-----------------------WARNINGS AND PRECAUTIONS------------------------ HIGHLIGHTS OF PRESCRIBING INFORMATION Embryo-Fetal Toxicity: May cause fetal harm. Patients should These highlights do not include all the information needed to use have a negative pregnancy test prior to therapy and use effective REBETOL safely and effectively. See full prescribing information contraception and undergo periodic pregnancy tests. (5.1, 8.1, for REBETOL. 8.3) ® REBETOL (ribavirin USP) capsules, for oral use Patients exhibiting the following conditions should be closely monitored ® REBETOL (ribavirin USP) oral solution and may require dose reduction or discontinuation of therapy: Initial U.S. Approval: 1998 Hemolytic anemia may occur with a significant initial drop in hemoglobin. (5.2) WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, Pancreatitis. (5.3) and MONOTHERAPY NOT RECOMMENDED Pulmonary infiltrates or pulmonary function impairment. (5.4) See full prescribing information for complete boxed warning. New or worsening ophthalmologic disorders. (5.5) Significant teratogenic and embryocidal effects have been Severe decreases in neutrophil and platelet counts, and demonstrated in all animal species exposed to ribavirin. hematologic, endocrine (e.g., TSH), and hepatic abnormalities. Therefore, REBETOL therapy is contraindicated in women (5.6) who are pregnant and in the male partners of women who are Dental/periodontal disorders reported with combination therapy. pregnant. Avoid pregnancy during therapy and for 6 months (5.7) after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL Concomitant administration of azathioprine. (5.8) therapy. (4, 5.1, 8.1, 8.3, 13.1) Weight loss and growth inhibition reported during combination The hemolytic anemia associated with REBETOL therapy may therapy in pediatric patients. Long-term growth inhibition (height) result in worsening of cardiac disease that has led to fatal reported in some patients. (5.9) and nonfatal myocardial infarctions. Patients with a history of Monotherapy with ribavirin is not permitted. (5.10) significant or unstable cardiac disease should not be treated -------------------------------ADVERSE REACTIONS------------------------------ with REBETOL. (2.5, 5.2, 6.1) Hemolytic anemia occurred in more than 10% of adult patients REBETOL monotherapy is not effective for the treatment of receiving REBETOL/PegIntron or INTRON A combination therapy. chronic hepatitis C. (5.10) (6.1) ---------------------------INDICATIONS AND USAGE----------------------------- Most common adverse reactions (40% or greater) in adult patients REBETOL is a nucleoside analogue indicated in combination with receiving REBETOL/PegIntron or INTRON A combination therapy are interferon alfa-2b (pegylated and nonpegylated) for the treatment of injection site reaction, fatigue/asthenia, headache, rigors, fevers, Chronic Hepatitis C (CHC) in patients 3 years of age or older with nausea, myalgia and anxiety/emotional lability/irritability. (6.1) Most compensated liver disease. (1.1) common adverse reactions (greater than 25%) in pediatric patients Patients with the following characteristics are less likely to benefit receiving REBETOL/PegIntron therapy are: pyrexia, headache, from re-treatment after failing a course of therapy: previous neutropenia, fatigue, anorexia, injection site erythema, and vomiting. nonresponse, previous pegylated interferon treatment, significant (6.1) bridging fibrosis or cirrhosis, and genotype 1 infection. To report SUSPECTED ADVERSE REACTIONS, contact Merck -------------------------DOSAGE AND ADMINISTRATION---------------------- Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., at 1-877- REBETOL is administered according to body weight. (2.1, 2.2, 2.3) 888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Dose reduction or discontinuation is recommended in patients -------------------------------DRUG INTERACTIONS------------------------------ experiencing certain adverse reactions or renal dysfunction. (2.5, 2.6, Nucleoside analogues: Closely monitor for toxicities. Discontinue 12.3) nucleoside reverse transcriptase inhibitors or reduce dose or -----------------------DOSAGE FORMS AND STRENGTHS-------------------- discontinue interferon, ribavirin or both with worsening toxicities. (7.2) REBETOL Capsules 200 mg (3) --------------------------USE IN SPECIFIC POPULATIONS--------------------- REBETOL Oral Solution 40 mg per mL (3) Pediatrics: Safety and efficacy in patients less than 3 years old have not been established. (8.4) -----------------------------CONTRAINDICATIONS--------------------------------- Organ transplant recipients: Safety and efficacy not studied. (8.6) Pregnancy and men whose female partners are pregnant (4, 5.1, 8.1, 8.3) Co-infected patients: Safety and efficacy with HIV or HBV co- infection have not been established. (8.7) Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to See 17 for PATIENT COUNSELING INFORMATION and Medication ribavirin or any component of the product (4) Guide. Autoimmune hepatitis (4) Hemoglobinopathies (4) Revised: 01/2020 Creatinine clearance less than 50 mL/min (4, 12.3) Coadministration with didanosine (4, 7.1) 1 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and 7.1 Didanosine MONOTHERAPY NOT RECOMMENDED 7.2 Nucleoside Analogues 7.3 Drugs Metabolized by Cytochrome P-450 1 INDICATIONS AND USAGE 7.4 Azathioprine 1.1 Chronic Hepatitis C (CHC) 8 USE IN SPECIFIC POPULATIONS 2 DOSAGE AND ADMINISTRATION 8.1 Pregnancy 2.1 General Dosing Information 8.2 Lactation 2.2 REBETOL/PegIntron Combination Therapy 8.3 Females and Males of Reproductive Potential 2.3 REBETOL/INTRON A Combination Therapy 8.4 Pediatric Use 2.4 Testing Prior to Initiation of REBETOL 8.5 Geriatric Use 2.5 Dose Modifications 8.6 Organ Transplant Recipients 2.6 Discontinuation of Dosing 8.7 HIV or HBV Co-infection 3 DOSAGE FORMS AND STRENGTHS 10 OVERDOSAGE 4 CONTRAINDICATIONS 11 DESCRIPTION 5 WARNINGS AND PRECAUTIONS 12 CLINICAL PHARMACOLOGY 5.1 Embryo-Fetal Toxicity 12.1 Mechanism of Action 5.2 Anemia 12.3 Pharmacokinetics 5.3 Pancreatitis 12.4 Microbiology 5.4 Pulmonary Disorders 13 NONCLINICAL TOXICOLOGY 5.5 Ophthalmologic Disorders 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Laboratory Tests 13.2 Animal Toxicology and Pharmacology 5.7 Dental and Periodontal Disorders 14 CLINICAL STUDIES 5.8 Concomitant Administration of Azathioprine 14.1 REBETOL/PegIntron Combination Therapy 5.9 Impact on Growth in Pediatric Patients 14.2 REBETOL/INTRON A Combination Therapy 5.10 Not Recommended for Monotherapy and Risks Associated 16 HOW SUPPLIED/STORAGE AND HANDLING with Combination Therapy 17 PATIENT COUNSELING INFORMATION 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience * Sections or subsections omitted from the full prescribing 6.2 Postmarketing Experiences information are not listed. 7 DRUG INTERACTIONS 2 FULL PRESCRIBING INFORMATION WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and MONOTHERAPY NOT RECOMMENDED 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 may persist in non-plasma 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. 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. Effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3), and Nonclinical Toxicology (13.1)]. Hemolytic anemia has been reported with ribavirin therapy. 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 (2.5), Warnings and Precautions (5.2), and Adverse Reactions (6.1)]. 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 (5.10)]. 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 (5.9, 5.10), and Use in Specific Populations (8.4)]. The following points should be considered when initiating REBETOL combination therapy with PegIntron® or INTRON A®: 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 duration lasting longer than