FDA label 22b86cb5-f78b-4cbe-ac35-5cc487814915

WARNING: FATAL OR LIFE-THREATENING DISORDERS Alpha interferons, including INFERGEN, 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 Patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping interferon alfacon-1 therapy. [see WARNINGS AND PRECAUTIONS ( 5 ) and ADVERSE REACTIONS ( 6.1 )]. Use with Ribavirin: Ribavirin may cause birth defects and/or 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 ribavirin therapy may result in a worsening of cardiac disease. [see WARNINGS AND PRECAUTIONS ( 5 ); and Ribavirin Labeling]. WARNING: FATAL OR LIFE-THREATENING 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. ( 5.2 ) 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 causes hemolytic anemia which may exacerbate cardiac disease ( 5.1 )

5 WARNINGS AND PRECAUTIONS Treatment with INFERGEN and combination treatment with INFERGEN/ribavirin should be administered under the guidance of a qualified physician, and may lead to moderate-to-severe adverse reactions requiring dose reduction, temporary dose cessation, or discontinuation of further therapy. • Birth defects and fetal death with ribavirin: Female 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 any of the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: • Use with ribavirin ( 5.1 ) • Neuropsychiatric Disorders ( 5.2 ) • Cardiovascular Events ( 5.3 ) • Pulmonary Disorders ( 5.4 ) • Hepatic Failure( 5.5 ) • Renal Insufficiency ( 5.6 ) • Cerebrovascular Disorders ( 5.7 ) • Bone Marrow Toxicity ( 5.8 ) • Colitis ( 5.9 ) • Pancreatitis ( 5.10 ) • Hypersensitivity ( 5.11 ) • Autoimmune Disorders ( 5.12 ) • Ophthalmologic Disorders ( 5.13 ) • Peripheral Neuropathy ( 5.14 ) • Endocrine Disorders ( 5.15 ) • Laboratory Tests ( 5.16 ) 5.1 Use with Ribavirin Pregnancy Ribavirin 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. Pregnancy should be avoided for at least six months after discontinuation of ribavirin [see BOXED WARNING , CONTRAINDICATIONS ( 4 ), Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 ) and Ribavirin Labeling]. Anemia Ribavirin caused hemolytic anemia in 30% of INFERGEN/ribavirin-treated subjects. 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 ribavirin therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of ribavirin may be necessary [see Dosage and Administration ( 2.3 ) and Ribavirin Labeling] . 5.2 Neuropsychiatric Disorders Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferon alphas, including INFERGEN. Depression, suicidal ideation, suicide attempt, suicide, and homicidal ideation may occur. Other prominent psychiatric adverse reactions including psychosis, aggressive behavior, nervousness, anxiety, emotional lability, abnormal thinking, agitation, apathy and relapse of drug addiction may occur. INFERGEN should be used with extreme caution in patients who report a history of depression. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Prior to initiation of INFERGEN therapy, physicians should inform patients of the possible development of depression and patients should be advised to report any sign or symptom of depression and/or suicidal ideation immediately. 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 are identified, it is recommended that treatment with INFERGEN be discontinued, and the patient followed, with psychiatric intervention as appropriate. In severe cases, INFERGEN should be stopped immediately and psychiatric intervention instituted [see DOSAGE AND ADMINISTRATION: Dose Modifications ( 2.3 )]. 5.3 Cardiovascular Events Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with INFERGEN. INFERGEN should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require INFERGEN therapy should be closely monitored [see WARNINGS and PRECAUTIONS ( 5 )] . Patients with a history of significant or unstable cardiac disease should not be treated with INFERGEN/ribavirin combination therapy [see Ribavirin Labeling] . 5.4 Pulmonary Disorders Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by interferon alpha therapy, including INFERGEN. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with INFERGEN. Recurrence of respiratory failure has been observed with interferon rechallenge. INFERGEN treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored. 5.5 Hepatic Failure Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when treated with interferon alphas, including INFERGEN. During treatment, patients’ clinical status and hepatic function should be closely monitored, and INFERGEN treatment should be immediately discontinued if symptoms of hepatic decompensation, such as jaundice, ascites, coagulopathy, or decreased serum albumin are observed [see CONTRAINDICATIONS ( 4 )] . 5.6 Renal Insufficiency Increases in serum creatinine levels, including renal failure, have been observed in patients receiving INFERGEN. INFERGEN has not been studied in patients with renal insufficiency. It is recommended that renal function be evaluated in all patients starting INFERGEN alone or with ribavirin therapy. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine. Combination treatment with INFERGEN/ribavirin should not be used in patients with creatinine clearance <50 mL/min. [see CONTRAINDICATIONS ( 4 ) and Ribavirin Labeling] . 5.7 Cerebrovascular Disorders Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha-based therapies, including INFERGEN. 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 alpha-based therapies and these events is difficult to establish. 5.8 Bone Marrow Toxicity Interferon alphas suppress bone marrow function and may result in severe cytopenias including aplastic anemia. It is advised that complete blood counts be obtained pretreatment and monitored routinely during therapy. INFERGEN therapy should be discontinued in patients who develop severe decreases in neutrophil (< 0.5 x 10 9 /L) or platelet counts (< 25 x 10 9 /L). INFERGEN should be used cautiously in patients with abnormally low peripheral blood cell counts or who are receiving agents that are known to cause myelosuppression. Transplantation patients or other chronically immunosuppressed patients should be treated with interferon alpha therapy with caution. The use of ribavirin may result in a worsening of INFERGEN-induced neutropenia. Therefore combination treatment with INFERGEN/ribavirin should be used with caution in patients with low baseline neutrophil counts (< 1500 cells/mm 3 ) and may require that therapy be discontinued in the event of a severe decrease in neutrophil count [see DOSAGE AND ADMINISTRATION: Dose Modifications ( 2.3 ) and WARNINGS AND PRECAUTIONS: Laboratory Tests ( 5.16 )]. 5.9 Colitis Hemorrhagic/ischemic colitis, sometimes fatal, has been observed within 12 weeks of interferon alpha therapies and has been reported in patients treated with INFERGEN. INFERGEN treatment should be discontinued immediately in patients who develop signs and symptoms of colitis. 5.10 Pancreatitis Pancreatitis, sometimes fatal, has been observed in patients treated with interferon alphas, including INFERGEN. INFERGEN should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis. 5.11 Hypersensitivity Serious acute hypersensitivity reactions have been reported following treatment with interferon alphas. If hypersensitivity reactions occur (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis), INFERGEN should be discontinued immediately and appropriate medical treatment instituted. 5.12 Autoimmune Disorders Development or exacerbation of autoimmune disorders (e.g., autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, thyroiditis, interstitial nephritis, systemic lupus erythematosus (SLE)) have been reported in patients receiving interferon alpha therapies, including INFERGEN. INFERGEN should not be used in patients with autoimmune hepatitis [see CONTRAINDICATIONS ( 4 )] and should be used with caution in patients with other autoimmune disorders. 5.13 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 are induced or aggravated by treatment with INFERGEN or other interferons alpha. 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. INFERGEN therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders. 5.14 Peripheral Neuropathy Peripheral neuropathy has been reported when interferon alphas 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. 5.15 Endocrine Disorders INFERGEN should be administered with caution to patients with a history of endocrine disorders. Occurrence or aggravation of hyperthyroidism or hypothyroidism have been reported with INFERGEN. Hyperglycemia and diabetes mellitus have also been observed in patients treated with INFERGEN. Patients who develop these conditions during treatment that cannot be controlled with medication should not continue INFERGEN therapy. 5.16 Laboratory Tests Laboratory tests are recommended for all patients on INFERGEN therapy, as follows: prior to beginning treatment (baseline), 2 weeks after initiation of therapy, and periodically thereafter during the 24 or 48 weeks of therapy at the discretion of the physician. Following completion of INFERGEN therapy, any abnormal test values should be monitored periodically. The entrance criteria that were used for the clinical study of INFERGEN may be considered as a guideline to acceptable baseline values for initiation of treatment: • Platelet count ≥ 75 × 10 9 /L • Hemoglobin concentration ≥ 10 g/dL • ANC ≥ 1500 × 10 6 /L • Serum creatinine concentration < 180 µmol/L (< 2.0 mg/dL) or creatinine clearance > 0.83 mL/second (> 50 mL/minute) • Serum albumin concentration ≥ 25 g/L • Bilirubin ≤ 1.4 mg/dL (with the exception of patients with Gilbert’s syndrome) • TSH and T 4 within normal limits Neutropenia, thrombocytopenia, hypertriglyceridemia and thyroid disorders have been reported with administration of INFERGEN [see ADVERSE REACTIONS ]. Therefore, these laboratory parameters should be monitored closely. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with INFERGEN/ribavirin.

6 ADVERSE REACTIONS INFERGEN alone or in combination with ribavirin causes a broad range of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5 )]. Most common adverse reactions (incidence > 40%) are fatigue, fever, rigors, body pain, headache, abdominal pain, nausea, granulocytopenia, arthralgia, myalgia, back pain, neutropenia, and influenza-like illness. ( 6.1 ) ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or Kadmon Pharmaceuticals, LLC at 1-877-377-7862 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. During clinical development, more than 560 subjects were exposed to 9 mcg or 15 mcg of INFERGEN monotherapy administered three times per week over a range of 24 to 48 weeks, and more than 480 subjects were exposed to 9 mcg or 15 mcg of INFERGEN, in combination with ribavirin, administered daily up to 48 weeks. INFERGEN Monotherapy Clinical Trials Adverse reactions that were reported, regardless of attribution to treatment, in ≥ 10% of subjects in INFERGEN monotherapy studies are presented in Table 4 . Flu-like symptoms (i.e., headache, fatigue, fever, rigors, myalgia, arthralgia, and sweating increased) were the most frequently reported treatment-related adverse reactions. In most cases, these events could be treated symptomatically. Depression of any severity was reported in 26% of subjects who received 9 mcg INFERGEN monotherapy and was the most common adverse reaction resulting in study drug discontinuation. INFERGEN 15 mcg three times a week monotherapy as subsequent treatment was associated with a greater incidence of leukopenia and granulocytopenia. One or more dose reductions for any causes were required in up to 36% of subjects. Table 4. Treatment Emergent Adverse Reactions Occurring in ≥10% of Subjects in INFERGEN Monotherapy Trials Initial Treatment Subsequent Treatment INFERGEN 9 mcg ( n = 231) IFN α-2b ( n = 236) INFERGEN 15 mcg 24 wks ( n = 165) INFERGEN 15 mcg 48 wks ( n = 168) Body System/Preferred Term (COSTART) % of Subjects % of Subjects APPLICATION SITE Injection Site Erythema 23 15 17 22 BODY AS A WHOLE Fatigue 69 67 65 71 Fever 61 45 58 55 Rigors 57 45 62 66 Body Pain 54 45 39 51 Influenza-like Symptoms 15 11 8 8 Chest Pain 13 14 5 9 Hot Flushes 13 7 7 4 Malaise 11 10 2 5 Asthenia 9 11 10 7 CNS/PNS Headache 82 83 78 80 Insomnia 39 30 24 28 Dizziness 22 25 18 25 Paresthesia 13 10 9 9 Hypoesthesia 10 8 8 10 Amnesia 10 6 2 5 GASTROINTESTINAL Abdominal Pain 41 40 24 32 Nausea 40 36 30 36 Diarrhea 29 24 24 22 Anorexia 24 17 21 14 Dyspepsia 21 18 12 10 Vomiting 12 11 13 11 MUSCULO-SKELETAL Myalgia 58 56 51 55 Arthralgia 51 44 43 46 Back Pain 42 37 29 23 Limb Pain 26 25 13 23 Skeletal Pain 14 14 10 12 Neck Pain 14 13 8 5 PSYCHIATRIC DISORDER Nervousness 31 29 16 22 Depression 26 25 18 19 Anxiety 19 18 9 14 Emotional Lability 12 11 6 3 Thinking Abnormal 8 12 10 20 RESPIRATORY Pharyngitis 34 31 17 21 Cough 22 17 12 11 Sinusitis 17 22 12 16 Dyspnea 7 12 8 7 SKIN AND APPENDAGES Alopecia 14 25 10 13 Pruritus 14 14 11 10 Rash 13 15 13 10 Sweating Increased 12 11 13 11 Combination Treatment with INFERGEN/Ribavirin Clinical Trials The most common adverse reactions in the combination treatment with INFERGEN/ribavirin trial are listed in Table 5 and included fatigue (76%), nausea (45%), flu-like symptoms (40%), headache (42%), arthralgia (31%), and myalgia (29%), neutropenia (40%), leukopenia (29%), insomnia (39%), and depression (26%). Adverse reactions led to early study discontinuation in 104 (21%) of subjects; more subjects discontinued from the 15 mcg INFERGEN group (64 versus 40). Fatigue, anemia, and depression were the most common adverse reactions resulting in study drug discontinuation. A higher proportion of subjects who received the recommended starting dose of 15 mcg (52%) than the 9 mcg dose group (40%) required INFERGEN dose modifications due to adverse reactions, primarily due to neutropenia/leukopenia, thrombocytopenia, and fatigue/weakness. A total of 14% of subjects experienced serious adverse reactions, the most common of which were neutropenia (2%), suicidal ideation (1%), and hyperuricemia (1%). Table 5. Treatment Emergent Adverse Reactions Occurring in the >10% of Subjects in Combination Treatment with INFERGEN/Ribavirin Phase 3 Trial Retreatment INFERGEN 9 mcg/RBV 48 wks ( n = 244) INFERGEN 15 mcg/RBV 48 wks ( n = 242) Body System/Preferred Term (MedDRA) % of Subjects GASTROINTESTINAL DISORDERS Abdominal pain 15 14 Constipation 9 10 Diarrhea 18 19 Nausea 45 45 Vomiting 12 19 GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONS (or BODY AS A WHOLE) Fatigue 75 77 Influenza-like Illness (or Symptoms) 40 42 Injection Site Erythema 16 16 Injection Site Reaction 15 12 Pyrexia (or Fever) 13 17 Rigors 19 22 INVESTIGATIONS Weight Decrease 16 22 METABOLISM and NUTRITION DISORDERS Anorexia 15 21 Decreased appetite 17 18 MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS Arthralgia 31 31 Back Pain 12 9 Myalgia 24 34 NERVOUS SYSTEM DISORDERS Dizziness 14 19 Headache 46 39 PSYCHIATRIC DISORDER Anxiety 12 11 Depression 27 25 Insomnia 39 38 Irritability 21 17 RESPIRATORY, THORACIC, and MEDIASTINAL DISORDERS Cough 14 17 Dyspnea 15 20 SKIN and SUBCUTANEOUS TISSUE DISORDERS Alopecia 10 10 Pruritus 15 11 Rash 17 12 Laboratory Values Hemoglobin and Hematocrit: Treatment with INFERGEN alone and in combination with ribavirin is associated with decreases in mean values for hemoglobin and hematocrit. In the INFERGEN monotherapy trials, 4% and 5% of subjects had decreases in hemoglobin and hematocrit levels. Decreases from baseline of 20% or more in hemoglobin or hematocrit were seen in ≤1% of subjects. In the combination INFERGEN/ribavirin trial, 88% of subjects had decreases in hemoglobin levels of ≥2 g/dL from baseline. Of these, 27% had hemoglobin levels decrease to ≤10 g/dL, and underwent dose reductions of ribavirin. Anemia or hemolytic anemia led to study drug discontinuation in 10 subjects. White Blood Cells: INFERGEN treatment is associated with decreases in mean values for both total white blood cell (WBC) count and ANC. By the end of initial monotherapy treatment, mean decreases from baseline of 19% for WBCs and 23% for ANC were observed. These effects reversed during the post treatment observation period. In two INFERGEN-monotherapy treated subjects ANC levels decreased to below 500 × 10 6 cells/L. In both cases, the ANC values returned to clinically acceptable levels with INFERGEN dose reductions and were not associated with infections. Mean decreases from baseline up to 23% for WBCs and up to 27% for ANC were observed for subjects subsequently retreated with INFERGEN monotherapy. Two subjects experienced reversible reductions in ANC to less than 500 × 10 6 cells/L. In the combination INFERGEN/ribavirin trial, leukopenia was reported in 24% and 34% of 9 mcg and 15 mcg treated subjects, respectively. More subjects treated with 15 mcg experienced lymphopenia than did those treated with 9 mcg: 14% versus 7%. ANC levels <0.75 x 10 9 /L were observed in 21% of subjects treated with 9 mcg and 27% of those treated with 15 mcg; no subjects experienced significant infections associated with low ANC levels. Platelets: INFERGEN treatment is associated with alterations in platelet count. Decreases in mean platelet count of 16% compared to baseline were seen by the end of INFERGEN monotherapy treatment. These decreases were reversed during the post treatment observation period. Three percent of subjects had platelets decrease to less than 50 × 10 9 cells/L, which necessitated dose reduction. More subjects treated with 15 mcg in the INFERGEN/ribavirin combination trial experienced a decrease in platelet counts <40 × 10 9 /L, 3% versus 1% in the 9 mcg dose group. None of the subjects had platelet counts <25 × 10 9 /L. One subject in the 15 mcg group had Grade 4 thrombocytopenia 127 days after the start of treatment, was hospitalized for this event, and treatment with both study drugs was discontinued; the event resolved 8 days later. Triglycerides: Mean values for serum triglyceride increased shortly after the start of administration of INFERGEN monotherapy, with increases of 41%, compared with baseline, at the end of the treatment period. Seven percent of the subjects developed values which were at least 3 times above pretreatment levels during treatment. This effect was reversed after discontinuation of treatment. In the INFERGEN/ribavirin combination trial, 7% of subjects in the 15 mcg dose group experienced increases in triglyceride levels over baseline levels at week 48 compared to 2% in the 9 mcg dose group. There were no differences in the proportion of subjects who had ≥Grade 3 triglyceride elevations: 2% in both dose groups. Thyroid Function: INFERGEN monotherapy treatment was associated with biochemical changes consistent with hypothyroidism including increases in TSH and decreases in T 4 mean values. Increases in TSH to greater than 7 mU/L were seen in 10% of 9 mcg INFERGEN-treated subjects either during the treatment period or the 24-week post treatment observation period. Thyroid supplements were instituted in approximately one-third of these subjects. In the combination INFERGEN/Ribavirin trial, mean increases in TSH levels from baseline were greater for the 15 mcg group compared with the 9 mcg group; 14% and 3%, respectively, at Week 12 and 54% and 0% at Week 48. No serious adverse events, discontinuations or dose modifications were related to abnormalities in thyroid function. Uric Acid: Grade 4 (>10 mg/dL) uric acid levels were commonly observed in both INFERGEN/ribavirin treatment groups: 23 in the 9 mcg and 26 in the 15 mcg group. One subject in the 9 mcg group and three in the 15 mcg group experienced serious adverse events related to elevated uric acid levels. Four subjects in the 15 mcg had INFERGEN/ribavirin temporarily interrupted due to elevated uric acid levels. 6.2 Immunogenicity The number of subjects developing positive binding antibody responses was similar in the 9 mcg INFERGEN (11%) and 3 MIU IFN α-2b groups (15%) in monotherapy studies. The titer of neutralizing antibodies to interferon was not measured. Following cessation of interferon therapy, the number of subjects with a positive antibody response declined. In the INFERGEN/ribavirin combination study, approximately 13% of subjects in the 15 mcg and 18% in the 9 mcg arms developed low-titer neutralizing antibodies to INFERGEN. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response was observed. The incidence of binding antibody was approximately 31%. The detection 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 for INFERGEN with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified and reported during post-approval use of INFERGEN. Because these reactions are reported voluntarily and from a population of uncertain size, it is not possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. Application site injection site reaction, including injection site necrosis ulcer, and bruising Ear and Labyrinth hearing loss, hearing impairment Gastrointestinal abdominal distention, gastrointestinal bleeding, gastritis Hepatobiliary hepatic enzyme elevations, including ALT and AST elevation, abnormal hepatic function, hyperbilirubinemia, jaundice, ascites, hepatic encephalopathy Infections sepsis Metabolism and Nutritional dehydration Musculoskeletal rhabdomyolysis, arthritis, bone pain Nervous speech disorder, ataxia, gait abnormal, convulsions, loss of consciousness, memory impairment, tremors, visual field defect Psychiatric delusions, hallucinations Skin and Subcutaneous bruising, pyoderma gangrenosum, toxic epidermal necrolysis Vascular Disorders Hemorrhage

<table ID="_Refid_1edc918f-7d23-4201-8a44-56d7c5607" width="100%"> <caption>Table 4. Treatment Emergent Adverse Reactions Occurring in &#x2265;10% of Subjects in INFERGEN Monotherapy Trials</caption> <col width="40%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule "/> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule "> <paragraph>Initial Treatment</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule "> <paragraph>Subsequent Treatment</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "/> <td align="center" styleCode="Rrule Botrule "> <paragraph>INFERGEN 9 mcg (<content styleCode="italics">n</content> = 231)</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>IFN &#x3B1;-2b (<content styleCode="italics">n</content> = 236) </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>INFERGEN 15 mcg 24 wks (<content styleCode="italics">n</content> = 165)</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>INFERGEN 15 mcg 48 wks (<content styleCode="italics">n</content> = 168)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Body System/Preferred Term</content> </paragraph> <paragraph> <content styleCode="bold">(COSTART)</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">% of Subjects</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">% of Subjects</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">APPLICATION SITE</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Injection Site Erythema</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">BODY AS A WHOLE</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Fatigue</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>69</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>67</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>65</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>71</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Fever</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>61</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>58</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>55</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Rigors</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>57</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>62</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>66</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Body Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>54</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>51</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Influenza-like Symptoms</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Chest Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Hot Flushes</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Malaise</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">CNS/PNS</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>82</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>83</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>78</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>80</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>28</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Paresthesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Hypoesthesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Amnesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">GASTROINTESTINAL </content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Abdominal Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>41</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>32</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>36</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">MUSCULO-SKELETAL</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Myalgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>58</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>56</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>51</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>55</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Arthralgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>51</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>44</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>43</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>46</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Back Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>23</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Limb Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>23</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Skeletal Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Neck Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">PSYCHIATRIC DISORDER</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Nervousness</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Emotional Lability</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Thinking Abnormal</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>20</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">RESPIRATORY</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Lrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Pharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>21</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Cough</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Sinusitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>16</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">SKIN AND APPENDAGES</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Alopecia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Pruritus</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph> Sweating Increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_b258b2a9-a113-4a16-b394-709701d48" width="100%"> <caption>Table 5. Treatment Emergent Adverse Reactions Occurring in the &gt;10% of Subjects in Combination Treatment with INFERGEN/Ribavirin Phase 3 Trial</caption> <col width="37%"/> <col width="32%"/> <col width="31%"/> <tbody> <tr> <td rowspan="2" styleCode="Rrule Botrule Lrule Toprule "/> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule "> <paragraph>Retreatment</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>INFERGEN 9 mcg/RBV </paragraph> <paragraph>48 wks</paragraph> <paragraph>(<content styleCode="italics">n</content> = 244)</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph> INFERGEN 15 mcg/RBV</paragraph> <paragraph>48 wks</paragraph> <paragraph>(<content styleCode="italics">n</content> = 242)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Body System/Preferred Term (MedDRA)</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule "> <paragraph> <content styleCode="bold">% of Subjects</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">GASTROINTESTINAL DISORDERS</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Abdominal pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Constipation</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>45</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">GENERAL DISORDERS and </content> </paragraph> <paragraph> <content styleCode="bold">ADMINISTRATION SITE CONDITIONS </content> </paragraph> <paragraph> <content styleCode="bold">(or BODY AS A WHOLE)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Fatigue</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>75</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>77</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Influenza-like Illness (or Symptoms)</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>42</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Injection Site Erythema</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>16</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Injection Site Reaction</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Pyrexia (or Fever)</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Rigors</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">INVESTIGATIONS</content> </paragraph> </td> <td styleCode="Rrule Botrule "/> <td styleCode="Rrule Botrule "/> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Weight Decrease</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>22</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">METABOLISM and NUTRITION DISORDERS</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>21</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Decreased appetite</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>18</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">MUSCULOSKELETAL and CONNECTIVE </content> </paragraph> <paragraph> <content styleCode="bold">TISSUE DISORDERS</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Arthralgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>31</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Back Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Myalgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>34</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">NERVOUS SYSTEM DISORDERS</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>46</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>39</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">PSYCHIATRIC DISORDER</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>25</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>38</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Irritability</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">RESPIRATORY, THORACIC, and </content> </paragraph> <paragraph> <content styleCode="bold">MEDIASTINAL DISORDERS</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Cough</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>20</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">SKIN and SUBCUTANEOUS </content> </paragraph> <paragraph> <content styleCode="bold">TISSUE DISORDERS</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Alopecia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Pruritus</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph> Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>12</paragraph> </td> </tr> </tbody> </table>