home > drugs a-z list > peg-intron (peginterferon alfa-2b) drug center > peg-intron (peginterferon alfa-2b) drug - side effects and drug interactions

Clinical trials with PegIntron (peginterferon alfa-2b) alone or in combination with REBETOL have been conducted in over 6900 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 BOXED WARNING, WARNINGS AND PRECAUTIONS]. The most common serious events occurring in subjects treated with PegIntron (peginterferon alfa-2b) and REBETOL were depression and suicidal ideation [see WARNINGS AND PRECAUTIONS], each occurring at a frequency of less than 1%. The most common fatal events occurring in subjects treated with PegIntron (peginterferon alfa-2b) and REBETOL were cardiac arrest, suicidal ideation, and suicide attempt [see WARNINGS AND PRECAUTIONS], 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 (peginterferon alfa-2b) or PegIntron (peginterferon alfa-2b) / 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.

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.

Adults

Study 1 compared PegIntron (peginterferon alfa-2b) monotherapy with INTRON® A monotherapy. Study 2 compared combination therapy of PegIntron (peginterferon alfa-2b) /REBETOL with combination therapy with INTRON A/ REBETOL. In these studies, nearly all study subjects in clinical trials experienced one or more adverse reactions. Study 3 compared a PegIntron (peginterferon alfa-2b) /weight-based REBETOL combination to a PegIntron (peginterferon alfa-2b) /flat-dose REBETOL regimen. Study 4 compared 2 PegIntron (peginterferon alfa-2b) (1.5 mcg/kg/week and 1 mcg/kg/week) doses 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 > 5%incidence are provided in Table 8 by treatment group. Due to potential differences in ascertainment procedures, adverse reaction rate comparisons across studies should not be made. Table9 summarizes the treatment-related/treatment emergent adverse reactions in Study 4 that occurred at a ≥ 10% incidence.

TABLE 8: Adverse Reactions Occurring in > 5%of Subjects

TABLE 9: Summary of Treatment-related/Treatment-emergent Adverse Reactions ( ≥ 10%Incidence) By Descending Frequency

The adverse reaction profile in Study 3, which compared PegIntron (peginterferon alfa-2b) /weight-based REBETOL combination to a PegIntron (peginterferon alfa-2b) /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 studies. In the PEG 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 (peginterferon alfa-2b) /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 with 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 which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron (peginterferon alfa-2b) monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PegIntron (peginterferon alfa-2b) /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 who received PegIntron (peginterferon alfa-2b) /REBETOL combination therapy, 5 in the PegIntron (peginterferon alfa-2b) 1.5 mcg/REBETOL arm (N=1019) and 1 in the PegIntron (peginterferon alfa-2b) 1mcg/REBETOL arm(N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides which occurred during the off-treatment follow-up period in subjects who received PegIntron (peginterferon alfa-2b) (1.5 mcg/kg)/REBETOL combination therapy.

In Studies 1 and 2, 10%to 14%of subjects receiving PegIntron (peginterferon alfa-2b) , 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 (peginterferon alfa-2b) in combination with weight-based REBETOL and 14%of subjects receiving PegIntron (peginterferon alfa-2b) 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 (peginterferon alfa-2b) 1.5 mcg/REBETOL arm, 10% in the PegIntron (peginterferon alfa-2b) 1 mcg/REBETOL arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PegIntron (peginterferon alfa-2b) (1.5mcg/kg)/REBETOL and in 34%of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (peginterferon alfa-2b) (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PegIntron (peginterferon alfa-2b) 1.5 mcg/kg > PegIntron (peginterferon alfa-2b) 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all 3 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 WBD compared to flat dosing (29%and 23%, respectively). In Study 4, 16%of subjects had a dose reduction of PegIntron (peginterferon alfa-2b) to 1 mcg/kg in combination with REBETOL, with an additional 4%requiring the second dose reduction of PegIntron (peginterferon alfa-2b) to 0.5mcg/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% in the Pegasys/Copegus armrequiring a second dose reduction to 90mcg/week with Pegasys.

In the PegIntron (peginterferon alfa-2b) /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] . In Study 4, psychiatric adverse reactions occurred in 58% of subjects in the PegIntron (peginterferon alfa-2b) 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron (peginterferon alfa-2b) 1 mcg/REBETOL arm, and 57%of subjects in the Pegasys 180 mcg/Copegus arm.

PegIntron (peginterferon alfa-2b) 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) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron (peginterferon alfa-2b) 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 (peginterferon alfa-2b) 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 ≤ 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 (peginterferon alfa-2b) /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 study, 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 study 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; 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations.

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 ≥ 10% incidence in the pediatric trial subjects are provided in Table 10.

TABLE 10: Percentage of Pediatric Subjects With Treatment-emergent/Treatment-related Adverse Reactions (in at Least 10%of All Subjects)

Laboratory Values

Adults: Changes in selected laboratory values during treatment with PegIntron (peginterferon alfa-2b) 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 and WARNINGS AND PRECAUTIONS].

Hemoglobin: Hemoglobin levels decreased to < 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 < 11 g/dL. Reductions in hemoglobin to < 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 (peginterferon alfa-2b) /REBETOL and INTRON A/REBETOL groups. In Study 4, patients receiving PegIntron (peginterferon alfa-2b) (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to < 10 g/dL (28%) and to < 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects, respectively. Hemoglobin levels become 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 (peginterferon alfa-2b) mono therapy trial, hemoglobin decreases were generally mild, and dose modifications were rarely necessary [see DOSAGE AND ADMINISTRATION].

Neutrophils: Decreases in neutrophil counts were observed in a majority of subjects treated with PegIntron (peginterferon alfa-2b) alone (70%) or as combination therapy with REBETOL in Study 2 (85%) and INTRON A/ REBETOL (60%). Severe potentially life-threatening neutropenia ( < 0.5 x 10⁹/L) occurred in 1% of subjects treated with PegIntron (peginterferon alfa-2b) monotherapy, 2%of subjects treated with INTRON A/REBETOL, and in approximately 4% of subjects treated with PegIntron (peginterferon alfa-2b) /REBETOL in Study 2. Two percent of subjects receiving PegIntron (peginterferon alfa-2b) monotherapy and 18% of subjects receiving PegIntron (peginterferon alfa-2b) /REBETOL in Study 2 required modification of interferon dosage. Few subjects ( < 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pretreatment levels 4 weeks after cessation of therapy [see DOSAGE AND ADMINISTRATION].

Platelets: Platelet counts decreased to < 100,000/mm³ in approximately 20%of subjects treated with PegIntron (peginterferon alfa-2b) alone or with REBETOL and in 6%of subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts ( < 50,000/mm³) occur in < 4% of subjects. Patients may require discontinuation or dose modification as a result of platelet decreases [see DOSAGE AND ADMINISTRATION]. In Study 2, 1%or 3%of subjects required dose modification of INTRON A or PegIntron (peginterferon alfa-2b) , 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].

Thyroid Function: Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or PegIntron (peginterferon alfa-2b) (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].

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]. Changes in selected laboratory values during treatment of 107 pediatric subjects with PegIntron (peginterferon alfa-2b) /REBETOL combination therapy are described in Table 11.Most of the changes in laboratory values in this study were mild or moderate.

TABLE 11: Selected Hematological Abnormalities During Treatment Phase with PegIntron (peginterferon alfa-2b) Plus REBETOL in Previously Untreated Pediatric Subjects

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Approximately 2% of subjects receiving PegIntron (peginterferon alfa-2b) (32/1759) or INTRON A (11/728) with or without REBETOL developed low-titer ( ≤ 160) neutralizing antibodies to PegIntron (peginterferon alfa-2b) 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 (peginterferon alfa-2b) with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of PegIntron (peginterferon alfa-2b) 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

Ear and Labyrinth Disorders

hearing loss, vertigo, hearing impairment

Endocrine disorders

diabetic ketoacidosis, diabetes

Eye Disorders

Vogt-Koyanagi-Harada syndrome

Gastrointestinal Disorders

aphthous stomatitis

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

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

Renal and Urinary Disorders

renal failure, renal insufficiency

Skin and Subcutaneous Tissue Disorders

psoriasis

Vascular Disorders

hypertension, hypotension

Drugs Metabolized by Cytochrome P-450

When administering PegIntron (peginterferon alfa-2b) with medications metabolized by CYP2C8/9 (e.g., warfarin and phenytoin) or CYP2D6 (e.g., flecainide), the therapeutic effect of these substrates may be decreased [see CLINICAL PHARMACOLOGY].

Methadone

PegIntron (peginterferon alfa-2b) may increase methadone concentrations [see CLINICAL PHARMACOLOGY]. The clinical significance of this finding is unknown; however, patients should bemonitored for the signs and symptoms of increased narcotic effect.

Use with Ribavirin (Nucleoside Analogues)

Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV coinfected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Adding treatment with alpha interferons alone or in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation 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 observed, including hepatic decompensation (e.g., Child-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 alpha, no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was seen when ribavirin was coadministered with zidovudine, lamivudine, or stavudine in HIV/HCV coinfected subjects [see CLINICAL PHARMACOLOGY].

HIV/HCV coinfected subjects who were administered zidovudine in combination with pegylated interferon alpha and ribavirin developed severe neutropenia (ANC < 500) and severe anemia (hemoglobin < 8 g/dL) more frequently than similar subjects not receiving zidovudine.

Didanosine

Coadministration 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/lactic acidosis have been reported in clinical trials [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 7/10/2009
This monograph has been modified to include the generic and brand name in many instances.