1 INDICATIONS AND USAGE Ribavirin tablets in combination with PEGASYS ® (peginterferon alfa-2a) are 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 combination therapy with PEGASYS ® : 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/mm 3 .

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 PEGASYS ® 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 therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established.

Ribavirin tablets 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.

Ribavirin tablets are a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with PEGASYS ® 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)

6 ADVERSE REACTIONS PEGASYS ® in combination with ribavirin 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/PEGASYS ® 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) ] .

The 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 Aurobindo Pharma USA, Inc.

at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 PEGASYS ® alone or in combination with ribavirin.

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 5 shows rates of adverse events occurring in greater than or equal to 5% of 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 PEGASYS ® in combination with ribavirin 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 PEGASYS ® and/or ribavirin therapy.

The most common reason for dose modification of PEGASYS ® 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 in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

PEGASYS ® dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7% of patients receiving 800 mg ribavirin for 24 weeks.

Ribavirin dose was reduced in 21% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 12% of patients receiving 800 mg ribavirin for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with PEGASYS ® and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs.

10%), hemoglobin less than 10 g/dL (3% vs.

15%), dose modification of PEGASYS ® (30% vs.

36%) and ribavirin (19% vs.

38%), and of withdrawal from treatment (5% vs.

15%) compared to patients treated for 48 weeks with PEGASYS ® and 1000 mg or 1200 mg ribavirin.

On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.

Table 5 Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801) * Severe hematologic abnormalities (lymphocyte less than 500 cells/mm 3 ; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm 3 ; platelet less than 50,000 cells/mm 3 ).

Body System CHC Combination Therapy Study NV15801 PEGASYS ® 180 mcg + 1000 mg or 1200 mg Ribavirin Tablets 48 weeks Interferon alfa-2b + 1000 mg or 1200 mg REBETOL ® 48 weeks N=451 N=443 % % Application Site Disorders Injection site reaction 23 16 Endocrine Disorders Hypothyroidism 4 5 Flu-like Symptoms and Signs Fatigue/Asthenia Pyrexia Rigors Pain 65 41 25 10 68 55 37 9 Gastrointestinal Nausea/Vomiting Diarrhea Abdominal pain Dry mouth Dyspepsia 25 11 8 4 6 29 10 9 7 5 Hematologic* Lymphopenia Anemia Neutropenia Thrombocytopenia 14 11 27 5 12 11 8 <1 Metabolic and Nutritional Anorexia Weight decrease 24 10 26 10 Musculoskeletal, Connective Tissue and Bone Myalgia Arthralgia Back pain 40 22 5 49 23 5 Neurological Headache Dizziness (excluding vertigo) Memory impairment 43 14 6 49 14 5 Psychiatric Irritability/Anxiety/Nervousness Insomnia Depression Concentration impairment Mood alteration 33 30 20 10 5 38 37 28 13 6 Resistance Mechanism Disorders Overall 12 10 Respiratory, Thoracic and Mediastinal Dyspnea Cough Dyspnea exertional 13 10 4 14 7 7 Skin and Subcutaneous Tissue Alopecia Pruritus Dermatitis Dry skin Rash Sweating increased Eczema 28 19 16 10 8 6 5 33 18 13 13 5 5 4 Visual Disorders Vision blurred 5 2 Pediatric Patients In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS ® 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 PEGASYS ® 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 PEGASYS ® 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 PEGASYS ® plus ribavirin combination therapy group (hyperglycemia and cholecystectomy).

Table 6 Percentage of Pediatric Subjects with Adverse Reactions* During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects) * Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.

** Subjects in the PEGASYS ® 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.

Study NV17424 System Organ Class PEGASYS ® 180 mcg/1.73 m² x BSA + Ribavirin 15 mg/kg (N=55) PEGASYS ® 180 mcg/1.73 m² x BSA + Placebo** (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 was 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.

Growth Inhibition in Pediatric Subjects [see Warnings and Precautions (5.8) ].

Pediatric subjects treated with PEGASYS ® plus ribavirin combination therapy showed a delay in weight and height increases with up to 48 weeks of therapy compared with baseline.

Both weight for age 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 curve percentiles for weight (64 th mean percentile at baseline, 60 th mean percentile at 2 years post-treatment) and height (54 th mean percentile at baseline, 56 th mean percentile at 2 years post-treatment).

At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves.

At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve.

Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years post-treatment.

For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults) The adverse event profile of coinfected patients treated with PEGASYS ® /ribavirin in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 ( Table 5 ).

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 and PEGASYS ® 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) ] .

Table 7 Selected Laboratory Abnormalities During Treatment with Ribavirin in Combination With Either PEGASYS ® or Interferon alfa-2b Laboratory Parameter PEGASYS ® + Ribavirin 1000/1200 mg 48 wks Interferon alfa-2b + Ribavirin 1000/1200 mg 48 wks (N=887) (N=443) Neutrophils (cells/mm 3 ) 1,000 <1,500 34% 38% 500 <1,000 49% 21% <500 5% 1% Platelets (cells/mm 3 ) 50,000 to <75,000 11% 4% 20,000 to <50,000 5% < 1% <20,000 0 0 Hemoglobin (g/dL) 8.5 to 9.9 11% 11% <8.5 2% < 1% 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 8 Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects * Subjects in the PEGASYS ® 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.

Laboratory Parameter PEGASYS ® 180 mcg/1.73 m² x BSA + Ribavirin 15 mg/kg (N=55) PEGASYS ® 180 mcg/1.73 m² x BSA + Placebo* (N=59) Neutrophils (cells/mm 3 ) 1,000 to <1,500 31% 39% 750 to <1,000 27% 17% 500 to <750 25% 15% <500 7% 5% Platelets (cells/mm 3 ) 75,000 to <100,000 4% 2% 50,000 to <75,000 0% 2% <50,000 0% 0% Hemoglobin (g/dL) 8.5 to <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 PEGASYS ® /ribavirin 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)