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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (greater than 40%) in adult patients receiving either PEGINTRON or PEGINTRON/REBETOL are injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability ( 6.1 ). Most common adverse reactions (greater than 25%) in pediatric patients receiving PEGINTRON/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection-site erythema, vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials with PEGINTRON alone or in combination with REBETOL® (ribavirin) have been conducted in over 6,900 subjects from 3 to 75 years of age. Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PEGINTRON with or without REBETOL [see Warnings and Precautions (5) ] . The most common serious events occurring in subjects treated with PEGINTRON and REBETOL were depression and suicidal ideation [see Warnings and Precautions (5.2) ], each occurring at a frequency of less than 1%. The most common fatal events occurring in subjects treated with PEGINTRON and REBETOL were cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions (5.2 , 5.3) ] , all occurring in less than 1% of subjects. Greater than 96% of all subjects in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions in adult subjects receiving either PEGINTRON or PEGINTRON/REBETOL were injection-site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and emotional lability/irritability. The most common adverse events in pediatric subjects, ages 3 and older, were pyrexia, headache, vomiting, neutropenia, fatigue, anorexia, injection-site erythema, and abdominal pain. Adults Study 1 compared PEGINTRON monotherapy with INTRON® A monotherapy. Study 2 compared combination therapy of PEGINTRON/REBETOL with combination therapy with INTRON A/REBETOL. In these clinical trials, nearly all subjects experienced one or more adverse reactions. Study 3 compared a PEGINTRON/weight-based REBETOL combination to a PEGINTRON/flat dose REBETOL regimen. Study 4 compared two PEGINTRON doses (1.5 mcg/kg/week and 1 mcg/kg/week) in combination with REBETOL and a third treatment group receiving Pegasys ® (180 mcg/week)/Copegus ® (1000-1200 mg/day). Adverse reactions that occurred in Studies 1 and 2 at greater than 5% incidence are provided in Table 7 by treatment group. Due to potential differences in ascertainment procedures, adverse reaction rate comparisons across trials should not be made. Table 8 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence. Table 7: Adverse Reactions Occurring in Greater than 5% of Subjects Percentage of Subjects Reporting Adverse Reactions Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category. Study 1 Study 2 Adverse Reactions PEGINTRON 1 mcg/kg INTRON A 3 MIU PEGINTRON 1.5 mcg/kg/ REBETOL INTRON A/ REBETOL (N=297) (N=303) (N=511) (N=505) Application Site Injection Site Inflammation/Reaction 47 20 75 49 Autonomic Nervous System Dry Mouth 6 7 12 8 Increased Sweating 6 7 11 7 Flushing 6 3 4 3 Body as a Whole Fatigue/Asthenia 52 54 66 63 Headache 56 52 62 58 Rigors 23 19 48 41 Fever 22 12 46 33 Weight Loss 11 13 29 20 Right Upper Quadrant Pain 8 8 12 6 Chest Pain 6 4 8 7 Malaise 7 6 4 6 Central/Peripheral Nervous System Dizziness 12 10 21 17 Endocrine Hypothyroidism 5 3 5 4 Gastrointestinal Nausea 26 20 43 33 Anorexia 20 17 32 27 Diarrhea 18 16 22 17 Vomiting 7 6 14 12 Abdominal Pain 15 11 13 13 Dyspepsia 6 7 9 8 Constipation 1 3 5 5 Hematologic Disorders Neutropenia 6 2 26 14 Anemia 0 0 12 17 Leukopenia <1 0 6 5 Thrombocytopenia 7 <1 5 2 Liver and Biliary System Hepatomegaly 6 5 4 4 Musculoskeletal Myalgia 54 53 56 50 Arthralgia 23 27 34 28 Musculoskeletal Pain 28 22 21 19 Psychiatric Insomnia 23 23 40 41 Depression 29 25 31 34 Anxiety/Emotional Lability/Irritability 28 34 47 47 Concentration Impaired 10 8 17 21 Agitation 2 2 8 5 Nervousness 4 3 6 6 Reproductive, Female Menstrual Disorder 4 3 7 6 Resistance Mechanism Viral Infection 11 10 12 12 Fungal Infection <1 3 6 1 Respiratory System Dyspnea 4 2 26 24 Coughing 8 5 23 16 Pharyngitis 10 7 12 13 Rhinitis 2 2 8 6 Sinusitis 7 7 6 5 Skin and Appendages Alopecia 22 22 36 32 Pruritus 12 8 29 28 Rash 6 7 24 23 Skin Dry 11 9 24 23 Special Senses, Other Taste Perversion <1 2 9 4 Vision Disorders Vision Blurred 2 3 5 6 Conjunctivitis 4 2 4 5 Table 8: Treatment-Related Adverse Reactions (Greater than or Equal to 10% Incidence) By Descending Frequency Percentage of Subjects Reporting Treatment-Related Adverse Reactions Study 4 Adverse Reactions PEGINTRON 1.5 mcg/kg with REBETOL PEGINTRON 1 mcg/kg with REBETOL Pegasys 180 mcg with Copegus (N=1019) (N=1016) (N=1035) Fatigue 67 68 64 Headache 50 47 41 Nausea 40 35 34 Chills 39 36 23 Insomnia 38 37 41 Anemia 35 30 34 Pyrexia 35 32 21 Injection Site Reactions 34 35 23 Anorexia 29 25 21 Rash 29 25 34 Myalgia 27 26 22 Neutropenia 26 19 31 Irritability 25 25 25 Depression 25 19 20 Alopecia 23 20 17 Dyspnea 21 20 22 Arthralgia 21 22 22 Pruritus 18 15 19 Influenza-like Illness 16 15 15 Dizziness 16 14 13 Diarrhea 15 16 14 Cough 15 16 17 Weight Decreased 13 10 10 Vomiting 12 10 9 Unspecified Pain 12 13 9 Dry Skin 11 11 12 Anxiety 11 11 10 Abdominal Pain 10 10 10 Leukopenia 9 7 10 The adverse reaction profile in Study 3, which compared PEGINTRON/weight-based REBETOL combination to a PEGINTRON/flat-dose REBETOL regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat-dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions. The incidence of serious adverse reactions was comparable in all trials. In the PEGINTRON monotherapy trial (Study 1) the incidence of serious adverse reactions was similar (about 12%) in all treatment groups. In Study 2, the incidence of serious adverse reactions was 17% in the PEGINTRON/REBETOL groups compared to 14% in the INTRON A/REBETOL group. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and for the flat-dose REBETOL regimen. In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period. There have been 31 subject deaths that occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PEGINTRON monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PEGINTRON/REBETOL combination therapy, and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of which were probable suicides, and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects receiving PEGINTRON/REBETOL combination therapy; 5 in the PEGINTRON 1.5 mcg/REBETOL arm (N=1019) and 1 in the PEGINTRON 1 mcg/REBETOL arm (n=1016); and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides that occurred during the off-treatment follow-up period in subjects who received PEGINTRON (1.5 mcg/kg)/REBETOL combination therapy. In Studies 1 and 2, 10% to 14% of subjects receiving PEGINTRON, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PEGINTRON in combination with weight-based REBETOL and 14% of subjects receiving PEGINTRON and flat-dose REBETOL discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In Study 4, 13% of subjects in the PEGINTRON 1.5 mcg/REBETOL arm, 10% in the PEGINTRON 1 mcg/REBETOL arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued therapy due to adverse events. In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PEGINTRON (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PEGINTRON (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PEGINTRON 1.5 mcg/kg more than PEGINTRON 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three groups, 33% to 35%. The most common reasons for dose modifications were neutropenia (18%) or anemia (9%). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with weight-based dosing (WBD) compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of PEGINTRON to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PEGINTRON to 0.5 mcg/kg due to adverse events, compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% requiring a second dose reduction to 90 mcg/week with Pegasys. In the PEGINTRON/REBETOL combination trials the most common adverse reactions were psychiatric, which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see Warnings and Precautions (5.2) ] . In Study 4, psychiatric adverse reactions occurred in 58% of subjects in the PEGINTRON 1.5 mcg/REBETOL arm, 55% of subjects in the PEGINTRON 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm. PEGINTRON induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tended to decrease as treatment continued. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PEGINTRON therapies (in up to 75% of subjects) compared with INTRON A. However, injection-site pain was infrequent (2-3%) in all groups. In Study 3, there was a 23% to 24% incidence overall for injection-site reactions or inflammation. In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing adverse reactions by body class in the PEGINTRON 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10% to 15% of subjects, weight loss, fatigue, and headache had not resolved. Individual serious adverse reactions in Study 2 occurred at a frequency less than or equal to 1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis; urticaria, injection-site necrosis, vasculitis, and phototoxicity. Subjects receiving PEGINTRON/REBETOL as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naïve subjects. Pediatric Subjects In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric trial, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%), and vomiting (27%). The majority of adverse reactions reported in the trial were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection-site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment; three with clinical hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric subjects treated with PEGINTRON plus REBETOL lagged behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment. Dose modifications were required in 25% of subjects, most commonly for anemia, neutropenia, and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction. Adverse reactions that occurred with a greater than or equal to 10% incidence in the pediatric trial subjects are provided in Table 9 . Table 9: Percentage of Pediatric Subjects with Treatment-related Adverse Reactions (in At Least 10% of All Subjects) System Organ Class Preferred Term All Subjects N=107 Blood and Lymphatic System Disorders Neutropenia 33% Anemia 11% Leukopenia 10% Gastrointestinal Disorders Abdominal Pain 21% Abdominal Pain Upper 12% Vomiting 27% Nausea 18% General Disorders and Administration Site Conditions Pyrexia 80% Fatigue 30% Injection-site Erythema 29% Chills 21% Asthenia 15% Irritability 14% Investigations Weight Decreased 19% Metabolism and Nutrition Disorders Anorexia 29% Decreased Appetite 22% Musculoskeletal and Connective Tissue Disorders Arthralgia 17% Myalgia 17% Nervous System Disorders Headache 62% Dizziness 14% Skin and Subcutaneous Tissue Disorders Alopecia 17% Ninety-four of 107 subjects enrolled in a 5-year long-term follow-up trial. The long-term effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a >15 percentile height-for-age decrease from pre-treatment to the end of the 5-year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of >30 height-for-age percentiles to the end of the 5-year long-term follow-up. While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to correlate with initiation of combination therapy during the years of expected peak growth velocity [see Warnings and Precautions (5.18) ] . Laboratory Values Adults Changes in selected laboratory values during treatment with PEGINTRON alone or in combination with REBETOL treatment are described below . Decreases in hemoglobin, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.3) and Warnings and Precautions (5.1 , 5.7) ] . Hemoglobin . Hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in hemoglobin levels less than 11 g/dL. Reductions in hemoglobin to less than 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the PEGINTRON/REBETOL and INTRON A/REBETOL groups. In Study 4, subjects receiving PEGINTRON (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 8.5 g/dL (3%), whereas in subjects receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects, respectively. Hemoglobin levels became stable by treatment Weeks 4 to 6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the PEGINTRON monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see Dosage and Administration (2.3) ] . Neutrophils . Decreases in neutrophil counts were observed in a majority of subjects treated with PEGINTRON alone (70%) or as combination therapy with REBETOL in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (less than 0.5 × 10 9 /L) occurred in 1% of subjects treated with PEGINTRON monotherapy, 2% of subjects treated with INTRON A/REBETOL, and in approximately 4% of subjects treated with PEGINTRON/REBETOL in Study 2. Two percent of subjects receiving PEGINTRON monotherapy and 18% of subjects receiving PEGINTRON/REBETOL in Study 2 required modification of interferon dosage. Few subjects (less than 1%) required permanent discontinuation of treatment. Neutrophil counts generally returned to pretreatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.3) ] . Platelets . Platelet counts decreased to less than 100,000/mm 3 in approximately 20% of subjects treated with PEGINTRON alone or with REBETOL and in 6% of subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (less than 50,000/mm 3 ) occur in less than 4% of subjects. Patients may require discontinuation or dose modification as a result of platelet decreases [see Dosage and Administration (2.3) ] . In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PEGINTRON, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy. Triglycerides. Elevated triglyceride levels have been observed in patients treated with interferon alphas, including PEGINTRON [see Warnings and Precautions (5.17) ]. Thyroid Function . Development of TSH abnormalities, with or without clinical manifestations, is associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with either INTRON A or PEGINTRON (with or without REBETOL) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new-onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period, 7% of subjects still had abnormal TSH values [see Warnings and Precautions (5.4) ]. Bilirubin and Uric Acid. In Study 2, 10% to 14% of subjects developed hyperbilirubinemia and 33% to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout. Pediatric Subjects Decreases in hemoglobin, white blood cells, platelets, and neutrophils may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.3) ] . Changes in selected laboratory values during treatment of 107 pediatric subjects with PEGINTRON/REBETOL combination therapy are described in Table 10. Most of the changes in laboratory values in this trial were mild or moderate. Table 10: Selected Laboratory Abnormalities during Treatment Phase with PEGINTRON Plus REBETOL in Previously Untreated Pediatric Subjects Laboratory Parameter The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included. All Subjects (N=107) Hemoglobin (g/dL) 9.5 to <11.0 30% 8.0 to <9.5 2% WBC (× 10 9 /L) 2.0-2.9 39% 1.5 to <2.0 3% Platelets (× 10 9 /L) 70-100 1% 50 to <70 — 25 to <50 1% Neutrophils (× 10 9 /L) 1.0-1.5 35% 0.75 to <1.0 26% 0.5 to <0.75 13% <0.5 3% Total Bilirubin 1.26-2.59 × ULN ULN=Upper limit of normal. 7% Evidence of Hepatic Failure — 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Approximately 2% of subjects receiving PEGINTRON (32/1759) or INTRON A (11/728) with or without REBETOL developed low-titer (less than or equal to 160) neutralizing antibodies to PEGINTRON or INTRON A. The clinical and pathological significance of the appearance of serum-neutralizing antibodies is unknown. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PEGINTRON with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PEGINTRON therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders Pure red cell aplasia, thrombotic thrombocytopenic purpura Cardiac Disorders Palpitations, pericarditis Ear and Labyrinth Disorders Hearing loss, vertigo, hearing impairment Endocrine Disorders Diabetic ketoacidosis, diabetes Eye Disorders Vogt-Koyanagi-Harada syndrome, serous retinal detachment Gastrointestinal Disorders Aphthous stomatitis, tongue pigmentation General Disorders and Administration Site Conditions Asthenic conditions (including asthenia, malaise, fatigue) Immune System Disorders Cases of acute hypersensitivity reactions (including anaphylaxis, angioedema, urticaria); Stevens-Johnson syndrome, toxic epidermal necrolysis, systemic lupus erythematosus, erythema multiforme Infections and Infestations Bacterial infection including sepsis, Hepatitis B virus reactivation in HCV/HBV co-infected patients Metabolism and Nutrition Disorders Dehydration, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis, myositis Nervous System Disorders Seizures, memory loss, peripheral neuropathy, paraesthesia, migraine headache Psychiatric Disorders Homicidal ideation Respiratory, Thoracic, and Mediastinal Disorders Pulmonary hypertension, pulmonary fibrosis Renal and Urinary Disorders Renal failure, renal insufficiency Skin and Subcutaneous Tissue Disorders Psoriasis Vascular Disorders Hypertension, hypotension