Ribavirin

Sandoz Inc

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use RIBAVIRIN TABLETS USP safely and effectively. See full prescribing information for RIBAVIRIN TABLETS USP. RIBAVIRIN TABLETS USP, for oral useInitial U.S. Approval: 2002BOXED WARNING WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS See full prescribing information for complete boxed warning. • Ribavirin monotherapy, including ribavirin tablets, is not effective for the treatment of chronic hepatitis C virus infection (Boxed Warning). • The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin tablets (2.3, 5.2, 6.1 ). • Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Therefore, ribavirin tablets are 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 ribavirin tablets therapy (4, 5.1, 8.1 ). INDICATIONS AND USAGERibavirin tablets, USP are a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with peginterferon alfa-2a in patients 5 years of age and older with compensated liver disease not previously treated with interferon alpha, and in adult CHC patients coinfected with HIV (1).DOSAGE AND ADMINISTRATION •CHC: Ribavirin tablets are administered according to body weight and genotype (2.1) •CHC with HIV coinfection: 800 mg by mouth daily for a total of 48 weeks, regardless of genotype (2.2) •Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal impairment (2.3, 2.4) DOSAGE FORMS AND STRENGTHSRibavirin tablets 200 mg (3)CONTRAINDICATIONS •Pregnant women and men whose female partners are pregnant (4, 5.1, 8.1) •Hemoglobinopathies (4) •Coadministration with didanosine (4, 7.1) Ribavirin tablets in combination with peginterferon alfa-2a is contraindicated in patients with: •Autoimmune hepatitis (4) •Hepatic decompensation in cirrhotic patients (4, 5.3) WARNINGS AND PRECAUTIONS •Birth defects and fetal death with ribavirin: Do not use in pregnancy and for 6 months after treatment. Patients must have a negative pregnancy test prior to therapy, use at least 2 forms of contraception and undergo monthly pregnancy tests (4, 5.1, 8.1) Peginterferon alfa-2a/ribavirin tablets: 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. This may result in worsening cardiac disease leading to fatal or nonfatal myocardial infarctions (5.2, 6.1) •Risk of hepatic failure and death: Monitor hepatic function during treatment and discontinue treatment for hepatic decompensation (5.3) •Severe hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, and anaphylaxis, and serious skin reactions such as Stevens-Johnson Syndrome (5.4) •Pulmonary disorders, including pulmonary function impairment and pneumonitis, including fatal cases of pneumonia (5.5) •Severe depression and suicidal ideation, autoimmune and infectious disorders, suppression of bone marrow function, pancreatitis, and diabetes (5) •Bone marrow suppression with azathioprine coadministration (5.6) •Growth impairment with combination therapy in pediatric patients (5.8) Side EffectsThe most common adverse reactions (frequency greater than 40%) in adults receiving combination therapy are fatigue/asthenia, pyrexia, myalgia, and headache (6.1)The most common adverse reactions in pediatric subjects were similar to those seen in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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 (7.1) •Azathioprine: Concomitant use of azathioprine with ribavirin has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity (7.3) USE IN SPECIFIC POPULATIONS • Ribavirin Pregnancy Registry (8.1) •Pediatrics: Safety and efficacy in pediatric patients less than 5 years old have not been established (8.4) •Renal Impairment: Do not use in patients with GFR less than 50 mL/min (8.7) •Organ Transplant: Safety and efficacy have not been studied (8.10)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS
• 1 RIBAVIRIN INDICATIONS AND USAGE
• 2 RIBAVIRIN DOSAGE AND ADMINISTRATION
  • 2.1 Chronic Hepatitis C Monoinfection
  • 2.4 Renal Impairment
  • 2.5 Discontinuation of Dosing
• 3 DOSAGE FORMS AND STRENGTHS
• 4 RIBAVIRIN CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Pregnancy
  • 5.2 Anemia
  • 5.3 Hepatic Failure
  • 5.4 Hypersensitivity
  • 5.5 Pulmonary Disorders
  • 5.6 Bone Marrow Suppression
  • 5.7 Pancreatitis
  • 5.8 Impact on Growth in Pediatric Patients
  • 5.9 Laboratory Tests
  • 5.10 Renal Impairment
• 6 RIBAVIRIN ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
  • 7.2 Drugs Metabolized by Cytochrome P450
  • 7.3 Azathioprine
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Race
  • 8.7 Renal Impairment
  • 8.8 Hepatic Impairment
  • 8.9 Gender
  • 8.10 Organ Transplant Recipients
• 10 OVERDOSAGE
• 11 RIBAVIRIN 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
• 14 CLINICAL STUDIES
  • 14.1 Chronic Hepatitis C Patients
  • 14.2 Other Treatment Response Predictors
  • 14.3 Chronic Hepatitis C/HIV Coinfected Patients
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• MEDICATION GUIDE
• 200 mg Label

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Ribavirin tablets, USP in combination with peginterferon alfa-2a is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha.

The following points should be considered when initiating ribavirin tablets, USP combination therapy with peginterferon alfa-2a:

• •This indication is based on clinical trials of combination therapy in patients with CHC and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm³.
• •This indication is based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks, based on HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
• •Safety and efficacy data are not available for treatment longer than 48 weeks.
• •The safety and efficacy of ribavirin tablets and peginterferon alfa-2a therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy.
• •The safety and efficacy of ribavirin tablets, USP therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Ribavirin tablets, USP 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.

2 DOSAGE AND ADMINISTRATION

Ribavirin should be taken with food. Ribavirin should be given in combination with peginterferon alfa-2a; it is important to note that ribavirin should never be given as monotherapy. See peginterferon alfa-2a package insert for all instructions regarding peginterferon alfa-2a dosing and administration.

2.1 Chronic Hepatitis C Monoinfection

Adult Patients

The recommended dose of ribavirin tablets is provided in Table 1 . The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.

The daily dose of ribavirin tablets is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 1 ).

Pediatric Patients

Peginterferon alfa-2a is administered as 180 mcg/1.73m² x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

Ribavirin should be given in combination with peginterferon alfa-2a. Ribavirin is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for ribavirin are provided in Table2 . Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.

Adult Patients

The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is peginterferon alfa-2a 180 mcg subcutaneous once weekly and ribavirin tablets 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

Adult and Pediatric Patients

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin tablets/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, ribavirin tablets/peginterferon alfa-2a therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status.

Ribavirin tablets 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)].

The guidelines for ribavirin dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once ribavirin tablets have been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin tablets be increased to the original assigned dose (1000 mg to 1200 mg).

Pediatric Patients

Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in ribavirin dose to the original dose may be attempted depending upon the physician's judgment. If ribavirin has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin at one-half the full dose.

2.4 Renal Impairment

Ribavirin tablets should not be used in patients with creatinine clearance <50 mL/min [see Use in Specific Populations (8.7)]

2.5 Discontinuation of Dosing

Discontinuation of peginterferon alfa-2a/ribavirin tablets therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

Peginterferon alfa-2a/ribavirin tablets therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].

3 DOSAGE FORMS AND STRENGTHS

Ribavirin tablets are available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin.

4 CONTRAINDICATIONS

Ribavirin tablets are contraindicated in:

• •Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. Ribavirin tablets are 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 the fetus [see Warnings and Precautions (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17)].
• •Men whose female partners are pregnant.
• •Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
• •In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug Interactions (7.1)].

Ribavirin tablets and peginterferon alfa-2a combination therapy is contraindicated in patients with:

• •Autoimmune hepatitis.
• •Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment [see Warnings and Precautions (5.3)].
• •Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

Significant adverse reactions associated with ribavirin tablets/peginterferon alfa-2a combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.

The peginterferon alfa-2a package insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.

5.1 Pregnancy

Ribavirin tablets may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or 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.

Ribavirin tablets therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during ribavirin tablets therapy and for 6 months after therapy has stopped [see Boxed Warning, Contraindications (4), Use in Specific Populations (8.1), and Patient Counseling Information (17)].

5.2 Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin tablets/peginterferon alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin tablets 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. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding) [see Dosage and Administration (2.3)].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin tablets. 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 (2.3)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin tablets [see Boxed Warning, and Dosage and Administration (2.3)].

5.3 Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961 [see Clinical Studies (14.3)], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with peginterferon alfa-2a/ribavirin tablets should be discontinued immediately in patients with hepatic decompensation [see Contraindications (4)].

5.4 Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and ribavirin tablets should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].

5.5 Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. 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, patients should be closely monitored and, if appropriate, combination ribavirin tablets/peginterferon alfa-2a treatment should be discontinued.

5.6 Bone Marrow Suppression

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Peginterferon alfa-2a, ribavirin tablets, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7.3)].

5.7 Pancreatitis

Ribavirin tablets and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

5.8 Impact on Growth in Pediatric Patients

Pediatric subjects treated with peginterferon alfa-2a plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve

5.9 Laboratory Tests

Before beginning peginterferon alfa-2a/ribavirin tablets combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin tablets.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of ribavirin tablets and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

• •Platelet count greater than or equal to 90,000 cells/mm³ (as low as 75,000 cells/mm³ in HCV patients with cirrhosis or 70,000 cells/mm³ in patients with CHC and HIV)
• •Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm³
• •TSH and T₄ within normal limits or adequately controlled thyroid function
• •CD4+ cell count greater than or equal to 200 cells/mm³ or CD4+ cell count greater than or equal to 100 cells/mm³ but less than 200 cells/mm³ and HIV-1 RNA less than 5000 cells/mm³ in patients coinfected with HIV
• •Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected patients
• •Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV

5.10 Renal Impairment

Ribavirin tablets should not be used in patients with creatinine clearance <50 mL/min [see Use in Specific Populations (8.7)]

6 ADVERSE REACTIONS

Peginterferon alfa-2a in combination with ribavirin tablets causes a broad variety of serious adverse reactions [see Boxed Warning and Warnings and Precautions (5)]. The most common serious or life-threatening adverse reactions induced or aggravated by ribavirin tablets/peginterferon alfa-2a include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see Warnings and Precautions (5.3)].

6.1 Clinical Studies 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.

Adult Patients

In the pivotal registration trials NV15801 and NV15942, 886 patients received ribavirin tablets for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving peginterferon alfa-2a alone or in combination with ribavirin tablets. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia).

Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 4 shows rates of adverse events occurring in greater than or equal to 5% subjects receiving pegylated interferon and ribavirin combination therapy in the CHC Clinical Trial, NV15801.

Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with ribavirin tablets discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of patients with CHC or CHC/HIV required modification of peginterferon alfa-2a and/or ribavirin tablets therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of ribavirin tablets in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin tablets for 48 weeks and in 7% of patients receiving 800 mg ribavirin tablets for 24 weeks. Ribavirin tablets dose was reduced in 21% of patients receiving 1000 mg to 1200 mg ribavirin tablets for 48 weeks and in 12% of patients receiving 800 mg ribavirin tablets for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg ribavirin tablets were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10g/dL (3% vs. 15%), dose modification of peginterferon alfa-2a (30% vs. 36%) and ribavirin tablets (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg ribavirin tablets. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.

Pediatric Subjects

In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with peginterferon alfa-2a alone or in combination with ribavirin, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy peginterferon alfa-2a and ribavirin for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination peginterferon alfa-2a and ribavirin treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the peginterferon alfa-2a plus ribavirin combination therapy group (hyperglycemia and cholecystectomy).

Growth inhibition was observed in pediatric subjects. During combination therapy for up to 48 weeks with peginterferon alfa-2a and ribavirin, negative changes in weight for age z-score and height for age z-score after 48 weeks of therapy compared with baseline were observed [see Warnings and Precautions (5.8)].

Table 5 Percentage of Pediatric Subjects with Adverse ReactionsDisplayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug. During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects)

	Study NV17424
System Organ Class	Peginterferon alfa-2a 180 mcg/ 1.73 m2 x BSA + Ribavirin 15 mg/kg (N=55)	Peginterferon alfa-2a 180 mcg/ 1.73 m2 x BSA + Placebo Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. (N=59)
	%	%
General disorders and administration site conditions
Influenza like illness	91	81
Injection site reaction	44	42
Fatigue	25	20
Irritability	24	14
Gastrointestinal disorders
Gastrointestinal disorder	49	44
Nervous system disorders
Headache	51	39
Skin and subcutaneous tissue disorders
Rash	15	10
Pruritus	11	12
Musculoskeletal, connective tissue and bone disorders
Musculoskeletal pain	35	29
Psychiatric disorders
Insomnia	9	12
Metabolism and nutrition disorders
Decreased appetite	11	14

In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions were similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

The adverse event profile of coinfected patients treated with peginterferon alfa-2a/ribavirin tablets in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 ( Table 4 ). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Laboratory Test Abnormalities

Adult Patients

Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all ribavirin tablets and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy [see Dosage and Administration (2.3)].

Pediatric Patients

Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see Dosage and Administration (2.4)]. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.

Table 7. Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects

	Peginterferon alfa-2a + 180 mcg/1.73 m2 x BSA + Ribavirin 15 mg/kg (N=55)	Peginterferon alfa-2 + 180 mcg/1.73 m2 x BSA + Placebo Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. (N=59)
Laboratory Parameter
Neutrophils (cells/mm3)
1,000 - <1,500	31%	39%
750 - <1,000	27%	17%
500 - <750	25%	15%
<500	7%	5%
Platelets (cells/mm3)
75,000 - <100,000	4%	2%
50,000 - <75,000	0%	2%
<50,000	0%	0%
Hemoglobin (g/dL)
8.5 - <10	7%	3%
<8.5	0%	0%

In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm³ and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a/ribavirin tablets combination 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

Ear and Labyrinth disorders

Hearing impairment, hearing loss

Eye disorders

Serous retinal detachment

Immune disorders

Liver and renal graft rejection

Metabolism and Nutrition disorders

Dehydration

Skin and Subcutaneous Tissue disorders

Stevens-Johnson Syndrome (SJS)

Toxic epidermal necrolysis (TEN)

7 DRUG INTERACTIONS

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.

7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, 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 HCV/HIV coinfected patients.

In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.3)].

Patients receiving peginterferon alfa-2a/ribavirin tablets and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, ribavirin tablets or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see Warnings and Precautions (5.3) and Dosage and Administration (2.3)].

Didanosine

Co-administration of ribavirin tablets and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4)].

Zidovudine

In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin tablets developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.

7.2 Drugs Metabolized by Cytochrome P450

In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

7.3 Azathioprine

The use of ribavirin to treat 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 (5.7)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

[ see Contraindications (4)]

Ribavirin produced significant embryocidal and/or teratogenic effects 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)].

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 daily human 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 (approximately 0.01 times the maximum recommended daily human dose of ribavirin).

Treatment and Post Treatment: 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 is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. 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.

Ribavirin tablets should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin tablets unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy [see Contraindications (4)].

Ribavirin Pregnancy Registry

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.

8.3 Nursing Mothers

It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with ribavirin tablets, based on the importance of the therapy to the mother.

8.4 Pediatric Use

Pharmacokinetic evaluations in pediatric patients have not been performed.

Safety and effectiveness of ribavirin tablets have not been established in patients below the age of 5 years.

8.5 Geriatric Use

Clinical studies of ribavirin tablets and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. The dose of ribavirin tablets should be reduced in patients with creatinine clearance less than or equal to 50 mL/min, and the dose of peginterferon alfa-2a should be reduced in patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.4); Use in Specific Populations (8.7)].

8.6 Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

8.7 Renal Impairment

The pharmacokinetics of ribavirin following administration of ribavirin tablets have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin tablets in patients with creatinine clearance less than 50 mL/min. Therefore, patients with creatinine clearance less than 50 mL/min should not be treated with ribavirin tablets [see Warnings and Precautions (5.10) and Dosage and Administration (2.4)].

8.8 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin tablets has not been evaluated. The clinical trials of ribavirin tablets were restricted to patients with Child-Pugh class A disease.

8.9 Gender

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.

Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

8.10 Organ Transplant Recipients

The safety and efficacy of peginterferon alfa-2a and ribavirin tablets treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on peginterferon alfa-2a, alone or in combination with ribavirin tablets [see Adverse Reactions (6.2)].

10 OVERDOSAGE

No cases of overdose with ribavirin tablets have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.

11 DESCRIPTION

Ribavirin is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-ß-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:

The empirical formula of ribavirin is C₈H₁₂N₄O₅ and the molecular weight is 244.2. Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.

Ribavirin tablets USP are available as round, film-coated white, tablets. Each tablet, for oral administration, contains 200 mg ribavirin. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol, povidone, sodium starch glycolate, titanium dioxide, Macrogol/PEG 400 and polysorbate 80.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ribavirin is an antiviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC_0-12hr was 25,361±7110 ng·hr/mL and C_max was 2748±818 ng/mL. The average time to reach C_max was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight greater than 75 kg).

The terminal half-life of ribavirin following administration of a single oral dose of ribavirin tablets is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin tablets is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the C_max at steady state was four-fold higher than that of a single dose.

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (T_max was doubled) and the AUC_0-192h and C_max increased by 42% and 66%, respectively, when ribavirin tablets were taken with a high-fat meal compared with fasting conditions [see Dosage and Administration (2.1) and Patient Counseling Information (17)].

Elimination and Metabolism

The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin tablets is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.

12.4 Microbiology

Mechanism of Action

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 RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV RNA replication with a 50% effective concentration (EC₅₀) value of 11-21 mcM. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC₅₀ value of 0.1-3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance

Cross-resistance between IFN α and ribavirin has not been observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a p53 (+/-) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2-year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively.

Mutagenesis

Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. 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

In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.

Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin tablets 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 (i.e., 15 half-lives of clearance for ribavirin).

No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with ribavirin tablets. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.

13.2 Animal Toxicology

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 (up to 1.7 times the maximum recommended human dose of ribavirin).

Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C Patients

Adult Patients

The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin tablets for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.

In Study NV15801, patients were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly with an oral placebo, peginterferon alfa-2a 180 mcg once weekly with ribavirin tablets 1000 mg by mouth (body weight less than 75 kg) or 1200 mg by mouth (body weight greater than or equal to 75 kg) or interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin tablets or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin tablets resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin ( Table 8 ). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with ribavirin tablets compared to patients with other viral genotypes.

Table 8. Sustained Virologic Response (SVR) to Combination Therapy (Study NV15801)

Difference in overall treatment response (peginterferon alfa-2a/ribavirin tablets–Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).
	Interferon alfa-2b + Ribavirin 1000 mg or 1200 mg	Peginterferon alfa-2a + placebo	Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg
All patients	197/444 (44%)	65/224 (29%)	241/453 (53%)
Genotype 1	103/285 (36%)	29/145 (20%)	132/298 (44%)
Genotypes 2-6	94/159 (59%)	36/79 (46%)	109/155 (70%)

In Study NV15942, all patients received peginterferon alfa-2a 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a ribavirin tablets dose of either 800 mg or 1000 mg/1200 mg (for body weight less than 75 kg/greater than or equal to 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as greater than 2 x 10⁶ HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

Sustained Virologic Response (SVR) and HCV Genotype

HCV 1 and 4- Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin tablets resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin tablets.

HCV 2 and 3- Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin tablets resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin tablets (see Table 9 ).

The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

Table 9. Sustained Virologic Response as a Function of Genotype (Study NV15942)

	24 Weeks Treatment		48 Weeks Treatment
	Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=207)	Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg 1000 mg for body weight less than 75 kg; 1200 mg for body weight greater than or equal to 75 kg. (N=280)	Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=361)	Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg 1000 mg for body weight less than 75 kg; 1200 mg for body weight greater than or equal to 75 kg. (N=436)
Genotype 1	29/101 (29%)	48/118 (41%)	99/250 (40%)	138/271 (51%)
Genotypes 2, 3	79/96 (82%)	116/144 (81%)	75/99 (76%)	117/153 (76%)
Genotype 4	0/5 (0%)	7/12 (58%)	5/8 (63%)	9/11 (82%)

Pediatric Patients

Previously untreated pediatric subjects 5 through 17 years of age (55% less than 12 years old) with chronic hepatitis C, compensated liver disease and detectable HCV RNA were treated with ribavirin approximately 15 mg/kg/day plus peginterferon alfa-2a 180 mcg/1.73 m² × body surface area once weekly for 48 weeks. All subjects were followed for 24 weeks post-treatment. Sustained virological response (SVR) was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of 114 subjects were randomized to receive either combination treatment of ribavirin plus peginterferon alfa-2a or peginterferon alfa-2a monotherapy; subjects failing peginterferon alfa-2a monotherapy at 24 weeks or later could receive open-label ribavirin plus peginterferon alfa-2a. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of ribavirin plus peginterferon alfa-2a and 59 received peginterferon alfa-2a plus placebo; in the overall intent-to-treat population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are summarized in Table 10 .

Table 10. Sustained Virologic Response (Study NV17424)

	Peginterferon alfa-2a 180 mcg/1.73 m2 x BSA + Ribavirin 15 mg/kg Results indicate undetectable HCV-RNA defined as HCV RNA less than 50 IU/mL at 24 weeks post treatment using the AMPLICOR HCV test v2 (N=55)	Peginterferon alfa-2a 180 mcg/1.73 m2 x BSA + Placebo Results indicate undetectable HCV-RNA defined as HCV RNA less than 50 IU/mL at 24 weeks post treatment using the AMPLICOR HCV test v2 (N=59)
All HCV genotypesScheduled treatment duration was 48 weeks regardless of the genotype	29 (53%)	12 (20%)
HCV genotype 1	21/45 (47%)	8/47 (17%)
HCV non genotype 1Includes HCV genotypes 2, 3 and others	8/10 (80%)	4/12 (33%)

14.2 Other Treatment Response Predictors

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.

In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log₁₀ lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

14.3 Chronic Hepatitis C/HIV Coinfected Patients

In Study NR15961, patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly plus an oral placebo, peginterferon alfa-2a 180 mcg once weekly plus ribavirin tablets 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus ribavirin tablets 800 mg by mouth daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Ribavirin tablets or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count greater than or equal to 200 cells/mm³ or CD4+ cell count greater than or equal to 100 cells/mm³ but less than 200 cells/mm³ and HIV-1 RNA less than 5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 11 .

Table 11. Sustained Virologic Response in Patients with Chronic Hepatitis C Coinfected with HIV (Study NR15961)

	Interferon alfa-2a + Ribavirin Tablets 800 mg (N=289)	Peginterferon alfa-2a + Placebo (N=289)	Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=290)
All patients	33 (11%)	58 (20%)	116 (40%)
Genotype 1	12/171 (7%)	24/175 (14%)	51/176 (29%)
Genotypes 2, 3	18/89 (20%)	32/90 (36%)	59/95 (62%)

Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.

Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin tablets combination therapy, 2% (2/85) achieved an SVR.

In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with ribavirin tablets treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ribavirin tablets USP, 200 mg, are available for oral administration. Each tablet is round, debossed SZ over 395 on one side and plain on the reverse side, film-coated white, and is supplied as follows:

NDC 0781-5177-42 in bottles of 42 tablets

NDC 0781-5177-16 in bottles of 56 tablets

NDC 0781-5177-67 in bottles of 70 tablets

NDC 0781-5177-04 in bottles of 84 tablets

NDC 0781-5177-01 in bottles of 100 tablets

NDC 0781-5177-28 in bottles of 168 tablets

NDC 0781-5177-10 in bottles of 1000 tablets

Storage and Handling

Store the ribavirin tablets, USP bottle at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Keep bottle tightly closed.

17 PATIENT COUNSELING INFORMATION

“See FDA-approved patient labeling (Medication Guide)”

Pregnancy

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin tablets therapy 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 ribavirin tablets therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking ribavirin tablets therapy and for 6 months post therapy. Ribavirin tablets therapy 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.

Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin tablets therapy and for 6 months post therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy [see Contraindications (4) and Warnings and Precautions (5.1)].

Anemia

The most common adverse event associated with ribavirin is anemia, which may be severe [see Boxed Warning, Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Patients should be advised that laboratory evaluations are required prior to starting ribavirin tablets therapy and periodically thereafter [see Warnings and Precautions (5.9)]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

Patients should be advised to take ribavirin tablets with food.

Patients should be questioned about prior history of drug abuse before initiating ribavirin tablets/peginterferon alfa-2a, as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.

Patients should be advised not to drink alcohol, as alcohol may exacerbate chronic hepatitis C infection.

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

Patients should be informed that the effect of peginterferon alfa-2a/ribavirin tablets treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of hepatitis C virus during treatment or in the event of treatment failure should be taken.

Patients should be informed regarding the potential benefits and risks attendant to the use of ribavirin tablets. Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects.

MEDICATION GUIDE

Ribavirin Tablets, USP

200 mg

Read this Medication Guide carefully before you start taking ribavirin tablets and read the Medication Guide each time you get more ribavirin tablets. 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.

Also read the Medication Guide for peginterferon alfa-2a.

What is the most important information I should know about ribavirin tablets?

• 1. You should not take ribavirin tablets alone to treat chronic hepatitis C infection. Ribavirin tablets should be used with peginterferon alfa-2a to treat chronic hepatitis C infection.
• 2. Ribavirin tablets 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. Ribavirin tablets may not be right for you. If you have chest pain while you take ribavirin tablets, get emergency medical attention right away.
• 3. Ribavirin tablets may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take ribavirin tablets. You or your sexual partner should not become pregnant while you take ribavirin tablets and for 6 months after treatment is over. You must use two forms of birth control when you take ribavirin tablets and for the 6 months after treatment.
  • ∘Females must have a pregnancy test before starting ribavirin tablets, every month while treated with ribavirin tablets, and every month for the 6 months after treatment with ribavirin tablets.
  • ∘ If you or your female sexual partner becomes pregnant while taking ribavirin tablets or within 6 months after you stop taking ribavirin tablets, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin tablets while she is pregnant.

What are ribavirin tablets?

Ribavirin tablets are a prescription medicine used with another medicine called peginterferon alfa-2a to treat chronic (lasting a long time) hepatitis C infection in people 5 years and older whose liver still works normally, and who have not been treated before with a medicine called an interferon alpha. It is not known if ribavirin tablets are safe and will work in children under 5 years of age.

Who should not take ribavirin tablets?

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

Do not take ribavirin tablets if you:

• • have certain types of hepatitis caused by your immune system attacking your liver (autoimmune hepatitis)
• • have certain blood disorders, such as thalassemia major or sickle-cell anemia (hemoglobinopathies)
• • have severe kidney disease
• • take didanosine (Videx or Videx EC)

Talk to your healthcare provider before starting treatment with ribavirin tablets if you have any of these medical conditions.

What should I tell my healthcare provider before taking ribavirin tablets?

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

• • treatment for hepatitis C that did not work for you
• • serious allergic reactions to ribavirin tablets or to any of the ingredients in ribavirin tablets. See the end of this Medication Guide for a list of ingredients.
• • breathing problems. Ribavirin tablets may cause or worsen your breathing problems you already have.
• • vision problems. Ribavirin tablets may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with ribavirin tablets.
• • certain blood disorders such as anemia
• • high blood pressure, heart problems or have had a heart attack. Your healthcare provider should test your blood and heart before you start treatment with ribavirin tablets.
• • thyroid problems
• • diabetes . Ribavirin tablets and peginterferon alfa-2a combination therapy may make your diabetes worse or harder to treat.
• • liver problems other than hepatitis C virus infection
• • human immunodeficiency virus (HIV) or other immunity problems
• • mental health problems, including depression or thoughts of suicide
• • kidney problems
• • an organ transplant
• • drug addiction or abuse
• • infection with hepatitis B virus
• • any other medical condition
• • are breast feeding. It is not known if ribavirin passes into your breast milk. You and your healthcare provider should decide if you will take ribavirin tablets or breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some medicines can cause serious side effects if taken while you also take ribavirin tablets. Some medicines may affect how ribavirin tablets work or ribavirin tablets may affect how your other medicines work.

Especially tell your healthcare provider if you take any medicines to treat HIV, including didanosine (Videx or Videx EC), or if you take azathioprine (Imuran or Azasan).

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 ribavirin tablets?

• •Take ribavirin tablets exactly as your healthcare provider tells you. Your healthcare provider will tell you how much ribavirin tablets to take and when to take it. For children 5 years of age and older your healthcare provider will prescribe the dose of ribavirin based on weight.
• •Take ribavirin tablets with food.
• •If you miss a dose of ribavirin tablets, 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 ribavirin tablets, call your healthcare provider or local Poison Control Center right away, or go the nearest hospital emergency room right away.
• •Your healthcare provider should do blood tests before you start treatment with ribavirin tablets, at weeks 2 and 4 of treatment, and then as needed to see how well you are tolerating treatment and to check for side effects. Your healthcare provider may change your dose of ribavirin tablets based on blood test results or side effects you may have.
• •If you have heart problems, your healthcare provider should check your heart by doing an electrocardiogram before you start treatment with ribavirin tablets, and if needed during treatment.

What should I avoid while taking ribavirin tablets?

• • Ribavirin tablets can make you feel tired, dizzy, or confused. You should not drive or operate machinery if you have any of these symptoms.
• • Do not drink alcohol, including beer, wine, and liquor. This may make your liver disease worse.

What are the possible side effects of ribavirin tablets? Ribavirin tablets may cause serious side effects including:

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

• • Swelling and irritation of your pancreas (pancreatitis). You may have stomach pain, nausea, vomiting or diarrhea.
• • Severe allergic reactions. Symptoms may include hives, wheezing, trouble breathing, chest pain, swelling of your mouth, tongue, or lips, or severe rash.
• • 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.
• • Liver problems. Some people may get worsening of liver function. Tell your healthcare provider right away if you have any of these symptoms: stomach bloating, confusion, brown urine, and yellow eyes.
• • Severe depression
• • Suicidal thoughts and attempts
• • Effect on growth in children. Children can experience a delay in weight gain and height increase while being treated with peginterferon alfa-2a and ribavirin tablets. Catch-up in growth happens after treatment stops, but some children may not reach the height that they were expected to have before treatment. Talk to your healthcare provider if you are concerned about your child's growth during treatment with peginterferon alfa-2a and ribavirin tablets.

Call your healthcare provider or get medical help right away if you have any of the symptoms listed above. These may be signs of a serious side effect of ribavirin tablets treatment.

Common side effects of ribavirin tablets taken with peginterferon alfa-2a include:

• •flu-like symptoms-feeling tired, headache, shaking along with high temperature (fever), and muscle or joint aches
• •mood changes, feeling irritable, anxiety, and difficulty sleeping
• •loss of appetite, nausea, vomiting, and diarrhea
• •hair loss
• •itching

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

These are not all the possible side effects of ribavirin tablets treatment. For more information, ask your healthcare provider or pharmacist.

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

You may also report side effects to Sandoz Inc. at 1-800-525-8747.

How should I store ribavirin tablets?

• •Store ribavirin tablets between 20° and 25°C (68° and 77°F).
• •Keep the bottle tightly closed.

Keep ribavirin tablets and all medicines out of the reach of children.

General information about the safe and effective use of ribavirin tablets

It is not known if treatment with ribavirin tablets in combination with peginterferon alfa-2a will prevent an infected person from spreading the hepatitis C virus to another person while on treatment.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ribavirin tablets for a condition for which it was not prescribed. Do not give ribavirin tablets 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 ribavirin tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ribavirin tablets that is written for healthcare professionals.

What are the ingredients in ribavirin tablets?

Active Ingredient: ribavirin

Inactive Ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol, povidone, sodium starch glycolate, titanium dioxide, Macrogol/PEG 400 and polysorbate 80.

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

11-2013M

7312

Sandoz Inc.

Princeton, NJ 08540

200 mg Label

NDC 0781-5177-42

Ribavirin

Tablets, USP

200 mg

Rx only

42 Tablets

SANDOZ

Ribavirin Ribavirin TABLET, FILM COATED Product Information Product Type Human prescription drug label Item Code (Source) NDC:0781-5177 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength RIBAVIRIN RIBAVIRIN 200 mg Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE mannitol POLYETHYLENE GLYCOLS polysorbate 80 POVIDONES SODIUM STARCH GLYCOLATE TYPE A POTATO titanium dioxide Product Characteristics Color Size Imprint Code Shape WHITE 11 mm SZ395 ROUND Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-5177-42 42 in 1 BOTTLE 2 NDC:0781-5177-16 56 in 1 BOTTLE 3 NDC:0781-5177-67 70 in 1 BOTTLE 4 NDC:0781-5177-04 84 in 1 BOTTLE 5 NDC:0781-5177-01 100 in 1 BOTTLE 6 NDC:0781-5177-28 168 in 1 BOTTLE 7 NDC:0781-5177-10 1000 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077743 2006-10-03