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.

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 attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [ see Warnings and Precautions (5.10) ].

The most common fatal reaction occurring in subjects treated with PegIntron and ribavirin was cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions (5.10)] , all occurring in less than 1% of subjects.

Adverse Reaction - Ribavirin/PegIntron Combination Therapy Adult Subjects Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by treatment group from the ribavirin/PegIntron Combination Therapy (Study 2) in Table 5.

Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects * A subject may have reported more than one adverse reaction within a body system/organ class category.

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

Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By Descending Frequency Study 4 Percentage of Subjects Reporting Treatment-Related Adverse Reactions Adverse Reactions PegIntron 1.5 mcg/kg with Ribavirin (N=1019) PegIntron 1 mcg/kg with Ribavirin (N=1016) Pegasys 180 mcg with Copegus (N=1035) Fatigue 67 68 64 Headache 50 47 41 Nausea 40 35 34 Chills 39 36 23 Insomnia 38 37 41 Anemia 35 30 34 Pyrexia 35 32 21 Injection Site Reactions 34 35 23 Anorexia 29 25 21 Rash 29 25 34 Myalgia 27 26 22 Neutropenia 26 19 31 Irritability 25 25 25 Depression 25 19 20 Alopecia 23 20 17 Dyspnea 21 20 22 Arthralgia 21 22 22 Pruritus 18 15 19 Influenza-like Illness 16 15 15 Dizziness 16 14 13 Diarrhea 15 16 14 Cough 15 16 17 Weight Decreased 13 10 10 Vomiting 12 10 9 Unspecified Pain 12 13 9 Dry Skin 11 11 12 Anxiety 11 11 10 Abdominal Pain 10 10 10 Leukopenia 9 7 10 The incidence of serious adverse reactions was comparable in all trials.

In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/ribavirin groups compared to 14% in the INTRON A/ribavirin group.

In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based ribavirin group (12%) and for the flat-dose ribavirin regimen.

In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy.

Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period.

In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy.

By the end of the 6-month follow-up period, the incidence of ongoing adverse reactions by body class in the PegIntron 1.5/ribavirin group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI).

In approximately 10 to 15% of subjects, weight loss, fatigue, and headache had not resolved.

There have been 28 subject deaths that occurred during treatment or follow-up in Studies 2, 3, and 4.

In Study 2, there was 1 suicide in a subject receiving PegIntron/ribavirin combination therapy; and 1 subject death in the INTRON A/ribavirin group (motor vehicle accident).

In Study 3, there were 14 deaths, 2 of which were probable suicides and 1 was an unexplained death in a person with a relevant medical history of depression.

In Study 4, there were 12 deaths, 6 of which occurred in subjects who received PegIntron/ribavirin combination therapy, 5 in the PegIntron 1.5 mcg/ribavirin arm (N=1019) and 1 in the PegIntron 1 mcg/ribavirin arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035); there were 3 suicides that occurred during the off treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/ribavirin combination therapy.

In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with ribavirin, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with ribavirin.

In Study 3, 15% of subjects receiving PegIntron in combination with weight-based ribavirin and 14% of subjects receiving PegIntron with flat-dose ribavirin discontinued therapy due to an adverse reaction.

The most common reasons for discontinuation were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions.

In Study 4, 13% of subjects in the PegIntron 1.5 mcg/ribavirin arm, 10% in the PegIntron 1 mcg/ribavirin arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions for ribavirin were similar across all three groups [see Clinical Studies (14.1)] , 33 to 35%.

The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values).

Other common reasons included depression, fatigue, nausea, and thrombocytopenia.

In Study 3, dose modifications due to adverse reactions occurred more frequently with weight-based ribavirin dosing compared to flat dosing (29% and 23%, respectively).

In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with ribavirin, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring a second dose reduction to 90 mcg/week with Pegasys.

In the PegIntron/ribavirin combination trials the most common adverse reactions were psychiatric, which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3.

These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups.

Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see Warnings and Precautions (5) ] .

In Study 4, psychiatric adverse reactions occurred in 58% of subjects in the PegIntron 1.5 mcg/ribavirin arm, 55% of subjects in the PegIntron 1 mcg/ribavirin arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm.

In Study 2, PegIntron/ribavirin combination therapy induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects.

The severity of some of these systemic symptoms (e.g., fever and headache) tended to decrease as treatment continued.

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

Pediatric Subjects In general, the adverse reaction profile in the pediatric population was similar to that observed in adults.

In the pediatric trial, the most prevalent adverse reactions were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%).

The majority of adverse reactions were mild or moderate in severity.

Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%).

Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107).

Five subjects received levothyroxine treatment, three with clinical hypothyroidism and two with asymptomatic TSH elevations.

Weight and height gain of pediatric subjects treated with PegIntron plus ribavirin lagged behind that predicted by normative population data for the entire length of treatment.

Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment.

Dose modifications of PegIntron and/or ribavirin were required in 25% of subjects due to treatment-related adverse reactions, most commonly for anemia, neutropenia and weight loss.

Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction.

Adverse reactions that occurred with a greater than or equal to 10% incidence in the pediatric trial subjects are provided in Table 7.

Table 7: Percentage of Pediatric Subjects with Treatment-Related Adverse Reactions (in At Least 10% of All Subjects) System Organ Class Preferred Term All Subjects (N=107) Blood and Lymphatic System Disorders Neutropenia 33% Anemia 11% Leukopenia 10% Gastrointestinal Disorders Abdominal Pain 21% Abdominal Pain Upper 12% Vomiting 27% Nausea 18% General Disorders and Administration Site Conditions Pyrexia 80% Fatigue 30% Injection-site Erythema 29% Chills 21% Asthenia 15% Irritability 14% Investigations Weight Loss 19% Metabolism and Nutrition Disorders Anorexia 29% Decreased Appetite 22% Musculoskeletal and Connective Tissue Disorders Arthralgia 17% Myalgia 17% Nervous System Disorders Headache 62% Dizziness 14% Skin and Subcutaneous Tissue Disorders Alopecia 17% Ninety-four of 107 subjects enrolled in a 5-year follow-up trial.

The long-term effects on growth were less in subjects treated for 24 weeks than in those treated for 48 weeks.

Twenty-four percent of subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a >15 percentile height-for-age decrease from pre-treatment baseline to the end of 5-year follow-up.

Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks had a >30 percentile height-for-age decrease from pre-treatment baseline to the end of the 5-year follow-up.

While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to be initiation of combination therapy during the years of expected peak growth velocity [see Warnings and Precautions (5.9) ].

Laboratory Values Adult and Pediatric Subjects The adverse reaction profile in Study 3, which compared PegIntron/weight-based ribavirin combination to a PegIntron/flat dose ribavirin regimen, revealed an increased rate of anemia with weight-based dosing (29% vs.

19% for weight-based vs.

flat dose regimens, respectively).

However, the majority of cases of anemia were mild and responded to dose reductions.

Changes in selected laboratory values during treatment in combination with ribavirin treatment are described below.

Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.5) ] .

Changes in selected laboratory values during therapy are described in Table 8.

Most of the changes in laboratory values in the PegIntron/ribavirin trial with pediatrics were mild or moderate.

Table 8: Selected Laboratory Abnormalities During Treatment with Ribavirin and PegIntron or Ribavirin and INTRON A in Previously Untreated Subjects * The table summarizes the worst category observed within the period per subject per laboratory test.

Only subjects with at least one treatment value for a given laboratory test are included.

† ULN=Upper limit of normal.

Laboratory Parameters * Percentage of Subjects Adults (Study 2) Pediatrics PegIntron/ Ribavirin (N=511) INTRON A/ Ribavirin (N=505) PegIntron/ Ribavirin (N=107) * Hemoglobin (g/dL) 9.5 to <11.0 26 27 30 8.0 to <9.5 3 3 2 6.5 to 7.9 0.2 0.2 - Leukocytes (x 10 9 /L) 2.0 to 2.9 46 41 39 1.5 to <2.0 24 8 3 1.0 to 1.4 5 1 - Neutrophils (x 10 9 /L) 1.0 to 1.5 33 37 35 0.75 to <1.0 25 13 26 0.5 to <0.75 18 7 13 <0.5 4 2 3 Platelets (x 10 9 /L) 70 to 100 15 5 1 50 to <70 3 0.8 - 30 to 49 0.2 0.2 - 25 to <50 - - 1 Total Bilirubin (mg/dL) (µmole/L) 1.5 to 3.0 10 13 - 1.26 to 2.59 x ULN † - - 7 3.1 to 6.0 0.6 0.2 - 2.6 to 5 x ULN † - - - 6.1 to 12.0 0 0.2 - ALT (U/L) 2 x Baseline 0.6 0.2 1 2.1 to 5 x Baseline 3 1 5 5.1 to 10 x Baseline 0 0 3 Hemoglobin .

In Study 2, hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects.

In Study 3, 47% of subjects receiving weight-based dosing of ribavirin and 33% on flat-dose ribavirin had decreases in hemoglobin levels to less than 11 g/dL.

Reductions in hemoglobin to less than 9 g/dL occurred more frequently in subjects receiving weight-based dosing compared to flat dosing (4% and 2%, respectively).

In Study 2, dose modification was required in 9% and 13% of subjects in the PegIntron/ribavirin and INTRON A/ribavirin groups.

In Study 4, subjects receiving PegIntron (1.5 mcg/kg)/ribavirin had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects, respectively.

On average, hemoglobin levels became stable by treatment Weeks 4 to 6.

The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment [see Dosage and Administration (2.5) ].

Neutrophils .

In Study 2, decreases in neutrophil counts were observed in a majority of adult subjects treated with PegIntron/ribavirin (85%) and INTRON A/ribavirin (60%).

Severe, potentially life-threatening neutropenia (less than 0.5 x 10 9 /L) occurred in approximately 4% of subjects treated with PegIntron/ribavirin and 2% of subjects treated with INTRON A/ribavirin.

Eighteen percent of subjects receiving PegIntron/ribavirin required modification of interferon dosage.

Few subjects (less than 1%) required permanent discontinuation of treatment.

Neutrophil counts generally returned to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.5) ] .

Platelets .

In Study 2, platelet counts decreased to less than 100,000/mm 3 in approximately 20% of subjects treated with PegIntron alone or with ribavirin and in 6% of adult subjects treated with INTRON A/ribavirin.

Severe decreases in platelet counts (less than 50,000/mm 3 ) occur in less than 4% of adult subjects.

In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron, respectively.

Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy [see Dosage and Administration (2.5) ] .

Thyroid Function .

In Study 2, clinically apparent thyroid disorders occurred among subjects treated with either INTRON A or PegIntron (with or without ribavirin) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism).

Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period.

At the end of the follow-up period, 7% of subjects still had abnormal TSH values.

Bilirubin and Uric Acid .

In Study 2, 10 to 14% of subjects developed hyperbilirubinemia and 33 to 38% developed hyperuricemia in association with hemolysis.

Six subjects developed mild to moderate gout.

Adverse Reactions with Ribavirin/INTRON A Combination Therapy Adult Subjects In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon-only arms.

Selected treatment-related adverse reactions that occurred in the U.S.

trials with incidence 5% or greater are provided by treatment group (see Table 9).

In general, the selected treatment-related adverse reactions were reported with lower incidence in the international trials as compared to the U.S.

trials, except for asthenia, influenza-like symptoms, nervousness, and pruritus.

Pediatric Subjects In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions.

Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia.

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults.

Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric subjects compared to adult subjects.

Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects.

Selected treatment-related adverse reactions that occurred with incidence 5% or greater among all pediatric subjects who received the recommended dose of ribavirin/INTRON A combination therapy are provided in Table 9.

Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects * Subjects reporting one or more adverse reactions.

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

Subjects Reporting Adverse Reactions* Percentage of Subjects U.S.

Previously Untreated Study U.S.

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

A general reversal of these trends was noted during the 24-week post-treatment period.

Long-term data in a limited number of patients, however, suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients [see Warnings and Precautions (5.9) ].

Laboratory Values Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 10).

Hemoglobin .

Hemoglobin decreases among subjects receiving ribavirin therapy began at Week 1, with stabilization by Week 4.

In previously untreated subjects treated for 48 weeks, the mean maximum decrease from baseline was 3.1 g/dL in the U.S.

trial and 2.9 g/dL in the international trial.

In relapse subjects, the mean maximum decrease from baseline was 2.8 g/dL in the U.S.

trial and 2.6 g/dL in the international trial.

Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most subjects.

Bilirubin and Uric Acid .

Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials.

Most changes were moderate and reversed within 4 weeks after treatment discontinuation.

This observation occurred most frequently in subjects with a previous diagnosis of Gilbert’s syndrome.

This has not been associated with hepatic dysfunction or clinical morbidity.

Table 10: Selected Laboratory Abnormalities During Treatment with Ribavirin and INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects Percentage of Subjects U.S.

Previously Untreated Study U.S.

Relapse Study Pediatric Subjects 24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment INTRON A/ Ribavirin (N=228) INTRON A / Placebo (N=231) INTRON A/ Ribavirin (N=228) INTRON A/ Placebo (N=225) INTRON A/ Ribavirin (N=77) INTRON A / Placebo (N=76) INTRON A/ Ribavirin (N=118) Hemoglobin (g/dL) 9.5 to 10.9 24 1 32 1 21 3 24 8.0 to 9.4 5 0 4 0 4 0 3 6.5 to 7.9 0 0 0 0.4 0 0 0 <6.5 0 0 0 0 0 0 0 Leukocytes (x 10 9 /L) 2.0 to 2.9 40 20 38 23 45 26 35 1.5 to 1.9 4 1 9 2 5 3 8 1.0 to 1.4 0.9 0 2 0 0 0 0 <1.0 0 0 0 0 0 0 0 Neutrophils (x 10 9 /L) 1.0 to 1.49 30 32 31 44 42 34 37 0.75 to 0.99 14 15 14 11 16 18 15 0.5 to 0.74 9 9 14 7 8 4 16 <0.5 11 8 11 5 5 8 3 Platelets (x 10 9 /L) 70 to 99 9 11 11 14 6 12 0.8 50 to 69 2 3 2 3 0 5 2 30 to 49 0 0.4 0 0.4 0 0 0 <30 0.9 0 1 0.9 0 0 0 Total Bilirubin (mg/dL) 1.5 to 3.0 27 13 32 13 21 7 2 3.1 to 6.0 0.9 0.4 2 0 3 0 0 6.1 to 12.0 0 0 0.4 0 0 0 0 >12.0 0 0 0 0 0 0 0 6.2 Postmarketing Experiences The following adverse reactions have been identified and reported during post approval use of ribavirin in combination with INTRON A or PegIntron.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System disorders Pure red cell aplasia, aplastic anemia Ear and Labyrinth disorders Hearing disorder, vertigo Respiratory, Thoracic and Mediastinal disorders Pulmonary hypertension Eye disorders Serous retinal detachment Endocrine disorders Diabetes