PEGASYS in combination with COPEGUS causes a broad variety of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. The most common serious or life-threatening adverse reactions induced or aggravated by COPEGUS/PEGASYS 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].
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.
In the pivotal registration trials NV15801 and NV15942, 886 patients received COPEGUS 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 PEGASYS alone or in combination with COPEGUS. 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 PEGASYS in combination with COPEGUS 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 PEGASYS and/or COPEGUS therapy. The most common reason for dose modification of PEGASYS 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 COPEGUS in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).
PEGASYS dose was reduced in 12% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 7% of patients receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 12% of patients receiving 800 mg COPEGUS for 24 weeks.
Chronic hepatitis C monoinfected patients treated for 24 weeks with PEGASYS and 800 mg COPEGUS 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 PEGASYS (30% vs. 36%) and COPEGUS (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with PEGASYS and 1000 mg or 1200 mg COPEGUS. 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
|PEGASYS 180 mcg + 1000 mg or 1200 mg COPEGUS
|Intron A + 1000 mg or 1200 mg Rebetol®
|Application Site Disorders|
|Injection site reaction||23||16|
|Flu-like Symptoms and Signs|
|Metabolic and Nutritional|
|Musculoskeletal, Connective Tissue and Bone|
|Dizziness (excluding vertigo)||14||14|
|Resistance Mechanism Disorders|
|Respiratory, Thoracic and Mediastinal|
|Skin and Subcutaneous Tissue|
|* Severe hematologic abnormalities (lymphocyte less than 500 cells/mm³; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm³; platelet less than 50,000 cells/mm³).|
In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS alone or in combination with COPEGUS, 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 PEGASYS and COPEGUS 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 PEGASYS and COPEGUS 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 PEGASYS plus COPEGUS combination therapy group (hyperglycemia and cholecystectomy).
Growth inhibition was observed in pediatric subjects. During combination therapy for up to 48 weeks with PEGASYS and COPEGUS, 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].
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)
|System Organ Class||Study NV17424|
|PEGASYS 180 mcg/1.73 m² x BSA + COPEGUS 15 mg/kg
|PEGASYS 180 mcg/1.73 m² x BSA + Placebo**
|General disorders and administration site conditions|
|Influenza like illness||91||81|
|Injection site reaction||44||42|
|Nervous system disorders|
|Skin and subcutaneous tissue disorders|
|Musculoskeletal, connective tissue and bone disorders|
|Metabolism and nutrition disorders|
|* Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.
**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.
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 PEGASYS/COPEGUS 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
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 COPEGUS and PEGASYS 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].
Table 7 : Selected Laboratory Abnormalities During Treatment With COPEGUS in Combination With Either PEGASYS or Intron A
|Laboratory Parameter||PEGASYS + Ribavirin 1000/1200 mg 48 wks
|Intron A + Ribavirin 1000/1200 mg 48 wks
|1,000 < 1,500||34%||38%|
|500 < 1,000||49%||21%|
|50,000 - < 75,000||11%||4%|
|20,000 - < 50,000||5%||< 1%|
|< 8.5||2%||< 1%|
Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see DOSAGE AND ADMINISTRATION]. 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||PEGASYS 180 mcg/1.73 m² x BSA + COPEGUS 15 mg/kg
|PEGASYS 180 mcg/1.73 m² x BSA + Placebo*
|1,000 - < 1,500||31%||39%|
|750 - < 1,000||27%||17%|
|500 - < 750||25%||15%|
|75,000 - < 100,000||4%||2%|
|50,000 - < 75,000||0%||2%|
|8.5 - < 10||7%||3%|
|* 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.|
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/mm³ and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.
The following adverse reactions have been identified and reported during post-approval use of PEGASYS/COPEGUS 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
Serous retinal detachment
Liver and renal graft rejection
Metabolism and Nutrition disorders
Skin and Subcutaneous Tissue disorders
Stevens-Johnson Syndrome (SJS)
Toxic epidermal necrolysis (TEN)