PEGASYS alone or in combination with COPEGUS causes a broad variety of serious adverse reactions (see BOXED WARNING and WARNINGS). The most common life- threatening or fatal events induced or aggravated by PEGASYS and COPEGUS were depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV patients (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations).

In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients and in 19% of CHC/HIV patients 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 SAEs occurred at a frequency of <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, and thrombotic thrombocytopenic purpura.

Nearly all patients in clinical trials experienced one or more adverse events. For hepatitis C patients, 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.

Overall 11% of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS either alone or 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%), Hgb <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.

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. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice.

Table 6 Adverse Reactions Occurring in ≥5% of Patients in Chronic Hepatitis C Clinical Trials (Pooled Studies 1, 2, 3, and 726 Study 4)

† Pooled studies 1, 2, and 3
Either 3 MIU or 6/3 MIU of ROFERON-A
**Study 4
† Severe hematologic abnormalities (lymphocyte <0.5 x 109 /L; hemoglobin <10 g/dL; neutrophil <0.75 x 109/L; platelet <50 x 109/L).

The adverse event profile of coinfected patients treated with PEGASYS and COPEGUS in Study 6 was generally similar to that shown for monoinfected patients in Study 4 (Table 6). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

In clinical trials of 48 week treatment duration, the adverse event profile of PEGASYS in chronic hepatitis B was similar to that seen in chronic hepatitis C PEGASYS monotherapy use, except for exacerbations of hepatitis (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations). Six percent of PEGASYS treated patients in the hepatitis B studies experienced one or more serious adverse events.

The most common or important serious adverse events in the hepatitis B studies were infections (sepsis, appendicitis, tuberculosis, influenza), hepatitis B flares, anaphylactic shock, thrombotic thrombocytopenic purpura.

The most commonly observed adverse reactions 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%) in the PEGASYS and lamivudine groups respectively.

Overall 5% of hepatitis B patients discontinued PEGASYS therapy and 40% of patients required modification of PEGASYS dose. The most common reason for dose modification in patients receiving PEGASYS therapy was for laboratory abnormalities including neutropenia (20%), thrombocytopenia (13%), and ALT disorders (11%).

The laboratory test values observed in the hepatitis B trials (except where noted below) were similar to those seen in the PEGASYS monotherapy hepatitis C trials.

Neutrophils

In the hepatitis C studies, decreases in neutrophil count below normal were observed in 95% of all patients treated with PEGASYS either alone or in combination with COPEGUS. Severe potentially life-threatening neutropenia (ANC <0.5 x 109/L) occurred in 5% of CHC patients and 12% of CHC/HIV patients receiving PEGASYS either alone or in combination with COPEGUS. Modification of PEGASYS dose for neutropenia occurred in 17% of patients receiving PEGASYS monotherapy and 22% of patients receiving PEGASYS/COPEGUS combination therapy. In the CHC/HIV patients 27% required modification of interferon dosage for neutropenia. Two percent of patients with CHC and 10% of patients with CHC/HIV required permanent reductions of PEGASYS dosage and <1% required permanent discontinuation. Median neutrophil counts return to pre-treatment levels 4 weeks after cessation of therapy (see DOSAGE AND ADMINISTRATION: Dose Modifications).

Lymphocytes

Decreases in lymphocyte count are induced by interferon alpha therapy. PEGASYS plus COPEGUS combination therapy induced decreases in median total lymphocyte counts (56% in CHC and 40% in CHC/HIV, with median decrease of 1170 cells/mm³ in CHC and 800 cells/mm³ in CHC/HIV). In the hepatitis C studies, lymphopenia was observed during both monotherapy (81%) and combination therapy with PEGASYS and COPEGUS (91%). Severe lymphopenia (<0.5 x 10⁹/L) occurred in approximately 5% of all monotherapy patients and 14% of all combination PEGASYS and COPEGUS 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/mm³) and CD8 counts decreased by 44% from baseline (median decrease of389cells/mm³) in the PEGASYS plus COPEGUS 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 patients and 51% of CHC/HIV patients treated with PEGASYS alone (respectively median decrease of 41% and 35% from baseline), and in 33% of CHC patients and 47% of CHC/HIV patients receiving combination therapy with COPEGUS (median decrease of 30% from baseline). Moderate to severe thrombocytopenia (<50,000/mm³) was observed in 4% of CHC and 8% of CHC/HIV patients. 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 patients. Severe anemia (Hgb <10 g/dL) was encountered in 13% of all patients receiving combination therapy and in 2% of CHC patients and 8% of CHC/HIV patients receiving PEGASYS monotherapy. Dose modification for anemia in COPEGUS recipients treated for 48 weeks occurred in 22% of CHC patients and 16% of CHC/HIV patients (see DOSAGE AND ADMINISTRATION:Dose Modifications).

Triglycerides

Triglyceride levels are elevated in patients receiving alfa interferon therapy and were elevated in the majority of patients participating in clinical studies receiving either PEGASYS alone or in combination with COPEGUS. Random levels ≥400 mg/dL were observed in about 20% of CHC patients. Severe elevations of triglycerides (>1000 mg/dL) occurred in 2% of CHC monoinfected patients.

In HCV/HIV coinfected patients, fasting levels ≥400 mg/dL were observed in up to 36% of patients receiving either PEGASYS alone or in combination with COPEGUS. Severe elevations of triglycerides (>1000 mg/dL) occurred in 7% of coinfected patients.

ALT Elevations

One percent of patients 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: Dose Modifications).

Transient ALT elevations are common during hepatitis B therapy with PEGASYS. Twenty-five percent and 27% of patients experienced elevations of 5 to 10 x ULN and 12% and 18% had elevations of >10 x 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 patients had dose modifications due to ALT flares and <1% of patients were withdrawn from treatment (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations and DOSAGE AND ADMINISTRATION: Dose Modifications).

ALT flares of 5 to 10 x ULN occurred in 13% and 16% of patients, while ALT flares of >10 x ULN occurred in 7% and 12% of patients in HBeAg negative and HBeAg positive disease, respectively, after discontinuation of PEGASYS therapy.

Thyroid Function

PEGASYS alone or in combination with COPEGUS 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 patients and 4% and 2% of PEGASYS and COPEGUS treated patients, respectively. Approximately half of the patients, who developed thyroid abnormalities during PEGASYS treatment, still had abnormalities during the follow-up period (see PRECAUTIONS: Laboratory Tests).

Immunogenicity

Chronic Hepatitis C

Nine percent (71/834) of patients treated with PEGASYS with or without COPEGUS developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Three percent of patients (25/835) receiving PEGASYS with or without COPEGUS, 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 patients treated with PEGASYS for 24 weeks developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Thirteen percent of patients (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 patients whose test results were considered positive for antibodies is highly dependent on the sensitivity and specificity of the assays.

Additionally, the observed incidence of antibody positivity in these assays may be influenced by several factors including sample timing and handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PEGASYS with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of PEGASYS therapy: hearing impairment, hearing loss. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting or (3) strength of causal connection to PEGASYS.

Theophylline

Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS (see CLINICAL PHARMACOLOGY: Drug Interactions).

Methadone

In a PK study of HCV patients concomitantly receiving methadone, treatment with PEGASYS once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline (see CLINICAL PHARMACOLOGY: Drug Interactions). The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity.

Nucleoside Analogues

NRTIs

In Study 6 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations).

Patients receiving PEGASYS/COPEGUS and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening toxicities are observed (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION: Dose Modifications).

Didanosine

Co-administration of COPEGUS and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions).

Zidovudine

In Study 6, patients who were administered zidovudine in combination with PEGASYS/COPEGUS developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%).

Lamivudine, Stavudine, and Zidovudine

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs such as lamivudine, stavudine, and zidovudine. No evidence of a pharmacokinetic or pharmacodynamic interaction was seen when ribavirin was co- administered with lamivudine, stavudine, and/or zidovudine in HIV/HCV coinfected patients (see CLINICAL PHARMACOLOGY: Drug Interactions).

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