palpitations

Ear and Labyrinth Disorders

hearing loss, vertigo, hearing impairment

Endocrine disorders

diabetic ketoacidosis, diabetes

Eye Disorders

Vogt-Koyanagi-Harada syndrome, serous retinal detachment

Gastrointestinal Disorders

aphthous stomatitis

General Disorders and Administration Site Conditions

asthenic conditions (including asthenia, malaise, fatigue)

Immune System Disorders

cases of acute hypersensitivity reactions (including anaphylaxis, angioedema, urticaria); Stevens Johnson syndrome, toxic epidermal necrolysis, systemic lupus erythematosus, erythema multiforme

Infections and Infestations

bacterial infection including sepsis

Metabolism and Nutrition Disorders

dehydration, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, myositis

Nervous System Disorders

seizures, memory loss, peripheral neuropathy, paraesthesia, migraine headache

Psychiatric Disorders

homicidal ideation

Respiratory, thoracic and mediastinal disorders

Pulmonary hypertension

Renal and Urinary Disorders

renal failure, renal insufficiency

Skin and Subcutaneous Tissue Disorders

psoriasis

Vascular Disorders

hypertension, hypotension

7 DRUG INTERACTIONS

7.1 Drugs Metabolized by Cytochrome P-450

When administering PegIntron with medications metabolized by CYP2C8/9 (e.g., warfarin and phenytoin) or CYP2D6 (e.g., flecainide), the therapeutic effect of these substrates may be decreased [see Clinical Pharmacology (12.3)].

7.2 Methadone

PegIntron may increase methadone concentrations [see Clinical Pharmacology (12.3)]. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of increased narcotic effect.

7.3 Use with Ribavirin (Nucleoside Analogues)

Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Adding treatment with alpha interferons alone or in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment- associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate [see Individual NRTI Product Information]. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6).

Stavudine, Lamivudine, and Zidovudine

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine, lamivudine, and zidovudine. In a study with another pegylated interferon alpha, no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was seen when ribavirin was co-administered with zidovudine, lamivudine, or stavudine in HIV/HCV co-infected subjects [see Clinical Pharmacology (12.3)].

HIV/HCV co-infected subjects who were administered zidovudine in combination with pegylated interferon alpha and ribavirin developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar subjects not receiving zidovudine.

Didanosine

Co-administration of REBETOL Capsules or Oral Solution and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

PegIntron Monotherapy

Pregnancy Category C: Non-pegylated interferon alfa-2b has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). PegIntron should be assumed to also have abortifacient potential. There are no adequate and well-controlled studies in pregnant women. PegIntron therapy is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Therefore, PegIntron is recommended for use in fertile women only when they are using effective contraception during the treatment period.

Use with Ribavirin

Pregnancy Category X: Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant [see Contraindications (4) and the REBETOL Package Insert].

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 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

8.3 Nursing Mothers

It is not known whether the components of PegIntron and/or REBETOL are excreted in human milk. Studies in mice have shown that mouse interferons are excreted in breast milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue the PegIntron and REBETOL treatment, taking into account the importance of the therapy to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 3 years have not been established. Clinical trials in pediatric patients < 3 years of age are not considered feasible due to the small proportion of patients in this age group requiring treatment for CHC.

8.5 Geriatric Use

In general, younger patients tend to respond better than older patients to interferon-based therapies. Clinical studies of PegIntron alone or in combination with REBETOL did not include sufficient numbers of subjects aged 65 and over, however, to determine whether they respond differently than younger subjects. Treatment with alpha interferons, including PegIntron, is associated with neuropsychiatric, cardiac, pulmonary, GI, and systemic (flu-like) adverse effects. Because these adverse reactions may be more severe in the elderly, caution should be exercised in the use of PegIntron in this population. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in patients with impaired renal function [see Clinical Pharmacology (12.3)]. When using PegIntron/REBETOL therapy, refer also to the REBETOL Package Insert.

8.6 Organ Transplant Recipients

The safety and efficacy of PegIntron alone or in combination with REBETOL for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. In a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.

8.7 HIV or HBV Co-infection

The safety and efficacy of PegIntron/REBETOL for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

10 OVERDOSAGE

There is limited experience with overdosage. In the clinical studies, a few subjects accidentally received a dose greater than that prescribed. There were no instances in which a participant in the monotherapy or combination therapy trials received more than 10.5 times the intended dose of PegIntron. The maximum dose received by any subject was 3.45 mcg/kg weekly over a period of approximately 12 weeks. The maximum known overdosage of REBETOL was an intentional ingestion of 10 g (fifty 200 mg capsules). There were no serious reactions attributed to these overdosages. In cases of overdosing, symptomatic treatment and close observation of the patient are recommended.

11 DESCRIPTION

PegIntron, peginterferon alfa-2b, Powder for Injection is a covalent conjugate of recombinant alfa-2b interferon with monomethoxy polyethylene glycol (PEG). The average molecular weight of the PEG portion of the molecule is 12,000 daltons. The average molecular weight of the PegIntron molecule is approximately 31,000 daltons. The specific activity of peginterferon alfa-2b is approximately 0.7 x 10⁸ IU/mg protein.

Interferon alfa-2b is a water-soluble protein with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon gene from human leukocytes.

PegIntron is supplied in both vials and the REDIPEN for subcutaneous use.

Vials

Each vial contains either 74 mcg, 118.4 mcg, 177.6 mcg, or 222 mcg of PegIntron as a white to off-white tablet-like solid that is whole/in pieces or as a loose powder, and 1.11 mg dibasic sodium phosphate anhydrous, 1.11 mg monobasic sodium phosphate dihydrate, 59.2 mg sucrose, and 0.074 mg polysorbate 80. Following reconstitution with 0.7 mL of the supplied Sterile Water for Injection USP, each vial contains PegIntron at strengths of either 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, or 150 mcg per 0.5 mL.

REDIPEN

REDIPEN is a dual-chamber glass cartridge containing lyophilized PegIntron as a white to off-white tablet or powder that is whole or in pieces in the sterile active chamber and a second chamber containing Sterile Water for Injection USP. Each PegIntron REDIPEN contains either 67.5 mcg, 108 mcg, 162 mcg, or 202.5 mcg of PegIntron, and 1.013 mg dibasic sodium phosphate anhydrous, 1.013 mg monobasic sodium phosphate dihydrate, 54 mg sucrose, and 0.0675 mg polysorbate 80. Each cartridge is reconstituted to allow for the administration of up to 0.5 mL of solution. Following reconstitution, each REDIPEN contains PegIntron at strengths of either 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, or 150 mcg per 0.5 mL for a single use. Because a small volume of reconstituted solution is lost during preparation of PegIntron, each REDIPEN contains an excess amount of PegIntron powder and diluent to ensure delivery of the labeled dose.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pegylated recombinant human interferon alfa-2b is an inducer of the innate antiviral immune response [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

The pharmacodynamic effects of peginterferon alfa-2b include inhibition of viral replication in virus-infected cells, the suppression of cell cycle progression/cell proliferation, induction of apoptosis, anti-angiogenic activities, and numerous immunomodulating activities, such as enhancement of the phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and the upregulation of the Th1 T-helper cell subset.

PegIntron raises concentrations of effector proteins such as serum neopterin and 2’5’ oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. The correlation between the in vitro and in vivo pharmacologic and pharmacodynamic and clinical effects is unknown.

12.3 Pharmacokinetics

Following a single subcutaneous dose of PegIntron, the mean absorption half-life (t ½ k_a) was 4.6 hours. Maximal serum concentrations (C_max) occur between 15 and 44 hours postdose, and are sustained for up to 48 to 72 hours. The C_max and AUC measurements of PegIntron increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PegIntron. Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean PegIntron elimination half-life is approximately 40 hours (range 22-60 hours) in patients with HCV infection. The apparent clearance of PegIntron is estimated to be approximately 22 mL/hr·kg. Renal elimination accounts for 30% of the clearance.

Pegylation of interferon alfa-2b produces a product (PegIntron) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON A, PegIntron (1 mcg/kg) has approximately a 7-fold lower mean apparent clearance and a 5-fold greater mean half-life, permitting a reduced dosing frequency. At effective therapeutic doses, PegIntron has approximately 10-fold greater C_max and 50-fold greater AUC than interferon alfa-2b.

Renal Dysfunction

Following multiple dosing of PegIntron (1 mcg/kg subcutaneously given every week for 4 weeks) the clearance of PegIntron is reduced by a mean of 17% in subjects with moderate renal impairment (creatinine clearance 30-49 mL/min) and by a mean of 44% in subjects with severe renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal function. Clearance was similar in subjects with severe renal impairment not on dialysis and subjects who are receiving hemodialysis. The dose of PegIntron for monotherapy should be reduced in patients with moderate or severe renal impairment [see Dosage and Administration (2.3) and REBETOL Package Insert]. REBETOL should not be used in patients with creatinine clearance <50 mL/min [see REBETOL Package Insert, WARNINGS].

Gender

During the 48-week treatment period with PegIntron, no differences in the pharmacokinetic profiles were observed between male and female subjects with chronic hepatitis C infection.

Geriatric Patients

The pharmacokinetics of geriatric subjects (>65 years of age) treated with a single subcutaneous dose of 1 mcg/kg of PegIntron were similar in C_max, AUC, clearance, or elimination half-life as compared to younger subjects (28-44 years of age).

Pediatric Patients

Population pharmacokinetics for PegIntron and REBETOL (Capsules and Oral Solution) were evaluated in pediatric subjects with chronic hepatitis C between 3 and 17 years of age. In pediatric patients receiving PegIntron 60 mcg/m²/week subcutaneously, exposure may be approximately 50% higher than observed in adults receiving 1.5 mcg/kg/week subcutaneously. The pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a prior study of REBETOL in combination with INTRON A in pediatric subjects and in adult subjects.

Effect of Food on Absorption of Ribavirin

Both AUC_tf and C_max increased by 70% when REBETOL Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study [see Dosage and Administration (2.2)].

Drug Interactions

Drugs Metabolized by Cytochrome P-450

The pharmacokinetics of representative drugs metabolized by CYP1A2 (caffeine), CYP2C8/9 (tolbutamide), CYP2D6 (dextromethorphan), CYP3A4 (midazolam), and N-acetyltransferase (dapsone) were studied in 22 subjects with chronic hepatitis C who received PegIntron (1.5 mcg/kg) once weekly for 4 weeks. PegIntron treatment resulted in a 28% (mean) increase in a measure of CYP2C8/9 activity. PegIntron treatment also resulted in a 66% (mean) increase in a measure of CYP2D6 activity; however, the effect was variable as 13 subjects had an increase, 5 subjects had a decrease, and 4 subjects had no significant change [see Drug Interactions (7.1)].

No significant effect was observed on the pharmacokinetics of representative drugs metabolized by CYP1A2, CYP3A4, or N-acetyltransferase. The effects of PegIntron on CYP2C19 activity were not assessed.

Methadone

The pharmacokinetics of concomitant administration of methadone and PegIntron were evaluated in 18 PegIntron-naïve chronic hepatitis C subjects receiving 1.5 mcg/kg PegIntron subcutaneously weekly. All subjects were on stable methadone maintenance therapy receiving ≥40 mg/day prior to initiating PegIntron. Mean methadone AUC was approximately 16% higher after 4 weeks of PegIntron treatment as compared to baseline. In 2 subjects, methadone AUC was approximately double after 4 weeks of PegIntron treatment as compared to baseline [see Drug Interactions (7.2)].

Use with Ribavirin

Zidovudine, Lamivudine, and Stavudine

Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine, lamivudine, and stavudine. However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HIV/HCV coinfected subjects [see Drug Interactions (7.3)].

Didanosine

Exposure to didanosine or its active metabolite (dideoxyadenosine 5'- triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities [see Drug Interactions (7.3)].

12.4 Microbiology

Mechanism of Action

The biological activity of PegIntron is derived from its interferon alfa-2b moiety. Peginterferon alfa-2b binds to and activates the human type 1 interferon receptor. Upon binding, the receptor subunits dimerize, and activate multiple intracellular signal transduction pathways. Signal transduction is initially mediated by the JAK/STAT activation, which may occur in a wide variety of cells. Interferon receptor activation also activates NFκB in many cell types. Given the diversity of cell types that respond to interferon alfa-2b, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon alfa-2b is expected to have pleiotropic biological effects in the body.

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity

The anti-HCV activity of interferon was demonstrated in cell culture using self-replicating HCV-RNA (HCV replicon cells) or HCV infection and resulted in an effective concentration (EC₅₀) value of 1 to 10 IU/mL.

The antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

PegIntron has not been tested for its carcinogenic potential. Neither PegIntron nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.

Use with Ribavirin: Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. See REBETOL package insert for additional warnings relevant to PegIntron therapy in combination with ribavirin.

Impairment of Fertility

PegIntron may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 mcg/m² PegIntron alone every other day for 1 month (approximately 345 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of PegIntron treatment. Every other day dosing with 262 mcg/m² (approximately 21 times the weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of PegIntron on male fertility have not been studied.

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C in Adults

PegIntron Monotherapy-Study 1

A randomized study compared treatment with PegIntron (0.5, 1, or 1.5 mcg/kg once weekly subcutaneously) to treatment with INTRON A (3 million units 3 times weekly subcutaneously) in 1219 adults with chronic hepatitis from HCV infection. The subjects were not previously treated with interferon alpha, had compensated liver disease, detectable HCV-RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. Subjects were treated for 48 weeks and were followed for 24 weeks post-treatment.

Seventy percent of all subjects were infected with HCV genotype 1, and 74 percent of all subjects had high baseline levels of HCV-RNA (more than 2 million copies per mL of serum), 2 factors known to predict poor response to treatment.

Response to treatment was defined as undetectable HCV-RNA and normalization of ALT at 24 weeks post-treatment. The response rates to the 1 and 1.5 mcg/kg PegIntron doses were similar (approximately 24%) to each other and were both higher than the response rate to INTRON A (12%) (see Table 12).

TABLE 12 Rates of Response to Treatment-Study 1
	A PegIntron 0.5 mcg/kg (N=315)	B PegIntron 1 mcg/kg (N=298)	C INTRON A 3 MIU three times weekly (N=307)	B - C (95% CI) Difference between PegIntron 1 mcg/kg and INTRON A
Treatment Response (Combined Virologic Response and ALT Normalization)	17%	24%	12%	11 (5, 18)
Virologic Response^*	18%	25%	12%	12 (6,19)
ALT Normalization	24%	29%	18%	11 (5,18)
^* Serum HCV is measured by a research-based quantitative polymerase chain reaction assay by a central laboratory.

Subjects with both viral genotype 1 and high serum levels of HCV-RNA at baseline were less likely to respond to treatment with PegIntron. Among subjects with the 2 unfavorable prognostic variables, 8% (12/157) responded to PegIntron treatment and 2% (4/169) responded to INTRON A. Doses of PegIntron higher than the recommended dose did not result in higher response rates in these subjects. Subjects receiving PegIntron with viral genotype 1 had a response rate of 14% (28/199) while subjects with other viral genotypes had a 45% (43/96) response rate.

Ninety-six percent of the responders in the PegIntron groups and 100% of responders in the INTRON A group first cleared their viral RNA by Week 24 of treatment [see Dosage and Administration (2)].

The treatment response rates were similar in men and women. Response rates were lower in African-American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (9% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 60% of subjects. A modest reduction in inflammation compared to baseline that was similar in all 4 treatment groups was observed.

PegIntron/REBETOL Combination Therapy-Study 2

A randomized study compared treatment with 2 PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg subcutaneously once weekly/REBETOL 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44 weeks/REBETOL 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously thrice weekly /REBETOL 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible subjects had compensated liver disease, detectable HCV-RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment. The response rate to the PegIntron 1.5 mcg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (see Table 13). The response rate to PegIntron 1.5→0.5 mcg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

TABLE 13 Rates of Response to Treatment – Study 2
	PegIntron 1.5 mcg/kg once weekly REBETOL 800 mg daily	INTRON A 3 MIU three times weekly REBETOL 1000/1200 mg daily
Overall response ^{* †}	52% (264/511)	46% (231/505)
Genotype 1	41% (141/348)	33% (112/343)
Genotype 2-6	75%(123/163)	73% (119/162)
^* Serum HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.
^† Difference in overall treatment response (PegIntron/REBETOL vs. INTRON A/REBETOL) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5 mcg/kg)/REBETOL (800 mg) compared to subjects with other viral genotypes. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/REBETOL.

Subjects with lower body weight tended to have higher adverse reaction rates [see Adverse Reactions (6.1)] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron/REBETOL were 49% in men and 56% in women. Response rates were lower in African American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors in this study.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline, approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

PegIntron/REBETOL Combination Therapy-Study 3

In a large United States community-based study (Study 3), 4913 subjects with chronic hepatitis C were randomized to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a REBETOL dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on an assay with a lower limit of detection of 125 IU/mL) at 24 weeks post-treatment.

Treatment with PegIntron 1.5 mcg/kg and REBETOL 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron in combination with a flat 800 mg daily dose of REBETOL. Subjects weighing >105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing >85 to 105 kg (see Table 14). The benefit of WBD in subjects weighing >85 kg was observed with HCV genotypes 1 through 3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see Adverse Reactions (6.1)].

TABLE 14 SVR Rate by Treatment and Baseline Weight- Study 3
Treatment Group	Subject Baseline Weight
Treatment Group	<65 kg (<143 lb)	65-85 kg (143-188 lb)	>85-105 kg (>188-231 lb)	>105 kg (>231 lb)
WBD*	50% (173/348)	45% (449/994)	42% (351/835)	47% (138/292)
Flat	51% (173/342)	44% (443/1011)	39% (318/819)	33% (91/272)
* P=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and presence/absence of advanced fibrosis, in the model).

A total of 1552 subjects weighing >65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

PegIntron/REBETOL Combination Therapy-Study 4

A large randomized study compared the safety and efficacy of treatment for 48 weeks with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in combination with REBETOL 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided doses) in 3070 treatment-naïve adults with chronic hepatitis C genotype 1. In this study, lack of early virologic response by treatment Week 12 (subjects who do not achieve undetectable HCV-RNA or ≥2 log₁₀ reduction from baseline) was the criteria for discontinuation of treatment. Sustained Virologic Response (SVR) to the treatment was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24 weeks posttreatment [see Table 15].

Table 15 Response Rate by Treatment
Treatment Group	% (number) of Patients
Treatment Group	PegIntron 1.5 mcg/kg /REBETOL	PegIntron 1 mcg/kg REBETOL	Pegasys 180 mcg /Copegus
SVR	40 (406/1019)	38 (386/1016)	41 (423/1035)

In all three treatment groups, overall SVR rates were similar. In subjects with poor prognostic factors, subjects randomized to PegIntron (1.5 mcg/kg)/REBETOL or Pegasys/Copegus achieved higher SVR rates compared to those randomized to the PegIntron 1 mcg/kg/REBETOL arm. In all arms, SVR rates were lower in subjects with poor prognostic factors compared to those without. For the PegIntron 1.5 mcg/kg plus REBETOL dose, SVR rates for those with and without, respectively, the following baseline factors were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load >600,000 IU/mL (35% vs. 61%), >40 years old (38% vs. 50%), and African American subjects (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment week 12 who received PegIntron (1.5 mcg/kg)/REBETOL, the SVR rate was 81% (328/407).

PegIntron/REBETOL Combination Therapy in Prior Treatment Failures-Study 5

In a noncomparative trial, 2293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with PegIntron, 1.5 mcg/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Eligible patients included prior nonresponders (patients who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (patients who were HCV-RNA negative at the end of a minimum 12 weeks of treatment and subsequently relapsed after posttreatment follow-up). Patients who were negative at week 12 were treated for 48 weeks and followed for 24 weeks posttreatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment (measured using a research-based test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9). Patients with the following characteristics were less likely to benefit from retreatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

The retreatment sustained virologic response rates by baseline characteristics are summarized in Table 16.

Table 16

SVR Rates by Baseline Characteristics of Prior Treatment Failures.

HCV

Genotype/

Metavir

Fibrosis Score

Overall SVR by Previous Response and Treatment

Nonresponder

Relapser

alfa interferon/ribavirin

% (number of patients)

peginterferon (2a and 2b

combined)/ribavirin

% (number of patients)

alfa interferon /ribavirin

% (number of patients)

peginterferon (2a and 2b

combined)/ribavirin

% (number of patients)

Overall

18 (158/903)

6 (30/476)

43 (130/300)

35 (113/344)

HCV 1

13 (98/761)

4 (19/431)

32 (67/208)

23 (56/243)

18 (36/202)

6 (7/117)

42 (33/79)

32 (23/72)

16 (38/233)

4 (4/112)

28 (16/58)

21 (14/67)

7 (24/325)

4 (8/202)

26 (18/70)

18 (19/104)

HCV 2/3

49 (53/109)

36 (10/28)

67 (54/81)

57 (52/92)

68 (23/34)

56 (5/9)

76 (19/25)

61 (11/18)

39 (11/28)

38 (3/8)

67 (18/27)

62 (18/29)

40 (19/47)

18 (2/11)

59 (17/29)

51 (23/45)

HCV 4

17 (5/29)

7 (1/15)

88 (7/8)

50 (4/8)

Achievement of an undetectable HCV-RNA at treatment week 12 was a strong predictor of sustained virologic response (SVR). In this trial, 1470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36%) subjects who were HCV-RNA undetectable at treatment week 12, those infected with genotype 1 had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39-55%. Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment week 12 had an overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60-83%. For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

14.2 Chronic Hepatitis C in Pediatrics

PegIntron/REBETOL Combination Therapy-Pediatric Study

Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with REBETOL 15 mg/kg/day plus PegIntron 60 mcg/m² once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks post-treatment. A total of 107 subjects received treatment of whom 52% were female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with Genotype 1, 4 or Genotype 3 with HCV-RNA ≥ 600,000 IU/mL received 48 weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA < 600,000 IU/mL received 24 weeks of therapy. The study results are summarized in Table 17.

Table 17 Sustained Virologic Response Rates by Genotype and Treatment Duration – Pediatric Study
	All Subjects n=107
	24 Weeks	48 Weeks
	Virologic Response n^{* †} (%)	Virologic Response n^{* †} (%)
Genotype
All	26/27(96.3)	44/80(55.0)
1	-	38/72(52.8)
2	14/15(93.3)	-
3^‡	12/12(100)	2/3(66.7)
4	-	4/5(80.0)
^* Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment. ^† n = number of responders/number of subjects with given genotype, and assigned treatment duration. ^‡ Subjects with genotype 3 low viral load (<600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

PegIntron REDIPEN

Each PegIntron REDIPEN Package Contains:
A box containing one 50 mcg per 0.5 mL PegIntron REDIPEN and 1 BD needle and 2 alcohol swabs.		(NDC 0085-1323-01)
A box containing one 80 mcg per 0.5 mL PegIntron REDIPEN and 1 BD needle and 2 alcohol swabs.		(NDC 0085-1316-01)
A box containing one 120 mcg per 0.5 mL PegIntron REDIPEN and 1 BD needle and 2 alcohol swabs.		(NDC 0085-1297-01)
A box containing one 150 mcg per 0.5 mL PegIntron REDIPEN and 1 BD needle and 2 alcohol swabs.		(NDC 0085-1370-01)

Each PegIntron REDIPEN PAK 4 Contains:
A box containing four 50 mcg per 0.5 mL PegIntron REDIPEN Units, each containing 1 BD needle and 2 alcohol swabs.		(NDC 0085-1323-02)
A box containing four 80 mcg per 0.5 mL PegIntron REDIPEN Units, each containing 1 BD needle and 2 alcohol swabs.		(NDC 0085-1316-02)
A box containing four 120 mcg per 0.5 mL PegIntron REDIPEN Units, each containing 1 BD needle and 2 alcohol swabs.		(NDC 0085-1297-02)
A box containing four 150 mcg per 0.5 mL PegIntron REDIPEN Units, each containing 1 BD needle and 2 alcohol swabs.		(NDC 0085-1370-02)

PegIntron Vials

Each PegIntron Package Contains:
A box containing one 50 mcg per 0.5 mL vial of PegIntron Powder for Injection and one 1.25 mL vial of Diluent (Sterile Water for Injection USP), 2 BD Safety Lok syringes with a safety sleeve and 2 alcohol swabs.		(NDC 0085-1368-01)
A box containing one 80 mcg per 0.5 mL vial of PegIntron Powder for Injection and one 1.25 mL vial of Diluent (Sterile Water for Injection USP), 2 BD Safety Lok syringes with a safety sleeve and 2 alcohol swabs.		(NDC 0085-1291-01)
A box containing one 120 mcg per 0.5 mL vial of PegIntron Powder for Injection and one 1.25 mL vial of Diluent (Sterile Water for Injection USP), 2 BD Safety Lok syringes with a safety sleeve and 2 alcohol swabs.		(NDC 0085-1304-01)
A box containing one 150 mcg per 0.5 mL vial of PegIntron Powder for Injection and one 1.25 mL vial of Diluent (Sterile Water for Injection USP), 2 BD Safety Lok syringes with a safety sleeve and 2 alcohol swabs.		(NDC 0085-1279-01)

Storage

PegIntron REDIPEN

PegIntron REDIPEN should be stored at 2°-8°C (36°-46°F).

After reconstitution, the solution should be used immediately, but may be stored up to 24 hours at 2°-8°C (36°-46°F). The reconstituted solution contains no preservative, and is clear and colorless. DO NOT FREEZE.

PegIntron Vials

PegIntron should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59-86°F) [see USP Controlled Room Temperature]. After reconstitution with supplied Diluent the solution should be used immediately, but may be stored up to 24 hours at 2°-8°C (36°-46°F). The reconstituted solution contains no preservative, and is clear and colorless. DO NOT FREEZE.

Disposal Instructions

Patients should be thoroughly instructed in the importance of proper disposal. After preparation and administration of PegIntron for Injection, patients should be advised to use a puncture-resistant container for the disposal of used syringes, needles, and the REDIPEN. The full container should be disposed of in accordance with state and local laws. Patients should also be cautioned against reusing or sharing needles, syringes, or the REDIPEN.

17 PATIENT COUNSELING INFORMATION

A patient should self-inject PegIntron only if it has been determined that it is appropriate, the patient agrees to medical follow-up as necessary, and training in proper injection technique has been given to him/her.

17.1 Medication Guide

Patients receiving PegIntron alone or in combination with REBETOL should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the MEDICATION GUIDES for PegIntron and, if applicable, REBETOL (ribavirin).

17.2 Pregnancy

Patients must be informed that REBETOL 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 during treatment with combination PegIntron/REBETOL therapy and for 6 months post-therapy. Combination PegIntron/REBETOL therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. It is recommended that patients undergo monthly pregnancy tests during therapy and for 6 months post-therapy [see Contraindications (4), Use in Specific Populations (8.1), and REBETOL package insert].

17.3 HCV Transmission

Inform patients that there are no data regarding whether PegIntron therapy will prevent transmission of HCV infection to others. Also, it is not known if treatment with PegIntron will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.

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

Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter [see Warnings and Precautions (5.15)]. It is advised that patients be well hydrated, especially during the initial stages of treatment. “Flu-like” symptoms associated with administration of PegIntron may be minimized by bedtime administration of PegIntron or by use of antipyretics.

Manufactured by Schering Corporation, a subsidiary of Schering-Plough Corporation, Kenilworth, NJ 07033 USA.

U.S. Patent Nos. 5,908,621; 5,951,974; 6,042,822; 6,177,074; 6,180,096; 6,250,469; 6,482,613; 6,524,570; and 6,610,830.

BD and Safety-Lok are registered trademarks of Becton, Dickinson and Company.

Rev 1/2010

B-33538820T

27662463T

MEDICATION GUIDE

PegIntron™ REDIPEN® Single-dose Delivery System

(Peginterferon alfa-2b)

Including appendix with instructions for using PegIntron™ REDIPEN® Single-dose Delivery System

Read this Medication Guide carefully before you start taking PegIntron® (Peg In-tron) or PegIntron/REBETOL® (REB-eh-tole) combination therapy. Read the Medication Guide each time you refill your prescription because there may be new information. The information in this Medication Guide does not take the place of talking with your health care provider (doctor, nurse, nurse practitioner, or physician’s assistant).

If you are taking PegIntron/REBETOL combination therapy, also read the Medication Guide for REBETOL (ribavirin USP) Capsules and Oral Solution.

What is the most important information I should know about PegIntron and PegIntron/REBETOL combination therapy?

PegIntron (peginterferon) is a treatment for some people who are infected with hepatitis C virus. However, PegIntron and PegIntron/REBETOL combination therapy can have serious side effects that may cause death in rare cases. Before you decide to start treatment, you should talk to your health care provider about the possible benefits and side effects of PegIntron or PegIntron/REBETOL combination therapy. If you begin treatment you will need to see your health care provider regularly for medical examinations and lab tests to make sure your treatment is working and to check for side effects.

REBETOL may cause birth defects and/or death of an unborn child. If you are pregnant, you or your male partner must not take PegIntron/REBETOL combination therapy. You must not become pregnant while either you or your partner are being treated with the combination PegIntron/REBETOL therapy, or for 6 months after stopping therapy. Men and women should use birth control while taking the combination therapy and for 6 months afterwards. If you or your partner are being treated and you become pregnant, either during treatment or within 6 months of stopping treatment, call your health care provider right away. There is a Ribavirin Pregnancy Registry that collects information about pregnancy outcomes of female patients and female partners of male patients exposed to ribavirin. You or your healthcare provider are encouraged to contact the Registry at 1-800-593-2214.

If you are taking PegIntron or PegIntron/REBETOL therapy you should call your health care provider immediately if you develop any of these symptoms:

New or worsening mental health problems such as thoughts about killing or hurting yourself or others, trouble breathing, chest pain, severe stomach or lower back pain, bloody diarrhea or bloody bowel movements, high fever, bruising, bleeding, or decreased vision.

The most serious possible side effects of PegIntron and PegIntron/REBETOL therapy include:

Problems with Pregnancy. Combination PegIntron/REBETOL therapy can cause death, serious birth defects, or other harm to your unborn child. If you are a woman of childbearing age, you must not become pregnant during treatment and for 6 months after you have stopped therapy. You must have a negative pregnancy test immediately before beginning treatment, during treatment, and for 6 months after you have stopped therapy. Both male and female patients must use effective forms of birth control during treatment and for the 6 months after treatment is completed. Male patients should use a condom. If you are a female, you must use birth control even if you believe that you are not fertile or that your fertility is low. You should talk to your health care provider about birth control for you and your partner.

Mental health problems and suicide. PegIntron and PegIntron/REBETOL therapies may cause patients to develop mood or behavioral problems. These can include irritability (getting easily upset) and depression (feeling low, feeling bad about yourself, or feeling hopeless). Some patients may have aggressive behavior. Former drug addicts may fall back into drug addiction or overdose. Some patients think about hurting or killing themselves or other people and some have killed (suicide) or hurt themselves or others. You must tell your health care provider if you are being treated for a mental illness or had treatment in the past for any mental illness, including depression and suicidal behavior. You should tell your health care provider if you have ever been addicted to drugs or alcohol.

Heart problems. Some patients taking PegIntron or PegIntron/REBETOL therapy may develop problems with their heart, including low blood pressure, fast heart rate, and very rarely, heart attacks. Tell your health care provider if you have had any heart problems in the past.

Blood problems. PegIntron and PegIntron/REBETOL therapies commonly lower two types of blood cells (white blood cells and platelets). In some patients, these blood counts may fall to dangerously low levels. If your blood counts become very low, this could lead to infections or bleeding.

REBETOL therapy causes a decrease in the number of red blood cells you have (anemia). This can be dangerous, especially for patients who already have heart or circulatory (cardiovascular) problems. Talk with your health care provider before taking combination

PegIntron/REBETOL therapy if you have or have ever had any cardiovascular problems.

Body organ problems. Certain symptoms like severe stomach pain may mean that your internal organs are being damaged. PegIntron may cause lung problems including: trouble breathing, pneumonia, inflammation of lung tissue, and new or worse high blood pressure of the lungs (pulmonary hypertension), which can be severe and may in some cases lead to death. Cases of weakness, loss of coordination, and numbness due to stroke have been reported in patients taking PegIntron, including patients with few or no reported risk factors for stroke.

Eye problems. Changes in vision such as a decrease or loss of vision (blindness) may happen in some patients. You should have an eye exam before you take PegIntron. If you have eye problems or have had them in the past, you may need eye exams while you are taking PegIntron. Tell your healthcare provider or eye doctor right away if you have changes in your vision while taking PegIntron.

For other possible side effects, see “What are the possible side effects of PegIntron and PegIntron/REBETOL combination therapy?” in this Medication Guide.

What is PegIntron and PegIntron/REBETOL combination therapy?

The PegIntron product is a drug used to treat adults who have a lasting (chronic) infection with hepatitis C virus and who show signs that the virus is damaging the liver.

PegIntron/REBETOL combination therapy consists of two medications also used to treat hepatitis C infection in adults and children 3 years of age and older. Patients with hepatitis C have the virus in their blood and in their liver. PegIntron reduces the amount of virus in the body and helps the body's immune system fight the virus. REBETOL (ribavirin) is a drug that helps to fight the viral infection, but does not work when used by itself to treat chronic hepatitis C.

It is not known if PegIntron or PegIntron/REBETOL therapies can cure hepatitis C (permanently eliminate the virus), or if it can prevent liver failure or liver cancer that is caused by hepatitis C infection.

It is also not known if PegIntron or PegIntron/REBETOL combination therapy will prevent one infected person from infecting another person with hepatitis C.

Who should not take PegIntron or PegIntron/REBETOL therapy?

Do not take PegIntron or PegIntron/REBETOL therapy if you:

are pregnant, planning to get pregnant during treatment or during the 6 months after treatment, or breastfeeding.
are a male patient with a female sexual partner who is pregnant, or plans to become pregnant at any time while you are being treated with REBETOL, or during the 6 months after your treatment has ended.
have hepatitis caused by your immune system attacking your liver (autoimmune hepatitis) or unstable liver disease
had an allergic reaction to another alpha interferon or are allergic to any of the ingredients in PegIntron or REBETOL Capsules or Oral Solution. If you have any doubts, ask your health care provider.
Do not take PegIntron/REBETOL combination therapy if you have abnormal red blood cells such as is seen in sickle-cell anemia or thalassemia major.

If you have any of the following conditions or serious medical problems, discuss them with your health care provider before taking PegIntron or PegIntron/REBETOL therapy:

depression or anxiety
sleep problems
high blood pressure
previous heart attack, or other heart problems
liver problems (other than hepatitis C infection)
any kind of autoimmune disease (where the body’s immune system attacks the body’s own cells), such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis
thyroid problems
diabetes
colitis (inflammation of the bowels)
cancer
hepatitis B infection
HIV infection
kidney problems
bleeding problems
alcoholism
drug abuse or addiction
body organ transplant and are taking medicine that keeps your body from rejecting your transplant (suppresses your immune system)

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. PegIntron and certain other medicines may affect each other and cause side effects.

Especially tell your doctor if you take the anti-hepatitis B medicine telbivudine (Tyzeka®). See “What are the possible side effects of PegIntron?”

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take PegIntron or PegIntron/REBETOL?

Your health care provider will decide whether you will take PegIntron therapy alone or the combination of PegIntron/REBETOL, as well as the correct dose ( for adults the dose of PegIntron is based on weight). For children 3 years of age and older, your healthcare provider will recommend the dose of PegIntron based on body surface area. PegIntron and PegIntron/REBETOL are given for up to 1 year. Take your prescribed dose of PegIntron ONCE A WEEK, on the same day of each week and at approximately the same time. Take the medicine for the full course of prescribed therapy and do not take more than the prescribed dose. REBETOL should be taken with food. When you take REBETOL with food, more of the medicine (70% more on average) is taken up by your body. You should take REBETOL the same way every day (twice a day with food) to keep the medicine in your body at a steady level. This will help your health care provider to decide how your treatment is working and how to change the dose of REBETOL you take if you have side effects from REBETOL. Be sure to read the Medication Guide for REBETOL (ribavirin USP) for complete instructions on how to take the REBETOL capsules and oral solution.

You should be completely comfortable with how to prepare PegIntron, how to set the dose you take, and how to inject yourself before you use PegIntron for the first time. PegIntron comes in two different forms, a powder in a single-use vial and a REDIPEN® single-use delivery system. See the attached appendix for detailed instructions for preparing and giving a dose of PegIntron.

If you miss a dose of the PegIntron product, take the missed dose as soon as possible during the same day or the next day, then continue on your regular dosing schedule. If several days go by after you miss a dose, check with your health care provider about what to do. Do not double the next dose or take more than one dose a week without talking to your health care provider. Call your health care provider right away if you take more than your prescribed PegIntron dose. Your health care provider may wish to examine you more closely, and take blood for testing.

If you miss a dose of REBETOL, take the missed dose as soon as possible during the same day. If an entire day has gone by, check with your health care provider about what to do. Do not double the next dose.

You must get regular blood tests to help your health care provider check how the treatment is working and to check for side effects.

Tell your health care provider if you are taking or planning to take other prescription or non-prescription medicines, including vitamin and mineral supplements and herbal medicines.

What should I avoid while taking PegIntron or PegIntron/REBETOL therapies?

If you are pregnant do not start taking PegIntron/REBETOL combination therapy.
Avoid becoming pregnant while taking PegIntron or PegIntron/REBETOL.
PegIntron and PegIntron/REBETOL may harm your unborn child (death or serious birth defects) or cause you to lose your baby (miscarry). If you or your partner become pregnant during treatment or during the 6 months after treatment with PegIntron/REBETOL combination therapy, immediately report the pregnancy to your health care provider. You or your health care provider should call 1-800-593-2214. By calling this number, information about you and/or your partner will be added to a pregnancy registry that will be used to help you and your health care provider make decisions about your treatment for hepatitis in the future. You, your partner, and/or your health care provider will be asked to provide follow-up information on the outcome of the pregnancy.

Do not breastfeed your baby while taking PegIntron.

What are the possible side effects of PegIntron and PegIntron/REBETOL combination therapy?

PegIntron may cause serious side effects including:

See “What is the most important information I should know about PegIntron and PegIntron/REBETOL combination therapy?”

Other body organ problems. A few patients have inflammation of the kidney.

New or worsening autoimmune disease. Some patients taking PegIntron or PegIntron/REBETOL develop autoimmune diseases (a condition where the body’s immune cells attack other cells or organs in the body), including rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. In some patients who already have an autoimmune disease, the disease worsens on PegIntron and PegIntron/REBETOL combination therapy.

Growth problems in children. Weight loss and slowed growth are common in children during treatment with PegIntron/REBETOL. Catch-up weight gain and some catch-up in growth happen after treatment stops, but some children may not reach the height that they were expected to have before treatment.

Nerve problems. People who take PegIntron or other alpha interferon products with telbivudine (Tyzeka®) can have nerve problems such as continuing numbness, tingling, or burning sensation in the arms or legs (peripheral neuropathy). Call your healthcare provider if you have any of these symptoms.

Common but less serious side effects include:

Flu-like symptoms. Most patients who take PegIntron or PegIntron/REBETOL therapy have "flu-like" symptoms (headache, muscle aches, tiredness, and fever). Some of these symptoms (fever, headache) usually lessen after the first few weeks of therapy. You can reduce some of these symptoms by injecting your PegIntron dose at bedtime. Over-the-counter pain and fever reducers, such as acetaminophen or ibuprofen, can be used to prevent or reduce the fever and headache.

Extreme fatigue (tiredness). Many patients become extremely tired while on PegIntron or PegIntron/REBETOL combination therapy.

Appetite problems. Nausea, loss of appetite, and weight loss occur commonly.

Thyroid problems. Some patients develop changes in the function of their thyroid. Symptoms of thyroid changes include the inability to concentrate, feeling cold or hot all the time, a change in your weight, and changes to your skin.

Blood sugar problems. Some patients develop problems with the way their body controls their blood sugar, and may develop high blood sugar or diabetes.

Skin reactions. Redness, swelling, and itching are common at the site of injection. If after several days these symptoms do not disappear contact your health care provider. You may get a rash during therapy. If this occurs, your health care provider may recommend medicine to treat the rash.

Hair thinning. Hair thinning is common during PegIntron and PegIntron/REBETOL treatment. Hair loss stops and hair growth returns after therapy is stopped.

These are not all of the side effects of PegIntron or PegIntron/REBETOL combination therapy. Your health care provider or pharmacist can give you a more complete list.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA–1088.

General advice about prescription medicines:

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any concerns about PegIntron, ask your health care provider. Your health care provider or pharmacist can give you information about PegIntron that was written for health care professionals. Do not use PegIntron for a condition for which it was not prescribed. Do not share this medication with other people.

If you are taking PegIntron/REBETOL combination therapy, also read the Medication Guide for REBETOL (ribavirin USP) Capsules and Oral Solution.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: August 2009

How do I prepare and inject the PegIntron REDIPEN dose?

The PegIntron REDIPEN system is for a single use, by one person only, ONCE A WEEK. The REDIPEN must not be shared. Use only the injection needle provided in the packaging for the PegIntron REDIPEN system. If you have problems with the REDIPEN system or the PegIntron solution, you should contact your health care provider or pharmacist.

The following instructions explain how to prepare and inject yourself with the PegIntron REDIPEN system. This product can also be administered by a parent or caretaker as instructed by your healthcare provider. Please read the instructions carefully and follow them step by step. Your health care provider will instruct you on how to self-inject with the PegIntron REDIPEN . Do not attempt to inject yourself unless you are sure you understand the procedure and requirements for self-injection.

How to Use the PegIntron® REDIPEN^®Single-dose Delivery System.

(Graphic Omitted)

Storing PegIntron

PegIntron REDIPEN should be stored in the refrigerator at 2° to 8°C (36° - 46°F); avoid exposure to heat. After mixing, the PegIntron solution should be used immediately but may be stored in the refrigerator up to 24 hours at 2° to 8°C (36° - 46°F). The solution contains no preservatives. DO NOT FREEZE.

Preparation

1. Find a clean, well-lit, non-slip flat working surface and assemble all of the supplies you will need for an injection. All of the supplies you will need are in the PegIntron REDIPEN package. The package contains:

a PegIntron REDIPEN single-dose delivery system
one disposable needle
two alcohol swabs, and
dosing tray (the dosing tray is the bottom half of the REDIPEN package).

2. Take the PegIntron REDIPEN out of the refrigerator and allow the medicine to come to room temperature. Before removing the REDIPEN from the carton, check the expiration date printed on the PegIntron REDIPEN carton to make sure that the expiration date has not passed. Do not use if the expiration date has passed.

3. After taking the PegIntron REDIPEN out of the carton, look in the window of the REDIPEN and make sure the PegIntron in the cartridge holder window is a white to off-white tablet that is whole, or in pieces, or powdered.

4. Wash your hands thoroughly with soap and water, rinse, and towel dry. It is important to keep your work area, your hands, and the injection site clean to minimize the risk of infection.

1. Mix the Drug

Key points:

Before you mix the PegIntron, make sure it is at room temperature. It is important that you keep the PegIntron REDIPEN UPRIGHT (dosing button down) as shown in Figure 1.

a. Hold the PegIntron REDIPEN UPRIGHT (Figure 1a) in the dosing tray on a hard, flat, non-slip surface with the dosing button down. You may want to hold the REDIPEN using the grip.

b. To mix the powder and the liquid, keep the REDIPEN upright in the dosing tray and press the top half of the REDIPEN downward toward the hard, flat, non-slip surface until you hear the click (Figure 1b).Once you’ve heard the click, you will notice in the window that both dark stoppers are now touching. The dosing button should be flush with the pen body.

(Graphic Omitted)

c. Wait several seconds for the powder to completely dissolve.

d. Gently turn the PegIntron REDIPEN upside down twice (Figure 2). To avoid excessive foaming, DO NOT SHAKE.

(Graphic Omitted)

e. Keep the PegIntron REDIPEN UPRIGHT, with the dosing button down. Then, look through the REDIPEN window to see that the mixed PegIntron solution is completely dissolved. The solution should be clear and colorless before use. Before attaching the needle, it is normal to see some small bubbles in the REDIPEN window, near the top of the solution. Do not use the solution if it is discolored, or not clear, or if particulates are present.

f. Place the PegIntron REDIPEN back into the dosing tray provided in the packaging (Figure 3). The dosing button will be on the bottom.

(Graphic Omitted)

2. Attach the Needle

a. Wipe the rubber membrane of the PegIntron REDIPEN with one alcohol swab.

b. Remove the protective paper tab from the injection needle, but do NOT remove either the outer cap or the yellow inner cap from the injection needle. Keeping the PegIntron REDIPEN UPRIGHT in the dosing tray, FIRMLY push the injection needle straight into the REDIPEN rubber membrane, and screw it firmly in place, in a clockwise direction (Figure 4). Remember to leave the needle caps in place when you attach the needle to the REDIPEN. Pushing the needle through the rubber membrane “primes” the needle and allows the extra liquid and air in the pen to be removed.

(Graphic Omitted)

NOTE: Some fluid will trickle out. This is normal. The dark stoppers move up and you will no longer see the fluid in the window once the needle is successfully primed.

3. Dialing the Dose

a. Remove the PegIntron REDIPEN from the dosing tray (Figure 5a).

Holding the PegIntron REDIPEN firmly, pull the dosing button out as far as it will go. You will see a dark band.

Do not push the dosing button in until you are ready to self-inject the PegIntron dose.

(Graphic Omitted)

b. Turn the dosing button until your prescribed dose is lined up with the dosing tab (Figure 5b). The dosing button will turn freely. If you have trouble dialing your dose, check to make sure the dosing button has been pulled out as far as it will go (Figure 5c).

(Graphic Omitted) (Graphic Omitted)

c. Carefully lay the PegIntron REDIPEN down on a hard, flat, non-slip surface. Do NOT remove either of the needle caps and do NOT push the dosing button in until you are ready to self-inject the PegIntron dose.

4. Injecting the PegIntron Dose

Choosing an Injection Site

The best sites for giving yourself an injection are those areas with a layer of fat between the skin and muscle, like your thigh, the outer surface of your upper arm, and abdomen. Do not inject yourself in the area near your navel or waistline. If you are very thin, you should only use the thigh or outer surface of the arm for injection.

You should use a different site each time you inject PegIntron to avoid soreness at any one site. Do not inject PegIntron into an area where the skin is irritated, red, bruised, infected, or has scars, stretch marks, or lumps.

a. Clean the skin where the injection is to be given with the second alcohol swab provided, and wait for the area to dry.

b. Remove the outer cap from the needle (Figure 6a). There may be some liquid around the yellow inner needle cap (Figure 6b). This is normal.

(Graphic Omitted)(Graphic Omitted)

c. Once the injection site is dry, remove the yellow inner needle cap (Figure 6c). You are now ready to inject.

(Graphic Omitted)

d. Hold the PegIntron REDIPEN with your fingers wrapped around the pen body barrel and your thumb on the dosing button (Figure 7).

With your other hand, pinch the skin in the area you have cleaned for injection.
Insert the needle into the pinched skin at an angle of 45° to 90°.
Press the dosing button down slowly and firmly until you can’t push it any further.
Keep your thumb pressed down on the dosing button for an additional 5 seconds to ensure that you get the complete dose.
Remove the needle from your skin.

(Graphic Omitted)

e. Gently press the injection site with a small bandage or sterile gauze if necessary for a few seconds but do not massage the injection site. If there is bleeding, cover with an adhesive bandage. DO NOT RECAP THE NEEDLE and DO NOT REUSE the REDIPEN.

How do I dispose of the REDIPEN?

Discard the REDIPEN and needle and any solution remaining in the REDIPEN in a Sharp’s container or other puncture-resistant container like a metal coffee can. DO NOT use glass or clear plastic containers. Ask your health care provider how to dispose of a full container. Always keep the container out of reach of children.

After 2 hours, check the injection site for redness, swelling, or tenderness. If you have a skin reaction and it doesn’t clear up in a few days, contact your health care provider.

Manufactured by Schering Corporation, a subsidiary of Schering-Plough Corporation, Kenilworth, NJ 07033 USA.

Rev 8/09

27662463T

__________________________________________________________________________________________________________________________

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use REBETOL safely and effectively. See full prescribing information for REBETOL.

REBETOL (ribavirin USP) Capsules, Oral Solution

Initial U.S. Approval: 1998

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-
ASSOCIATED EFFECTS

See full prescribing information for complete boxed warning.

• REBETOL monotherapy is not effective for the treatment of
chronic hepatitis C (5.9).

• The hemolytic anemia associated with REBETOL therapy may
result in worsening of cardiac disease that has led to fatal
and nonfatal myocardial infarctions. Patients with a history
of significant or unstable cardiac disease should not be
treated with REBETOL (2.4, 5.2, 6.1).

• Significant teratogenic and embryocidal effects have been
demonstrated in all animal species exposed to ribavirin.
Therefore, REBETOL therapy is contraindicated in women who are
pregnant and in the male partners of women who are pregnant.
Extreme care must be taken to avoid pregnancy during therapy
and for 6 months after completion of treatment in both female
patients and in female partners of male patients who are
taking REBETOL therapy (4, 5.1, 8.1, 13.1, 17.2).

--------------------------RECENT MAJOR CHANGES----------------------------
Indications and Usage, Chronic Hepatitis C (1.1)				11/2009
Dosage and Administration (2.1, 2.2, 2.4, 2.5)				11/2009
Warnings and Precautions (5.5, 5.7, 5.8)				11/2009

---------------------------INDICATIONS AND USAGE-----------------------------

REBETOL is a nucleoside analogue indicated in combination with interferon alfa-2b (pegylated and nonpegylated) for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age or older with compensated liver disease. (1.1)

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.

-------------------------DOSAGE AND ADMINISTRATION----------------------

REBETOL is administered according to body weight. (2.1, 2.2)

Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal dysfunction. (2.4, 2.5, 12.3)

-----------------------DOSAGE FORMS AND STRENGTHS--------------------

REBETOL Capsules 200 mg (3)

REBETOL Oral Solution 40 mg per mL (3)

-----------------------------CONTRAINDICATIONS---------------------------------

Pregnant women and men whose female partners are pregnant (4, 8.1)
Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product (4)
Autoimmune hepatitis (4)
Hemoglobinopathies (4)
Creatinine clearance < 50 mL/min (4)
Coadministration with didanosine (4, 7.1)

-----------------------WARNINGS AND PRECAUTIONS------------------------

Pregnancy Category X (5.1, 8.1, 8.3)
- 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.

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

Monotherapy with ribavirin is not permitted. (5.9)

Hemolytic anemia may occur with a significant initial drop in hemoglobin. (5.2)
Pancreatitis. (5.3)
Pulmonary infiltrates or pulmonary function impairment. (5.4)
New or worsening ophthalmologic disorders. (5.5)
Severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. (5.6)
Dental/periodontal disorders reported with combination therapy. (5.7)
Weight loss and growth inhibition reported with combination therapy in pediatric patients. (5.8)

-------------------------------ADVERSE REACTIONS------------------------------

Hemolytic anemia. (6.1)

Most common adverse reactions (approximately 40%) in adult patients receiving REBETOL/PegIntron or INTRON A combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. (6.1, 6.2) Most common adverse reactions (>25%) in pediatric patients receiving REBETOL/PegIntron therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Schering-Plough at 800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-------------------------------DRUG INTERACTIONS------------------------------

Nucleoside analogues: closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, ribavirin or both with worsening toxicities. (7.2)

--------------------------USE IN SPECIFIC POPULATIONS---------------------

Ribavirin Pregnancy Registry: 1-800-593-2214.
Nursing mothers: Potential adverse reactions from the drug in nursing infants. (8.1, 8.3)
Pediatrics: Safety and efficacy in patients < 3 years old have not been established. (8.4)
Organ transplant recipients: Safety and efficacy not studied. (8.6)
Co-infected Patients: Safety and efficacy with HIV or HBV co-infection have not been established. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised: 11/2009

S-018908-RIB-MTL-USPI-15

______________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-
ASSOCIATED EFFECTS

1		INDICATIONS AND USAGE
		1.1 Chronic Hepatitis C (CHC)
2		DOSAGE AND ADMINISTRATION
		2.1 REBETOL/PegIntron Combination Therapy
		2.2 REBETOL/INTRON A Combination Therapy
		2.3 Laboratory Tests
		2.4 Dose Modifications
		2.5 Discontinuation of Dosing
3		DOSAGE FORMS AND STRENGTHS
4		CONTRAINDICATIONS
5		WARNINGS AND PRECAUTIONS
		5.1 Pregnancy
		5.2 Anemia
		5.3 Pancreatitis
		5.4 Pulmonary Disorders
		5.5 Ophthalmologic Disorders
		5.6 Laboratory Tests
		5.7 Dental and Periodontal Disorders
		5.8 Impact on Growth - Pediatric Use
		5.9 Usage Safeguards
6		ADVERSE REACTIONS
		6.1 Clinical Studies Experience – REBETOL/PegIntron Combination Therapy
		6.2 Clinical Studies Experience – REBETOL/INTRON A Combination Therapy
		6.3 Postmarketing Experiences
7		DRUG INTERACTIONS
		7.1 Didanosine
		7.2 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
		12.3 Pharmacokinetics
		12.4 Microbiology
13		NONCLINICAL TOXICOLOGY
		13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
		13.2 Animal Toxicology and Pharmacology
14		CLINICAL STUDIES
		14.1 REBETOL/PegIntron Combination Therapy
		14.2 REBETOL/INTRON A Combination Therapy
16		HOW SUPPLIED/STORAGE AND HANDLING
17		PATIENT COUNSELING INFORMATION
		17.1 Anemia
		17.2 Pregnancy
		17.3 Risks versus Benefits
* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

REBETOL^®monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication [see Warnings and Precautions (5.9)].
The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with REBETOL therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL [see Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1)].
Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1), Nonclinical Toxicology (13.1), and Patient Counseling Information (17.2)].

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C (CHC)

REBETOL (ribavirin) in combination with interferon alfa-2b (pegylated and nonpegylated) is indicated for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver disease [see Warnings and Precautions (5.8, 5.9), and Use in Specific Populations (8.4)].

The following points should be considered when initiating REBETOL combination therapy with PegIntron or INTRON A:

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.
Combination therapy with REBETOL/PegIntron is preferred over REBETOL/INTRON A as this combination provides substantially better response rates [see Clinical Studies (14)].
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 [see Clinical Studies (14)].
No safety and efficacy data are available for treatment of longer than one year.

2 DOSAGE AND ADMINISTRATION

Under no circumstances should REBETOL Capsules be opened, crushed, or broken. REBETOL should be taken with food [see Clinical Pharmacology (12.3)]. REBETOL should not be used in patients with creatinine clearance <50 mL/min.

2.1 REBETOL/PegIntron Combination Therapy

Adult Patients

The recommended dose of PegIntron is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg REBETOL Capsules orally based on patient body weight (see Table 1). 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

Duration of Treatment – Retreatment 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 REBETOL/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 (<87)	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 (87-111)	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 mcg per 0.5 mL	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)		120	0.5	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 60 mcg/m²/week subcutaneously in combination with 15 mg/kg/day of REBETOL orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18^th 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 REBETOL/INTRON A Combination Therapy

Adults

Duration of Treatment – Interferon Alpha-naïve Patients

The recommended dose of INTRON A is 3 million IU three times weekly subcutaneously. The recommended dose of REBETOL Capsules depends on the patient’s body weight (refer to Table 3). The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical Studies (14)]. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

Duration of Treatment – Retreatment with INTRON A/REBETOL in Relapse Patients

In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

Table 3: Recommended Dosing


Body weight		REBETOL Capsules
≤75 kg		2 x 200-mg capsules AM 3 x 200-mg capsules PM daily orally
>75 kg		3 x 200-mg capsules AM 3 x 200-mg capsules PM daily orally

Pediatrics

The recommended dose of REBETOL is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of REBETOL in combination with INTRON A. INTRON A for Injection by body weight of 25 kg to 61 kg is 3 million IU/m² three times weekly subcutaneously. Refer to adult dosing table for > 61 kg body weight.

The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks.

2.3 Laboratory Tests

The following laboratory tests are recommended for all patients treated with REBETOL, prior to beginning treatment and then periodically thereafter.

Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions (5.2, 5.7)],complete and differential white blood cell counts, and platelet count.
Blood chemistries - liver function tests and TSH.
Pregnancy - including monthly monitoring for women of childbearing potential.
ECG [see Warnings and Precautions (5.2)].

2.4 Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy or REBETOL/PegIntron therapy, modified, or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of PegIntron in adult patients on REBETOL/PegIntron 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 of PegIntron in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 4.

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)].

TABLE 4: Two-Step Dose Reduction of PegIntron in Combination Therapy in Adults



First Dose Reduction to PegIntron 1 mcg/kg				Second Dose Reduction to PegIntron 0.5 mcg/kg
Body weight kg (lbs)	PegIntron REDIPEN/Vial Strength to Use	Amount of PegIntron (mcg) to Administer	Volume (mL) ^†of PegIntron to Administer	Body weight kg (lbs)	PegIntron REDIPEN/Vial Strength to Use	Amount of PegIntron (mcg) to Administer	Volume (mL) ^† of PegIntron to Administer
<40 (<88)	50 mcg per 0.5 mL	35	0.35	<40 (<88)	50 mcg per 0.5 mL*	20	0.2
40 – 50 (88 – 111)		45	0.45	40 – 50 (88 – 111)	50 mcg per 0.5 mL*	25	0.25
51 – 60 (112 – 133)		50	0.5	51 – 60 (112 – 133)	50 mcg per 0.5 mL	30	0.3
61 – 75 (134 – 166)	80 mcg per 0.5 mL	64	0.4	61 – 75 (134 –166)		35	0.35
76 – 85 (167 – 187)	80 mcg per 0.5 mL	80	0.5	76 – 85 (167 – 187)		45	0.45
86-104 (188 - 230)	120 mcg per 0.5 mL	96	0.4	86-104 (188-230)		50	0.5
105-125 (231 - 275)	120 mcg per 0.5 mL	108	0.45	105-125 (231-275)	80 mcg per 0.5 mL	64	0.4
>125 (>275)	150 mcg per 0.5 mL	135	0.45	>125 (>275)	80 mcg per 0.5 mL	72	0.45

* Must use vial. Minimum delivery for REDIPEN 0.3 mL.

^† When reconstituted as directed.

Dose reduction in pediatric patients is accomplished by modifying the recommended PegIntron dose in a two-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 Table 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. Dose reduction in pediatric patients is accomplished by modifying the recommended REBETOL dose from the original starting does of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 5).

REBETOL should not be used in patients with creatinine clearance < 50 mL/min. Subjects with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

REBETOL should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2)].

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ≥ 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains < 12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL dose modified or discontinued per Table 5 [see Warnings and Precautions (5.2)].

Table 5: Guidelines for Dose Modification and Discontinuation of PegIntron, INTRON A or PegIntron/REBETOL Based on Laboratory Parameters in Adults and Pediatrics


Laboratory Values	Adults	Pediatrics		Adults Pediatrics
	PegIntron/INTRON A	PegIntron	INTRON A	REBETOL
Hgb < 10g/dL	For patients with cardiac disease, reduce by 50%*	See footnote*	See footnote*	Adjust Dose^†	1^st reduction to 12 mg/kg/day 2^nd reduction to 8 mg/kg/day
WBC < 1.5 x 10⁹/L Neutrophils < 0.75 x 10⁹/L Platelets < 50 x 10⁹/L (Adults) < 70 x 10⁹/L (Pediatrics)	Adjust Dose^‡	1^st reduction to 40 mcg/m²/week 2^nd reduction to 20 mcg/m²/week	Reduce by 50%	No Dose Change	No Dose Change
Hgb < 8.5g/dL WBC < 1 x 10⁹/L Neutrophils < 0.5 x 10⁹/L Creatinine > 2 mg/dL (Pediatrics) Platelets < 25 x 10⁹/L (Adults) < 50 x 10⁹/L (Pediatrics)	Permanently Discontinue	Permanently Discontinue	Permanently Discontinue	Permanently Discontinue	Permanently Discontinue

* For adult patients with a history of stable cardiac disease receiving PegIntron or INTRON A in combination with ribavirin, the PegIntron or INTRON A dose should be reduced by half and the REBETOL dose by 200 mg/day if a > 2 g/dL decrease in hemoglobin is observed during any 4-week period. Both PegIntron and REBETOL or INTRON A and REBETOL should be permanently discontinued if patients have hemoglobin levels < 12 g/dL after this REBETOL dose reduction. Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease ≥ 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing.

^† 1^st dose reduction of REBETOL is by 200 mg/day, except in patients receiving the 1400 mg dose it is by 400 mg/day; 2^nd dose reduction of REBETOL (if needed) is by an additional 200 mg/day.

^‡ For patients on REBETOL/PegIntron combination therapy: 1^st dose reduction of PegIntron is to 1 mcg/kg/week, 2^nd dose reduction (if needed) of PegIntron is to 0.5 mcg/kg/week. For patients on REBETOL/INTRON A combination therapy, reduce INTRON A dose by 50%.

Refer to the INTRON A Package Insert or PegIntron Powder for Injection Package Insert for additional information about how to reduce an INTRON A or PegIntron dose.

2.5 Discontinuation of Dosing

Adults

It is recommended that HCV genotype 1 interferon-alfa-naïve patients receiving PegIntron in combination with ribavirin, be discontinued from therapy if there is not at least a 2 log₁₀ drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable (>10-20 IU/mL) after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Pediatrics (3-17 years of age)

It is recommended that patients receiving PegIntron/REBETOL combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped < 2 log₁₀ compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA (>10-20 IU/mL) at treatment Week 24.

3 DOSAGE FORMS AND STRENGTHS

REBETOL 200 mg Capsules

REBETOL Oral Solution 40 mg per mL

4 CONTRAINDICATIONS

REBETOL combination therapy is contraindicated in:

women who are pregnant. REBETOL may cause fetal harm when administered to a pregnant women. REBETOL is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17.2)]
men whose female partners are pregnant
patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product
patients with autoimmune hepatitis
patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
patients with creatinine clearance < 50 mL/min. [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]
Coadministration of REBETOL and didanosine is contraindicated as because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin [see Drug Interactions (7.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Pregnancy

REBETOL Capsules and Oral Solution may cause birth defects and death of the unborn child. REBETOL 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 forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL has demonstrated significant teratogenic and embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy [see Boxed Warning, Contraindications (4), Use in Specific Populations (8.1), and Patient Counseling Information (17.2)].

5.2 Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of REBETOL/INTRON A-treated subjects in clinical trials. The anemia associated with REBETOL capsules occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy, or more frequently if clinically indicated. Patients should then be followed as clinically appropriate [see Dosage and Administration (2.4, 2.5)].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by REBETOL. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.4, 2.5)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use REBETOL.

5.3 Pancreatitis

REBETOL and INTRON A or PegIntron therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.

5.4 Pulmonary Disorders

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during therapy with REBETOL with alpha interferon combination therapy; occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination therapy should be discontinued.

5.5 Ophthalmologic Disorders

Ribavirin is used in combination therapy with alpha interferons. 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 are induced or aggravated by treatment with alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferon treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

5.6 Laboratory Tests

PegIntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.

Patients on PegIntron/REBETOL combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial CBC (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week intervals or more frequently if abnormalities developed. In pediatric subjects the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see Dosage and Administration (2)].

5.7 Dental and Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of REBETOL and interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations If vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards.

5.8 Impact on Growth - Pediatric Use

Data on the effects of PegIntron plus REBETOL on growth come from an open-label study in subjects 3 through 17 years of age, and weight and height changes are compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lags behind that predicted by normative population data for the entire length of treatment. After about 6 months posttreatment (Follow-Up Week 24), subjects had weight gain rebounds and regained their weight to 53^rd percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57^th percentile). After about 6 months posttreatment, height gain stabilized and subjects treated with PegIntron plus REBETOL had an average height percentile of 44^th percentile, which was less than the average of the normative population and less than their average baseline height (51^st percentile). Severely inhibited growth velocity (< 3^rd percentile) was observed in 70% of the subjects while on treatment. Of the subjects experiencing severely inhibited growth, 20% had continued inhibited growth velocity (< 3^rd percentile) after 6 months of follow-up.

Among the boys studied, the age groups of 3-11 years old and 12-17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months posttreatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3-11 years old and treated for 48 weeks had the largest average drop in height and weight percentiles (13 percentiles and 7 percentiles, respectively), whereas girls 12-17 years old continued along their average baseline height and weight percentiles after 6 months posttreatment.

5.9 Usage Safeguards

Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, REBETOL Capsules or Oral Solution must not be used alone. The safety and efficacy of REBETOL Capsules and Oral Solution have only been established when used together with INTRON A or PegIntron (not other interferons) as a combination therapy.

The safety and efficacy of REBETOL/INTRON A and PegIntron therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. REBETOL Capsules should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

There are significant adverse reactions caused by REBETOL/INTRON A or PegIntron therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. The INTRON A and PegIntron package inserts should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

6 ADVERSE REACTIONS

Clinical trials with REBETOL in combination with PegIntron or INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age.

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [see Warnings and Precautions (5.2)].

Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving PegIntron or INTRON A in combination with REBETOL were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving REBETOL in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The Adverse Reactions section references the following clinical studies:

REBETOL/PegIntron Combination therapy studies:
- Clinical Study 1 - evaluated PegIntron monotherapy (not further described in this label; see PegIntron Powder for Injection Package Insert for information about this study).
- Study 2 - evaluated REBETOL 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A.
- Study 3 - evaluated PegIntron/weight-based REBETOL in combination with PegIntron/flat dose REBETOL regimen.
- Study 4- compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving Pegasys^® (180 mcg/week)/Copegus^® (1000-1200 mg/day).
- Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based REBETOL in prior treatment failure subjects.
PegIntron/REBETOL Combination Therapy in Pediatric Patients
REBETOL/INTRON A Combination Therapy studies for adults and pediatrics

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without REBETOL [see BOXED WARNING, Warnings and Precautions (5)]. The most common serious events occurring in subjects treated with PegIntron and REBETOL were depression and suicidal ideation [see Warnings and Precautions (5.2)], each occurring at a frequency of less than 1%. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [see Warnings and Precautions (5.9)]. The most common fatal reaction occurring in subjects treated with PegIntron and REBETOL was cardiac arrest, suicide ideation, and suicide attempt [see Warnings and Precautions (5.9)], all occurring in less than 1% of subjects.

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rated in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

6.1 Clinical Studies Experience – REBETOL/PegIntron Combination Therapy

Adult Subjects

Adverse reactions that occurred in the clinical trial at > 5% incidence are provided by treatment group from the REBETOL/PegIntron Combination Therapy (Study 2) in Table 6.

Table 6: Adverse Reactions Occurring in > 5% of Adult Subjects


Adverse reactions	Percentage of Subjects Reporting Adverse Reactions^*		Adverse Reactions	Percentage of Subjects Reporting Adverse Reactions^*
Adverse reactions	PegIntron 1.5 mcg/kg/ REBETOL (N=511)	INTRON A/ REBETOL (N=505)	Adverse Reactions	PegIntron 1.5 mcg/kg/ REBETOL (N=511)	INTRON A/ REBETOL (N=505)
Application Site			Musculoskeletal
Injection Site Inflammation Injection Site Reaction	25 58	18 36	Myalgia	56	50
Injection Site Inflammation Injection Site Reaction	25 58	18 36	Arthralgia	34	28
Autonomic Nervous System			Musculoskeletal Pain	21	19
Dry Mouth	12	8	Psychiatric
Increased Sweating	11	7	Insomnia	40	41
Flushing	4	3	Depression	31	34
Body as a Whole			Anxiety/Emotional Lability/Irritability	47	47
Fatigue/Asthenia	66	63	Concentration Impaired	17	21
Headache	62	58	Agitation	8	5
Rigors	48	41	Nervousness	6	6
Fever	46	33	Reproductive, Female
Weight Loss	29	20	Menstrual Disorder	7	6
Right Upper Quadrant Pain	12	6	Resistance Mechanism
Chest Pain	8	7	Viral Infection	12	12
Malaise	4	6	Fungal Infection	6	1
Central/Peripheral Nervous System			Respiratory System
Dizziness	21	17	Dyspnea	26	24
Endocrine			Coughing	23	16
Hypothyroidism	5	4	Pharyngitis	12	13
Gastrointestinal			Rhinitis	8	6
Nausea	43	33	Sinusitis	6	5
Anorexia	32	27	Skin and Appendages
Diarrhea	22	17	Alopecia	36	32
Vomiting	14	12	Pruritus	29	28
Abdominal Pain	13	13	Rash	24	23
Dyspepsia	9	8	Skin Dry	24	23
Constipation	5	5	Special Senses, Other
Hematologic Disorders			Taste Perversion	9	4
Neutropenia	26	14	Vision Disorders
Anemia	12	17	Vision Blurred	5	6
Leukopenia	6	5	Conjunctivitis	4	5
Thrombocytopenia	5	2
Liver and Biliary System
Hepatomegaly	4	4

^* A subject may have reported more than one adverse reaction within a body system/organ class category.

Table 7 summarizes the treatment related adverse reactions in Study 4 that occurred at a ≥10% incidence.

Table 7: Summary of Treatment-Related Adverse Reactions (≥10% Incidence) By Descending Frequency


	Study 4 Percentage of Patients Reporting Treatment-Related Adverse Reactions
Adverse Reactions	PegIntron 1.5 mcg/kg with REBETOL (n=1019)	PegIntron 1 mcg/kg with REBETOL (n=1016)	Pegasys 180 mcg with Copegus (n=1035)
Fatigue	67	68	64
Headache	50	47	41
Nausea	40	35	34
Chills	39	36	23
Insomnia	38	37	41
Anemia	35	30	34
Pyrexia	35	32	21
Injection Site Reactions	34	35	23
Anorexia	29	25	21
Rash	29	25	34
Myalgia	27	26	22
Neutropenia	26	19	31
Irritability	25	25	25
Depression	25	19	20
Alopecia	23	20	17
Dyspnea	21	20	22
Arthralgia	21	22	22
Pruritus	18	15	19
Influenza-like Illness	16	15	15
Dizziness	16	14	13
Diarrhea	15	16	14
Cough	15	16	17
Weight Decreased	13	10	10
Vomiting	12	10	9
Unspecified Pain	12	13	9
Dry Skin	11	11	12
Anxiety	11	11	10
Abdominal Pain	10	10	10
Leukopenia	9	7	10

The incidence of seri ous adverse reactions was comparable in all studies. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and with the flat-dose REBETOL regimen. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/REBETOL groups compared to 14% in the INTRON A/REBETOL group.

In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing adverse reactions by body class in the PegIntron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects’ weight loss, fatigue, and headache had not resolved.

There have been 31 subject deaths which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PegIntron/REBETOL combination therapy; and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). There have been 31 subject deaths which occurred during treatment or during follow-up in the three clinical trials. In Study 3, there were 14 deaths, 2 of which were probable suicides and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received PegIntron/REBETOL combination therapy, 5 in the PegIntron 1.5 mcg/REBETOL arm (N=1019) and 1 in the PegIntron 1 mcg/REBETOL arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides which occurred during the off treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/REBETOL combination therapy.

In studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based REBETOL and 14% of subjects receiving PegIntron and flat dose REBETOL discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In study 4, 13% of subjects in the PegIntron 1.5 mcg/REBETOL arm, 10% in the PegIntron 1 mcg/REBETOL arm and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PegIntron (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose related (PegIntron 1.5 mcg/kg > PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three groups, 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with WBD compared to flat dosing (29% and 23%, respectively). 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 compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 mcg/week with Pegasys.

In the PegIntron/REBETOL combination trials the most common adverse reactions were psychiatric which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see Warnings and Precautions (5)]. In study 4 psychiatric adverse reactions occurred in 58 % of subjects in the PegIntron 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron 1 mcg/REBETOL arm, 57% of subjects in the Pegasys 180 mcg/Copegus arm.

PegIntron induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection site pain was infrequent (2 to 3%) in all groups. In Study 3 there was a 23 to 24% incidence overall for injection site reactions or inflammation.

Subjects receiving REBETOL/PegIntron as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naïve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment, 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations.

Dose modifications of PegIntron and/or ribavirin were required in 25% of subjects due to treatment-related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction.

Adverse reactions that occurred with a ≥ 10% incidence in the pediatric trial subjects are provided in Table 8.

Table 8: Percentage (%) of Pediatric Subjects With Treatment-Related Adverse Reactions (in at Least 10% of All Subjects)


System Organ Class Preferred Term		All Subjects (N=107)
Blood and Lymphatic System Disorders
Neutropenia		33%
Anemia		11%
Leukopenia		10%
Gastrointestinal Disorders
Abdominal Pain		21%
Abdominal Pain Upper		12%
Vomiting		27%
Nausea		18%
General Disorders and Administration Site Conditions
Pyrexia		80%
Fatigue		30%
Injection-site Erythema		29%
Chills		21%
Asthenia		15%
Irritability		14%
Investigations
Weight Loss		19%
Metabolism and Nutrition Disorders
Anorexia		29%
Decreased Appetite		22%
Musculoskeletal and Connective Tissue Disorders
Arthralgia		17%
Myalgia		17%
Nervous System Disorders
Headache		62%
Dizziness		14%
Skin and Subcutaneous Tissue Disorders
Alopecia		17%

Laboratory Values

Adult and Pediatric Subjects

The adverse reaction profile in Study 3, which compared PegIntron/weight-based REBETOL combination to a PegIntron/flat dose REBETOL regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions.

Changes in selected laboratory values during treatment in combination with REBETOL treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.4)]. Changes in selected laboratory values during therapy are described in Table 9. Most of the changes in laboratory values in the PegIntron/REBETOL study with pediatric were mild or moderate.

Table 9: Selected Laboratory Values During Treatment With REBETOL Plus PegIntron or REBETOL Plus INTRON A in Previously Untreated Subjects


	Laboratory Parameters*	Percent of Subjects
		Adults (Study 2)		Pediatrics
		PegIntron plus REBETOL (N=511)	INTRON A plus REBETOL (N=505)	PegIntron plus REBETOL (N=107)^*
Hemoglobin (g/dL)
	9.5-<11.0	26	27	30
	8.0-<9.5	3	3	2
	6.5-7.9	0.2	0.2	-
Leukocytes (x10⁹/L)
	2.0-2.9	46	41	39
	1.5-<2.0	24	8	3
	1.0-1.4	5	1	-
Neutrophils (x10⁹/L)
	1.0-1.5	33	37	35
	0.75-<1.0	25	13	26
	0.5-<0.75	18	7	13
	<0.5	4	2	3
Platelets (x10⁹/L)
	70-100	15	5	1
	50-<70	3	0.8	-
	30-49	0.2	0.2	--
	25-<50	--	--	1
Total Bilirubin		(mg/dL)		(µmole/L)
	1.5 -3.0	10	13	--
	1.26-2.59 x N^†	--	--	7
	3.1-6.0	0.6	0.2	--
	2.6-5 x N^†	--	--	-
	6.1-12.0	0	0.2	--
ALT (U/L)
	2 x Baseline	0.6	0.2	1
	2.1-5 x Baseline	3	1	5
	5.1-10 x Baseline	0	0	3

* The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included.

^† N=Upper limit of normal.

Hemoglobin. Hemoglobin levels decreased to < 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat dose REBETOL had decreases in hemoglobin levels <11 g/dl. Reductions in hemoglobin to < 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the PegIntron/REBETOL and INTRON A /REBETOL groups. In Study 4, patients receiving PegIntron (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to <10 g/dL (28%) and to <8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects respectively. Hemoglobin levels become stable by treatment Weeks 4-6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the PegIntron monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see Dosage and Administration (2.4)].

Neutrophils. Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with REBETOL in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (<0.5 x 10⁹/L) occurred in 2% of subjects treated with INTRON A/REBETOL and in approximately 4% of subjects treated with PegIntron/REBETOL in Study 2. Eighteen percent of subjects receiving PegIntron/REBETOL in Study 2 required modification of interferon dosage. Few subjects (< 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.4)].

Platelets. Platelet counts decreased to < 100,000/mm³ in approximately 20% of subjects treated with PegIntron alone or with REBETOL and in 6% of adult subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (< 50,000/mm³) occur in < 4% of adult subjects. Subjects may require discontinuation or dose modification as a result of platelet decreases [see Dosage and Administration (2.4)]. In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or PegIntron (with or without REBETOL) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still had abnormal TSH values.

Bilirubin and uric acid. In Study 2, 10 to 14% of subjects developed hyperbilirubinemia and 33 to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.

6.2 Clinical Studies Experience – REBETOL/INTRON A Combination Therapy

Adult Subjects

In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-related adverse reactions that occurred in the US studies with ≥ 5% incidence are provided by treatment group (see Table 10). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.

Pediatric Subjects

In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric subjects compared to adult subjects. Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with ≥ 5% incidence among all pediatric subjects who received the recommended dose of REBETOL/INTRON A combination therapy are provided in Table 10.

Table 10: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects


Patients Reporting Adverse reactions^*	Percentage of Subjects
	US Previously Untreated Study				US Relapse Study		Pediatric Subjects
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment		48 weeks of treatment
	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus REBETOL (N=77)	INTRON A plus Placebo (N=76)	INTRON A plus REBETOL (N=118)
Application Site Disorders
Injection Site Inflammation	13	10	12	14	6	8	14
Injection Site Reaction	7	9	8	9	5	3	19
Body as a Whole - General Disorders
Headache	63	63	66	67	66	68	69
Fatigue	68	62	70	72	60	53	58
Rigors	40	32	42	39	43	37	25
Fever	37	35	41	40	32	36	61
Influenza-like Symptoms	14	18	18	20	13	13	31
Asthenia	9	4	9	9	10	4	5
Chest Pain	5	4	9	8	6	7	5
Central & Peripheral Nervous System Disorders
Dizziness	17	15	23	19	26	21	20
Gastrointestinal System Disorders
Nausea	38	35	46	33	47	33	33
Anorexia	27	16	25	19	21	14	51
Dyspepsia	14	6	16	9	16	9	<1
Vomiting	11	10	9	13	12	8	42
Musculoskeletal System Disorders
Myalgia	61	57	64	63	61	58	32
Arthralgia	30	27	33	36	29	29	15
Musculoskeletal Pain	20	26	28	32	22	28	21
Psychiatric Disorders
Insomnia	39	27	39	30	26	25	14
Irritability	23	19	32	27	25	20	10
Depression	32	25	36	37	23	14	13
Emotional Lability	7	6	11	8	12	8	16
Concentration Impaired	11	14	14	14	10	12	5
Nervousness	4	2	4	4	5	4	3
Respiratory System Disorders
Dyspnea	19	9	18	10	17	12	5
Sinusitis	9	7	10	14	12	7	<1
Skin and Appendages Disorders
Alopecia	28	27	32	28	27	26	23
Rash	20	9	28	8	21	5	17
Pruritus	21	9	19	8	13	4	12
Special Senses, Other Disorders
Taste Perversion	7	4	8	4	6	5	<1

^* Subjects reporting one or more adverse reactions. A patient may have reported more than one adverse reaction within a body system/organ class category.

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 11).

Hemoglobin. Hemoglobin decreases among subjects receiving REBETOL therapy began at Week 1, with stabilization by Week 4. In previously untreated subjects treated for 48 weeks, the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse subjects the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most subjects.

Bilirubin and Uric Acid. Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in subjects with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 11: Selected Hematologic Abnormalities During Treatment With REBETOL Plus INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects


	Percentage of Subjects
	US Previously Untreated Study				US Relapse Study		Pediatric Subjects
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment		48 weeks of treatment
	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus REBETOL (N=77)	INTRON A plus Placebo (N=76)	INTRON A plus REBETOL (N=118)
Hemoglobin (g/dL)
9.5 to 10.9	24	1	32	1	21	3	24
8.0 to 9.4	5	0	4	0	4	0	3
6.5 to 7.9	0	0	0	0.4	0	0	0
< 6.5	0	0	0	0	0	0	0
Leukocytes (x10⁹/L)
2.0 to 2.9	40	20	38	23	45	26	35
1.5 to 1.9	4	1	9	2	5	3	8
1.0 to 1.4	0.9	0	2	0	0	0	0
< 1.0	0	0	0	0	0	0	0
Neutrophils (x10⁹/L)
1.0 to 1.49	30	32	31	44	42	34	37
0.75 to 0.99	14	15	14	11	16	18	15
0.5 to 0.74	9	9	14	7	8	4	16
< 0.5	11	8	11	5	5	8	3
Platelets (x10⁹/L)
70 to 99	9	11	11	14	6	12	0.8
50 to 69	2	3	2	3	0	5	2
30 to 49	0	0.4	0	0.4	0	0	0
< 30	0.9	0	1	0.9	0	0	0
Total Bilirubin (mg/dL)
1.5 to 3.0	27	13	32	13	21	7	2
3.1 to 6.0	0.9	0.4	2	0	3	0	0
6.1 to 12.0	0	0	0.4	0	0	0	0
> 12.0	0	0	0	0	0	0	0

6.3 Postmarketing Experiences

The following adverse reactions have been identified and reported during post approval use of REBETOL in combination with INTRON A or PegIntron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System disorders

Pure red cell aplasia, aplastic anemia

Ear and Labyrinth disorders

Hearing disorder, vertigo

Respiratory, Thoracic and mediastinal disorders

Pulmonary hypertension

Eye disorders

Serous retinal detachment

Endocrine disorders

Diabetes

7 DRUG INTERACTIONS

7.1 Didanosine

Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore, coadministration of REBETOL Capsules or Oral Solution and didanosine is contraindicated. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials.

7.2 Nucleoside Analogues

Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Adding treatment with alpha interferons alone or in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment- associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate (see Individual NRTI Product Information). Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6).

Ribavirin may antagonize the cell culture antiviral activity of stavudine and zidovudine against HIV. Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine, and zidovudine, which could lead to decreased antiretroviral activity. However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen to HIV/HCV co-infected subjects. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution.

7.3 Drugs Metabolized by Cytochrome P-450

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A for Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

[See Contraindications (4), Warnings and Precautions (5.1), and Nonclinical Toxicology (13.1)].

Treatment and Posttreatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Women of childbearing potential should not receive REBETOL unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months post-therapy based on a multiple-dose half-life (t_1/2) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with REBETOL and for the 6-month post-therapy period (e.g., 15 half-lives for ribavirin clearance from the body).

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 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

8.3 Nursing Mothers

It is not known whether the REBETOL product is excreted in human milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue REBETOL.

8.4 Pediatric Use

Safety and effectiveness of REBETOL in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with REBETOL/INTRON A, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the safety findings observed.

Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see Warnings and Precautions (5.9)]. As in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see Warnings and Precautions (5.2)].

8.5 Geriatric Use

Clinical studies of REBETOL/INTRON A or PegIntron therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

REBETOL is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments should be made accordingly. REBETOL should not be used in patients with creatinine clearance < 50 mL/min [see Contraindications (4)].

In general, REBETOL Capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) [see Warnings and Precautions (5.2)].

8.6 Organ Transplant Recipients

The safety and efficacy of INTRON A and PegIntron alone or in combination with REBETOL for the treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.

8.7 HIV or HBV Co-infection

The safety and efficacy of PegIntron/REBETOL and INTRON A/REBETOL for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

10 OVERDOSAGE

There is limited experience with overdosage. Acute ingestion of up to 20 g of REBETOL Capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse reactions related to the therapeutic use of INTRON A and REBETOL. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

There is no specific antidote for INTRON A or REBETOL overdose, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of these agents.

11 DESCRIPTION

REBETOL is Schering Corporation’s brand name for ribavirin, a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula (see Figure 1).

(Graphic Omitted)

Figure 1: Structural Formula

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C₈H₁₂N₄O₅ and the molecular weight is 244.21.

REBETOL Capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin, sodium lauryl sulfate, silicon dioxide, and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, and FD&C Blue #2 aluminum lake.

REBETOL Oral Solution is a clear, colorless to pale or light yellow bubble gum-flavored liquid. Each milliliter of the solution contains 40 mg of ribavirin and the inactive ingredients sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ribavirin is an antiviral agent [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 12. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUC_tf (AUC from time zero to last measurable concentration) following single doses of 200 to 1200 mg ribavirin. The relationship between dose and C_max was curvilinear, tending to asymptote above single doses of 400 to 600 mg.

Upon multiple oral dosing, based on AUC_12hr, a 6-fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Antacid on Absorption of Ribavirin

Coadministration of REBETOL Capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta^®) resulted in a 14% decrease in mean ribavirin AUC_tf. The clinical relevance of results from this single-dose study is unknown.

Table 12: Mean (% CV) Pharmacokinetic Parameters for REBETOL When Administered Individually to Adults


Parameter	REBETOL
Parameter	Single-Dose 600 mg Oral Solution (N=14)	Single-Dose 600 mg Capsules (N=12)	Multiple-Dose 600 mg Capsules twice daily (N=12)
T_max (hr)	1.00 (34)	1.7 (46)^*	3 (60)
C_max (ng/mL)	872 (42)	782 (37)	3680 (85)
AUC_tf (ng^.hr/mL)	14,098 (38)	13,400 (48)	228,000 (25)
T_1/2 (hr)		43.6 (47)	298 (30)
Apparent Volume of Distribution (L)		2825 (9)^†
Apparent Clearance (L/hr)		38.2 (40)
Absolute Bioavailability		64% (44)^‡

^* N = 11

^† Data obtained from a single-dose pharmacokinetic study using ¹⁴C labeled ribavirin; N = 5

^‡ N = 6

Tissue Distribution

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an e_s-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Metabolism and Excretion

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of ¹⁴C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Special Populations

Renal Dysfunction

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction. The mean AUC_tf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance > 90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUC_tf was twofold greater when compared to control subjects. The increased AUC_tf appears to be due to reduction of renal and nonrenal clearance in these subjects. Phase III efficacy trials included subjects with creatinine clearance values > 50 mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance < 50 mL/min should not be treated with REBETOL [see Contraindications (4)].

Hepatic Dysfunction

The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUC_tf values were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean C_max values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Elderly Patients

Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender

There were no clinically significant pharmacokinetic differences noted in a single-dose study of 18 male and 18 female subjects.

Pediatric Patients

Multiple-dose pharmacokinetic properties for REBETOL Capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 13. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric subjects.

Complete pharmacokinetic characteristics of REBETOL Oral Solution have not been determined in pediatric subjects. Ribavirin C_min values were similar following administration of REBETOL Oral Solution or REBETOL Capsules during 48 weeks of therapy in pediatric patients (3 to 16 years of age).

Table 13: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and REBETOL Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C


Parameter	REBETOL 15 mg/kg/day as 2 divided doses (N=17)	INTRON A 3 MIU/m²three times weekly (N=54)
T_max (hr)	1.9 (83)	5.9 (36)
C_max (ng/mL)	3275 (25)	51 (48)
AUC^*	29774 (26)	622 (48)
Apparent Clearance L/hr/kg	0.27 (27)	ND^†

^* AUC₁₂ (ng·hr/mL) for REBETOL; AUC_0-24 (IU·hr/mL) for INTRON A

^† ND=not done

Note: numbers in parenthesis indicate % coefficient of variation.

A clinical study in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was conducted in which pharmacokinetics for PegIntron and REBETOL (Capsules and Oral Solution) were evaluated. In pediatric subjects receiving body surface area-adjusted dosing of PegIntron at 60 mcg/m²/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58% [90% CI: 141%, 177%] higher than observed in adults receiving 1.5 mcg/kg/week. The pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a prior study of REBETOL in combination with INTRON A in pediatric subjects and in adults subjects.

Effect of Food on Absorption of Ribavirin

12.4 Microbiology

Mechanism of Action

Antiviral Activity in Cell Culture

The anti-viral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin. Direct anti-viral activity has been observed in tissue culture of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell containing self-replicating HCV-RNS (HCV replicon cells) or HCV infection.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/nonpegylated interferons and ribavirin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, Mutagenesis

Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was noncarcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult). However, this dose was less than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin.

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Impairment of Fertility

Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin) [see Contraindications (4), and Warnings and Precautions (5.1)].

Fertile women and partners of fertile women should not receive REBETOL unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple-dose half-life (t_1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months post-therapy (e.g., 15 half-lives of clearance for ribavirin).

REBETOL should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60-kg adult; 0.1-0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

13.2 Animal Toxicology and Pharmacology

Long-term studies in the mouse and rat [18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively {estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum human 24-hour dose of ribavirin] have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.

14 CLINICAL STUDIES

Clinical Study 1 evaluated PegIntron monotherapy. See PegIntron Powder for Injection Package Insert for information about this study.

14.1 REBETOL/PegIntron Combination Therapy

Adult Subjects

Study 2

A randomized study compared treatment with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg subcutaneously once weekly/REBETOL 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44 weeks/REBETOL 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously three times weekly/REBETOL 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks posttreatment. Eligible subjects had compensated liver disease, detectable HCV-RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment (see Table 14). The response rate to the PegIntron 1.5 mcg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (see Table 14).The response rate to PegIntron 1.5→0.5 mcg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Table 14: Rates of Response to Combination Treatment


	PegIntron 1.5 mcg/kg once weekly REBETOL 800 mg once daily	INTRON A 3 MIU three times weekly REBETOL 1000/1200 mg once daily
Overall response^*,†	52% (264/511)	46% (231/505)
Genotype 1	41% (141/348)	33% (112/343)
Genotype 2-6	75% (123/163)	73% (119/162)

^* Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.

^† Difference in overall treatment response (PegIntron/REBETOL vs. INTRON A/REBETOL) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment.

Subjects with lower body weight tended to have higher adverse-reaction rates [see Adverse Reactions (6.1)] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron/REBETOL combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors in this study.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

Study 3

In a large, United States, community-based study (Study 3), 4913 subjects with chronic hepatitis C were randomized to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a REBETOL dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on an assay with a lower limit of detection of 125 IU/mL) at 24 weeks posttreatment.

Treatment with PegIntron 1.5 mcg/kg and REBETOL 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron in combination with a flat 800 mg daily dose of REBETOL. Subjects weighing > 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing > 85 to 105 kg (see Table 15). The benefit of WBD in subjects weighing > 85 kg was observed with HCV genotypes 1-3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see Adverse Reactions (6.1)].

Table 15: SVR Rate by Treatment and Baseline Weight - Study 3


Treatment Group	Subject Baseline Weight
Treatment Group	< 65 kg (< 143 lb)	65-85 kg (143-188 lb)	> 85-105 kg (> 188-231 lb)	> 105 kg (> 231 lb)
WBD*	50% (173/348)	45% (449/994)	42% (351/835)	47% (138/292)
Flat	51% (173/342)	44% (443/1011)	39% (318/819)	33% (91/272)

* p=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and presence/absence of advanced fibrosis, in the model).

A total of 1552 subjects weighing > 65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

Study 4

Table 16: Response Rate by Treatment


Treatment Group	% (number) of Patients
Treatment Group	PegIntron 1.5 mcg/kg /REBETOL	PegIntron 1 mcg/kg REBETOL	Pegasys 180 mcg /Copegus
SVR	40 (406/1019)	38 (386/1016)	41 (423/1035)

Study 5 - REBETOL/PegIntron Combination Therapy in Prior Treatment Failures

In a noncomparative trial, 2293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were re-treated with PegIntron, 1.5 mcg/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Eligible patients included prior nonresponders (patients who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (patients who were HCV-RNA negative at the end of a minimum 12 weeks of treatment and subsequently relapsed after posttreatment follow-up). Patients who were negative at Week 12 were treated for 48 weeks and followed for 24 weeks posttreatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment (measured using a research-based test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9). Patients with the following characteristics were less likely to benefit from retreatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

The retreatment sustained virologic response rates by baseline characteristics are summarized in Table 17.

Table 17: SVR Rates by Baseline Characteristics of Prior Treatment Failures


HCV Genotype/ Metavir Fibrosis Score	Overall SVR by Previous Response and Treatment
	Nonresponder		Relapser
	alfa interferon/ribavirin % (number of patients)	peginterferon (2a and 2b combined)/ribavirin % (number of patients)	alfa interferon/ribavirin % (number of patients)	peginterferon (2a and 2b combined)/ribavirin % (number of patients)
Overall	18 (158/903)	6 (30/476)	43 (130/300)	35 (113/344)
HCV 1	13 (98/761)	4 (19/431)	32 (67/208)	23 (56/243)
F2	18 (36/202)	6 (7/117)	42 (33/79)	32 (23/72)
F3	16 (38/233)	4 (4/112)	28 (16/58)	21 (14/67)
F4	7 (24/325)	4 (8/202)	26 (18/70)	18 (19/104)
HCV 2/3	49 (53/109)	36 (10/28)	67 (54/81)	57 (52/92)
F2	68 (23/34)	56 (5/9)	76 (19/25)	61 (11/18)
F3	39 (11/28)	38 (3/8)	67 (18/27)	62 (18/29)
F4	40 (19/47)	18 (2/11)	59 (17/29)	51 (23/45)
HCV 4	17 (5/29)	7 (1/15)	88 (7/8)	50 (4/8)

Pediatric Subjects

Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with REBETOL 15 mg/kg per day plus PegIntron 60 mcg/m² once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks posttreatment. A total of 107 subjects received treatment of whom 52% were female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with Genotypes 1, 4 or Genotype 3 with HCV-RNA ≥ 600,000 IU/mL received 48 weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA < 600,000 IU/mL received 24 weeks of therapy. The study results are summarized in Table 18.

Table 18: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration – Pediatric Study


Genotype	All Subjects n=107
	24 Weeks	48 Weeks
	Virologic Response n^,†(%)*	Virologic Response n^,†(%)*
All	26/27 (96.3)	44/80 (55.0)
1	-	38/72 (52.8)
2	14/15 (93.3)	-
3^‡	12/12 (100)	2/3 (66.7)
4	-	4/5 (80.0)
*: Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment. ^†: n = number of responders/number of subjects with given genotype, and assigned treatment duration. ^‡: Subjects with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment.

14.2 REBETOL/INTRON A Combination Therapy

Adult Subjects

Previously Untreated Subjects

Adults with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL Capsules 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) plus INTRON A for Injection 3 MIU three times weekly or INTRON A for Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 subjects who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in Table 19.

Table 19: Virologic and Histologic Responses: Previously Untreated Subjects*


	US Study				International Study
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment	48 weeks of treatment
	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus REBETOL (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus REBETOL (N=265)	INTRON A plus REBETOL (N=268)	INTRON A plus Placebo (N=266)
Virologic Response
Responder^†	65 (29)	13 (6)	85 (37)	27 (12)	86 (32)	113 (42)	46 (17)
Nonresponder	147 (64)	194 (84)	110 (48)	168 (75)	158 (60)	120 (45)	196 (74)
Missing Data	16 (7)	24 (10)	33 (14)	30 (13)	21 (8)	35 (13)	24 (9)
Histologic Response
Improvement^‡	102 (45)	77 (33)	96 (42)	65 (29)	103 (39)	102 (38)	69 (26)
No improvement	77 (34)	99 (43)	61 (27)	93 (41)	85 (32)	58 (22)	111 (41)
Missing Data	49 (21)	55 (24)	71 (31)	67 (30)	77 (29)	108 (40)	86 (32)

* Number (%) of subjects.

^† Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.

^‡ Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥ 2 points.

Of subjects who had not achieved HCV-RNA below the limit of detection of the research-based assay by Week 24 of REBETOL/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among subjects with HCV Genotype 1 treated with REBETOL/INTRON A therapy who achieved HCV-RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24-week treatment group. There was no observed increase in response rates for subjects with HCV nongenotype 1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Subjects

Subjects with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) plus INTRON A 3 MIU three times weekly or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 subjects who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1). Study results are summarized in Table 20.

Table 20: Virologic and Histologic Responses: Relapse Subjects*


	US Study		International Study
	INTRON A plus REBETOL (N=77)	INTRON A plus Placebo (N=76)	INTRON A plus REBETOL (N=96)	INTRON A plus Placebo (N=96)
Virologic Response
Responder^†	33 (43)	3 (4)	46 (48)	5 (5)
Nonresponder	36 (47)	66 (87)	45 (47)	91 (95)
Missing Data	8 (10)	7 (9)	5 (5)	0 (0)
Histologic Response
Improvement^‡	38 (49)	27 (36)	49 (51)	30 (31)
No improvement	23 (30)	37 (49)	29 (30)	44 (46)
Missing Data	16 (21)	12 (16)	18 (19)	22 (23)

* Number (%) of subjects.

^† Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.

^‡ Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥ 2 points.

Virologic and histologic responses were similar among male and female subjects in both the previously untreated and relapse studies.

Pediatric Subjects

Pediatric subjects 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were treated with REBETOL 15 mg/kg per day plus INTRON A 3 MIU/m² three times weekly for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 subjects received treatment who were 57% male, 80% Caucasian, and 78% genotype 1. Subjects < 5 years of age received REBETOL Oral Solution and those ≥ 5 years of age received either REBETOL Oral Solution or Capsules.

Study results are summarized in Table 21.

Table 21: Virologic Response: Previously Untreated Pediatric Subjects*


		INTRON A 3 MIU/m²three times weekly plus REBETOL 15 mg/kg/day
Overall Response^† (N=118)		54 (46)
Genotype 1 (N=92)		33 (36)
Genotype non-1 (N=26)		21 (81)

* Number (%) of subjects.

^† Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to INTRON A/REBETOL combination therapy compared to subjects with genotype non-1, 36% vs. 81%. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).

16 HOW SUPPLIED/STORAGE AND HANDLING

REBETOL 200 mg Capsules are white, opaque capsules with REBETOL, 200 mg, and the Schering Corporation logo imprinted on the capsule shell; the capsules are packaged in a bottle containing 56 capsules (NDC 0085-1351-05), 70 capsules (NDC 0085-1385-07), and 84 capsules (NDC 0085-1194-03).

REBETOL Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble gum-flavored liquid and it is packaged in 4-oz amber glass bottles (100 mL/bottle) with child-resistant closures (NDC 0085-1318-01).

The bottle of REBETOL Capsules should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

REBETOL Oral Solution should be stored between 2° to 8°C (36° to 46°F) or at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

_________________________________________________________________________________________________________________________

17 PATIENT COUNSELING INFORMATION

[See FDA-Approved Medication Guide.]

17.1 Anemia

The most common adverse experience occurring with REBETOL Capsules is anemia, which may be severe [see Warnings and Precautions (5.2) and Adverse Reactions]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see Dosage and Administration (2.3)]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

17.2 Pregnancy

Patients must be informed that REBETOL Capsules and Oral Solution may cause birth defects and death of the unborn child. REBETOL must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking REBETOL. REBETOL should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months post therapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during REBETOL and for 6 months post therapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].

If pregnancy does occur during treatment or during 6 months post therapy, the patient must be advised of the teratogenic risk of REBETOL therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians should report such cases by calling 1-800-593-2214.

17.3 Risks versus Benefits

Patients receiving REBETOL Capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient MEDICATION GUIDE. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

Patients should be informed about what to do in the event they miss a dose of REBETOL; the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to contact their healthcare provider if they have questions.

Schering Plough

Manufactured by Schering Corporation, a subsidiary of Schering-Plough Corporation, Kenilworth, NJ 07033 USA.

U.S. Patent Nos. 5,914,128; 6,051,252; 6,172,046; 6,177,074; 6,335,032; 6,337,090; 6,461,605; 6,472,373; 6,524,570; and 6,790,837.

B-XXXXXXXX Rev 11/09

_________________________________________________________________________________________________________________________

MEDICATION GUIDE

REBETOL^® (REB-eh-tol)

(ribavirin)

Capsules and Oral Solution

Read this Medication Guide before you start taking REBETOL, and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about REBETOL?

You should not take REBETOL alone to treat chronic hepatitis C infection. REBETOL should be used with another medicine to treat chronic hepatitis C infection.
REBETOL may cause you to have a blood problem (hemolytic anemia) that can worsen any heart problems you have, and cause you to have a heart attack or die. Tell your healthcare provider if you have ever had any heart problems. REBETOL may not be right for you. If you have chest pain while you take REBETOL, get emergency medical attention right away.
REBETOL may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take REBETOL. You or your sexual partner should not become pregnant or plan to become pregnant while you take REBETOL and for 6 months after treatment is over. You must use 2 forms of birth control when you take REBETOL and for the 6 months after treatment.

Females must have a pregnancy test before starting REBETOL, every month while taking REBETOL, and every month for the 6 months after treatment with REBETOL.

If you or your female sexual partner becomes pregnant while taking REBETOL, tell your healthcare provider right away. You or your healthcare provider should contact the REBETOL pregnancy registry by calling 1-800-593-2214. The REBETOL pregnancy registry collects information about what happens to mothers and their babies if the mother takes REBETOL while she is pregnant.

What is REBETOL?

REBETOL is a medicine used with interferon alfa-2b (Intron A) or peginterferon alfa-2b (PegIntron) to treat chronic (lasting a long time) hepatitis C infection in people 3 years and older with liver disease.

It is not known if REBETOL use for longer than one year is safe and will work.

It is not known if REBETOL use in children younger than 3 years old is safe and will work.

Who should not take REBETOL?

See “What is the most important information I should know about REBETOL?”

Do not take REBETOL if you:

have had serious allergic reactions to the ingredients in REBETOL. See the end of this Medication Guide for a complete list of ingredients.
have certain types of hepatitis (autoimmune hepatitis).
have certain blood disorders (hemoglobinopathies).
have severe kidney disease.
take didanosine (VIDEX^®).

Talk to your healthcare provider before taking REBETOL if you have any of these conditions.

LRN#: 018908-RIB-MTL-MG-9

What should I tell my healthcare provider before taking REBETOL?

Before you take REBETOL, tell your healthcare provider if you have or have had:

treatment for hepatitis C that did not work for you.
breathing problems. REBETOL may cause or worsen breathing problems you already have.
vision problems. REBETOL may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with REBETOL.
certain blood disorders such as anemia
high blood pressure, heart problems, or have had a heart attack. Your healthcare provider should check your blood and heart before you start treatment with REBETOL.
thyroid problems
liver problems other than hepatitis C infection
human immunodeficiency virus (HIV) or any immunity problems
mental health problems, including depression or thoughts of suicide
kidney problems
an organ transplant
diabetes. REBETOL may make your diabetes worse or harder to treat.
any other medical condition
are breast feeding. It is not known if REBETOL passes into your breast milk. You and your healthcare provider should decide if you will take REBETOL or breast feed.

Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins, and herbal supplements. REBETOL may affect the way other medicines work.

Especially tell your healthcare provider if you take didanosine (VIDEX).

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take REBETOL?

Take REBETOL exactly as your healthcare provider tells you. Your healthcare provider will tell you the how much REBETOL to take and when to take it.
Take REBETOL with food.
Take REBETOL Capsules whole. Do not open, break, or crush REBETOL Capsules before swallowing. If you cannot swallow REBETOL Capsules whole, tell your healthcare provider.
If you miss a dose of REBETOL, take the missed dose as soon as possible during the same day. Do not double the next dose. If you have questions about what to do, call your healthcare provider.
If you take too much REBETOL, call your healthcare provider or Poison Control Center at 1-800-222-1222, or go to the nearest hospital emergency room right away.

What are the possible side effects of REBETOL?

REBETOL may cause serious side effects, including:

See “What is the most important information I should know about REBETOL?”

Swelling and irritation of your pancreas (pancreatitis). You may have stomach pain, nausea, vomiting, or diarrhea.
Serious breathing problems. Difficulty breathing may be a sign of a serious lung infection (pneumonia) that can lead to death.
Serious eye problems that may lead to vision loss or blindness.
Dental problems. Your mouth may be very dry, which can lead to problems with your teeth and gums.
Severe depression
Suicidal thoughts and attempts. Adults and children who take REBETOL, especially teenagers may be more likely to have suicidal thoughts or attempt to hurt themselves while taking REBETOL with alpha interferons. Call your healthcare provider right away or go to the nearest hospital emergency room if you have new or worse depression or thoughts about suicide or dying.
Weight loss and slowed growth in children

Tell your provider right away if you have any side effect that bothers you or that does not go away.

The most common side effects of REBETOL in all patients include:

flu-like symptoms - feeling tired, headache, shaking along with high temperature (fever), nausea, and muscle aches.
mood changes, feeling irritable.

The most common side effects of REBETOL in children include:

a decrease in the blood cells that fight infection (neutropenia).
a decrease in appetite.
stomach pain and vomiting.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of REBETOL. For more information ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REBETOL?

• Store REBETOL Capsules between 59˚F to 86˚F (15˚C to 30˚C).

• Store REBETOL Oral Solution between 59˚F to 86˚F (15˚C to 30˚C) or in the refrigerator between 36°F to 46°F (2°C to 8°C).

Keep REBETOL and all medicines out of the reach of children.

General information about the safe and effective use of REBETOL

It is not known if treatment with REBETOL will cure hepatitis C virus infections or prevent cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known if taking REBETOL will prevent you from infecting another person with the hepatitis C virus.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REBETOL for a condition for which it was not prescribed. Do not give REBETOL to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about REBETOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or health care provider for information about REBETOL that is written for health professionals.

What are the ingredients in REBETOL?

Active ingredients: ribavirin

REBETOL Capsules

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin, sodium lauryl sulfate, silicon dioxide, and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, and FD&C Blue #2 aluminum lake.

REBETOL Oral Solution

Inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric acid, sodium benzoate, natural and artificial flavor for bubble gum # 15864, and water.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by Schering Corporation, a subsidiary of Schering-Plough corporation, Kenilworth, NJ 07033 USA

Schering Plough

VIDEX^® is a registered trademark of Bristol-Myers Squibb Company.

CONTACT:

Merck
Media:
Pamela Eisele, 908-423-5042
Robert Consalvo, 908-295-0928
or
Investors:
Joe Romanelli, 908-423-5088

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