FDA label d8ae9c44-2bed-443b-a064-563060ec610e

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication [see Warnings and Precautions ( 5.10 ) ]. The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin [see Dosage and Administration ( 2.4 ) , Warnings and Precautions ( 5.2 ) , and Adverse Reactions ( 6.1 ) ]. Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, ribavirin therapy is 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 therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period [see Contraindications ( 4 ) , Warnings and Precautions ( 5.1 ) , Use in Specific Populations ( 8.1 ) , Nonclinical Toxicology ( 13.1 ), and Patient Counseling Information ( 17.2 ) ]. WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS See full prescribing information for complete boxed warning Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C ( 5.10 ). The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin capsules ( 2.4 , 5.2 , 6.1 ). Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Therefore, ribavirin therapy is 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 the therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking ribavirin therapy ( 4 , 5.1 , 8.1 , 13.1 , 17.2 ).

5 WARNINGS AND PRECAUTIONS Pregnancy Category X ( 5.1 , 8.1 , 8.3 ) Birth Defects and fetal death with ribavirin: Patients must have a negative pregnancy test prior to therapy; use at least 2 forms of contraception and undergo monthly pregnancy tests. Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: Monotherapy with ribavirin is not permitted. ( 5.10 ) Hemolytic anemia may occur with a significant initial drop in hemoglobin. ( 5.2 ) Pancreatitis. ( 5.3 ) Pulmonary infiltrates or pulmonary function impairment. ( 5.4 ) New or worsening ophthalmologic disorders. ( 5.5 ) Severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. ( 5.6 ) Dental/periodontal disorders reported with combination therapy. ( 5.7 ) Concomitant administration of azathioprine. ( 5.8 ) Weight loss and growth inhibition reported with combination therapy in pediatric patients. ( 5.9 ) 5.1 Pregnancy Ribavirin capsules may cause birth defects and death of the unborn child. Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin has demonstrated significant teratogenic and embryocidal effects in all animal species 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 therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy [see Boxed Warning , Contraindications ( 4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17.2 ) ]. 5.2 Anemia The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of ribavirin/interferon alfa-2b-treated subjects in clinical trials. The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, 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 [see Dosage and Administration ( 2.4 , 2.5 ) ]. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration ( 2.4 , 2.5 ) ]. Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin capsules. 5.3 Pancreatitis Ribavirin capsules and interferon alfa-2b or peginterferon alfa-2b therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. 5.4 Pulmonary Disorders Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during therapy with ribavirin with alpha interferon combination therapy; occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination therapy should be discontinued. 5.5 Ophthalmologic Disorders Ribavirin is used in combination therapy with alpha interferons. Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by treatment with alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferon treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders. 5.6 Laboratory Tests Peginterferon alfa-2b in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. Patients on peginterferon alfa-2b/ribavirin combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial CBC (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week intervals or more frequently if abnormalities developed. In pediatric subjects the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see Dosage and Administration ( 2 ) ]. 5.7 Dental and Periodontal Disorders Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ribavirin and interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards. 5.8 Concomitant Administration of Azathioprine Pancytopenia (marked decreases in red blood cells, 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-2b, ribavirin and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interaction ( 7.4 ) ]. 5.9 Impact on Growth - Pediatric Use Data on the effects of peginterferon alfa-2b plus ribavirin on growth come from an open-label study in subjects 3 through 17 years of age, and weight and height changes are compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with peginterferon alfa-2b plus ribavirin lags behind that predicted by normative population data for the entire length of treatment. After about 6 months posttreatment (Follow-Up Week 24), subjects had weight gain rebounds and regained their weight to 53 rd percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57 th percentile). After about 6 months posttreatment, height gain stabilized and subjects treated with peginterferon alfa-2b plus ribavirin had an average height percentile of 44 th percentile, which was less than the average of the normative population and less than their average baseline height (51 st percentile). Severely inhibited growth velocity (< 3 rd percentile) was observed in 70% of the subjects while on treatment. Of the subjects experiencing severely inhibited growth, 20% had continued inhibited growth velocity (< 3 rd percentile) after 6 months of follow-up. Among the boys studied, the age groups of 3-11 years old and 12-17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months posttreatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3-11 years old and treated for 48 weeks had the largest average drop in height and weight percentiles (13 percentiles and 7 percentiles, respectively), whereas girls 12-17 years old continued along their average baseline height and weight percentiles after 6 months posttreatment. 5.10 Usage Safeguards Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, ribavirin capsules must not be used alone. The safety and efficacy of ribavirin have only been established when used together with interferon alfa-2b or peginterferon alfa-2b (not other interferons) as a combination therapy. The safety and efficacy of ribavirin/interferon alfa-2b and peginterferon alfa-2b therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. Ribavirin capsules 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. There are significant adverse reactions caused by ribavirin/interferon alfa-2b or peginterferon alfa-2b therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. 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. The interferon alfa-2b and peginterferon alfa-2b package inserts should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

6 ADVERSE REACTIONS Clinical trials with ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b have been conducted in over 7800 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 peginterferon alfa-2b or interferon alfa-2b 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 peginterferon alfa-2b or interferon alfa-2b were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. The Adverse Reactions section references the following clinical studies: Ribavirin/Peginterferon alfa-2b Combination therapy studies: Clinical Study 1 - evaluated peginterferon alfa-2b monotherapy (not further described in this label; see Peginterferon alfa-2b Powder for Injection Package Insert for information about this study). Study 2 - evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week peginterferon alfa-2b or with interferon alfa-2b. Study 3 - evaluated peginterferon alfa-2b/weight-based ribavirin in combination with peginterferon alfa-2b/flat dose ribavirin regimen. Study 4- compared two peginterferon alfa-2b (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 ® (1000-1200 mg/day). Study 5 – evaluated peginterferon alfa-2b (1.5 mcg/kg/week) in combination with weight-based ribavirin in prior treatment failure subjects. Peginterferon alfa-2b/ribavirin Combination Therapy in Pediatric Patients Ribavirin/interferon alfa-2b Combination Therapy studies for adults and pediatrics Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with peginterferon alfa-2b with or without ribavirin [see BOXED WARNING , Warnings and Precautions ( 5 ) ]. The most common serious events occurring in subjects treated with peginterferon alfa-2b and ribavirin were depression and suicidal ideation [see Warnings and Precautions ( 5.2 ) ], 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 peginterferon alfa-2b and ribavirin was cardiac arrest, suicide ideation, and suicide attempt [see Warnings and Precautions ( 5.10 ) ], all occurring in less than 1% of subjects. 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 rated in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Hemolytic anemia ( 6.1 ) Most common adverse reactions (approximately 40%) in adult patients receiving ribavirin/peginterferon alfa-2b or interferon alfa-2b combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. ( 6.1 , 6.2 ) Most common adverse reactions (>25%) in pediatric patients receiving ribavirin/peginterferon alfa-2b therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Richmond Pharmaceuticals at 1-804-270-4498 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience-Ribavirin/Peginterferon alfa-2b Combination Therapy Adult Subjects Adverse reactions that occurred in the clinical trial at > 5% incidence are provided by treatment group from the ribavirin/peginterferon alfa-2b Combination Therapy (Study 2) in Table 6 . Table 6. Adverse Reactions Occurring in >5% of Adult Subjects Percentage of Subjects Reporting Adverse Reactions A subject may have reported more than one adverse reaction within a body system/organ class category. Percentage of Subjects Reporting Adverse Reactions Adverse Reactions Peginterferon alfa-2b 1.5 mcg/kg/ Ribavirin (N=511) Interferon alfa-2b/ Ribavirin (N=505) Adverse Reactions Peginterferon alfa-2b 1.5 mcg/kg/ Ribavirin (N=511) Interferon alfa-2b/ Ribavirin (N=505) Application Site Musculoskeletal Injection site Inflammation 25 18 Myalgia 56 50 Injection Site Reaction 58 36 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 7 summarizes the treatment related adverse reactions in Study 4 that occurred at a ≥10% incidence. Table 7: Summary of Treatment-Related Adverse Reactions (≥10% Incidence) by Descending Frequency Study 4 Percentage of Patients Reporting Treatment-Related Adverse Reactions Adverse Reactions Peginterferon alfa-2b 1.5 mcg/kg with Ribavirin (n=1019) Peginterferon alfa-2b 1 mcg/kg with Ribavirin (n=1016) Peginterferon alfa-2a 180 mcg with Ribavirin Tablets (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 studies. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based ribavirin group (12%) and with the flat-dose ribavirin regimen. In Study 2, the incidence of serious adverse reactions was 17% in the peginterferon alfa-2b/ribavirin groups compared to 14% in the interferon alfa-2b/ribavirin group. 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 peginterferon alfa-2b 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 31 subject deaths which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving peginterferon alfa-2b monotherapy and 2 deaths among subjects receiving interferon alfa-2b monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving peginterferon alfa-2b/ribavirin combination therapy; and 1 subject death in the interferon alfa-2b/ribavirin group (motor vehicle accident). There have been 31 subject deaths which occurred during treatment or during follow-up in the three clinical trials. 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 peginterferon alfa-2b/ribavirin combination therapy, 5 in the peginterferon alfa-2b 1.5 mcg/ribavirin arm (N=1019) and 1 in the peginterferon alfa-2b 1 mcg/ribavirin arm (N=1016), and 6 of which occurred in subjects receiving peginterferon alfa-2a/ribavirin tablets (N=1035). There were 3 suicides which occurred during the off treatment follow-up period in subjects who received peginterferon alfa-2b (1.5 mcg/kg)/ribavirin combination therapy. In studies 1 and 2, 10 to 14% of subjects receiving peginterferon alfa-2b, alone or in combination with ribavirin, discontinued therapy compared with 6% treated with interferon alfa-2b alone and 13% treated with interferon alfa-2b in combination with ribavirin. Similarly in Study 3, 15% of subjects receiving peginterferon alfa-2b in combination with weight-based ribavirin and 14% of subjects receiving peginterferon alfa-2b and flat dose ribavirin discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy 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 peginterferon alfa-2b 1.5 mcg/ribavirin arm, 10% in the peginterferon alfa-2b 1 mcg/ribavirin arm and 13% in the peginterferon alfa-2a 180 mcg/ribavirin tablets arm discontinued due to adverse events. In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving peginterferon alfa-2b (1.5 mcg/kg)/ribavirin and in 34% of those receiving interferon alfa-2b/ribavirin. The majority of subjects (57%) weighing 60 kg or less receiving peginterferon alfa-2b (1.5 mcg/kg)/ribavirin required dose reduction. Reduction of interferon was dose related (peginterferon alfa-2b 1.5 mcg/kg > peginterferon alfa-2b 0.5 mcg/kg or interferon alfa-2b), 40%, 27%, 28%, respectively. Dose reduction for ribavirin was similar across all three groups, 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values ). Other common reasons include depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with WBD compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of peginterferon alfa-2b to 1 mcg/kg in combination with ribavirin, with an additional 4% requiring the second dose reduction of peginterferon alfa-2b to 0.5 mcg/kg due to adverse events compared to 15% of subjects in the peginterferon alfa-2a/ribavirin tablets arm, who required a dose reduction to 135 mcg/week with peginterferon alfa-2a, with an additional 7% in the peginterferon alfa-2a/ribavirin tablets arm requiring second dose reduction to 90 mcg/week with peginterferon alfa-2a. In the peginterferon alfa-2b/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 peginterferon alfa-2b 1.5 mcg/ribavirin arm, 55% of subjects in the peginterferon alfa-2b 1 mcg/ribavirin arm, 57% of subjects in the peginterferon alfa-2a 180 mcg/ribavirin tablets arm. Peginterferon alfa-2b 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) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with peginterferon alfa-2b therapies (in up to 75% of subjects) compared with interferon alfa-2b . However, injection site pain was infrequent (2 to 3%) in all groups. In Study 3 there was a 23 to 24% incidence overall for injection site reactions or inflammation. Subjects receiving ribavirin/peginterferon alfa-2b retreatment 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 study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions reported in the study 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, 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations. Dose modifications of peginterferon alfa-2b 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 ≥ 10% incidence in the pediatric trial subjects are provided in Table 8 . Table 8: 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% Laboratory Values Adult and Pediatric Subjects The adverse reaction profile in Study 3, which compared peginterferon alfa-2b/weight-based ribavirin combination to a peginterferon alfa-2b/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 ( 2.4 ) ]. Changes in selected laboratory values during therapy are described in Table 9 . Most of the changes in laboratory values in the peginterferon alfa-2b/ribavirin study with pediatric were mild or moderate. Table 9: Selected Laboratory Values During Treatment With Ribavirin Plus Peginterferon alfa-2b or Ribavirin Plus Interferon alfa-2b in Previously Untreated Subjects Laboratory Parameters 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. Percent of Subjects Adults (Study 2) Pediatrics Peginterferon alfa-2b plus Ribavirin (N=511) Interferon alfa-2b plus Ribavirin (N=505) Peginterferon alfa-2b plus Ribavirin (N=107) Hemoglobin (g/dL) 9.5-<11.0 26 27 30 8.0-<9.5 3 3 2 6.5-7.9 0.2 0.2 - Leukocytes (x10 9 /L) 2.0-2.9 46 41 39 1.5-<2.0 24 8 3 1.0-1.4 5 1 - Neutrophils (x10 9 /L) 1.0-1.5 33 37 35 0.75-<1.0 25 13 26 0.5-<0.75 18 7 13 <0.5 4 2 3 Platelets (x10 9 /L) 70-100 15 5 1 50-<70 3 0.8 - 30-49 0.2 0.2 -- 25-<50 -- -- 1 Total Bilirubin (mg/dL) (µmole/L) 1.5 -3.0 10 13 -- 1.26-2.59 x N N=Upper limit of normal -- -- 7 3.1-6.0 0.6 0.2 -- 2.6-5 x N -- -- - 6.1-12.0 0 0.2 -- ALT (U/L) 2 x Baseline 0.6 0.2 1 2.1-5 x Baseline 3 1 5 5.1-10 x Baseline 0 0 3 Hemoglobin . Hemoglobin levels decreased to < 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD ribavirin and 33% on flat dose ribavirin had decreases in hemoglobin levels <11 g/dL. Reductions in hemoglobin to < 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the peginterferon alfa-2b/ribavirin and interferon alfa-2b/ribavirin groups. In Study 4, patients receiving peginterferon alfa-2b (1.5 mcg/kg)/ribavirin had decreases in hemoglobin levels to between 8.5 to <10 g/dL (28%) and to <8.5 g/dL (3%), whereas in patients receiving peginterferon alfa-2a 180 mcg/ribavirin tablets these decreases occurred in 26% and 4% of subjects respectively. Hemoglobin levels become stable by treatment Weeks 4-6 on average. 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. In the peginterferon alfa-2b monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see Dosage and Administration ( 2.4 ) ]. Neutrophils . Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with ribavirin in Study 2 (85%) and interferon alfa-2b/ribavirin (60%). Severe potentially life-threatening neutropenia (<0.5 x 10 9 /L) occurred in 2% of subjects treated with interferon alfa-2b/ribavirin and in approximately 4% of subjects treated with peginterferon alfa-2b/ribavirin in Study 2. Eighteen percent of subjects receiving peginterferon alfa-2b/ribavirin in Study 2 required modification of interferon dosage. Few subjects (< 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration ( 2.4 ) ]. Platelets. Platelet counts decreased to < 100,000/mm 3 in approximately 20% of subjects treated with peginterferon alfa-2b alone or with ribavirin and in 6% of adult subjects treated with interferon alfa-2b/ribavirin. Severe decreases in platelet counts (< 50,000/mm 3 ) occur in < 4% of adult subjects. Subjects may require discontinuation or dose modification as a result of platelet decreases [see Dosage and Administration ( 2.4 ) ]. In Study 2, 1% or 3% of subjects required dose modification of interferon alfa-2b or peginterferon alfa-2b, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy. Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either interferon alfa-2b or peginterferon alfa-2b (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. 6.2 Clinical Studies Experience-Ribavirin/Interferon alfa-2b 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 arms. Selected treatment-related adverse reactions that occurred in the US studies with ≥5% incidence are provided by treatment group (see Table 10 ). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international studies as compared to the US studies with the exception of 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 ≥5% incidence among all pediatric subjects who received the recommended dose of ribavirin/interferon alfa-2b combination therapy are provided in Table 10 . Table 10: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects Patients Reporting Adverse reactions Percentage of Subjects US Previously Untreated Study US Relapse Study Pediatric Subjects 24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment interferon alfa-2b plus ribavirin (N=228) interferon alfa-2b plus Placebo (N=231) interferon alfa-2b plus ribavirin (N=228) interferon alfa-2b plus Placebo (N=225) interferon alfa-2b plus ribavirin (N=77) interferon alfa-2b plus Placebo (N=76) interferon alfa-2b plus 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 Laboratory Values Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 11 ). 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 US study and 2.9 g/dL in the International study. In relapse subjects the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. 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 were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in subjects with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity. Table 11: Selected Hematologic Abnormalities During Treatment with Ribavirin Plus Interferon alfa-2b: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects Percentage of Subjects US Previously Untreated Study US Relapse Study Pediatric Subjects 24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment interferon alfa-2b plus ribavirin (N=228) interferon alfa-2b plus Placebo (N=231) interferon alfa-2b plus ribavirin (N=228) interferon alfa-2b plus Placebo (N=225) interferon alfa-2b plus ribavirin (N=77) interferon alfa-2b plus Placebo (N=76) interferon alfa-2b plus 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 (x10 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 (x10 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 (x10 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 6.3 Postmarketing Experiences The following adverse reactions have been identified and reported during post approval use of ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b. 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

<table width="490" ID="id_dd5e7ef3-b117-4b62-9f3f-4cca6cd339cb"> <caption ID="id_9d460be3-1f20-4050-bd98-3d5a7f5058b4">Table 6. Adverse Reactions Occurring in &gt;5% of Adult Subjects</caption> <col width="23.1%"/> <col width="13.9%"/> <col width="13.5%"/> <col width="22.4%"/> <col width="13.5%"/> <col width="13.7%"/> <tbody> <tr ID="id_02c91cdd-0738-4fb3-85cd-6aac52aa13e0"> <td align="left" valign="bottom" styleCode="Toprule"> </td> <td align="center" valign="bottom" colspan="2" styleCode="Toprule"> <content styleCode="bold"> <content styleCode="italics">Percentage of Subjects Reporting Adverse Reactions<footnote ID="id-53773249-f649-4c21-b55d-7025c4803ae5">A subject may have reported more than one adverse reaction within a body system/organ class category.</footnote> </content> </content> </td> <td align="left" valign="bottom" styleCode="Toprule"> </td> <td align="center" valign="bottom" colspan="2"> <content styleCode="bold"> <content styleCode="italics">Percentage of Subjects Reporting Adverse Reactions<footnoteRef IDREF="id-53773249-f649-4c21-b55d-7025c4803ae5"/> </content> </content> </td> </tr> <tr ID="id_0be0e3d8-9ddb-43f0-a170-f263ed6e42e9"> <td align="left" valign="bottom"> <content styleCode="bold">Adverse Reactions</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Peginterferon alfa-2b 1.5 mcg/kg/ Ribavirin (N=511)</content> </td> <td align="left" valign="bottom"> <content styleCode="bold">Interferon alfa-2b/ Ribavirin (N=505)</content> </td> <td align="left" valign="bottom"> <content styleCode="bold">Adverse Reactions</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Peginterferon alfa-2b 1.5 mcg/kg/ Ribavirin (N=511)</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Interferon alfa-2b/ Ribavirin (N=505)</content> </td> </tr> <tr ID="id_4ae9dfbc-a496-47b3-8ea6-61f2d94b2901"> <td align="left" valign="top"> <content styleCode="bold">Application Site</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> <content styleCode="bold">Musculoskeletal</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_e3e6d5cf-bc2a-4ca3-bd5e-f38d10d1bc0b"> <td align="left" valign="top"> Injection site Inflammation</td> <td align="center" valign="top">25</td> <td align="center" valign="top">18</td> <td align="left" valign="top"> Myalgia</td> <td align="center" valign="top">56</td> <td align="center" valign="top">50</td> </tr> <tr ID="id_39a046b1-31ed-4d71-a037-5447a73335ff"> <td align="left" valign="top"> Injection Site Reaction</td> <td align="center" valign="top">58</td> <td align="center" valign="top">36</td> <td align="left" valign="top"> Arthralgia</td> <td align="center" valign="top">34</td> <td align="center" valign="top">28</td> </tr> <tr ID="id_09bd632a-ae26-44f5-b052-8d39488f67c3"> <td align="left" valign="top"> <content styleCode="bold">Autonomic Nervous System </content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> Musculoskeletal Pain</td> <td align="center" valign="top">21</td> <td align="center" valign="top">19</td> </tr> <tr ID="id_1c769d6f-ca73-4784-818b-e58a9c34fb8a"> <td align="left" valign="top"> Dry Mouth</td> <td align="center" valign="top">12</td> <td align="center" valign="top">8</td> <td align="left" valign="top"> <content styleCode="bold">Psychiatric</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_4c1384af-c7fb-44a5-a845-19fdc5ac16ff"> <td align="left" valign="top"> Increased Sweating</td> <td align="center" valign="top">11</td> <td align="center" valign="top">7</td> <td align="left" valign="top"> Insomnia</td> <td align="center" valign="top">40</td> <td align="center" valign="top">41</td> </tr> <tr ID="id_4e480443-ab9b-4a95-b630-a6005e091873"> <td align="left" valign="top"> Flushing</td> <td align="center" valign="top">4</td> <td align="center" valign="top">3</td> <td align="left" valign="top"> Depression</td> <td align="center" valign="top">31</td> <td align="center" valign="top">34</td> </tr> <tr ID="id_1b39d73e-a02f-49ed-98d4-3c50977e62ba"> <td align="left" valign="bottom"> <content styleCode="bold">Body as a Whole</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> Anxiety/Emotional Lability/Irritability</td> <td align="center" valign="top">47</td> <td align="center" valign="top">47</td> </tr> <tr ID="id_396ff43b-8268-4c07-8f02-453a0168482b"> <td align="left" valign="top"> Fatigue/Asthenia</td> <td align="center" valign="top">66</td> <td align="center" valign="top">63</td> <td align="left" valign="top"> Concentration Impaired</td> <td align="center" valign="top">17</td> <td align="center" valign="top">21</td> </tr> <tr ID="id_e1f5665a-6802-4fc1-bcf6-69d70dc82549"> <td align="left" valign="top"> Headache</td> <td align="center" valign="top">62</td> <td align="center" valign="top">58</td> <td align="left" valign="top"> Agitation</td> <td align="center" valign="top">8</td> <td align="center" valign="top">5</td> </tr> <tr ID="id_31fd24e5-f38e-4b14-bb3e-655fb198441e"> <td align="left" valign="top"> Rigors</td> <td align="center" valign="top">48</td> <td align="center" valign="top">41</td> <td align="left" valign="top"> Nervousness</td> <td align="center" valign="top">6</td> <td align="center" valign="top">6</td> </tr> <tr ID="id_accfb034-0c6d-4fef-accf-bcf59307f3f7"> <td align="left" valign="top"> Fever </td> <td align="center" valign="top">46</td> <td align="center" valign="top">33</td> <td align="left" valign="top"> <content styleCode="bold">Reproductive, Female</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_1cd0f452-ea5f-4e2b-a967-258b0ace99cd"> <td align="left" valign="top"> Weight Loss</td> <td align="center" valign="top">29</td> <td align="center" valign="top">20</td> <td align="left" valign="top"> Menstrual Disorder</td> <td align="center" valign="top">7</td> <td align="center" valign="top">6</td> </tr> <tr ID="id_487a4b00-9b57-43d3-ba29-aa703719bfda"> <td align="left" valign="top"> Right Upper Quadrant Pain </td> <td align="center" valign="top">12</td> <td align="center" valign="top">6</td> <td align="left" valign="top"> <content styleCode="bold">Resistance Mechanism</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_df5748ed-f377-4311-98aa-b025fba6d3cd"> <td align="left" valign="top"> Chest Pain</td> <td align="center" valign="top">8</td> <td align="center" valign="top">7</td> <td align="left" valign="top"> Viral Infection</td> <td align="center" valign="top">12</td> <td align="center" valign="top">12</td> </tr> <tr ID="id_ec334ebe-7b41-4f2a-b2ad-11b0bbe2e747"> <td align="left" valign="top"> Malaise</td> <td align="center" valign="top">4</td> <td align="center" valign="top">6</td> <td align="left" valign="top"> Fungal Infection</td> <td align="center" valign="top">6</td> <td align="center" valign="top">1</td> </tr> <tr ID="id_c4fa2950-a6e3-480a-9a02-144fa4cb7391"> <td align="left" valign="top"> <content styleCode="bold">Central/Peripheral Nervous System</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> <content styleCode="bold">Respiratory System</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_cc209c2b-f4ff-416c-9386-7da6effcd5bd"> <td align="left" valign="top"> Dizziness</td> <td align="center" valign="top">21</td> <td align="center" valign="top">17</td> <td align="left" valign="top"> Dyspnea</td> <td align="center" valign="top">26</td> <td align="center" valign="top">24</td> </tr> <tr ID="id_f72c93eb-eec8-4242-8de4-aef77556f6dd"> <td align="left" valign="top"> <content styleCode="bold">Endocrine</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> Coughing</td> <td align="center" valign="top">23</td> <td align="center" valign="top">16</td> </tr> <tr ID="id_2c14d293-bf01-41e3-8f4d-f6844193e8ac"> <td align="left" valign="top"> Hypothyroidism</td> <td align="center" valign="top">5</td> <td align="center" valign="top">4</td> <td align="left" valign="top"> Pharyngitis</td> <td align="center" valign="top">12</td> <td align="center" valign="top">13</td> </tr> <tr ID="id_cc91bf77-cc69-460b-b526-0686bdf19652"> <td align="left" valign="top"> <content styleCode="bold">Gastrointestinal</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> Rhinitis</td> <td align="center" valign="top">8</td> <td align="center" valign="top">6</td> </tr> <tr ID="id_adfe43b7-7074-4e4c-9964-def79ecbb394"> <td align="left" valign="top"> Nausea</td> <td align="center" valign="top">43</td> <td align="center" valign="top">33</td> <td align="left" valign="top"> Sinusitis</td> <td align="center" valign="top">6</td> <td align="center" valign="top">5</td> </tr> <tr ID="id_6007530f-2d04-4d2b-9c7d-72d7458beb2c"> <td align="left" valign="top"> Anorexia</td> <td align="center" valign="top">32</td> <td align="center" valign="top">27</td> <td align="left" valign="top"> <content styleCode="bold">Skin and Appendages</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_8dbcc125-4679-44cd-b830-5363a9700ce9"> <td align="left" valign="top"> Diarrhea</td> <td align="center" valign="top">22</td> <td align="center" valign="top">17</td> <td align="left" valign="top"> Alopecia</td> <td align="center" valign="top">36</td> <td align="center" valign="top">32</td> </tr> <tr ID="id_e5ff697f-794f-4ecc-81bc-91ff0e9ef17a"> <td align="left" valign="top"> Vomiting</td> <td align="center" valign="top">14</td> <td align="center" valign="top">12</td> <td align="left" valign="top"> Pruritus</td> <td align="center" valign="top">29</td> <td align="center" valign="top">28</td> </tr> <tr ID="id_7a6c480d-7490-4b32-b983-657b786eb53f"> <td align="left" valign="top"> Abdominal Pain</td> <td align="center" valign="top">13</td> <td align="center" valign="top">13</td> <td align="left" valign="top"> Rash</td> <td align="center" valign="top">24</td> <td align="center" valign="top">23</td> </tr> <tr ID="id_3c1deddf-2028-4f0d-a827-dad87e42a4a5"> <td align="left" valign="top"> Dyspepsia</td> <td align="center" valign="top">9</td> <td align="center" valign="top">8</td> <td align="left" valign="top"> Skin Dry</td> <td align="center" valign="top">24</td> <td align="center" valign="top">23</td> </tr> <tr ID="id_3493dc7f-61c0-4c48-b591-814645c6210c"> <td align="left" valign="top"> Constipation</td> <td align="center" valign="top">5</td> <td align="center" valign="top">5</td> <td align="left" valign="top"> <content styleCode="bold">Special Senses, Other</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_455d5481-7cc5-40c7-9921-c7e1a536ba04"> <td align="left" valign="top"> <content styleCode="bold">Hematologic Disorders</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"> Taste Perversion</td> <td align="center" valign="top">9</td> <td align="center" valign="top">4</td> </tr> <tr ID="id_f38861c7-fd3b-4cd0-a37d-28d921188d98"> <td align="left" valign="top"> Neutropenia</td> <td align="center" valign="top">26</td> <td align="center" valign="top">14</td> <td align="left" valign="top"> <content styleCode="bold">Vision Disorders</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_067a787d-e966-4245-b562-59aea09e1c82"> <td align="left" valign="top"> Anemia </td> <td align="center" valign="top">12</td> <td align="center" valign="top">17</td> <td align="left" valign="top"> Vision Blurred</td> <td align="center" valign="top">5</td> <td align="center" valign="top">6</td> </tr> <tr ID="id_11ce2982-237f-437c-b662-f53e8bca5429"> <td align="left" valign="top"> Leukopenia</td> <td align="center" valign="top">6</td> <td align="center" valign="top">5</td> <td align="left" valign="top"> Conjunctivitis</td> <td align="center" valign="top">4</td> <td align="center" valign="top">5</td> </tr> <tr ID="id_9b864620-bd8e-45f0-bb96-c57d22804b49"> <td align="left" valign="top"> Thrombocytopenia</td> <td align="center" valign="top">5</td> <td align="center" valign="top">2</td> <td align="left" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_98480aa9-1f97-4df5-a82e-90db9b7d71f3"> <td align="left" valign="top"> <content styleCode="bold">Liver and Biliary System</content> </td> <td align="center" valign="top"/> <td align="center" valign="top"/> <td align="left" valign="top"/> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr ID="id_a510bb01-31a4-488c-8f65-4fa15e2d88ce"> <td align="left" valign="top" styleCode="Botrule"> Hepatomegaly</td> <td align="center" valign="top" styleCode="Botrule">4</td> <td align="center" valign="top" styleCode="Botrule">4</td> <td align="left" valign="top" styleCode="Botrule"/> <td align="center" valign="top" styleCode="Botrule"/> <td align="center" valign="top" styleCode="Botrule"/> </tr> </tbody> </table>

<table width="443" ID="id_59fe8e30-9285-422f-ac31-145bab69872d"> <caption ID="id_4a20763f-8cb4-404c-b6df-886f979811ac">Table 7: Summary of Treatment-Related Adverse Reactions (&#x2265;10% Incidence) by Descending Frequency</caption> <col width="24.0%"/> <col width="26.4%"/> <col width="25.0%"/> <col width="24.6%"/> <tbody> <tr ID="id_ab42e29c-10ad-4829-b8ec-9215b8d4c3eb"> <td align="center" valign="top" colspan="4"> <content styleCode="bold">Study 4 <content styleCode="italics">Percentage of Patients Reporting Treatment-Related Adverse Reactions</content> </content> </td> </tr> <tr ID="id_072b5a58-a097-451b-91c2-735081d71a34"> <td align="left" valign="bottom"> <content styleCode="bold">Adverse Reactions</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Peginterferon alfa-2b 1.5 mcg/kg with Ribavirin (n=1019)</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Peginterferon alfa-2b 1 mcg/kg with Ribavirin (n=1016)</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Peginterferon alfa-2a 180 mcg with Ribavirin Tablets (n=1035)</content> </td> </tr> <tr ID="id_08ed90ea-2823-4b4e-a6a7-1ab8d1ab7b33"> <td align="left" valign="top">Fatigue</td> <td align="center" valign="top">67</td> <td align="center" valign="top">68</td> <td align="center" valign="top">64</td> </tr> <tr ID="id_a9c8cd1f-ae6a-4247-983e-328eb2a02fbe"> <td align="left" valign="top">Headache</td> <td align="center" valign="top">50</td> <td align="center" valign="top">47</td> <td align="center" valign="top">41</td> </tr> <tr ID="id_0606bd5e-fc7e-411a-a26d-a137c8e55e9d"> <td align="left" valign="top">Nausea</td> <td align="center" valign="top">40</td> <td align="center" valign="top">35</td> <td align="center" valign="top">34</td> </tr> <tr ID="id_1af48e5c-1ae0-4841-abac-833591f419e0"> <td align="left" valign="top">Chills</td> <td align="center" valign="top">39</td> <td align="center" valign="top">36</td> <td align="center" valign="top">23</td> </tr> <tr ID="id_68468ef1-1e70-4b36-8432-942313cc861c"> <td align="left" valign="top">Insomnia</td> <td align="center" valign="top">38</td> <td align="center" valign="top">37</td> <td align="center" valign="top">41</td> </tr> <tr ID="id_c7f59f5a-c860-44e3-bbaf-4c65920eab5f"> <td align="left" valign="top">Anemia</td> <td align="center" valign="top">35</td> <td align="center" valign="top">30</td> <td align="center" valign="top">34</td> </tr> <tr ID="id_fc98c9a2-c1b0-4b35-86d0-3f930a358705"> <td align="left" valign="top">Pyrexia</td> <td align="center" valign="top">35</td> <td align="center" valign="top">32</td> <td align="center" valign="top">21</td> </tr> <tr ID="id_f06c3ff8-0479-4e62-b063-89b4dfe7b7a6"> <td align="left" valign="top">Injection Site Reactions </td> <td align="center" valign="top">34</td> <td align="center" valign="top">35</td> <td align="center" valign="top">23</td> </tr> <tr ID="id_94729b59-6b6b-45da-9365-d0c01c334438"> <td align="left" valign="top">Anorexia</td> <td align="center" valign="top">29</td> <td align="center" valign="top">25</td> <td align="center" valign="top">21</td> </tr> <tr ID="id_1540a088-2e16-452f-bb2a-0e20ef00cad5"> <td align="left" valign="top">Rash</td> <td align="center" valign="top">29</td> <td align="center" valign="top">25</td> <td align="center" valign="top">34</td> </tr> <tr ID="id_cedd3a89-3633-45ac-9d17-a976f3aebfe1"> <td align="left" valign="top">Myalgia</td> <td align="center" valign="top">27</td> <td align="center" valign="top">26</td> <td align="center" valign="top">22</td> </tr> <tr ID="id_5621b9bc-933a-4cc5-ae8a-c433314ae34a"> <td align="left" valign="top">Neutropenia</td> <td align="center" valign="top">26</td> <td align="center" valign="top">19</td> <td align="center" valign="top">31</td> </tr> <tr ID="id_8d60bc2b-3105-4a5e-a69f-905fb380071c"> <td align="left" valign="top">Irritability</td> <td align="center" valign="top">25</td> <td align="center" valign="top">25</td> <td align="center" valign="top">25</td> </tr> <tr ID="id_8f5d98bc-6516-4044-b293-daae8c60d807"> <td align="left" valign="top">Depression</td> <td align="center" valign="top">25</td> <td align="center" valign="top">19</td> <td align="center" valign="top">20</td> </tr> <tr ID="id_80e9cc1f-7737-4d5c-b3bb-cc98a3451d91"> <td align="left" valign="top">Alopecia</td> <td align="center" valign="top">23</td> <td align="center" valign="top">20</td> <td align="center" valign="top">17</td> </tr> <tr ID="id_322d65d1-ab1c-4f5d-8dff-d90db910f18a"> <td align="left" valign="top">Dyspnea</td> <td align="center" valign="top">21</td> <td align="center" valign="top">20</td> <td align="center" valign="top">22</td> </tr> <tr ID="id_8affb6ca-4c9b-4fc9-8d8c-463eaf294d85"> <td align="left" valign="top">Arthralgia</td> <td align="center" valign="top">21</td> <td align="center" valign="top">22</td> <td align="center" valign="top">22</td> </tr> <tr ID="id_e702ca34-954d-4697-a033-8a6130bc0ffd"> <td align="left" valign="top">Pruritus</td> <td align="center" valign="top">18</td> <td align="center" valign="top">15</td> <td align="center" valign="top">19</td> </tr> <tr ID="id_dcb7a93e-7aaf-406c-a904-96144e6ca8cf"> <td align="left" valign="top">Influenza-like Illness</td> <td align="center" valign="top">16</td> <td align="center" valign="top">15</td> <td align="center" valign="top">15</td> </tr> <tr ID="id_4f30954b-027b-4487-b0e0-bb3dc1f7b3d5"> <td align="left" valign="top">Dizziness</td> <td align="center" valign="top">16</td> <td align="center" valign="top">14</td> <td align="center" valign="top">13</td> </tr> <tr ID="id_04ffcf8d-0332-4b05-827a-53162cb4985f"> <td align="left" valign="top">Diarrhea</td> <td align="center" valign="top">15</td> <td align="center" valign="top">16</td> <td align="center" valign="top">14</td> </tr> <tr ID="id_8970bf14-1458-487b-a156-6c7ad802fb5a"> <td align="left" valign="top">Cough</td> <td align="center" valign="top">15</td> <td align="center" valign="top">16</td> <td align="center" valign="top">17</td> </tr> <tr ID="id_68d92ac7-3126-412d-aa57-84fba611f214"> <td align="left" valign="top">Weight Decreased</td> <td align="center" valign="top">13</td> <td align="center" valign="top">10</td> <td align="center" valign="top">10</td> </tr> <tr ID="id_23afac93-230c-4212-90e5-537bdeacd428"> <td align="left" valign="top">Vomiting</td> <td align="center" valign="top">12</td> <td align="center" valign="top">10</td> <td align="center" valign="top">9</td> </tr> <tr ID="id_135cbc30-1d09-4adc-838d-ad7d8f9195f3"> <td align="left" valign="top">Unspecified Pain</td> <td align="center" valign="top">12</td> <td align="center" valign="top">13</td> <td align="center" valign="top">9</td> </tr> <tr ID="id_8e57f56a-cc2f-4120-b8ef-f54e126ac09f"> <td align="left" valign="top">Dry Skin</td> <td align="center" valign="top">11</td> <td align="center" valign="top">11</td> <td align="center" valign="top">12</td> </tr> <tr ID="id_26ade3ad-6d94-425e-adb7-0c2dc14e6c83"> <td align="left" valign="top">Anxiety</td> <td align="center" valign="top">11</td> <td align="center" valign="top">11</td> <td align="center" valign="top">10</td> </tr> <tr ID="id_2cc4695b-e395-4a0d-8613-cc7e2556e155"> <td align="left" valign="top">Abdominal Pain</td> <td align="center" valign="top">10</td> <td align="center" valign="top">10</td> <td align="center" valign="top">10</td> </tr> <tr ID="id_2ccfaf25-5a4a-43cc-b027-58dcca486185"> <td align="left" valign="top" styleCode="Botrule">Leukopenia</td> <td align="center" valign="top" styleCode="Botrule">9</td> <td align="center" valign="top" styleCode="Botrule">7</td> <td align="center" valign="top" styleCode="Botrule">10</td> </tr> </tbody> </table>

<table width="443" ID="id_9289d9a3-6b82-4cd9-b1b3-5d176b083c4d"> <caption ID="id_3cd52a41-93f4-48d9-bd59-3866af3414d2">Table 8: Percentage (%) of Pediatric Subjects With Treatment-Related Adverse Reactions (in at Least 10% of All Subjects)</caption> <col width="63.5%"/> <col width="36.6%"/> <tbody> <tr ID="id_91ecb8da-fd45-41fd-9862-1441e5a2be6c"> <td align="left" valign="middle" styleCode="Toprule"> <content styleCode="bold">System Organ Class Preferred Term</content> </td> <td align="center" valign="middle"> <content styleCode="bold">All Subjects (N=107)</content> </td> </tr> <tr ID="id_28d49417-aaaa-4e47-a5fa-a2a67ef56585"> <td align="left" valign="middle"> <content styleCode="bold">Blood and Lymphatic System Disorders</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_e3c5201c-d1fc-4476-8f12-e9aad01783e9"> <td align="left" valign="middle"> Neutropenia</td> <td align="center" valign="middle">33%</td> </tr> <tr ID="id_2e5afc18-2bd1-47f5-ab75-4abc5e4111a7"> <td align="left" valign="middle"> Anemia</td> <td align="center" valign="middle">11%</td> </tr> <tr ID="id_e1cf59b8-f509-4512-826f-4d9fa89e9133"> <td align="left" valign="middle"> Leukopenia</td> <td align="center" valign="middle">10%</td> </tr> <tr ID="id_5c9cbdb6-1160-4512-9b51-5a5215c7fc1f"> <td align="left" valign="middle"> <content styleCode="bold">Gastrointestinal Disorders</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_797ca94c-93c2-4a10-829b-d69f86f99492"> <td align="left" valign="middle"> Abdominal Pain</td> <td align="center" valign="middle">21%</td> </tr> <tr ID="id_5b201f88-c147-4ac4-9927-1dd998eeea96"> <td align="left" valign="middle"> Abdominal Pain Upper</td> <td align="center" valign="middle">12%</td> </tr> <tr ID="id_e3579208-b8ad-4ba0-b27e-e67e048f8274"> <td align="left" valign="middle"> Vomiting</td> <td align="center" valign="middle">27%</td> </tr> <tr ID="id_9c93a128-5c96-4249-85fe-e7d87d8732e7"> <td align="left" valign="middle"> Nausea</td> <td align="center" valign="middle">18%</td> </tr> <tr ID="id_79cdc51b-3480-4217-9a70-8d1137426e49"> <td align="left" valign="middle"> <content styleCode="bold">General Disorders and Administration Site Conditions </content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_a775b1f1-3b2a-40ce-9df2-04b3cfc20466"> <td align="left" valign="middle"> Pyrexia</td> <td align="center" valign="middle">80%</td> </tr> <tr ID="id_ecd8f0dc-0af0-48a2-b021-1105790eb754"> <td align="left" valign="middle"> Fatigue</td> <td align="center" valign="middle">30%</td> </tr> <tr ID="id_f4bb0256-b2a4-4101-a1d0-bb0be9008d88"> <td align="left" valign="middle"> Injection-Site Erythema</td> <td align="center" valign="middle">29%</td> </tr> <tr ID="id_a3d49ae7-09ac-414e-a2af-17c52580c20d"> <td align="left" valign="middle"> Chills</td> <td align="center" valign="middle">21%</td> </tr> <tr ID="id_561c1ca7-7225-4cb8-a04c-cc5c8d8b48e6"> <td align="left" valign="middle"> Asthenia</td> <td align="center" valign="middle">15%</td> </tr> <tr ID="id_dc5e3a56-000c-44ac-aa70-9edaaf305d6b"> <td align="left" valign="middle"> Irritability</td> <td align="center" valign="middle">14%</td> </tr> <tr ID="id_365d4fae-b3a9-4a04-813a-ce8904ee92c1"> <td align="left" valign="middle"> <content styleCode="bold">Investigations</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_638ccb9b-2c59-4836-b219-5c1673ae616f"> <td align="left" valign="middle"> Weight Loss</td> <td align="center" valign="middle">19%</td> </tr> <tr ID="id_7a2d9afa-03ab-4763-9d81-10cb506c4773"> <td align="left" valign="middle"> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_12e50188-344a-4599-82ca-a1f8c2e03868"> <td align="left" valign="middle"> Anorexia</td> <td align="center" valign="middle">29%</td> </tr> <tr ID="id_4be9053f-4bc3-4ed7-b490-dbca5f364df5"> <td align="left" valign="middle"> Decreased Appetite</td> <td align="center" valign="middle">22%</td> </tr> <tr ID="id_0c8d53bf-1c4a-4a40-b963-a0e6a65d80a7"> <td align="left" valign="middle"> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_dfaaab11-06a8-4d47-8155-62fc5159382e"> <td align="left" valign="middle"> Arthralgia</td> <td align="center" valign="middle">17%</td> </tr> <tr ID="id_474b732a-cf58-432a-ac93-6c17e2180902"> <td align="left" valign="middle"> Myalgia</td> <td align="center" valign="middle">17%</td> </tr> <tr ID="id_f84d02f2-5136-4de4-80a5-b7abfa378983"> <td align="left" valign="middle"> <content styleCode="bold">Nervous System Disorders</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_7cb304b4-4901-4bc5-b188-675b2822f85f"> <td align="left" valign="middle"> Headache</td> <td align="center" valign="middle">62%</td> </tr> <tr ID="id_b1141c9b-ff28-418d-8ae3-2e57b13a0858"> <td align="left" valign="middle"> Dizziness</td> <td align="center" valign="middle">14%</td> </tr> <tr ID="id_4e12adbf-8f85-48ba-9b6f-44b4269c5976"> <td align="left" valign="middle"> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td> <td align="center" valign="middle"/> </tr> <tr ID="id_635c41bd-a9a7-405a-8530-07cb06140c48"> <td align="left" valign="middle" styleCode="Botrule"> Alopecia</td> <td align="center" valign="middle" styleCode="Botrule">17%</td> </tr> </tbody> </table>