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adverse reactions
6 ADVERSE REACTIONS In clinical trials, a broad variety of serious adverse reactions were observed in 1,010 subjects who received PEGASYS at doses of 180 mcg for 48 weeks, alone or in combination with ribavirin [see Boxed Warning and Warnings and Precautions (5) ] . The most common life-threatening or fatal events induced or aggravated by PEGASYS and ribavirin 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) of CHC/HIV subjects [see Warnings and Precautions (5.9) ] . Adult subjects: The most common adverse reactions (incidence greater than 40%) are fatigue/asthenia, pyrexia, myalgia, and headache ( 6.1 ) Pediatric subjects: The most common adverse reactions are similar to those seen in adults ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact pharma& agent at 1-888-814-7734 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in 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. Chronic Hepatitis C Adult Subjects In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in combination with ribavirin. The most common serious adverse reactions (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of less than 1% and included: suicide, suicidal ideation, 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. In clinical trials, 98 to 99 percent of subjects experienced one or more adverse reactions. For hepatitis C subjects, 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 7 displays pooled rates of adverse reactions occurring in greater than 5% of subjects in the PEGASYS monotherapy and PEGASYS/ribavirin combination therapy clinical trials. Overall, 11% of CHC monoinfected subjects receiving 48 weeks of therapy with PEGASYS either alone or in combination with ribavirin discontinued therapy; 16% of CHC/HIV coinfected subjects 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 subjects with CHC or CHC/HIV required modification of PEGASYS and/or ribavirin therapy. The most common reasons for dose modification of PEGASYS in CHC and CHC/HIV subjects was for 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 subjects was anemia (22% and 16%, respectively). PEGASYS dose was reduced in 12% of subjects receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7% of subjects receiving 800 mg ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of subjects receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 12% of subjects receiving 800 mg ribavirin for 24 weeks. Chronic hepatitis C monoinfected subjects treated for 24 weeks with PEGASYS and 800 mg ribavirin were observed to have lower incidence of serious adverse reactions (3% vs. 10%), Hgb less than 10 g/dL (3% vs. 15%), dose modification of PEGASYS (30% vs. 36%) and ribavirin (19% vs. 38%) and of withdrawal from treatment (5% vs. 15%) compared to subjects treated for 48 weeks with PEGASYS and 1000 mg or 1200 mg ribavirin. The overall incidence of adverse reactions appeared to be similar in the two treatment groups. Table 7 Adverse Reactions Occurring in Greater Than or Equal to 5% of Subjects in Chronic Hepatitis C Clinical Trials (Pooled Studies 1, 2, 3, and Study 4) CHC Monotherapy (Pooled Studies 1-3) CHC Combination Therapy (Study 4) Body System PEGASYS 180 mcg 48 week Pooled studies 1, 2, and 3 ROFERON-A Either 3 MIU An induction dose of 6 million international units (MIU) three times a week for the first 12 weeks followed by 3 million international units three times a week for 36 weeks given subcutaneously. or 6/3 MIU of ROFERON-A 48 week PEGASYS 180 mcg + 1000 mg or 1200 mg Ribavirin 48 week Study 4 Intron ® A + 1000 mg or 1200 mg Rebetol ® 48 week N=559 N=554 N=451 N=443 % % % % Application Site Disorders Injection site reaction 22 18 23 16 Endocrine Disorders Hypothyroidism 3 2 4 5 Flu-like Symptoms and Signs Fatigue/Asthenia 56 57 65 68 Pyrexia 37 41 41 55 Rigors 35 44 25 37 Pain 11 12 10 9 Gastrointestinal Nausea/Vomiting 24 33 25 29 Diarrhea 16 16 11 10 Abdominal pain 15 15 8 9 Dry mouth 6 3 4 7 Dyspepsia <1 1 6 5 Hematologic 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). Lymphopenia 3 5 14 12 Anemia 2 1 11 11 Neutropenia 21 8 27 8 Thrombocytopenia 5 2 5 <1 Metabolic and Nutritional Anorexia 17 17 24 26 Weight decrease 4 3 10 10 Musculoskeletal, Connective Tissue and Bone Myalgia 37 38 40 49 Arthralgia 28 29 22 23 Back pain 9 10 5 5 Neurological Headache 54 58 43 49 Dizziness (excluding vertigo) 16 12 14 14 Memory impairment 5 4 6 5 Resistance Mechanism Disorders Overall 10 6 12 10 Psychiatric Irritability/Anxiety/Nervousness 19 22 33 38 Insomnia 19 23 30 37 Depression 18 19 20 28 Concentration impairment 8 10 10 13 Mood alteration 3 2 5 6 Respiratory, Thoracic and Mediastinal Dyspnea 4 2 13 14 Cough 4 3 10 7 Dyspnea exertional <1 <1 4 7 Skin and Subcutaneous Tissue Alopecia 23 30 28 33 Pruritus 12 8 19 18 Dermatitis 8 3 16 13 Dry skin 4 3 10 13 Rash 5 4 8 5 Sweating increased 6 7 6 5 Eczema 1 1 5 4 Visual Disorders Vision blurred 4 2 5 2 Pediatric Subjects In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS 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 prevalent adverse events in subjects treated with combination therapy for up to 48 weeks with PEGASYS and ribavirin 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 PEGASYS 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). Most of the adverse events reported in the study were mild or moderate in severity. Severe adverse events were reported in 2 subjects in the PEGASYS plus ribavirin combination therapy group (hyperglycemia and cholecystectomy). Table 8 Percentage of Pediatric Subjects with Adverse Reactions Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug. During First 24 Weeks of Treatment by Treatment Group (in at Least 10% of Subjects) Study NV17424 System Organ Class PEGASYS 180 mcg/1.73 m 2 × BSA + Ribavirin 15 mg/kg (N=55) PEGASYS 180 mcg/1.73 m 2 × BSA + Placebo Subjects in the PEGASYS 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. (N=59) % % 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. Growth inhibition in CHC pediatric subjects [see Warnings and Precautions (5.15) ] . Pediatric subjects treated with PEGASYS plus ribavirin combination therapy showed a delay in weight and height increases up to 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 curve percentiles for weight (64 th mean percentile at baseline, 60 th mean percentile at 2 years post-treatment) and height (54 th mean percentile at baseline, 56 th mean percentile at 2 years post-treatment). At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve. Thirty-eight of the 114 subjects enrolled in the long-term follow-up study extending up to 6 years post-treatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment. CHC with HIV Coinfection (Adults) The adverse reaction profile of coinfected subjects treated with PEGASYS/ribavirin in Study 7 was generally similar to that shown for monoinfected subjects in Study 4 ( Table 7 ). Events occurring more frequently in coinfected subjects were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%). Chronic Hepatitis B Adult Subjects In clinical trials of 48 week treatment duration, the adverse reaction profile of PEGASYS in CHB was similar to that seen in CHC PEGASYS monotherapy use, except for exacerbations of hepatitis [see Warnings and Precautions (5.9) ] . Six percent of PEGASYS-treated subjects in the hepatitis B studies experienced one or more serious adverse reactions. The most common or important serious adverse reactions, all of which occurred at a frequency of less than or equal to 1%, in the hepatitis B studies were infections (sepsis, appendicitis, tuberculosis, influenza), hepatitis B flares, and thrombotic thrombocytopenic purpura. One serious adverse reaction of anaphylactic shock occurred in a dose ranging study of 191 subjects in a subject taking a higher than the approved dose of PEGASYS. The most commonly observed adverse reactions in the PEGASYS and lamivudine groups, respectively, were pyrexia (54% vs. 4%), headache (27% vs. 9%), fatigue (24% vs. 10%), myalgia (26% vs. 4%), alopecia (18% vs. 2%), and anorexia (16% vs. 3%). Overall 5% of hepatitis B subjects discontinued PEGASYS therapy and 40% of subjects required modification of PEGASYS dose. The most common reason for dose modification in subjects receiving PEGASYS therapy was for laboratory abnormalities including neutropenia (20%), thrombocytopenia (13%), and ALT elevation (11%). Pediatric Subjects In a clinical trial with 111 subjects 3 to 17 years of age treated with PEGASYS for 48 weeks, the safety profile was consistent with that seen in adults with CHB and in pediatric subjects with CHC. The most commonly observed adverse reactions in PEGASYS-treated patients were pyrexia (51%), headache (21%), abdominal pain (17%), cough (15%), vomiting (15%), influenza-like illness (14%), alanine aminotransferase increased (10%), aspartate aminotransferase increased (10%), rash (10%), asthenia (9.0%), epistaxis (9.0%), nausea (9.0%), fatigue (8%), upper respiratory tract infection (8%), alopecia (6%), decreased appetite (6%), dizziness (6%), and nasopharyngitis (6%). Growth inhibition in CHB pediatric subjects [see Warnings and Precautions (5.15) ] . The mean changes from baseline in z-scores for height and weight for age were -0.07 and -0.21 for PEGASYS-treated subjects at Week 48. Comparable findings were observed in untreated patients at Week 48 (changes in z-scores for height and weight for age were -0.01 and -0.08, respectively). At Week 48 of PEGASYS treatment, a height or weight decrease of more than 15 percentiles on the normative growth curves was observed in 6% of subjects for height and 13% of subjects for weight. At 24 weeks after the end of PEGASYS treatment the percentage of subjects with decrease of more than 15 percentiles from baseline was 12% for height and 11% for weight. At 5 years post-treatment, the percentage of subjects with decrease of more than 15 percentiles from baseline was 18% for height and 29% for weight. Laboratory Values Adult Subjects The laboratory test values observed in the hepatitis B trials (except where noted below) were similar to those seen in the PEGASYS monotherapy CHC trials. Neutrophils In the hepatitis C studies, decreases in neutrophil count below normal were observed in 95% of all subjects treated with PEGASYS either alone or in combination with ribavirin. Severe potentially life-threatening neutropenia (ANC less than 500 cells/mm 3 ) occurred in 5% of CHC subjects and 12% of CHC/HIV subjects receiving PEGASYS either alone or in combination with ribavirin. Modification of PEGASYS dose for neutropenia occurred in 17% of subjects receiving PEGASYS monotherapy and 22% of subjects receiving PEGASYS/ribavirin combination therapy. In the CHC/HIV subjects 27% required modification of interferon dosage for neutropenia. Two percent of subjects with CHC and 10% of subjects with CHC/HIV required permanent reductions of PEGASYS dosage and less than 1% required permanent discontinuation. Median neutrophil counts return to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.6) ]. Lymphocytes Decreases in lymphocyte count are induced by interferon alpha therapy. PEGASYS plus ribavirin combination therapy induced decreases in median total lymphocyte counts (56% in CHC and 40% in CHC/HIV, with median decrease of 1170 cells/mm 3 in CHC and 800 cells/mm 3 in CHC/HIV). In the hepatitis C studies, lymphopenia was observed during both monotherapy (81%) and combination therapy with PEGASYS and ribavirin (91%). Severe lymphopenia (less than 500 cells/mm 3 ) occurred in approximately 5% of all monotherapy subjects and 14% of all combination PEGASYS and ribavirin therapy recipients. Dose adjustments were not required by protocol. The clinical significance of the lymphopenia is not known. In CHC with HIV coinfection, CD4 counts decreased by 29% from baseline (median decrease of 137 cells/mm 3 ) and CD8 counts decreased by 44% from baseline (median decrease of 389 cells/mm 3 ) in the PEGASYS plus ribavirin combination therapy arm. Median lymphocyte CD4 and CD8 counts return to pre-treatment levels after 4 to 12 weeks of the cessation of therapy. CD4% did not decrease during treatment. Platelets In the hepatitis C studies, platelet counts decreased in 52% of CHC subjects and 51% of CHC/HIV subjects treated with PEGASYS alone (respectively median decrease of 41% and 35% from baseline), and in 33% of CHC subjects and 47% of CHC/HIV subjects receiving combination therapy with ribavirin (median decrease of 30% from baseline). Moderate to severe thrombocytopenia (less than 50,000 cells/mm 3 ) was observed in 4% of CHC and 8% of CHC/HIV subjects. Median platelet counts return to pre-treatment levels 4 weeks after the cessation of therapy. Hemoglobin In the hepatitis C studies, the hemoglobin concentration decreased below 12 g/dL in 17% (median Hgb reduction of 2.2 g/dL) of monotherapy and 52% (median Hgb reduction of 3.7 g/dL) of combination therapy subjects. Severe anemia (Hgb less than 10 g/dL) was encountered in 13% of all subjects receiving combination therapy and in 2% of CHC subjects and 8% of CHC/HIV subjects receiving PEGASYS monotherapy. Dose modification for anemia in ribavirin recipients treated for 48 weeks occurred in 22% of CHC subjects and 16% of CHC/HIV subjects [see Dosage and Administration (2.6) ]. Triglycerides Triglyceride levels are elevated in subjects receiving alfa interferon therapy and were elevated in the majority of subjects participating in clinical studies receiving either PEGASYS alone or in combination with ribavirin. Random levels greater than or equal to 400 mg/dL were observed in about 20% of CHC subjects. Severe elevations of triglycerides (greater than 1000 mg/dL) occurred in 2% of CHC monoinfected subjects. In HCV/HIV coinfected subjects, fasting levels greater than or equal to 400 mg/dL were observed in up to 36% of subjects receiving either PEGASYS alone or in combination with ribavirin. Severe elevations of triglycerides (greater than 1000 mg/dL) occurred in 7% of coinfected subjects. ALT Elevations Chronic Hepatitis C One percent of subjects in the hepatitis C trials experienced marked elevations (5- to 10-fold above the upper limit of normal) in ALT levels during treatment and follow-up. These transaminase elevations were on occasion associated with hyperbilirubinemia and were managed by dose reduction or discontinuation of study treatment. Liver function test abnormalities were generally transient. One case was attributed to autoimmune hepatitis, which persisted beyond study medication discontinuation [see Dosage and Administration (2.6) ]. Chronic Hepatitis B Transient ALT elevations are common during hepatitis B therapy with PEGASYS. Twenty-five percent and 27% of subjects experienced elevations of 5 to 10 × ULN and 12% and 18% had elevations of greater than 10 × ULN during treatment of HBeAg negative and HBeAg positive disease, respectively. Flares have been accompanied by elevations of total bilirubin and alkaline phosphatase and less commonly with prolongation of PT and reduced albumin levels. Eleven percent of subjects had dose modifications due to ALT flares and less than 1% of subjects were withdrawn from treatment [see Warnings and Precautions (5.9) and Dosage and Administration (2.6) ]. ALT flares of 5 to 10 × ULN occurred in 13% and 16% of subjects, while ALT flares of greater than 10 × ULN occurred in 7% and 12% of subjects in HBeAg-negative and HBeAg-positive disease, respectively, after discontinuation of PEGASYS therapy. Thyroid Function PEGASYS alone or in combination with ribavirin was associated with the development of abnormalities in thyroid laboratory values, some with associated clinical manifestations. In the hepatitis C studies, hypothyroidism or hyperthyroidism requiring treatment, dose modification or discontinuation occurred in 4% and 1% of PEGASYS treated subjects and 4% and 2% of PEGASYS and ribavirin treated subjects, respectively. Approximately half of the subjects, who developed thyroid abnormalities during PEGASYS treatment, still had abnormalities during the follow-up period [see Warnings and Precautions (5.6) ] . Pediatric Subjects Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment in pediatric subjects [see Dosage and Administration (2.3 , 2.5 , 2.6) ] . Most laboratory abnormalities noted during the CHC clinical trial ( Table 9 ) returned to baseline levels shortly after completion of treatment. Table 9 Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects with CHC Laboratory Parameter PEGASYS 180 mcg/1.73 m 2 × BSA + Ribavirin 15 mg/kg (N=55) PEGASYS 180 mcg/1.73 m 2 × BSA + Placebo Subjects in the PEGASYS 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. (N=59) 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. The hematologic laboratory abnormalities observed in the CHB pediatric trial were similar to those observed in the CHC pediatric trial. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. 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 to peginterferon alfa-2a in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Chronic Hepatitis C Nine percent (71/834) of subjects treated with PEGASYS with or without ribavirin developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Three percent of subjects (25/835) receiving PEGASYS with or without ribavirin, developed low-titer neutralizing antibodies (using an assay with a sensitivity of 100 INU/mL). Chronic Hepatitis B Twenty-nine percent (42/143) of hepatitis B subjects treated with PEGASYS for 24 weeks developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Thirteen percent of subjects (19/143) receiving PEGASYS developed low-titer neutralizing antibodies (using an assay with a sensitivity of 100 INU/mL). The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The percentage of subjects whose test results were considered positive for antibodies is highly dependent on the sensitivity and specificity of the assays. 6.3 Postmarketing Experience The following adverse reactions have been identified and reported during post-approval use of PEGASYS 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 Gastrointestinal disorders: tongue pigmentation Immune system disorders: liver graft rejection and renal graft rejection [see Use in Specific Populations (8.8) ] Infections and infestations: limb abscess Metabolism and nutrition disorders: dehydration Skin and subcutaneous tissue disorders: serious skin reactions Neurological: seizures