Ribavirin

1 INDICATIONS AND USAGE Ribavirin capsules are 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 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 Chronic Hepatitis C (CHC) Ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are 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 ribavirin capsules combination therapy with PegIntron ® or INTRON A ® : Combination therapy with ribavirin capsules/PegIntron is preferred over ribavirin capsules/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 one year.

2 DOSAGE AND ADMINISTRATION Ribavirin capsules are administered according to body weight. ( 2.1 , 2.2 , 2.3 ) Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal dysfunction. ( 2.5 , 2.6 , 12.3 ) 2.1 General Dosing Information Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food [see Clinical Pharmacology (12.3) ]. 2.2 Ribavirin capsules/PegIntron Combination Therapy Adult Patients The recommended dose of ribavirin capsules when used in combination with PegIntron is 800 mg to 1,400 mg based on patient body weight in two divided doses (see Table 1). Refer to PegIntron labeling for PegIntron dosing information. 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 log 10 drop or loss of hepatitis C virus (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/Ribavirin capsules 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 Adult Dosing for Ribavirin capsules in Combination with PegIntron Body Weight (kg) Ribavirin capsules Daily Dose Ribavirin Number of Capsules Less than 66 800 mg/day 2 x 200 mg capsules AM 2 x 200 mg capsules PM 66 to 80 1,000 mg/day 2 x 200 mg capsules AM 3 x 200 mg capsules PM 81 to 105 1,200 mg/day 3 x 200 mg capsules AM 3 x 200 mg capsules PM Greater than 105 1,400 mg/day 3 x 200 mg capsules AM 4 x 200 mg capsules PM Pediatric Patients Dosing of ribavirin in pediatric patients is determined by body weight. The recommended dose of ribavirin when used in combination with PegIntron in pediatric patients ages 3 to 17 years is 15 mg/kg/day in two divided doses (see Table 2). Refer to PegIntron labeling for PegIntron dosing information. 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 Pediatric Ribavirin Dosing in Combination with PegIntron * Ribavirin Oral Solution may be used in any patient regardless of body weight. Body Weight (kg) Ribavirin Daily Dose Ribavirin Number of Capsules Less than 47 15 mg/kg/day Use Ribavirin Oral Solution* 47 to 59 800 mg/day 2 x 200 mg capsules AM 2 x 200 mg capsules PM 60 to 73 1,000 mg/day 2 x 200 mg capsules AM 3 x 200 mg capsules PM Greater than 73 1,200 mg/day 3 x 200 mg capsules AM 3 x 200 mg capsules PM 2.3 Ribavirin capsules/INTRON A Combination Therapy Adults Duration of Treatment – Interferon Alpha-naïve Patients The recommended dose of ribavirin capsules when used in combination with INTRON A depends on the patient’s body weight (see Table 3). Refer to Intron A labeling for interferon dosing information. 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 for treatment duration lasting longer than 48 weeks in the previously untreated patient population. Dur…

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: May cause fetal harm. Patients should have a negative pregnancy test prior to therapy and use effective contraception and undergo periodic pregnancy tests. ( 5.1 , 8.1 , 8.3 ) Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: 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 ) Concomitant administration of azathioprine. ( 5.8 ) Weight loss and growth inhibition reported during combination therapy in pediatric patients. Long-term growth inhibition (height) reported in some patients. ( 5.9 ) Monotherapy with ribavirin is not permitted. ( 5.10 ) 5.1 Embryo-Fetal Toxicity Ribavirin capsules may cause birth defects, miscarriage or stillbirth. Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Female patients should use effective contraception and have periodic monitoring with pregnancy tests during treatment and during the 9-month period after treatment has been stopped. Male patients and their female partners should use effective contraception 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. Ribavirin has demonstrated significant teratogenic and embryocidal effects in all animal species tested. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. [see Boxed Warning , Contraindications (4) , and Use in Specific Populations (8.1 , 8.3) ]. 5.2 Anemia Hemolytic anemia was observed in approximately 10% of ribavirin/INTRON A-treated subjects in clinical trials. The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, obtain hemoglobin or hematocrit levels before the start of treatment 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 (2.5 , 2.6) ]. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. 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 (2.5 , 2.6) ]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin. 5.3 Pancreatitis Suspend ribavirin and INTRON A or PegIntron combination therapy in patients with signs and symptoms of pancreatitis and discontinue in patients with confirmed pancreatitis. 5.4 Pulmonary Disorders Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during ribavirin 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, closely monitor the patient, and if appropriate, discontinue combination therapy. 5.5 Ophthalmologic Disorders Ribavirin is used in combination therap…

4 CONTRAINDICATIONS Ribavirin capsules combination therapy is contraindicated in: pregnancy. Ribavirin capsules may cause fetal harm when administered to a pregnant woman. Ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant. If a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1, 8.3) ]. men whose female partners are pregnant [see Use in Specific Populations (8.3) ] 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 less than 50 mL/min [see Clinical Pharmacology (12.3) ] when coadministered with didanosine because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in patients receiving didanosine in combination with ribavirin [see Drug Interactions (7.1) ]. Pregnancy and men whose female partners are pregnant ( 4 , 5.1 , 8.1 , 8.3 ) 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 less than 50 mL/min ( 4 , 12.3 ) Coadministration with didanosine ( 4 , 7.1 )

7 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 ) 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 ribavirin capsules and didanosine is contraindicated [see Contraindications (4) ] . Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/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. 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 labeling for individual NRTI product). 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 greater than 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 in HIV/HCV co-infected subjects. Concomitant use of ribavirin with any of these drugs should be done 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 P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme-based drug interactions. No pharmacokinetic interactions were noted between INTRON A and ribavirin capsules in a multiple-dose pharmacokinetic study. 7.4 Azathioprine The use of ribavirin for the treatment of chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions (5.8) ].

8.1 Pregnancy Risk Summary Ribavirin is contraindicated for use in pregnant women and in men whose female partners are pregnant [see Contraindications (4) ] . Based on animal data, ribavirin use in pregnancy may be associated with birth defects. Data from the Ribavirin Pregnancy Registry are insufficient to identify a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. In animal studies, ribavirin exposure was shown to have teratogenic and/or embryocidal effects (see Data) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from the Ribavirin Pregnancy Registry on 88 live births from pregnancies in women directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects (9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the Metropolitan Atlanta Congenital Defects Program (MACDP) birth defects surveillance system. No pattern of birth defects can be identified from these reports. The miscarriage rate was approximately 21%. The current sample size is insufficient for reaching definitive conclusions based on statistical analysis. Trends suggesting a common etiology or relationship with ribavirin exposure were not observed. Methodologic limitations of the Ribavirin Pregnancy Registry include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease and comorbidities. Animal Data Embryotoxicity/teratogenicity studies with ribavirin were conducted in rats (oral doses of 0.3, 1 and 10 mg/kg on Gestation Days 6 to 15) and rabbits (oral dose of 0.1, 0.3 and 1 mg/kg on Gestation Days 6 to 18). 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 [see Contraindications (4) and Warnings and Precautions (5.1) ].

8.3 Females and Males of Reproductive Potential Ribavirin may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of treatment. Patients should have periodic pregnancy tests during treatment and during the 9-month period after treatment has been stopped [see Warnings and Precautions (5.1) ]. Contraception Female patients of reproductive potential should use effective contraception during treatment and for 9 months post-therapy. Male patients and their female partners should use effective contraception during treatment with ribavirin and for the 6-month post-therapy period [see Warnings and Precautions (5.1) ] . Infertility Based on animal data, ribavirin may impair male fertility. In animal studies, these effects were mostly reversible within a few months after drug cessation [see Nonclinical Toxicology (13.1) ] .

6 ADVERSE REACTIONS The following serious adverse drug reactions are discussed in other sections of the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] Anemia [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.3) ] Pulmonary Disorders [see Warnings and Precautions (5.4) ] Ophthalmic Disorders [see Warnings and Precautions (5.5) ] Dental and Periodontal Disorders [see Warnings and Precautions (5.7) ] Impact on Growth in Pediatric Patients [see Warnings and Precautions (5.9) ] Hemolytic anemia occurred in more than 10% of adult patients receiving ribavirin/PegIntron or INTRON A combination therapy. ( 6.1 ) Most common adverse reactions (40% or greater) in adult patients receiving ribavirin/PegIntron or INTRON A combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. ( 6.1 ) Most common adverse reactions (greater than 25%) in pediatric patients receiving ribavirin/PegIntron therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Clinical trials with ribavirin in combination with PegIntron or INTRON A have been conducted in over 7,800 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 ribavirin 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 ribavirin 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 trials: Ribavirin/PegIntron Combination therapy trials: Clinical Study 1 – evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial). Study 2 – evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A. Study 3 – evaluated PegIntron/weight-based ribavirin in combination with PegIntron/flat dose ribavirin regimen. Study 4 – compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with ribavirin and a third treatment group receiving Pegasys ® (180 mcg/week)/Copegus ® (1000 to 1200 mg/day). Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based ribavirin in prior treatment failure subjects. PegIntron/Ribavirin Combination Therapy in Pediatric Patients Ribavirin/INTRON A Combination Therapy trials for adults and pediatrics Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without ribavirin [see Boxed Warning , Warnings and Precautions (5) ]. The most common serious events occurring in subjects treated with PegIntron and ribavirin were depression and suicidal ideation [see Warnings and Precautions (5.10) ], each occurring at a frequency of less than 1%. Suicidal ideation or a…