Pegintron and Rebetol
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PegIntron and Rebetol Combo Pack
PegIntron and Rebetol Combo Pack
- Clinician Information:
Pegintron and Rebetol Side Effects Center
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Pegintron and Rebetol FDA Prescribing Information: Side Effects
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1-4 weeks of therapy. Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients. (See WARNINGS.)
Clinical Trial Experience
Clinical Study 1 evaluated Peglntron monotherapy. See Peglntron Powder for Injection Package Insert for information about this study.
Study 2 compared combination therapy of Peglntron™/REBETOL® with combination therapy with INTRON® A/REBETOL®. In this study, nearly all study patients in clinical trials experienced one or more adverse events. As shown in Table 4 the most common adverse events ( > 5%) in this study were comparable for both the Peglntron™/REBETOL® and INTRON® A/REBETOL® combination therapies.
Table 4: Adverse Events Occurring in > 5% of
|Adverse Events||Percentage of Patients Reporting Adverse Events* Study 2|
|Peglntron™ 1.5 mcg/kg/ REBETOL®
|Autonomic Nervous Sys.|
|Body as a Whole|
|Central/Periph. Nerv. Sys.|
|Liver and Biliary System|
|Skin and Appendages|
|Special Senses Other,|
|*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.|
The adverse event profile in Study 3, which compared Peglntron/weight-based REBETOL combination to a Peglntron/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 events was comparable in all studies. In Study 2, the incidence of serious adverse events was 17% in the Peglntron™/REBETOL® group. In Study 3, there was a similar incidence of serious adverse events reported for the weight-based REBETOL® group (12%) and with the flat dose REBETOL® regimen.
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. There have been 19 patient deaths which occurred during treatment or during follow-up in these clinical trials. There was one suicide in a patient receiving Peglntron monotherapy and two deaths among patients receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was one suicide in a patient receiving Peglntron/REBETOL combination therapy; and 1 patient death in the INTRON A/REBETOL group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of which were probable suicides and one was an unexplained death in a person with a relevant medical history of depression.
In Study 2, 14% of patients receiving Peglntron™ in combination with REBETOL®, discontinued therapy compared with 13% treated with INTRON® A in combination with REBETOL®. Similarly in Study 3, 15% of patients receiving Peglntron™ in combination with weight-based REBETOL® and 14% of patients receiving Peglntron™ and flat dose REBETOL® discontinued therapy. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse events.
In Study 2, dose reductions due to adverse reactions occurred in 42% of patients receiving Peglntron™ (1.5 mcg/kg)/REBETOL® and in 34% of those receiving INTRON® A/REBETOL®. The majority of patients (57%) weighing 60 kg or less receiving Peglntron™ (1.5 mcg/kg)/REBETOL® required dose reduction. Reduction of interferon was dose related (Peglntron 1.5 mcg/kg > Peglntron 0.5 mcg/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 Study 3, dose modifications due to adverse events occurred more frequently with WBD compared flat dosing (29% and 23%, respectively).
In the Peglntron™/REBETOL® combination trials, the most common adverse events were psychiatric which occurred among 77% of patients in Study 2 and 68-69% of patients in Study 3. These psychiatric adverse events 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).
Peglntron™ induces fatigue or headache in approximately two-thirds of patients, with fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues.
In Study 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with Peglntron™ therapies (in up to 75% of patients) compared with INTRON® A. However, injection site pain was infrequent (2-3%) in all groups. In Study 3 there was a 23-24% incidence overall for injection site reactions or inflammation.
In Study 2, 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 Peglntron™ 1.5/REBETOL® group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for Gl). 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, and phototoxicity.
Changes in selected laboratory values during treatment with Peglntron™ 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 levels decreased to < 11 g/dL in about 30% of patients in Study 2. In Study 3, 47% of patients receiving WBD REBETOL® and 33% on flat dose REBETOL® had decreases in hemoglobin levels < 11 g/dL. Reduction in hemoglobin to < 9 g/dL occurred more frequently in patients receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of patients in the Peglntron™/REBETOL® and INTRON® A/REBETOL® groups. 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. Hemoglobin levels return to baseline between 4 and 12 weeks posttreatment (see DOSAGE AND ADMINISTRATION: Dose Reduction).
Decreases in neutrophil counts were observed in a majority of patients treated with Peglntron™/REBETOL® combination therapy (85%) and INTRON® A/REBETOL® (60%) in Study 2. Severe potentially life-threatening neutropenia ( < 0.5 x 109/L) occurred in 2% of patients treated with INTRON® A/REBETOL®, and in approximately 4% of patients treated with Peglntron™/REBETOL®. In Study 2, 18% of patients receiving Peglntron™/REBETOL® required modification of interferon dosage. Few patients ( < 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)
Platelet counts decreased to < 100,000/mm³ in approximately 20% of patients treated with Peglntron™/REBETOL® and in 6% of patients treated with INTRON® A/REBETOL®. Severe decreases in platelet counts ( < 50,000/mm³) occur in < 4% of patients. Patients may require discontinuation or dose modification as a result of platelet decreases. (See DOSAGE AND ADMINISTRATION: Dose Reduction.) In Study 2, 1% or 3% of patients required dose modification of INTRON® A or Peglntron™, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.
Elevated triglyceride levels have been observed in patients treated with interferon alphas including Peglntron™.
Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among patients treated with either INTRON® A or Peglntron™ (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 Study 2, 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 postapproval use of Peglntron™ therapy: aphthous stomatitis, erythema multiforme, hearing impairment, hearing loss, memory loss, migraine headache, myositis, peripheral neuropathy, renal insufficiency, renal failure, rhabdomyolysis, seizures, Stevens Johnson syndrome, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, and vertigo. In addition, the following adverse reactions have been identified during use with Peglntron™/REBETOL® combination therapy: hearing disorder, aplastic anemia and pure red cell aplasia. 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.
Approximately 2% of patients receiving Peglntron™ (32/1759) or INTRON® A (11/728) with or without REBETOL® developed low-titer ( < 160) neutralizing antibodies to Peglntron™ or INTRON® A. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. The incidence of posttreatment-binding antibody ranged from 8 to 15 percent. The data reflect the percentage of patients whose test results were considered positive for antibodies to Peglntron™ in a Biacore assay that is used to measure binding antibodies, and in an antiviral neutralization assay, which measures serumneutralizing 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 Peglntron™ with the incidence of antibodies to other products may be misleading.
Read the entire FDA prescribing information for Pegintron and Rebetol (Peginterferon alfa-2b and Ribavirin Combo Pack) »
Additional PegIntron and Rebetol Combo Pack Information
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