Experience from clinical trials:
The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a. The most frequently reported adverse reactions with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.
Chronic Hepatitis B: In clinical trials of 48 week treatment and 24 weeks follow-up, the safety profile for Pegasys in chronic hepatitis B was similar to that seen in chronic hepatitis C, although the frequency of reported adverse reactions was notably less in CHB (see Table 18). Eighty eight (88%) percent of Pegasys-treated patients experienced adverse reactions, as compared to 53% of patients in the lamivudine comparator group, while 6% of the Pegasys treated and 4% of the lamivudine treated patients experienced serious adverse events during the studies. Five percent of patients withdrew from Pegasys treatment due to adverse events or laboratory abnormalities, while less than 1% withdrew from lamivudine treatment for safety reasons. The withdrawal rates for patients with cirrhosis were similar to those of the overall population in each treatment group. The addition of lamivudine had no effect on the safety profile of Pegasys.
Chronic Hepatitis C: In clinical trials, the incidence of withdrawal from treatment for all patients due to adverse events and laboratory abnormalities was 9% for Pegasys monotherapy and 13% for Pegasys in combination with Copegus (ribavirin) 1000/1200 mg given for 48 weeks. Respectively, only 1% or 3% of patients required discontinuation of either Pegasys or Pegasys/ribavirin for laboratory abnormalities. The withdrawal rates for patients with cirrhosis were similar to those of the overall population. In comparison to 48 weeks of treatment with Pegasys and Copegus 1000/1200 mg, reducing treatment exposure to 24 weeks and daily dose of Copegus to 800 mg resulted in a reduction in serious adverse events (11% vs 3%), premature withdrawals for safety reasons (13% vs 5%) and the need for Copegus dose modification (39% vs 19%).
Chronic Hepatitis C prior non-responder patients:
In a clinical trial which included 72 and 48 weeks treatments of prior pegylated interferon alfa-2b/ribavirin non-responder patients, the frequency of withdrawal from Pegasys treatment was 12% and Copegus treatment was 13% due to adverse events or laboratory abnormalities, for patients in the 72-week arms. In comparison, in 48 week treatment arms, 6% withdrew from Pegasys and 7% withdrew from Copegus treatment. Similarly for patients with cirrhosis, withdrawal rates from Pegasys and Copegus treatment were higher in the 72-week treatment arms, (13% and 15%) compared to the 48-week arms which were (6% and 6%). Patients who withdrew from previous therapy due to hematological toxicity were excluded from enrolling in this trial.
In another clinical trial, patients with advanced fibrosis or cirrhosis (Ishak score of 3 to 6) who had not responded to previous treatment were enrolled with baseline platelet counts as low as 50,000/mm3
and treated for 48 weeks. Due to a high prevalence of the advanced cirrhosis/fibrosis state and the low baseline platelet counts among patients in this study, the frequency of haematologic lab abnormalities in the first 20 weeks of the trial were as follows: hemoglobin <10 g/dL, 26.3%;, ANC <750/mm3
, 30%;, and platelet <50,000/mm3
HIV-HCV Co-infection: In HIV-HCV co-infected patients, the clinical adverse events reported on Pegasys, alone or in combination with Copegus, were similar to that observed in HCV mono-infected patients. Limited safety data (N= 51) is available in co-infected patients with CD4+ cell counts <200/μl. In study NR15961, the incidence of withdrawal from treatment for clinical adverse events, laboratory abnormalities or AIDS-defining events was 16% for Pegasys monotherapy, and 15% for Pegasys in combination with Copegus 800 mg, given for 48 weeks. Respectively, 4% or 3% of patients required discontinuation of Pegasys or Pegasys/Copegus for laboratory abnormalities. In combination therapy, Pegasys dose modification occurred in 39%, and Copegus dose modification occurred in 37%, of the co-infected patients. Serious adverse events were reported in 21% and 17% of those receiving Pegasys monotherapy or in combination with Copegus, respectively.
Pegasys containing treatment was associated with an on-treatment reduction in absolute CD4+ cell count without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. Pegasys containing treatment had no apparent negative impact on the control of HIV viremia during therapy or follow-up.
Table 17 summarises the safety overview of different treatment regimens of Pegasys in combination with ribavirin for HCV and HIV-HCV patients. (See Table 17.)
Click on icon to see table/diagram/image
Table 18 shows those adverse reactions occurring in ≥ 10% of patients who have received Pegasys, Pegasys plus ribavirin or interferon alfa-2b plus ribavirin in different indications. (See Tables 18 and 19.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Adverse reactions reported in ≥1% but <10% on Pegasys/Copegus combination or Pegasys monotherapy in HBV, HCV and HIV-HCV patients were: Infections and Infestations:
Herpes simplex, URI infection, bronchitis, oral candidiasis.
Blood and the lymphatic system disorders:
Lymphadenopathy, anemia, thrombocytopenia.
Memory impairment, taste disturbance, paraesthesia, hypoesthesia, tremor, weakness, emotional disorders, mood alteration, nervousness, aggression, libido decreased, migraine, somnolence, hyperesthesia, nightmares, syncope.
Vision blurred, xerophthalmia, eye inflammation, eye pain.
Ear and labyrinth disorders:
Palpitations, edema peripheral, tachycardia.
Respiratory, thoracic and mediastinal disorders:
Sore throat, rhinitis, nasopharyngitis, sinus congestion, dyspnea exertional, epistaxis.
Vomiting, dyspepsia, flatulence, dry mouth, mouth ulceration, gingival bleeding, stomatitis, dysphagia, glossitis.
Skin and subcutaneous tissue disorders:
Skin disorder, rash, eczema, psoriasis, urticaria, photosensitivity reaction, sweating increased, night sweats.
Musculoskeletal, connective tissue and bone disorders:
Bone pain, back pain, neck pain, muscle cramps, muscle weakness, musculoskeletal pain, arthritis.
Reproductive system and breast disorders:
General disorders and administration site conditions:
Influenza-like illness, malaise, lethargy, hot flushes, chest pain, thirst.
Other adverse reactions reported in ≥ 1% to ≤ 2% of HIV-HCV patients receiving Pegasys/Copegus combination included: hyperlactacidemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia.
As with other alpha interferon therapies, uncommon to rare cases of the following serious adverse events have been reported in patients receiving Pegasys/ribavirin combination or Pegasys monotherapy during clinical trials: lower respiratory tract infection, skin infection, otitis externa, endocarditis, suicide, substance overdose, hepatic dysfunction, fatty liver, cholangitis, malignant hepatic neoplasm, peptic ulcer, gastrointestinal bleeding, pancreatitis, arrhythmia, atrial fibrillation, pericarditis, autoimmune phenomena (e.g., ITP, thyroiditis, psoriasis, rheumatoid arthritis, SLE), myositis, peripheral neuropathy, sarcoidosis, interstitial pneumonitis with fatal outcome, pulmonary embolism, corneal ulcer, coma, cerebral hemorrhage, TTP, psychotic disorder, and hallucination.
Based on cumulative data set, rarely, alpha interferon including Pegasys, used alone or in combination with Copegus, may be associated with pancytopenia, and very rarely, aplastic anemia has been reported. For HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects have been reported in ≥ 1% to ≤ 2% of patients: hyperlactacidemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia.
For combination therapy in HCV patients, please refer also to the approved ribavirin prescribing information for the effects of ribavirin on laboratory parameters.
As with other interferons, treatment with either Pegasys or Pegasys/ribavirin was associated with decreases in hematological values, which generally improved with dosage modification and returned to pretreatment levels within 4 to 8 weeks upon cessation of therapy (see Dosage & Administration and Precautions). Although hematological toxicities of neutropenia, thrombocytopenia and anemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment.
Hemoglobin and hematocrit:
Although treatment with Pegasys monotherapy was associated with small gradual decreases in hemoglobin and hematocrit, less than 1% of all patients, including those with cirrhosis, required dose modification for anemia. Approximately 10% of patients on 48 weeks Pegasys/ribavirin 1000/1200 mg combination therapy required dose modification for anemia. Anemia (hemoglobin < 10g/dL) was reported in 7% and 14% of HIV-HCV co-infected patients treated with Pegasys monotherapy or in combination with Copegus, respectively.
White blood cells:
Pegasys treatment was associated with decreases in values for both total WBC count and ANC. Approximately 4% of HBV or HCV patients receiving Pegasys and 5% of HCV patients receiving Pegasys/ribavirin had transient decreases in ANC to levels below 500 cells/mm3
at some time during therapy. In HIV-HCV co-infected patients, 13% and 11% of those receiving Pegasys monotherapy and combination therapy, respectively, had decreases in ANC levels below 500 cells/mm3
Pegasys treatment was associated with decreases in values for platelet counts. In clinical trials, approximately 5% of patients had decreases in platelet counts to levels below 50,000/mm3
, mostly in patients with cirrhosis and who entered the study with baseline platelet counts as low as 75,000/mm3
. In clinical trials for hepatitis B, 14% of patients had decreases in platelet counts to below 50,000/mm3
, mostly in patients who entered the study with low baseline platelet counts. In HIV-HCV patients, 10% and 8% of those receiving Pegasys monotherapy and combination therapy, respectively, had decreases in platelets below 50,000/mm3
Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention (see Precautions). The frequencies observed with Pegasys were similar to those observed with other interferons.
Triglyceride levels are found to be elevated in patients receiving alpha interferon therapy, including Pegasys.
Three percent of HCV patients (25/835) receiving Pegasys with or without Copegus (ribavirin) developed low-titer neutralizing anti-interferon antibodies. 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.
Laboratory values for HIV-HCV co-infected patients:
Although hematological toxicities of neutropenia, thrombocytopenia and anemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm3
was observed in 13% and 11% of patients receiving Pegasys monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm3
was observed in 10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. Anemia (hemoglobin < 10g/dL) was reported in 7% and 14% of patients treated with Pegasys monotherapy or in combination therapy, respectively.
During the post-marketing period, erythema multiforme, Stevens Johnson Syndrome, toxic epidermal necrolysis, pure red cell aplasia (PRCA) and homicidal ideation have been reported very rarely with combination therapy of Pegasys and ribavirin.
Dehydration has been reported rarely with combination therapy of Pegasys and ribavirin.
As with other alpha interferons, serous retinal detachment has been reported with Pegasys and Copegus combination therapy.
As with other alpha interferons, liver and renal graft rejections have been reported on Pegasys, alone or in combination with Copegus.
Adverse reactions reported in a post-marketing setting are: tongue pigmentation.
Facial palsy has been reported with Pegasys.
Respiratory, thoracic and mediastinal disorders: Pulmonary arterial hypertension (Frequency unknown).
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis).
Events were reported at various time points typically several months after starting treatment with interferon alfa.