FDA label 34cbe3e9-5828-03fb-e054-00144ff8d46c

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS Ribasphere monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Ribasphere [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 ), and Dosage and Administration ( 2.3 )] . Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, ribavirin, including Ribasphere, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post treatment follow-up period [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 )] . WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS See full prescribing information for complete boxed warning. Ribavirin monotherapy, including Ribasphere, is not effective for the treatment of chronic hepatitis C virus infection ( Boxed Warning ). The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Ribasphere ( 2.3 , 5.2 , 6.1 ). Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Therefore, Ribasphere is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking Ribasphere therapy ( 4 , 5.1 , 8.1 ).

5 WARNINGS AND PRECAUTIONS Significant adverse reactions associated with Ribasphere (ribavirin, USP)/peginterferon alfa-2a combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes. The Peginterferon alfa-2a Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment. Birth defects and fetal death with ribavirin: Do not use in pregnancy and for 6 months after treatment. Patients must have a negative pregnancy test prior to therapy, use at least 2 forms of contraception and undergo monthly pregnancy tests ( 4 , 5.1 , 8.1 ) Peginterferon alfa-2a/Ribasphere: Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: Hemolytic anemia may occur with a significant initial drop in hemoglobin. This may result in worsening cardiac disease leading to fatal or nonfatal myocardial infarctions ( 5.2 , 6.1 ) Risk of hepatic failure and death: Monitor hepatic function during treatment and discontinue treatment for hepatic decompensation ( 5.3 ) Severe hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, and anaphylaxis, and serious skin reactions such as Stevens-Johnson Syndrome ( 5.4 ) Pulmonary disorders, including pulmonary function impairment and pneumonitis, including fatal cases of pneumonia ( 5.5 ) Severe depression and suicidal ideation, autoimmune and infectious disorders, suppression of bone marrow function, pancreatitis, and diabetes ( 5 ) Bone marrow suppression with azathioprine coadministration ( 5.6 ) Growth impairment with combination therapy in pediatric patients ( 5.8 ) 5.1 Pregnancy Ribasphere may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or 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 unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during Ribasphere therapy and for 6 months after therapy has stopped [see Boxed Warning , Contraindications ( 4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17 )]. 5.2 Anemia The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding) [see Dosage and Administration ( 2.3 )] . 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 ( 2.3 )] . Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use Ribasphere [see Boxed Warning and Dosage and Administration ( 2.3 )] . 5.3 Hepatic Failure Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961 [see Clinical Studies ( 14.3 )], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with peginterferon alfa-2a/Ribasphere should be discontinued immediately in patients with hepatic decompensation [see Contraindications ( 4 )]. 5.4 Hypersensitivity Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and Ribasphere should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions ( 6.2 )] . 5.5 Pulmonary Disorders Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. 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, patients should be closely monitored and, if appropriate, combination Ribasphere/Peginterferon alfa-2a treatment should be discontinued. 5.6 Bone Marrow Suppression Pancytopenia (marked decreases in RBCs, 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-2a, Ribasphere, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions ( 7.3 )] . 5.7 Pancreatitis Ribasphere and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis. 5.8 Impact on Growth in Pediatric Patients Pediatric subjects treated with peginterferon alfa-2a plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve. 5.9 Laboratory Tests Before beginning peginterferon alfa-2a/Ribasphere combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/Ribasphere. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy. The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment: Platelet count greater than or equal to 90,000 cells/mm 3 (as low as 75,000 cells/mm 3 in HCV patients with cirrhosis or 70,000 cells/mm 3 in patients with CHC and HIV) Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm 3 TSH and T 4 within normal limits or adequately controlled thyroid function CD4+ cell count greater than or equal to 200 cells/mm 3 or CD4+ cell count greater than or equal to 100 cells/mm 3 but less than 200 cells/mm 3 and HIV-1 RNA less than 5,000 copies/mm 3 in patients coinfected with HIV Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected patients Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV

6 ADVERSE REACTIONS Peginterferon alfa-2a in combination with ribavirin causes a broad variety of serious adverse reactions [see Boxed Warning and Warnings and Precautions ( 5 )] . The most common serious or life-threatening adverse reactions induced or aggravated by ribavirin/peginterferon alfa-2a include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see Warnings and Precautions ( 5.3 )] . The most common adverse reactions (frequency greater than 40%) in adults receiving combination therapy are fatigue/asthenia, pyrexia, myalgia, and headache. ( 6.1 ) The most common adverse reactions in pediatric subjects were similar to those seen in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kadmon Pharmaceuticals at 1-877-377-7862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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. Adult Patients In the pivotal registration trials NV15801 and NV15942, 886 patients received ribavirin for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving peginterferon alfa-2a alone or in combination with ribavirin. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination. The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 5 shows rates of adverse events occurring in greater than or equal to 5% subjects receiving pegylated interferon and ribavirin combination therapy in the CHC Clinical Trial, NV15801. Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with ribavirin discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia). Overall 39% of patients with CHC or CHC/HIV required modification of peginterferon alfa-2a and/or ribavirin therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of ribavirin in CHC and CHC/HIV patients was anemia (22% and 16%, respectively). Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7% of patients receiving 800 mg ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 12% of patients receiving 800 mg ribavirin for 24 weeks. Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10 g/dL (3% vs. 15%), dose modification of peginterferon alfa-2a (30% vs. 36%) and ribavirin (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg ribavirin. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups. Table 5 Adverse Reactions Occurring in greater than or equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801) Body System CHC Combination Therapy Study NV15801 peginterferon alfa-2a 180 mcg + 1000 mg or 1200 mg ribavirin tablets 48 weeks interferon alfa-2b + 1000 mg or 1200 mg ribavirin capsules 48 weeks N=451 N=443 % % * Severe hematologic abnormalities (lymphocyte less than 500 cells/mm 3 ; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm 3 ; platelet less than 50,000 cells/mm 3 ). Application Site Disorders Injection site reaction 23 16 Endocrine Disorders Hypothyroidism 4 5 Flu-like Symptoms and Signs Fatigue/Asthenia 65 68 Pyrexia 41 55 Rigors 25 37 Pain 10 9 Gastrointestinal Nausea/Vomiting 25 29 Diarrhea 11 10 Abdominal pain 8 9 Dry mouth 4 7 Dyspepsia 6 5 Hematologic* Lymphopenia 14 12 Anemia 11 11 Neutropenia 27 8 Thrombocytopenia 5 <1 Metabolic and Nutritional Anorexia 24 26 Weight decrease 10 10 Musculoskeletal, Connective Tissue and Bone Myalgia 40 49 Arthralgia 22 23 Back pain 5 5 Neurological Headache 43 49 Dizziness (excluding vertigo) 14 14 Memory impairment 6 5 Psychiatric Irritability/Anxiety/Nervousness 33 38 Insomnia 30 37 Depression 20 28 Concentration impairment 10 13 Mood alteration 5 6 Resistance Mechanism Disorders Overall 12 10 Respiratory, Thoracic and Mediastinal Dyspnea 13 14 Cough 10 7 Dyspnea exertional 4 7 Skin and Subcutaneous Tissue Alopecia 28 33 Pruritus 19 18 Dermatitis 16 13 Dry skin 10 13 Rash 8 5 Sweating increased 6 5 Eczema 5 4 Visual Disorders Vision blurred 5 2 Pediatric Subjects In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with peginterferon alfa-2a alone or in combination with ribavirin, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy peginterferon alfa-2a and ribavirin for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination peginterferon alfa-2a and ribavirin treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the peginterferon alfa-2a plus ribavirin combination therapy group (hyperglycemia and cholecystectomy). Growth inhibition was observed in pediatric subjects. During combination therapy for up to 48 weeks with peginterferon alfa-2a and ribavirin, negative changes in weight for age z-score and height for age z-score after 48 weeks of therapy compared with baseline were observed [see Warnings and Precautions ( 5.8 )] . Table 6 Percentage of Pediatric Subjects with Adverse Reactions* During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects) Study NV17424 System Organ Class peginterferon alfa-2a 180 mcg/1.73 m 2 x BSA + ribavirin tablets 15 mg/kg (N=55) peginterferon alfa-2a 180 mcg/1.73 m 2 x BSA + Placebo** (N=59) % % * Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug. ** Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. General disorders and administration site conditions Influenza like illness 91 81 Injection site reaction 44 42 Fatigue 25 20 Irritability 24 14 Gastrointestinal disorders Gastrointestinal disorder 49 44 Nervous system disorders Headache 51 39 Skin and subcutaneous tissue disorders Rash 15 10 Pruritus 11 12 Musculoskeletal, connective tissue and bone disorders Musculoskeletal pain 35 29 Psychiatric disorders Insomnia 9 12 Metabolism and nutrition disorders Decreased appetite 11 14 In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions were similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment. Common Adverse Reactions in CHC with HIV Coinfection (Adults) The adverse event profile of coinfected patients treated with peginterferon alfa-2a/ribavirin in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 ( Table 5 ). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%). Laboratory Test Abnormalities Adult Patients Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all ribavirin and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy [see Dosage and Administration ( 2.3 )] . Table 7 Selected Laboratory Abnormalities During Treatment With Ribavirin in Combination With Either Peginterferon alfa-2a or Interferon alfa-2b Laboratory Parameter Peginterferon alfa-2a + Ribavirin 1000/1200 mg 48 wks Interferon alfa-2b + Ribavirin 1000/1200 mg 48 wks (N=887) (N=443) Neutrophils (cells/mm 3 ) 1,000 <1,500 34% 38% 500 <1,000 49% 21% <500 5% 1% Platelets (cells/mm 3 ) 50,000 - <75,000 11% 4% 20,000 - <50,000 5% < 1% <20,000 0 0 Hemoglobin (g/dL) 8.5 - 9.9 11% 11% <8.5 2% < 1% Pediatric Patients Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see Dosage and Administration ( 2.4 )] . Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment. Table 8 Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects Laboratory Parameter Peginterferon alfa-2a 180 mcg/1.73 m 2 x BSA + Ribavirin tablets 15 mg/kg (N=55) Peginterferon alfa-2a 180 mcg/1.73 m 2 x BSA + Placebo* (N=59) * Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. Neutrophils (cells/mm 3 ) 1,000 - <1,500 31% 39% 750 - <1,000 27% 17% 500 - <750 25% 15% <500 7% 5% Platelets (cells/mm 3 ) 75,000 - <100,000 4% 2% 50,000 - <75,000 0% 2% <50,000 0% 0% Hemoglobin (g/dL) 8.5 - <10 7% 3% <8.5 0% 0% In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm 3 and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment. 6.2 Postmarketing Experience The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a/ribavirin combination 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 Ear and Labyrinth disorders Hearing impairment, hearing loss Eye disorders Serous retinal detachment Immune disorders Liver and renal graft rejection Metabolism and Nutrition disorders Dehydration Skin and Subcutaneous Tissue disorders Stevens-Johnson Syndrome (SJS) Toxic epidermal necrolysis (TEN)

<table ID="_Ref395611378" width="100%"> <caption>Table 5 Adverse Reactions Occurring in greater than or equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801)</caption> <col width="36%"/> <col width="33%"/> <col width="31%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Toprule " valign="top"> <content styleCode="bold">Body System</content> </th> <th align="center" colspan="2" styleCode="Toprule " valign="top"> <content styleCode="bold">CHC Combination Therapy </content> <content styleCode="bold">Study NV15801 </content> </th> </tr> <tr> <th align="center" valign="top"> <content styleCode="bold">peginterferon alfa-2a</content> <content styleCode="bold">180 mcg + 1000 mg or 1200 mg</content> <content styleCode="bold">ribavirin tablets 48 weeks </content> </th> <th align="center" valign="top"> <content styleCode="bold">interferon alfa-2b +</content> <content styleCode="bold">1000 mg or 1200 mg</content> <content styleCode="bold"> ribavirin capsules 48 weeks </content> </th> </tr> <tr> <th align="center" valign="top"> <content styleCode="bold"> </content> </th> <th align="center" valign="top"> <content styleCode="bold">N=451</content> </th> <th align="center" valign="top"> <content styleCode="bold">N=443</content> </th> </tr> <tr> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold"> </content> </th> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold">%</content> </th> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold">%</content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3" styleCode="Botrule" valign="top"> ^*Severe hematologic abnormalities (lymphocyte less than 500 cells/mm ³; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm ³; platelet less than 50,000 cells/mm ³). </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Toprule "> <paragraph> <content styleCode="bold">Application Site Disorders</content> </paragraph> </td> <td align="center" styleCode="Toprule "> <paragraph> </paragraph> </td> <td align="center" styleCode="Toprule "> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Injection site reaction </paragraph> </td> <td align="center"> <paragraph> 23 </paragraph> </td> <td align="center"> <paragraph> 16 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Endocrine Disorders</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Hypothyroidism </paragraph> </td> <td align="center"> <paragraph> 4 </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Flu-like Symptoms and Signs</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Fatigue/Asthenia </paragraph> </td> <td align="center"> <paragraph> 65 </paragraph> </td> <td align="center"> <paragraph> 68 </paragraph> </td> </tr> <tr> <td> <paragraph> Pyrexia </paragraph> </td> <td align="center"> <paragraph> 41 </paragraph> </td> <td align="center"> <paragraph> 55 </paragraph> </td> </tr> <tr> <td> <paragraph> Rigors </paragraph> </td> <td align="center"> <paragraph> 25 </paragraph> </td> <td align="center"> <paragraph> 37 </paragraph> </td> </tr> <tr> <td> <paragraph> Pain </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> <td align="center"> <paragraph> 9 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Gastrointestinal</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Nausea/Vomiting </paragraph> </td> <td align="center"> <paragraph> 25 </paragraph> </td> <td align="center"> <paragraph> 29 </paragraph> </td> </tr> <tr> <td> <paragraph> Diarrhea </paragraph> </td> <td align="center"> <paragraph> 11 </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> </tr> <tr> <td> <paragraph> Abdominal pain </paragraph> </td> <td align="center"> <paragraph> 8 </paragraph> </td> <td align="center"> <paragraph> 9 </paragraph> </td> </tr> <tr> <td> <paragraph> Dry mouth </paragraph> </td> <td align="center"> <paragraph> 4 </paragraph> </td> <td align="center"> <paragraph> 7 </paragraph> </td> </tr> <tr> <td> <paragraph> Dyspepsia </paragraph> </td> <td align="center"> <paragraph> 6 </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Hematologic*</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Lymphopenia </paragraph> </td> <td align="center"> <paragraph> 14 </paragraph> </td> <td align="center"> <paragraph> 12 </paragraph> </td> </tr> <tr> <td> <paragraph> Anemia </paragraph> </td> <td align="center"> <paragraph> 11 </paragraph> </td> <td align="center"> <paragraph> 11 </paragraph> </td> </tr> <tr> <td> <paragraph> Neutropenia </paragraph> </td> <td align="center"> <paragraph> 27 </paragraph> </td> <td align="center"> <paragraph> 8 </paragraph> </td> </tr> <tr> <td> <paragraph> Thrombocytopenia </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> <td align="center"> <paragraph> &lt;1 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Metabolic and Nutritional</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Anorexia </paragraph> </td> <td align="center"> <paragraph> 24 </paragraph> </td> <td align="center"> <paragraph> 26 </paragraph> </td> </tr> <tr> <td> <paragraph> Weight decrease </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Musculoskeletal, Connective Tissue and Bone</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Myalgia </paragraph> </td> <td align="center"> <paragraph> 40 </paragraph> </td> <td align="center"> <paragraph> 49 </paragraph> </td> </tr> <tr> <td> <paragraph> Arthralgia </paragraph> </td> <td align="center"> <paragraph> 22 </paragraph> </td> <td align="center"> <paragraph> 23 </paragraph> </td> </tr> <tr> <td> <paragraph> Back pain </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Neurological</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Headache </paragraph> </td> <td align="center"> <paragraph> 43 </paragraph> </td> <td align="center"> <paragraph> 49 </paragraph> </td> </tr> <tr> <td> <paragraph> Dizziness (excluding vertigo) </paragraph> </td> <td align="center"> <paragraph> 14 </paragraph> </td> <td align="center"> <paragraph> 14 </paragraph> </td> </tr> <tr> <td> <paragraph> Memory impairment </paragraph> </td> <td align="center"> <paragraph> 6 </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Psychiatric</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Irritability/Anxiety/Nervousness </paragraph> </td> <td align="center"> <paragraph> 33 </paragraph> </td> <td align="center"> <paragraph> 38 </paragraph> </td> </tr> <tr> <td> <paragraph> Insomnia </paragraph> </td> <td align="center"> <paragraph> 30 </paragraph> </td> <td align="center"> <paragraph> 37 </paragraph> </td> </tr> <tr> <td> <paragraph> Depression </paragraph> </td> <td align="center"> <paragraph> 20 </paragraph> </td> <td align="center"> <paragraph> 28 </paragraph> </td> </tr> <tr> <td> <paragraph> Concentration impairment </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> <td align="center"> <paragraph> 13 </paragraph> </td> </tr> <tr> <td> <paragraph> Mood alteration </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> <td align="center"> <paragraph> 6 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Resistance Mechanism Disorders</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Overall </paragraph> </td> <td align="center"> <paragraph> 12 </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Respiratory, Thoracic and Mediastinal</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Dyspnea </paragraph> </td> <td align="center"> <paragraph> 13 </paragraph> </td> <td align="center"> <paragraph> 14 </paragraph> </td> </tr> <tr> <td> <paragraph> Cough </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> <td align="center"> <paragraph> 7 </paragraph> </td> </tr> <tr> <td> <paragraph> Dyspnea exertional </paragraph> </td> <td align="center"> <paragraph> 4 </paragraph> </td> <td align="center"> <paragraph> 7 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Skin and Subcutaneous Tissue</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td> <paragraph> Alopecia </paragraph> </td> <td align="center"> <paragraph> 28 </paragraph> </td> <td align="center"> <paragraph> 33 </paragraph> </td> </tr> <tr> <td> <paragraph> Pruritus </paragraph> </td> <td align="center"> <paragraph> 19 </paragraph> </td> <td align="center"> <paragraph> 18 </paragraph> </td> </tr> <tr> <td> <paragraph> Dermatitis </paragraph> </td> <td align="center"> <paragraph> 16 </paragraph> </td> <td align="center"> <paragraph> 13 </paragraph> </td> </tr> <tr> <td> <paragraph> Dry skin </paragraph> </td> <td align="center"> <paragraph> 10 </paragraph> </td> <td align="center"> <paragraph> 13 </paragraph> </td> </tr> <tr> <td> <paragraph> Rash </paragraph> </td> <td align="center"> <paragraph> 8 </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> </tr> <tr> <td> <paragraph> Sweating increased </paragraph> </td> <td align="center"> <paragraph> 6 </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> </tr> <tr> <td> <paragraph> Eczema </paragraph> </td> <td align="center"> <paragraph> 5 </paragraph> </td> <td align="center"> <paragraph> 4 </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Visual Disorders</content> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> <td align="center"> <paragraph> </paragraph> </td> </tr> <tr> <td styleCode="Botrule "> <paragraph> Vision blurred </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph> 5 </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph> 2 </paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <caption>Table 6 Percentage of Pediatric Subjects with Adverse Reactions* During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects)</caption> <col width="35%"/> <col width="33%"/> <col width="33%"/> <thead> <tr> <th align="left" styleCode="Toprule " valign="top"/> <th align="center" colspan="2" styleCode="Toprule " valign="top"> <content styleCode="bold">Study NV17424 </content> </th> </tr> <tr> <th align="left" valign="top"> <content styleCode="bold">System Organ Class</content> </th> <th align="center" valign="top"> <content styleCode="bold">peginterferon alfa-2a 180 mcg/1.73 m ² x BSA + ribavirin tablets 15 mg/kg (N=55) </content> </th> <th align="center" valign="top"> <content styleCode="bold">peginterferon alfa-2a 180 mcg/1.73 m ² x BSA + Placebo** (N=59) </content> </th> </tr> <tr> <th align="left" styleCode="Botrule " valign="top"/> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold">%</content> </th> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold">%</content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6" styleCode="Botrule" valign="top"> ^*Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug. ^**Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Toprule "> <paragraph> <content styleCode="bold">General disorders and administration site conditions</content> </paragraph> </td> <td styleCode="Toprule "/> <td styleCode="Toprule "/> </tr> <tr> <td> <paragraph>Influenza like illness</paragraph> </td> <td align="center"> <paragraph>91</paragraph> </td> <td align="center"> <paragraph>81</paragraph> </td> </tr> <tr> <td> <paragraph>Injection site reaction</paragraph> </td> <td align="center"> <paragraph>44</paragraph> </td> <td align="center"> <paragraph>42</paragraph> </td> </tr> <tr> <td> <paragraph>Fatigue</paragraph> </td> <td align="center"> <paragraph>25</paragraph> </td> <td align="center"> <paragraph>20</paragraph> </td> </tr> <tr> <td> <paragraph>Irritability</paragraph> </td> <td align="center"> <paragraph>24</paragraph> </td> <td align="center"> <paragraph>14</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Gastrointestinal disorders</content> </paragraph> </td> <td/> <td/> </tr> <tr> <td> <paragraph>Gastrointestinal disorder</paragraph> </td> <td align="center"> <paragraph>49</paragraph> </td> <td align="center"> <paragraph>44</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Nervous system disorders</content> </paragraph> </td> <td/> <td/> </tr> <tr> <td> <paragraph>Headache</paragraph> </td> <td align="center"> <paragraph>51</paragraph> </td> <td align="center"> <paragraph>39</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </paragraph> </td> <td valign="bottom"/> <td valign="bottom"/> </tr> <tr> <td> <paragraph>Rash</paragraph> </td> <td align="center"> <paragraph>15</paragraph> </td> <td align="center"> <paragraph>10</paragraph> </td> </tr> <tr> <td> <paragraph>Pruritus</paragraph> </td> <td align="center"> <paragraph>11</paragraph> </td> <td align="center"> <paragraph>12</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Musculoskeletal, connective tissue and bone disorders</content> </paragraph> </td> <td/> <td/> </tr> <tr> <td> <paragraph>Musculoskeletal pain</paragraph> </td> <td align="center"> <paragraph>35</paragraph> </td> <td align="center"> <paragraph>29</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Psychiatric disorders</content> </paragraph> </td> <td/> <td/> </tr> <tr> <td> <paragraph>Insomnia</paragraph> </td> <td align="center"> <paragraph>9</paragraph> </td> <td align="center"> <paragraph>12</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Metabolism and nutrition disorders</content> </paragraph> </td> <td/> <td/> </tr> <tr> <td styleCode="Botrule "> <paragraph>Decreased appetite</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>11</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>14</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0EBC1EFD4612423E92BC88D335107B0E" width="100%"> <caption>Table 7 Selected Laboratory Abnormalities During Treatment With Ribavirin in Combination With Either Peginterferon alfa-2a or Interferon alfa-2b </caption> <col width="33%"/> <col width="34%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Toprule "> <paragraph> <content styleCode="bold">Laboratory Parameter </content> </paragraph> </td> <td align="center" styleCode="Toprule "> <paragraph> <content styleCode="bold">Peginterferon alfa-2a + Ribavirin 1000/1200 mg </content> <content styleCode="bold">48 wks</content> </paragraph> </td> <td align="center" styleCode="Toprule "> <paragraph> <content styleCode="bold">Interferon alfa-2b + Ribavirin 1000/1200 mg</content> <content styleCode="bold">48 wks</content> </paragraph> </td> </tr> <tr> <td styleCode="Botrule "/> <td align="center" styleCode="Botrule "> <paragraph> <content styleCode="bold">(N=887)</content> </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph> <content styleCode="bold">(N=443)</content> </paragraph> </td> </tr> <tr> <td styleCode="Toprule " valign="middle"> <paragraph> <content styleCode="bold">Neutrophils (cells/mm ³) </content> </paragraph> </td> <td styleCode="Toprule "/> <td styleCode="Toprule "/> </tr> <tr> <td valign="middle"> <paragraph>1,000 &lt;1,500</paragraph> </td> <td align="center"> <paragraph>34%</paragraph> </td> <td align="center"> <paragraph>38%</paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>500 &lt;1,000</paragraph> </td> <td align="center"> <paragraph>49%</paragraph> </td> <td align="center"> <paragraph>21%</paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>&lt;500</paragraph> </td> <td align="center"> <paragraph>5%</paragraph> </td> <td align="center"> <paragraph>1%</paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> <content styleCode="bold">Platelets (cells/mm ³) </content> </paragraph> </td> <td/> <td/> </tr> <tr> <td valign="middle"> <paragraph>50,000 - &lt;75,000 </paragraph> </td> <td align="center"> <paragraph>11%</paragraph> </td> <td align="center"> <paragraph>4%</paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>20,000 - &lt;50,000</paragraph> </td> <td align="center"> <paragraph>5%</paragraph> </td> <td align="center"> <paragraph>&lt; 1%</paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph>&lt;20,000 </paragraph> </td> <td align="center"> <paragraph>0</paragraph> </td> <td align="center"> <paragraph>0</paragraph> </td> </tr> <tr> <td valign="middle"> <paragraph> <content styleCode="bold">Hemoglobin (g/dL)</content> </paragraph> </td> <td/> <td/> </tr> <tr> <td valign="middle"> <paragraph>8.5 - 9.9 </paragraph> </td> <td align="center"> <paragraph>11%</paragraph> </td> <td align="center"> <paragraph>11%</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="middle"> <paragraph>&lt;8.5 </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>&lt; 1%</paragraph> </td> </tr> </tbody> </table>