insurance [66:<144) 800 mg/day 2 x 200-mg capsules A.M. 2 x 200-mg capsules P.M. 66-80 (145-177) 1000 mg/day 2 x 200-mg capsules A.M. 3 x 200-mg capsules P.M. 81-105 (178-231) 1200 mg/day 3 x 200-mg capsules A.M. 3 x 200-mg capsules P.M.> 105 (231) 1400 mg/day 3 x 200-mg capsules A.M. 4 x 200-mg capsules P.M. Pediatric Patients Dosing for pediatric patients is determined by body surface area for peginterferon alfa-2b and by body weight for Ribasphere. The recommended dose of peginterferon alfa-2b is 60 mcg/m 2 /week subcutaneously in combination with 15 mg/kg/day of Ribasphere orally in two divided doses (see Table 2 ) for pediatric patients ages 3-17 years. Patients who reach their 18 th birthday while receiving peginterferon alfa-2b/Ribasphere should remain on the pediatric dosing regimen. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks. Table 2: Recommended Ribasphere * Dosing in Combination Therapy (Pediatrics) * Ribasphere to be used in combination with peginterferon alfa-2b 60 mcg/m 2 weekly. Body Weight kg (lbs) Ribasphere Daily Dose Ribasphere Number of Capsules 47 59 (103 131) 800 mg/day 2 x 200-mg capsules A.M. 2 x 200-mg capsules P.M. 60 73 (132 162) 1000 mg/day 2 x 200-mg capsules A.M. 3 x 200-mg capsules P.M. >73 (>162) 1200 mg/day 3 x 200-mg capsules A.M. 3 x 200-mg capsules P.M. Ribasphere/Interferon alfa-2b Combination Therapy Adults Duration of Treatment Interferon Alpha-naïve Patients The recommended dose of interferon alfa-2b is 3 million IU three times weekly subcutaneously. The recommended dose of Ribasphere capsules depends on the patient s body weight (refer to Table 3 ). The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage ( 1.1 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14 ) ]. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population. Duration of Treatment Re-treatment with Interferon alfa-2b/Ribasphere in Relapse Patients In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks. Table 3: Recommended Dosing Body Weight Ribasphere (ribavirin capsules) 75 kg 2 200-mg capsules AM 3 200-mg capsules PM daily orally >75 kg 3 200-mg capsules AM 3 200-mg capsules PM daily orally Pediatrics The recommended dose of Ribasphere is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of Ribasphere in combination with interferon alfa-2b. Interferon alfa-2b for Injection by body weight of 25 kg to 61 kg is 3 million IU/m 2 three times weekly subcutaneously. Refer to adult dosing table for greater than 61 kg body weight. The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks. Laboratory Tests The following laboratory tests are recommended for all patients treated with Ribasphere, prior to beginning treatment and then periodically thereafter. Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions ( 5.2 , 5.7 ) ]), complete and differential white blood cell counts, and platelet count. Blood chemistries - liver function tests and TSH. Pregnancy - including monthly monitoring for women of childbearing potential. ECG [see Warnings and Precautions ( 5.2 ) ]. Dose Modifications If severe adverse reactions or laboratory abnormalities develop during combination Ribasphere/interferon alfa-2b therapy or Ribasphere/peginterferon alfa-2b therapy, modify, or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions ( 5 ) ]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of peginterferon alfa-2b in adult patients on Ribasphere/peginterferon alfa-2b combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Refer to labeling for peginterferon alfa-2b for additional information regarding dose reduction of peginterferon alfa-2b. In the adult combination therapy Study 2, dose reductions occurred in 42% of subjects receiving peginterferon alfa-2b 1.5 mcg/kg and Ribasphere 800 mg daily, including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of peginterferon alfa-2b to 1 mcg/kg in combination with Ribasphere, with an additional 4% requiring the second dose reduction of peginterferon alfa-2b to 0.5 mcg/kg due to adverse events [see Adverse Reactions ( 6.1 ) ]. Dose reduction in pediatric patients is accomplished by modifying the recommended peginterferon alfa-2b dose in a two-step process from the original starting dose of 60 mcg/m 2 /week, to 40 mcg/m 2 /week, then to 20 mcg/m 2 /week, if needed (see Table 4 ). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving peginterferon alfa-2b 60 mcg/m 2 weekly and Ribasphere 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended Ribasphere dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 4 ). Ribasphere should not be used in patients with creatinine clearance less than 50 mL/min. Patients with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions ( 5.2 ) , Use in Specific Populations ( 8.5 ) , and Clinical Pharmacology ( 12.3 ) ]. Ribasphere should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions ( 5.2 ) ]. For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by greater than or equal to 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains less than 12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy. It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her Ribasphere dose modified or discontinued per Table 4 [see Warnings and Precautions ( 5.2 ) ]. Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin in combination with Peginterferon alfa-2b or Interferon alfa-2b Based on Laboratory Parameters in Adults and Pediatrics Laboratory Parameters Reduce Ribasphere Daily Dose (see note 1) if: Reduce Peginterferon alfa 2b or Interferon alfa 2b Dose (see note 2) if: Discontinue Therapy if: Note 1: Adult patients: 1 st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2 nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. Pediatric patients: 1 st dose reduction of ribavirin is to 12 mg/kg/day, 2 nd dose reduction of ribavirin is to 8 mg/kg/day. Note 2: Adult patients treated with Ribasphere and Peginterferon alfa-2b: 1 st dose reduction of Peginterferon alfa-2b is to 1 mcg/kg/week. If needed, 2 nd dose reduction of Peginterferon alfa-2b is to 0.5 mcg/kg/week. Pediatric patients treated with Ribasphere and Peginterferon alfa-2b: 1 st dose reduction of Peginterferon alfa-2b is to 40 mcg/m2/week, 2nd dose reduction of Peginterferon alfa-2b is to 20 mcg/m2/week. For patients on Ribavirin/Interferon alfa-2b combination therapy: reduce Interferon alfa-2b dose by 50%. * Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing. These guidelines are for patients with stable cardiac disease. Patients with a history of significant or unstable cardiac disease should not be treated with Peginterferon alfa-2b /Ribavirin combination therapy [see Warnings and Precautions ( 5.2 )]. WBC N/A 1.0 to <1.5 x 10 9 /L> <1.0 x 10 9 /L Neutrophils N/A 0.5 to> <0.75 x 10 9 /L> <0.5 x 10 9 /L Platelets N/A 25 to> <50 x 10 9 /L (adults)> <25 x 10 9 /L (adults) N/A 50 to> <70 x 10 9 /L (pediatrics)> <50 x 10 9 /L (pediatrics) Creatinine N/A N/A> 2 mg/dL (pediatrics) Hemoglobin in patients without history of cardiac disease 8.5 to <10 g/dL N/A> <8.5 g/dL Reduce Ribasphere Dose by 200 mg/day and Peginterferon alfa-2b or Interferon alfa-2b Dose by Half if: Hemoglobin in patients with history of stable cardiac disease * 2 g/dL decrease in hemoglobin during any four week period during treatment> <8.5 g/dL or> <12 g/dL after four weeks of dose reduction Refer to labeling for interferon alfa-2b or peginterferon alfa-2b for additional information about how to reduce an interferon alfa-2b or peginterferon alfa-2b dose. Discontinuation of Dosing Adults In HCV genotype 1, interferon-alfa-naïve patients receiving peginterferon alfa-2b in combination with ribavirin, discontinuation of therapy is recommended if there is not at least a 2 log 10 drop or loss of HCV-RNA at 12 weeks of therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at Week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered. Pediatrics (3-17 years of age) It is recommended that patients receiving peginterferon alfa-2b/Ribasphere combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped less than 2 log 10 compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24. Dosage Forms and Strengths Ribasphere 200 mg Capsules Contraindications Ribasphere combination therapy is contraindicated in: women who are pregnant. Ribasphere may cause fetal harm when administered to a pregnant woman. Ribasphere is contraindicated in women who are or may become pregnant. If Ribasphere is used during pregnancy, or if the patient becomes pregnant while taking Ribasphere, the patient should be apprised of the potential hazard to her fetus [see Warnings and Precautions ( 5.1 ) , Use in Specific Populations ( 8.1 ) , and Patient Counseling Information ( 17.2 ) ] men whose female partners are pregnant patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product patients with autoimmune hepatitis patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) patients with creatinine clearance less than 50 mL/min. [see Use in Specific Populations ( 8.5 ) and Clinical Pharmacology ( 12.3 ) ] Coadministration of Ribasphere and didanosine is contraindicated because exposure to the active metabolite of didanosine (dideoxyadenosine 5 -triphosphate) is increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving didanosine in combination with ribavirin [see Drug Interactions ( 7.1 ) ]. Warnings and Precautions Pregnancy Ribasphere (ribavirin capsules) may cause birth defects and death of the unborn child. Ribasphere 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. Ribasphere 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 ) ]. Anemia The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of Ribasphere/interferon alfa-2b treated subjects in clinical trials. The anemia associated with Ribasphere capsules 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 before the start of treatment 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 Ribasphere. Pancreatitis Ribasphere 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. 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. 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. 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/ Ribasphere combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood counts (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 ) ]. 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 pegylated or nonpegylated 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. 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, Ribasphere and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be reintroduced with concomitant azathioprine [see Drug Interactions ( 7.4 ) ]. Impact on Growth - Pediatric Use Data on the effects of peginterferon alfa-2b and ribavirin on growth come from an open-label study in subjects 3 through 17 years of age, in which weight and height changes are compared to US normative population data. In general, the weight and height gain of pediatric subjects treated with peginterferon alfa-2b and ribavirin lags behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that peginterferon alfa-2b in combination therapy with ribavirin may induce a growth inhibition that results in reduced adult height in some patients [ see Adverse Reactions ( 6.1 ) ]. Similarly, an impact on growth was seen in subjects after treatment with ribavirin and interferon alfa-2b combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects, combination therapy resulted in reduced final adult height in some subjects [ see Adverse Reactions ( 6.2 ) ]. Usage Safeguards Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, Ribasphere capsules must not be used alone. The safety and efficacy of ribavirin capsules have only been established when used together with interferon alfa-2b or peginterferon alfa-2b (not other interferons) as 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. Ribasphere capsules should not be used for these indications. Ribavirin for inhalation has separate labeling, 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. Labeling for interferon alfa-2b and peginterferon alfa-2b should be reviewed in their entirety for additional safety information prior to initiation of combination treatment. 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 trials: Ribavirin/Peginterferon alfa-2b Combination therapy trials: Clinical Study 1 - evaluated peginterferon alfa-2b monotherapy (not further described in this label; see labeling for peginterferon alfa-2b for information about this trial). Study 2 - evaluated ribavirin capsules 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 capsules in combination with peginterferon alfa-2b/flat dose ribavirin capsules regimen. Study 4- compared two peginterferon alfa-2b (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with ribavirin capsules and a third treatment group receiving peginterferon alfa-2a (180 mcg/week)/ribavirin tablets (1000-1200 mg/day). Study 5 evaluated peginterferon alfa-2b (1.5 mcg/kg/week) in combination with weight-based ribavirin capsules in prior treatment failure subjects. Peginterferon alfa-2b/ribavirin capsules Combination Therapy in Pediatric Patients Ribavirin capsules/interferon alfa-2b Combination Therapy trials 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 reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience - Ribavirin/Peginterferon alfa-2b Combination Therapy Adult Subjects Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by treatment group from the ribavirin/peginterferon alfa-2b Combination Therapy (Study 2) in Table 5 . Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects * A subject may have reported more than one adverse reaction within a body system/organ class category. Percentage of Subjects Reporting Adverse Reactions * 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 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence. Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By Descending Frequency Study 4 Percentage of Subjects Reporting Treatment-Related Adverse Reactions Adverse Reactions Peginterferon alfa-2b 1.5 mcg/kg with Ribavirin Capsules (N=1019) Peginterferon alfa-2b 1 mcg/kg with Ribavirin Capsules (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 trials. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based ribavirin group (12%) and for the flat-dose ribavirin regimen. In 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 that 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). 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 that 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 greater than 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 included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with weight-based dosing (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 pe ahead of
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