FDA label 090ce577-7488-4e3a-b7ff-32b1b7cc7f44

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS Alpha interferons, including PegIntron, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PegIntron therapy [see Warnings and Precautions (5) and Adverse Reactions (6.1) ]. WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS See full prescribing information for complete boxed warning . May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders. ( 5 ) Use with Ribavirin Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients. ( 5.1 ) Ribavirin is a potential carcinogen. ( 5.1 , 13.1 ) Use with Ribavirin Ribavirin may cause birth defects and death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. [See REBETOL package insert.]

5 WARNINGS AND PRECAUTIONS Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should be withdrawn from therapy. 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. ( 5.1 ) Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: Hemolytic anemia with ribavirin. ( 5.1 ) Neuropsychiatric events. ( 5.2 ) History of significant or unstable cardiac disease. ( 5.3 ) Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication. ( 5.4) New or worsening ophthalmologic disorders. ( 5.5 ) Ischemic and hemorrhagic cerebrovascular events. ( 5.6 ) Severe decreases in neutrophil or platelet counts. ( 5.7 ) History of autoimmune disorders. ( 5.8 ) Pancreatitis and ulcerative or hemorrhagic/ischemic colitis and pancreatitis. ( 5.9 , 5.10 ) Pulmonary infiltrates or pulmonary function impairment. ( 5.11 ) Child-Pugh score greater than 6 (class B and C). ( 4 , 5.12 ) Increased creatinine levels in patients with renal insufficiency. ( 5.13 ) Serious, acute hypersensitivity reactions and cutaneous eruptions. ( 5.14 ) Dental/periodontal disorders reported with combination therapy. ( 5.16 ) Hypertriglyceridemia may result in pancreatitis (e.g., triglycerides greater than 1000 mg/dL). ( 5.17 ) Weight loss and growth inhibition reported with combination therapy in pediatric patients. ( 5.18 ) Peripheral neuropathy when used in combination with telbivudine. ( 5.19 ) 5.1 Use with Ribavirin Pregnancy REBETOL may cause birth defects and death of the unborn child. REBETOL 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 2 forms of contraception and have monthly pregnancy tests [see BOXED WARNING , Contraindications (4) , Patient Counseling Information (17) , and REBETOL package insert]. Anemia Ribavirin caused hemolytic anemia in 10% of PegIntron/REBETOL-treated subjects within 1 to 4 weeks of initiation of therapy. Complete blood counts should be obtained pretreatment and at Week 2 and Week 4 of therapy or more frequently if clinically indicated. Anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of REBETOL may be necessary [see Dosage and Administration (2.3) and REBETOL package insert] . 5.2 Neuropsychiatric Events Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior sometimes directed towards others have occurred in patients with and without a previous psychiatric disorder during PegIntron treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with interferon alpha. PegIntron should be used with caution in patients with a history of psychiatric disorders. Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is initiated in patients with prior history or existence of psychiatric condition or with a history of substance use disorders, treatment considerations should include the need for drug screening and periodic health evaluation, including psychiatric symptom monitoring. Early intervention for re-emergence or development of neuropsychiatric symptoms and substance use is recommended. Patients should be advised to report immediately any symptoms of depression or suicidal ideation to their prescribing physicians. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with PegIntron be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, PegIntron should be stopped immediately and psychiatric intervention instituted [see Dosage and Administration (2.3) ] . Cases of encephalopathy have been observed in some patients, usually elderly, treated at higher doses of PegIntron. 5.3 Cardiovascular Events Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with PegIntron. PegIntron should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require PegIntron therapy should be closely monitored [see Warnings and Precautions (5.15) ] . Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron /REBETOL combination therapy [see REBETOL package insert] . 5.4 Endocrine Disorders PegIntron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with PegIntron. Diabetes mellitus, including cases of new onset Type 1 diabetes, has been observed in patients treated with alpha interferons, including PegIntron. Patients with these conditions who cannot be effectively treated by medication should not begin PegIntron therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue PegIntron therapy. 5.5 Ophthalmologic Disorders 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 may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Peginterferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders. 5.6 Cerebrovascular Disorders Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PegIntron. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made, and a causal relationship between interferon alfa-based therapies and these events is difficult to establish. 5.7 Bone Marrow Toxicity PegIntron suppresses bone marrow function, sometimes resulting in severe cytopenias. PegIntron should be discontinued in patients who develop severe decreases in neutrophil or platelet counts [see Dosage and Administration (2.3) ] . Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia. 5.8 Autoimmune Disorders Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis) has been observed in patients receiving PegIntron. PegIntron should be used with caution in patients with autoimmune disorders. 5.9 Pancreatitis Fatal and nonfatal pancreatitis have been observed in patients treated with alpha interferon. PegIntron therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis. 5.10 Colitis Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. PegIntron treatment should be discontinued immediately in patients who develop these signs and symptoms. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferons. 5.11 Pulmonary Disorders Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure or patient deaths, may be induced or aggravated by PegIntron or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PegIntron combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored. Because of the fever and other "flu-like" symptoms associated with PegIntron administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease). 5.12 Hepatic Failure Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PegIntron. Cirrhotic CHC patients co-infected with HIV receiving highly active antiretroviral therapy (HAART) and alpha interferons with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients' clinical status and hepatic function should be closely monitored, and PegIntron treatment should be immediately discontinued if decompensation (Child-Pugh score greater than 6) is observed [see Contraindications (4) ] . 5.13 Patients with Renal Insufficiency Increases in serum creatinine levels have been observed in patients with renal insufficiency receiving interferon alpha products, including PegIntron. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and PegIntron dosing should be adjusted accordingly or discontinued [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3) ] . PegIntron monotherapy should be used with caution in patients with creatinine clearance less than 50 mL/min; the potential risks should be weighed against the potential benefits in these patients. Combination therapy with REBETOL must not be used in patients with creatinine clearance less than 50 mL/min [see REBETOL Package Insert] . 5.14 Hypersensitivity Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) and cutaneous eruptions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment. 5.15 Laboratory Tests PegIntron alone or in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. Transient elevations in ALT (2- to 5-fold above baseline) were observed in 10% of subjects treated with PegIntron, and were not associated with deterioration of other liver functions. Triglyceride levels are frequently elevated in patients receiving alpha interferon therapy including PegIntron and should be periodically monitored. Patients on PegIntron or PegIntron/REBETOL 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, and 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) ] . Patients who have pre-existing cardiac abnormalities should have electrocardiograms done before treatment with PegIntron/REBETOL. 5.16 Dental and Periodontal Disorders Dental and periodontal disorders have been reported in patients receiving PegIntron/REBETOL 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 REBETOL and PegIntron. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, patients should be advised to rinse out their mouth thoroughly afterwards. 5.17 Triglycerides Elevated triglyceride levels have been observed in patients treated with interferon alpha, including PegIntron therapy. Hypertriglyceridemia may result in pancreatitis [see Warnings and Precautions (5.9) ] . Elevated triglyceride levels should be managed as clinically appropriate. Discontinuation of PegIntron therapy should be considered for patients with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting, and persistently elevated triglycerides (e.g., triglycerides greater than 1000 mg/dL). 5.18 Impact on Growth-Pediatric Use Data on the effects of PegIntron plus REBETOL on growth come from an open-label trial in subjects 3 through 17 years of age, and weight and height changes are compared to US normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lags behind that predicted by normative population data for the entire length of treatment. After about 6 months post-treatment (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 post-treatment, height gain stabilized and subjects treated with PegIntron plus REBETOL 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 (less than 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 (less than 3 rd percentile) after 6 months of follow-up. Among the boys studied, the age groups of 3 to 11 years old and 12 to 17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months post-treatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3 to 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 to 17 years old continued along their average baseline height and weight percentiles after 6 months post-treatment. 5.19 Peripheral Neuropathy Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated.

6 ADVERSE REACTIONS Clinical trials with PegIntron alone or in combination with REBETOL have been conducted in over 6900 subjects from 3 to 75 years of age. Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without REBETOL [see BOXED WARNING , Warnings and Precautions (5)] . The most common serious events occurring in subjects treated with PegIntron and REBETOL were depression and suicidal ideation [see Warnings and Precautions (5.2) ], each occurring at a frequency of less than 1%. The most common fatal events occurring in subjects treated with PegIntron and REBETOL were cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions (5.2, 5.3) ] , all occurring in less than 1% of subjects. Greater than 96% of all subjects in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions in adult subjects receiving either PegIntron or PegIntron/REBETOL were injection-site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and emotional lability/irritability. The most common adverse events in pediatric subjects, ages 3 and older, were pyrexia, headache, vomiting, neutropenia, fatigue, anorexia, injection-site erythema, and abdominal pain. Most common adverse reactions (greater than 40%) in adult patients receiving either PegIntron or PegIntron/REBETOL are injection site inflammation/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 PegIntron/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection-site erythema, vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099 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. Adults Study 1 compared PegIntron monotherapy with INTRON® A monotherapy. Study 2 compared combination therapy of PegIntron/REBETOL with combination therapy with INTRON A/REBETOL. In these trials, nearly all study subjects in clinical trials experienced one or more adverse reactions. Study 3 compared a PegIntron/weight-based REBETOL combination to a PegIntron/flat dose REBETOL regimen. Study 4 compared 2 PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving Pegasys ® (180 mcg/week)/Copegus ® (1000–1200 mg/day). Adverse reactions that occurred in Studies 1 and 2 at greater than 5% incidence are provided in Table 8 by treatment group. Due to potential differences in ascertainment procedures, adverse reaction rate comparisons across trials should not be made. Table 9 summarizes the treatment-related/treatment emergent adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence. TABLE 8 Adverse Reactions Occurring in Greater than 5% of Subjects Percentage of Subjects Reporting Adverse Reactions Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category. Study 1 Study 2 Adverse Reactions PegIntron 1 mcg/kg (n=297) INTRON A 3 MIU (n=303) PegIntron 1.5 mcg/kg/ REBETOL (n=511) INTRON A/ REBETOL (n=505) Application Site Injection Site Inflammation/Reaction 47 20 75 49 Autonomic Nervous System Dry Mouth 6 7 12 8 Increased Sweating 6 7 11 7 Flushing 6 3 4 3 Body as a Whole Fatigue/Asthenia 52 54 66 63 Headache 56 52 62 58 Rigors 23 19 48 41 Fever 22 12 46 33 Weight Loss 11 13 29 20 Right Upper Quadrant Pain 8 8 12 6 Chest Pain 6 4 8 7 Malaise 7 6 4 6 Central/Peripheral Nervous System Dizziness 12 10 21 17 Endocrine Hypothyroidism 5 3 5 4 Gastrointestinal Nausea 26 20 43 33 Anorexia 20 17 32 27 Diarrhea 18 16 22 17 Vomiting 7 6 14 12 Abdominal Pain 15 11 13 13 Dyspepsia 6 7 9 8 Constipation 1 3 5 5 Hematologic Disorders Neutropenia 6 2 26 14 Anemia 0 0 12 17 Leukopenia <1 0 6 5 Thrombocytopenia 7 <1 5 2 Liver and Biliary System Hepatomegaly 6 5 4 4 Musculoskeletal Myalgia 54 53 56 50 Arthralgia 23 27 34 28 Musculoskeletal Pain 28 22 21 19 Psychiatric Insomnia 23 23 40 41 Depression 29 25 31 34 Anxiety/Emotional Lability/Irritability 28 34 47 47 Concentration Impaired 10 8 17 21 Agitation 2 2 8 5 Nervousness 4 3 6 6 Reproductive, Female Menstrual Disorder 4 3 7 6 Resistance Mechanism Viral Infection 11 10 12 12 Fungal Infection <1 3 6 1 Respiratory System Dyspnea 4 2 26 24 Coughing 8 5 23 16 Pharyngitis 10 7 12 13 Rhinitis 2 2 8 6 Sinusitis 7 7 6 5 Skin and Appendages Alopecia 22 22 36 32 Pruritus 12 8 29 28 Rash 6 7 24 23 Skin Dry 11 9 24 23 Special Senses, Other Taste Perversion <1 2 9 4 Vision Disorders Vision Blurred 2 3 5 6 Conjunctivitis 4 2 4 5 TABLE 9 Summary of Treatment-related/Treatment-emergent Adverse Reactions (Greater than or Equal to 10% Incidence) by Descending Frequency Percentage of Patients Reporting Treatment-related/Treatment-emergent Adverse Reactions Study 4 Adverse Reactions PegIntron 1.5 mcg/kg with REBETOL PegIntron 1 mcg/kg with REBETOL Pegasys 180 mcg with Copegus (n=1019) (n=1016) (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 adverse reaction profile in Study 3, which compared PegIntron/weight-based REBETOL combination to a PegIntron/flat-dose REBETOL 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. The incidence of serious adverse reactions was comparable in all trials. In the PegIntron monotherapy trial (Study 1) the incidence of serious adverse reactions was similar (about 12%) in all treatment groups. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/REBETOL groups compared to 14% in the INTRON A/REBETOL group. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and with the flat-dose REBETOL 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. 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 PegIntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PegIntron/REBETOL combination therapy, and 1 subject death in the INTRON A/REBETOL 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 receiving PegIntron/REBETOL combination therapy; 5 in the PegIntron 1.5 mcg/REBETOL arm (n=1019) and 1 in the PegIntron 1 mcg/REBETOL arm (n=1016); and 6 of which occurred in subjects receiving Pegasys/Copegus (n=1035). There were 3 suicides which occurred during the off-treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/REBETOL combination therapy. In Studies 1 and 2, 10% to 14% of subjects receiving PegIntron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based REBETOL and 14% of subjects receiving PegIntron and flat-dose REBETOL 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 PegIntron 1.5 mcg/REBETOL arm, 10% in the PegIntron 1 mcg/REBETOL arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued therapy due to adverse events. In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PegIntron (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PegIntron 1.5 mcg/kg more than PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all 3 groups, 33% to 35%. The most common reasons for dose modifications were neutropenia (18%) or anemia (9%). Other common reasons included 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 PegIntron to 1 mcg/kg in combination with REBETOL, 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% requiring a second dose reduction to 90 mcg/week with Pegasys. In the PegIntron/REBETOL 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 (5.2) ] . In Study 4, psychiatric adverse reactions occurred in 58 % of subjects in the PegIntron 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm. PegIntron 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 PegIntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection-site pain was infrequent (2–3%) in all groups. In Study 3 there was a 23% to 24% incidence overall for injection-site reactions or inflammation. 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/REBETOL 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. Individual serious adverse reactions in Study 2 occurred at a frequency less than or equal to 1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis; urticaria, injection-site necrosis, vasculitis, and phototoxicity. Subjects receiving PegIntron/REBETOL as 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 trial, 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 trial 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 were required in 25% of subjects, 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 10. TABLE 10 Percentage of Pediatric Subjects with Treatment-emergent/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 Decreased 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 Adults Changes in selected laboratory values during treatment with PegIntron alone or in combination with REBETOL treatment are described below . Decreases in hemoglobin, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.3) and Warnings and Precautions (5.1, 5.7) ] . Hemoglobin . Hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in hemoglobin levels less than 11 g/dL. Reductions in hemoglobin to less than 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 PegIntron/REBETOL and INTRON A/REBETOL groups. In Study 4, subjects receiving PegIntron (1.5 mcg/kg)/REBETOL 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 subjects receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects, respectively. Hemoglobin levels become stable by treatment Weeks 4 to 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 PegIntron monotherapy trial, hemoglobin decreases were generally mild, and dose modifications were rarely necessary [see Dosage and Administration (2.3) ] . Neutrophils . Decreases in neutrophil counts were observed in a majority of subjects treated with PegIntron alone (70%) or as combination therapy with REBETOL in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (less than 0.5 x 10 9 /L) occurred in 1% of subjects treated with PegIntron monotherapy, 2% of subjects treated with INTRON A/REBETOL, and in approximately 4% of subjects treated with PegIntron/REBETOL in Study 2. Two percent of subjects receiving PegIntron monotherapy and 18% of subjects receiving PegIntron/REBETOL in Study 2 required modification of interferon dosage. Few subjects (less than 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pretreatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.3) ] . Platelets . Platelet counts decreased to less than 100,000/mm 3 in approximately 20% of subjects treated with PegIntron alone or with REBETOL and in 6% of subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (less than 50,000/mm 3 ) occur in less than 4% of subjects. Patients may require discontinuation or dose modification as a result of platelet decreases [see Dosage and Administration (2.3) ] . 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. Triglycerides. Elevated triglyceride levels have been observed in patients treated with interferon alphas, including PegIntron [see Warnings and Precautions (5.17) ]. Thyroid Function . Development of TSH abnormalities, with or without clinical manifestations, is associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or PegIntron (with or without REBETOL) 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 [see Warnings and Precautions (5.4) ]. 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. Pediatric Subjects Decreases in hemoglobin, white blood cells, platelets, and neutrophils may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.3) ] . Changes in selected laboratory values during treatment of 107 pediatric subjects with PegIntron/REBETOL combination therapy are described in Table 11 . Most of the changes in laboratory values in this trial were mild or moderate. TABLE 11 Selected Hematological Abnormalities during Treatment Phase with PegIntron Plus REBETOL in Previously Untreated Pediatric Subjects Laboratory Parameter 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. All Subjects (n=107) Hemoglobin (g/dL) 9.5 – <11.0 30% 8.0 – <9.5 2% WBC (×10 9 /L) 2.0 – 2.9 39% 1.5 – <2.0 3% Platelets (×10 9 /L) 70 – 100 1% 50 – <70 - 25 – <50 1% Neutrophils (×10 9 /L) 1.0 – 1.5 35% 0.75 – <1.0 26% 0.5 – <0.75 13% <0.5 3% Total Bilirubin 1.26 – 2.59 ×N N=Upper limit of normal 7% Evidence of Hepatic Failure - 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Approximately 2% of subjects receiving PegIntron (32/1759) or INTRON A (11/728) with or without REBETOL developed low-titer (less than or equal to 160) neutralizing antibodies to PegIntron or INTRON A. The clinical and pathological significance of the appearance of serum-neutralizing antibodies is unknown. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PegIntron with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PegIntron therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders pure red cell aplasia, thrombotic thrombocytopenic purpura Cardiac Disorders palpitations Ear and Labyrinth Disorders hearing loss, vertigo, hearing impairment Endocrine Disorders diabetic ketoacidosis, diabetes Eye Disorders Vogt-Koyanagi-Harada syndrome, serous retinal detachment Gastrointestinal Disorders aphthous stomatitis General Disorders and Administration Site Conditions asthenic conditions (including asthenia, malaise, fatigue) Immune System Disorders cases of acute hypersensitivity reactions (including anaphylaxis, angioedema, urticaria); Stevens-Johnson syndrome, toxic epidermal necrolysis, systemic lupus erythematosus, erythema multiforme Infections and Infestations bacterial infection including sepsis Metabolism and Nutrition Disorders dehydration, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, myositis Nervous System Disorders seizures, memory loss, peripheral neuropathy, paraesthesia, migraine headache Psychiatric Disorders homicidal ideation Respiratory, Thoracic and Mediastinal Disorders Pulmonary hypertension Renal and Urinary Disorders renal failure, renal insufficiency Skin and Subcutaneous Tissue Disorders psoriasis Vascular Disorders hypertension, hypotension

<table width="100%" ID="table8"> <caption>TABLE 8 Adverse Reactions Occurring in Greater than 5% of Subjects</caption> <col width="40%" align="left" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <col width="15%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="4"> <content styleCode="italics">Percentage of Subjects Reporting Adverse Reactions<footnote>Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category.</footnote> </content> </th> </tr> <tr> <th/> <th styleCode="Botrule" colspan="2">Study 1</th> <th styleCode="Botrule" colspan="2">Study 2</th> </tr> <tr> <th styleCode="Botrule">Adverse Reactions</th> <th styleCode="Botrule">PegIntron 1 mcg/kg (n=297)</th> <th styleCode="Botrule Rrule">INTRON A 3 MIU (n=303)</th> <th styleCode="Botrule">PegIntron 1.5 mcg/kg/ REBETOL (n=511)</th> <th styleCode="Botrule">INTRON A/ REBETOL (n=505)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Application Site</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Injection Site Inflammation/Reaction</td> <td>47</td> <td styleCode="Rrule">20</td> <td>75</td> <td>49</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Autonomic Nervous System</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Dry Mouth </td> <td>6</td> <td styleCode="Rrule">7</td> <td>12</td> <td>8</td> </tr> <tr styleCode="Botrule"> <td> Increased Sweating</td> <td>6</td> <td styleCode="Rrule">7</td> <td>11</td> <td>7</td> </tr> <tr styleCode="Botrule"> <td> Flushing</td> <td>6</td> <td styleCode="Rrule">3</td> <td>4</td> <td>3</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Body as a Whole</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Fatigue/Asthenia</td> <td>52</td> <td styleCode="Rrule">54</td> <td>66</td> <td>63</td> </tr> <tr styleCode="Botrule"> <td> Headache</td> <td>56</td> <td styleCode="Rrule">52</td> <td>62</td> <td>58</td> </tr> <tr styleCode="Botrule"> <td> Rigors</td> <td>23</td> <td styleCode="Rrule">19</td> <td>48</td> <td>41</td> </tr> <tr styleCode="Botrule"> <td> Fever</td> <td>22</td> <td styleCode="Rrule">12</td> <td>46</td> <td>33</td> </tr> <tr styleCode="Botrule"> <td> Weight Loss</td> <td>11</td> <td styleCode="Rrule">13</td> <td>29</td> <td>20</td> </tr> <tr styleCode="Botrule"> <td> Right Upper Quadrant Pain</td> <td>8</td> <td styleCode="Rrule">8</td> <td>12</td> <td>6</td> </tr> <tr styleCode="Botrule"> <td> Chest Pain</td> <td>6</td> <td styleCode="Rrule">4</td> <td>8</td> <td>7</td> </tr> <tr styleCode="Botrule"> <td> Malaise</td> <td>7</td> <td styleCode="Rrule">6</td> <td>4</td> <td>6</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Central/Peripheral Nervous System</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Dizziness</td> <td>12</td> <td styleCode="Rrule">10</td> <td>21</td> <td>17</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Endocrine</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Hypothyroidism</td> <td>5</td> <td styleCode="Rrule">3</td> <td>5</td> <td>4</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Gastrointestinal</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Nausea</td> <td>26</td> <td styleCode="Rrule">20</td> <td>43</td> <td>33</td> </tr> <tr styleCode="Botrule"> <td> Anorexia</td> <td>20</td> <td styleCode="Rrule">17</td> <td>32</td> <td>27</td> </tr> <tr styleCode="Botrule"> <td> Diarrhea</td> <td>18</td> <td styleCode="Rrule">16</td> <td>22</td> <td>17</td> </tr> <tr styleCode="Botrule"> <td> Vomiting</td> <td>7</td> <td styleCode="Rrule">6</td> <td>14</td> <td>12</td> </tr> <tr styleCode="Botrule"> <td> Abdominal Pain</td> <td>15</td> <td styleCode="Rrule">11</td> <td>13</td> <td>13</td> </tr> <tr styleCode="Botrule"> <td> Dyspepsia</td> <td>6</td> <td styleCode="Rrule">7</td> <td>9</td> <td>8</td> </tr> <tr styleCode="Botrule"> <td> Constipation</td> <td>1</td> <td styleCode="Rrule">3</td> <td>5</td> <td>5</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Hematologic Disorders</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Neutropenia</td> <td>6</td> <td styleCode="Rrule">2</td> <td>26</td> <td>14</td> </tr> <tr styleCode="Botrule"> <td> Anemia</td> <td>0</td> <td styleCode="Rrule">0</td> <td>12</td> <td>17</td> </tr> <tr styleCode="Botrule"> <td> Leukopenia</td> <td>&lt;1</td> <td styleCode="Rrule">0</td> <td>6</td> <td>5</td> </tr> <tr styleCode="Botrule"> <td> Thrombocytopenia</td> <td>7</td> <td styleCode="Rrule">&lt;1</td> <td>5</td> <td>2</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Liver and Biliary System </content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Hepatomegaly</td> <td>6</td> <td styleCode="Rrule">5</td> <td>4</td> <td>4</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Musculoskeletal</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Myalgia</td> <td>54</td> <td styleCode="Rrule">53</td> <td>56</td> <td>50</td> </tr> <tr styleCode="Botrule"> <td> Arthralgia</td> <td>23</td> <td styleCode="Rrule">27</td> <td>34</td> <td>28</td> </tr> <tr styleCode="Botrule"> <td> Musculoskeletal Pain</td> <td>28</td> <td styleCode="Rrule">22</td> <td>21</td> <td>19</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Psychiatric</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Insomnia</td> <td>23</td> <td styleCode="Rrule">23</td> <td>40</td> <td>41</td> </tr> <tr styleCode="Botrule"> <td> Depression</td> <td>29</td> <td styleCode="Rrule">25</td> <td>31</td> <td>34</td> </tr> <tr styleCode="Botrule"> <td> Anxiety/Emotional Lability/Irritability</td> <td>28</td> <td styleCode="Rrule">34</td> <td>47</td> <td>47</td> </tr> <tr styleCode="Botrule"> <td> Concentration Impaired</td> <td>10</td> <td styleCode="Rrule">8</td> <td>17</td> <td>21</td> </tr> <tr styleCode="Botrule"> <td> Agitation</td> <td>2</td> <td styleCode="Rrule">2</td> <td>8</td> <td>5</td> </tr> <tr styleCode="Botrule"> <td> Nervousness</td> <td>4</td> <td styleCode="Rrule">3</td> <td>6</td> <td>6</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Reproductive, Female</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Menstrual Disorder</td> <td>4</td> <td styleCode="Rrule">3</td> <td>7</td> <td>6</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Resistance Mechanism </content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Viral Infection</td> <td>11</td> <td styleCode="Rrule">10</td> <td>12</td> <td>12</td> </tr> <tr styleCode="Botrule"> <td> Fungal Infection</td> <td>&lt;1</td> <td styleCode="Rrule">3</td> <td>6</td> <td>1</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Respiratory System</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Dyspnea</td> <td>4</td> <td styleCode="Rrule">2</td> <td>26</td> <td>24</td> </tr> <tr styleCode="Botrule"> <td> Coughing</td> <td>8</td> <td styleCode="Rrule">5</td> <td>23</td> <td>16</td> </tr> <tr styleCode="Botrule"> <td> Pharyngitis</td> <td>10</td> <td styleCode="Rrule">7</td> <td>12</td> <td>13</td> </tr> <tr styleCode="Botrule"> <td> Rhinitis</td> <td>2</td> <td styleCode="Rrule">2</td> <td>8</td> <td>6</td> </tr> <tr styleCode="Botrule"> <td> Sinusitis</td> <td>7</td> <td styleCode="Rrule">7</td> <td>6</td> <td>5</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Skin and Appendages</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Alopecia</td> <td>22</td> <td styleCode="Rrule">22</td> <td>36</td> <td>32</td> </tr> <tr styleCode="Botrule"> <td> Pruritus</td> <td>12</td> <td styleCode="Rrule">8</td> <td>29</td> <td>28</td> </tr> <tr styleCode="Botrule"> <td> Rash</td> <td>6</td> <td styleCode="Rrule">7</td> <td>24</td> <td>23</td> </tr> <tr styleCode="Botrule"> <td> Skin Dry</td> <td>11</td> <td styleCode="Rrule">9</td> <td>24</td> <td>23</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Special Senses, Other </content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Taste Perversion</td> <td>&lt;1</td> <td styleCode="Rrule">2</td> <td>9</td> <td>4</td> </tr> <tr styleCode="Botrule"> <td colspan="3" styleCode="Rrule"> <content styleCode="bold">Vision Disorders</content> </td> <td/> <td/> </tr> <tr styleCode="Botrule"> <td> Vision Blurred</td> <td>2</td> <td styleCode="Rrule">3</td> <td>5</td> <td>6</td> </tr> <tr> <td> Conjunctivitis</td> <td>4</td> <td styleCode="Rrule">2</td> <td>4</td> <td>5</td> </tr> </tbody> </table>

<table width="100%" ID="table9"> <caption>TABLE 9 Summary of Treatment-related/Treatment-emergent Adverse Reactions (Greater than or Equal to 10% Incidence) by Descending Frequency </caption> <col width="40%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th/> <th colspan="3" align="center"> <content styleCode="italics">Percentage of Patients Reporting Treatment-related/Treatment-emergent Adverse Reactions</content> </th> </tr> <tr> <th/> <th styleCode="Botrule" colspan="3" align="center">Study 4</th> </tr> <tr> <th>Adverse Reactions</th> <th>PegIntron 1.5 mcg/kg with REBETOL </th> <th>PegIntron 1 mcg/kg with REBETOL </th> <th>Pegasys 180 mcg with Copegus</th> </tr> <tr> <th/> <th>(n=1019) </th> <th>(n=1016)</th> <th>(n=1035)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fatigue</td> <td styleCode="Rrule">67 </td> <td styleCode="Rrule">68</td> <td styleCode="Rrule">64</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">50 </td> <td styleCode="Rrule">47</td> <td styleCode="Rrule">41</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">40 </td> <td styleCode="Rrule">35</td> <td styleCode="Rrule">34</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Chills</td> <td styleCode="Rrule">39 </td> <td styleCode="Rrule">36</td> <td styleCode="Rrule">23</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Insomnia</td> <td styleCode="Rrule">38 </td> <td styleCode="Rrule">37</td> <td styleCode="Rrule">41</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Anemia</td> <td styleCode="Rrule">35 </td> <td styleCode="Rrule">30</td> <td styleCode="Rrule">34</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pyrexia</td> <td styleCode="Rrule">35 </td> <td styleCode="Rrule">32</td> <td styleCode="Rrule">21</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Injection Site Reactions</td> <td styleCode="Rrule">34 </td> <td styleCode="Rrule">35</td> <td styleCode="Rrule">23</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Anorexia</td> <td styleCode="Rrule">29 </td> <td styleCode="Rrule">25</td> <td styleCode="Rrule">21</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Rash</td> <td styleCode="Rrule">29 </td> <td styleCode="Rrule">25</td> <td styleCode="Rrule">34</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Myalgia</td> <td styleCode="Rrule">27 </td> <td styleCode="Rrule">26</td> <td styleCode="Rrule">22</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Neutropenia</td> <td styleCode="Rrule">26 </td> <td styleCode="Rrule">19</td> <td styleCode="Rrule">31</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Irritability</td> <td styleCode="Rrule">25</td> <td styleCode="Rrule">25</td> <td styleCode="Rrule">25</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Depression </td> <td styleCode="Rrule">25 </td> <td styleCode="Rrule">19</td> <td styleCode="Rrule">20</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Alopecia</td> <td styleCode="Rrule">23 </td> <td styleCode="Rrule">20</td> <td styleCode="Rrule">17</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dyspnea</td> <td styleCode="Rrule">21 </td> <td styleCode="Rrule">20</td> <td styleCode="Rrule">22</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Arthralgia</td> <td styleCode="Rrule">21</td> <td styleCode="Rrule">22</td> <td styleCode="Rrule">22</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pruritus</td> <td styleCode="Rrule">18 </td> <td styleCode="Rrule">15</td> <td styleCode="Rrule">19</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Influenza-like Illness</td> <td styleCode="Rrule">16 </td> <td styleCode="Rrule">15</td> <td styleCode="Rrule">15</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dizziness</td> <td styleCode="Rrule">16 </td> <td styleCode="Rrule">14</td> <td styleCode="Rrule">13</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea</td> <td styleCode="Rrule">15 </td> <td styleCode="Rrule">16</td> <td styleCode="Rrule">14</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Cough</td> <td styleCode="Rrule">15 </td> <td styleCode="Rrule">16</td> <td styleCode="Rrule">17</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Weight Decreased</td> <td styleCode="Rrule">13</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">10</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">12 </td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">9</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Unspecified Pain</td> <td styleCode="Rrule">12 </td> <td styleCode="Rrule">13</td> <td styleCode="Rrule">9</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dry Skin</td> <td styleCode="Rrule">11 </td> <td styleCode="Rrule">11</td> <td styleCode="Rrule">12</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Anxiety</td> <td styleCode="Rrule">11 </td> <td styleCode="Rrule">11</td> <td styleCode="Rrule">10</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abdominal Pain</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">10</td> </tr> <tr> <td styleCode="Lrule Rrule">Leukopenia</td> <td styleCode="Rrule">9 </td> <td styleCode="Rrule">7 </td> <td styleCode="Rrule">10</td> </tr> </tbody> </table>

<table width="80%" ID="table10"> <caption>TABLE 10 Percentage of Pediatric Subjects with Treatment-emergent/Treatment-related Adverse Reactions (in at Least 10% of All Subjects)</caption> <col width="70%" align="left" valign="top"/> <col width="30%" align="left" valign="top"/> <thead> <tr> <th>System Organ Class Preferred Term</th> <th>All Subjects n=107</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Blood and Lymphatic System Disorders</content> </td> </tr> <tr styleCode="Botrule"> <td> Neutropenia</td> <td>33%</td> </tr> <tr styleCode="Botrule"> <td> Anemia</td> <td>11%</td> </tr> <tr styleCode="Botrule"> <td> Leukopenia</td> <td>10%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Gastrointestinal Disorders</content> </td> </tr> <tr styleCode="Botrule"> <td> Abdominal Pain</td> <td>21%</td> </tr> <tr styleCode="Botrule"> <td> Abdominal Pain Upper</td> <td>12%</td> </tr> <tr styleCode="Botrule"> <td> Vomiting</td> <td>27%</td> </tr> <tr styleCode="Botrule"> <td> Nausea</td> <td>18%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </td> </tr> <tr styleCode="Botrule"> <td> Pyrexia</td> <td>80%</td> </tr> <tr styleCode="Botrule"> <td> Fatigue</td> <td>30%</td> </tr> <tr styleCode="Botrule"> <td> Injection-site Erythema</td> <td>29%</td> </tr> <tr styleCode="Botrule"> <td> Chills</td> <td>21%</td> </tr> <tr styleCode="Botrule"> <td> Asthenia</td> <td>15%</td> </tr> <tr styleCode="Botrule"> <td> Irritability</td> <td>14%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Investigations</content> </td> </tr> <tr styleCode="Botrule"> <td> Weight Decreased</td> <td>19%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </td> </tr> <tr styleCode="Botrule"> <td> Anorexia</td> <td>29%</td> </tr> <tr styleCode="Botrule"> <td> Decreased Appetite</td> <td>22%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </td> </tr> <tr styleCode="Botrule"> <td> Arthralgia</td> <td>17%</td> </tr> <tr styleCode="Botrule"> <td> Myalgia</td> <td>17%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Nervous System Disorders</content> </td> </tr> <tr styleCode="Botrule"> <td> Headache</td> <td>62%</td> </tr> <tr styleCode="Botrule"> <td> Dizziness</td> <td>14%</td> </tr> <tr styleCode="Botrule"> <td colspan="2"> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td> </tr> <tr> <td> Alopecia</td> <td>17%</td> </tr> </tbody> </table>