Nearly all study patients in clinical trials experienced one or more adverse events. In the PEG monotherapy trial the incidence of serious adverse events was similar (about 12%) in all treatment groups. In the PEG-Intron/ REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-Intron/REBETOL groups compared to 14% in the INTRON A/REBETOL group.

In many but not all cases, adverse events resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse events during the 6-month follow-up period. In the PEG-Intron/REBETOL trial 13 patients experienced life-threatening psychiatric events (suicidal ideation or attempt) and one patient accomplished suicide.

There have been five patient deaths which occurred in clinical trials: one suicide in a patient receiving PEG-Intron monotherapy and one suicide in a patient receiving PEG-Intron/REBETOL combination therapy; two deaths among patients receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death) and one patient death in the INTRON A/REBETOL group (motor vehicle accident).

Overall, 10-14% of patients receiving PEG-Intron, 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. The most common reasons for discontinuation of therapy were related to psychiatric, systemic (eg, fatigue, headache), or gastrointestinal adverse events.

In the combination therapy trial, dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-Intron (1.5 mg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of patients (57%) weighing 60 kg or less receiving PEG-Intron (1.5 mg/kg)/REBETOL required dose reduction. Reduction of interferon was dose related (PEG-Intron 1.5 mg/kg >PEG-Intron 0.5 mg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three groups, 33-35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia.

In the PEG-Intron/REBETOL combination trial the most common adverse events were psychiatric which occurred among 77% of patients and included most commonly depression, irritability, and insomnia, each reported by approximately 30-40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all patients during treatment or during follow-up after treatment cessation (see WARNINGS).

PEG-Intron induced fatigue or headache in approximately two-thirds of patients, and induced fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (eg, fever and headache) tended to decrease as treatment continues. The incidence tends to be higher with PEG-Intron than with INTRON A therapy alone or in combination with REBETOL.

Application site inflammation and reaction (eg, bruise, itchiness, irritation) occurred at approximately twice the incidence with PEG-Intron therapies (in up to 75% of patients) compared with INTRON A. However injection site pain was infrequent (2-3%) in all groups.

Other common adverse events in the PEG-Intron/REBETOL group included myalgia (56%), arthralgia (34%), nausea (43%), anorexia (32%), weight loss (29%), alopecia (36%), and pruritus (29%).

In the PEG-Intron monotherapy trial the incidence of severe adverse events was 13% in the INTRON A group and 17% in the PEG-Intron groups. In the PEG-Intron/REBETOL combination therapy trial the incidence of severe adverse events was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-Intron/REBETOL groups. The incidence of life-threatening adverse events was ≤ 1% across all groups in the monotherapy and combination therapy trials.

Adverse events that occurred in the clinical trial at >5% incidence are provided in Table 3 by treatment group. Due to potential differences in ascertainment procedures, adverse event rate comparisons across studies should not be made.

Table 3. Adverse Events Occurring in > 5% of Patients

*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.

Many patients continued to experience adverse events several months after discontinuation of therapy. By the end of the 6-month follow-up period the incidence of ongoing adverse events by body class in the PEG-Intron 1.5/ REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10-15% of patients weight loss, fatigue, and headache had not resolved.

Individual serious adverse events occurred at a frequency ≤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, phototoxicity.

Changes in selected laboratory values during treatment with PEG-Intron 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: Dose Reduction.)

Hemoglobin. REBETOL induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to <11 g/dL in about 30% of patients. Severe anemia (<8 g/dL) occurred in <1% of patients. Dose modification was required in 9 and 13% of patients in the PEG-Intron/REBETOL and INTRON A/REBETOL groups. Hemoglobin levels become stable by treatment week 4-6 on average. Hemoglobin levels return to baseline between 4 and 12 weeks post-treatment. In the PEG-Intron monotherapy trial hemoglobin decreases were generally mild and dose modifications were rarely necessary. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)

Neutrophils. Decreases in neutrophil counts were observed in a majority of patients treated with PEG-Intron alone (70%) or as combination therapy with REBETOL (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (<0.5 x 10⁹/L) occurred in 1% of patients treated with PEG-Intron monotherapy, 2% of patients treated with INTRON A/REBETOL and in 4% of patients treated with PEG-Intron/REBETOL. Two percent of patients receiving PEG-Intron monotherapy and 18% of patients receiving PEG-Intron/REBETOL required modification of interferon dosage. Few patients (< 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels within 4 weeks of cessation of therapy. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)

Platelets. Platelet counts decrease in approximately 20% of patients treated with PEG-Intron alone or with REBETOL and in 6% of patients treated with INTRON A/REBETOL. Severe decreases in platelet counts (<50,000/mm³) occur in <1% of patients. Patients may require discontinuation or dose modification as a result of platelet decreases. (See DOSAGE AND ADMINISTRATION: Dose Reduction.) In the PEG-Intron/REBETOL combination therapy trial 1% or 3% of patients required dose modification of INTRON A or PEG-Intron respectively. Platelet counts generally returned to pretreatment levels within 4 weeks of the cessation of therapy.

Triglycerides. Elevated triglyceride levels have been observed in patients treated with interferon alfas including PEG-Intron.

Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. Clinically apparent thyroid disorders occur among patients treated with either INTRON A or PEG-Intron (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.

Bilirubin and uric acid. In the PEG-Intron/REBETOL trial 10-14% of patients developed hyperbilirubinemia and 33-38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout.

The following adverse reactions have been identified and reported during post-approval use of PEG-Intron therapy: aphthous stomatitis, erythema multiforme, hearing impairment, hearing loss, memory loss, migraine headache, peripheral neuropathy, renal insufficiency, renal failure, rhabdomyolysis, seizures, Stevens Johnson syndrome, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, vertigo. Because the reports of these reactions are voluntary and the population of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Immunogenicity: Approximately 2% of patients receiving PEG-Intron (32/1759) or INTRON A (11/728) with or with-out REBETOL developed low-titer (≤160) neutralizing antibodies to PEG-Intron or INTRON A. 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 incidence of post-treatment binding antibody ranged from 8 to 15 percent. The data reflect the percentage of patients whose test results were considered positive for antibodies to PEG-Intron in a Biacore assay that is used to measure binding antibodies, and in an antiviral neutralization assay, which measures serum-neutralizing antibodies. 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 PEG-Intron with the incidence of antibodies to other products may be misleading.

Caution should be used when administering PEG-Intron with medications metabolized by CYP2C8/9 (e.g., warfarin and phenytoin) or CYP2D6 (e.g., flecainide) (see CLINICAL PHARMACOLOGY : Drug Interactions ).

In a pharmacokinetic study of 18 chronic hepatitis C patients concomitantly receiving methadone, treatment with PEG-Intron once weekly for 4 weeks was associated with a mean increase of 16% in methadone AUC; in 2 out of 18 patients, methadone AUC doubled (see CLINICAL PHARMACOLOGY: Drug Interactions). The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of increased narcotic effect.

Hepatic decomposition (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa and ribavirin. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and Nucleotide Reverse Transcriptase Inhibitors (NRTIs) should be closely monitored for treatment associated toxicities, especially hepatic decomposition and anemia. Discontinuation of NRTIs should be considered as medically appropriate (see Individual NRTI Product Information). Dose reduction or discontinuation of interferon, ribavirin or both should also be considered if worsening clinical toxicities are obseved, inculding hepatic decompensation (e.g., Childs Pugh > 6).

Stavudine, Lamivudine and Zidovudine: In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine, lamivudine and zidovudine, In a study with another pegylated interferon alfa, no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was seen when ribavirin was co-administered with zidovudine, lamivudine or stavudine in HIV/HCV coinfected patients (See CLINICAL PHARMACOLOGY: Drug Interactions).

Although there was no evidence of loss of HIV/HCV virologic suppression when ribavirin was co-administered with zidovudine HIV/HCV co-infected patients who were administered zidovudine in combination with pegylated interferon alfa and ribavirin developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8g/dl) more frequently than similar patients not receiving zidovudine.

Didanosine: Co-administration of REBETOL Capsules or Oral Solution and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/latic acidosis have been reported in clinical trials (See CLINICAL PHARMACOLOGY: Drug Interactions).

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