"The European Medicines Agency (EMA) has launched a review of the six direct-acting antivirals approved for use in the European Union for treating chronic hepatitis C virus infection, the agency said today.
They are daclatasvir (Dak"...
Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should be withdrawn from therapy.
Use With Ribavirin
Ribavirin may cause birth defects and death of the unborn child. Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least 2 forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped [see CONTRAINDICATIONS and ribavirin labeling].
Ribavirin caused hemolytic anemia in 10% of PegIntron/REBETOL-treated subjects within 1 to 4 weeks of initiation of therapy. Complete blood counts should be obtained pretreatment and at Week 2 and Week 4 of therapy or more frequently if clinically indicated. Anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of ribavirin may be necessary [see DOSAGE AND ADMINISTRATION and ribavirin labeling].
Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior sometimes directed towards others have occurred in patients with and without a previous psychiatric disorder during PegIntron treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with interferon alpha.
PegIntron should be used with caution in patients with a history of psychiatric disorders. Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is initiated in patients with prior history or existence of psychiatric condition or with a history of substance use disorders, treatment considerations should include the need for drug screening and periodic health evaluation, including psychiatric symptom monitoring. Early intervention for re-emergence or development of neuropsychiatric symptoms and substance use is recommended.
Patients should be advised to report immediately any symptoms of depression or suicidal ideation to their prescribing physicians. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation or aggressive behavior towards others is identified, discontinue treatment with PegIntron and follow the patient closely, with psychiatric intervention as appropriate. In severe cases, PegIntron should be stopped immediately and psychiatric intervention instituted [see DOSAGE AND ADMINISTRATION]. Cases of encephalopathy have been observed in some patients, usually elderly, treated at higher doses of PegIntron.
Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with PegIntron. PegIntron should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require PegIntron therapy should be closely monitored [see Laboratory Tests]. Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron/ribavirin combination therapy [see ribavirin labeling].
PegIntron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with PegIntron. Diabetes mellitus, including cases of new onset Type 1 diabetes, has been observed in patients treated with alpha interferons, including PegIntron.
Patients with these conditions who cannot be effectively treated by medication should not begin PegIntron therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue PegIntron therapy.
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Peginterferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PegIntron. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made, and a causal relationship between interferon alfa-based therapies and these events is difficult to establish.
Bone Marrow Toxicity
PegIntron suppresses bone marrow function, sometimes resulting in severe cytopenias. PegIntron should be discontinued in patients who develop severe decreases in neutrophil or platelet counts [see DOSAGE AND ADMINISTRATION]. Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia.
Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis) has been observed in patients receiving PegIntron.
PegIntron should be used with caution in patients with autoimmune disorders.
Fatal and nonfatal pancreatitis has been observed in patients treated with alpha interferon. PegIntron therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.
Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. PegIntron treatment should be discontinued immediately in patients who develop these signs and symptoms. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferons.
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure or patient deaths, may be induced or aggravated by PegIntron or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PegIntron combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.
Because of the fever and other “flu-like” symptoms associated with PegIntron administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease).
Chronic Hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PegIntron. Cirrhotic CHC patients co-infected with HIV receiving highly active antiretroviral therapy (HAART) and alpha interferons with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients' clinical status and hepatic function should be closely monitored, and PegIntron treatment should be immediately discontinued if decompensation (Child-Pugh score greater than 6) is observed [see CONTRAINDICATIONS].
Patients With Renal Insufficiency
Increases in serum creatinine levels have been observed in patients with renal insufficiency receiving interferon alpha products, including PegIntron. Patients with impaired renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and PegIntron dosing should be adjusted accordingly or discontinued [see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION]. PegIntron monotherapy should be used with caution in patients with creatinine clearance less than 50 mL/min; the potential risks should be weighed against the potential benefits in these patients. Combination therapy with ribavirin must not be used in patients with creatinine clearance less than 50 mL/min [see ribavirin labeling].
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) and cutaneous eruptions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.
PegIntron alone or in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. Transient elevations in ALT (2-to 5-fold above baseline) were observed in 10% of subjects treated with PegIntron, and were not associated with deterioration of other liver functions. Triglyceride levels are frequently elevated in patients receiving alpha interferon therapy including PegIntron and should be periodically monitored.
Patients on PegIntron or PegIntron/REBETOL combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood counts (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at Weeks 2, 4, 8, and 12, and then at 6-week intervals, or more frequently if abnormalities developed. In pediatric subjects, the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment Week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see DOSAGE AND ADMINISTRATION].
Patients who have pre-existing cardiac abnormalities should have electrocardiograms done before treatment with PegIntron/ribavirin.
Dental And Periodontal Disorders
Dental and periodontal disorders have been reported in patients receiving PegIntron/REBETOL combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of REBETOL and PegIntron. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, patients should be advised to rinse out their mouth thoroughly afterwards.
Elevated triglyceride levels have been observed in patients treated with interferon alpha, including PegIntron therapy. Hypertriglyceridemia may result in pancreatitis [see Pancreatitis]. Elevated triglyceride levels should be managed as clinically appropriate. Discontinuation of PegIntron therapy should be considered for patients with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting, and persistently elevated triglycerides (e.g., triglycerides greater than 1000 mg/dL).
Impact On Growth — Pediatric Use
Data on the effects of PegIntron plus REBETOL on growth come from an open-label trial in 107 subjects, 3 through 17 years of age, in which weight and height changes are compared to US normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lags behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with REBETOL may induce a growth inhibition that results in reduced adult height in some patients [see ADVERSE REACTIONS].
Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated.
Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)
A patient should self-inject PegIntron only if it has been determined that it is appropriate, the patient agrees to medical follow-up as necessary, and training in proper injection technique has been given to him/her.
Patients must be informed that REBETOL (ribavirin) may cause birth defects and death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during treatment with combination PegIntron/ribavirin therapy and for 6 months post-therapy. Combination PegIntron/ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. It is recommended that patients undergo monthly pregnancy tests during therapy and for 6 months post-therapy [see CONTRAINDICATIONS, Use In Specific Populations, and ribavirin labeling].
Inform patients that there are no data regarding whether PegIntron therapy will prevent transmission of HCV infection to others. Also, it is not known if treatment with PegIntron will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.
Laboratory Evaluations, Hydration, “Flu-like” Symptoms
Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS]. It is advised that patients be well hydrated, especially during the initial stages of treatment. “Flu-like” symptoms associated with administration of PegIntron may be minimized by bedtime administration of PegIntron or by use of antipyretics.
Patients developing fever, cough, shortness of breath or other symptoms of a lung problem during treatment with PegIntron may need to have a chest X-ray or other tests to adequately treat them.
Instructions for Use
Patients receiving PegIntron should be directed in its appropriate preparation, handling, measurement, and injection, and referred to the Instructions for Use for PegIntron Powder for Solution and PegIntron REDIPEN Single-use Pre-filled pen.
Patients should be directed to store PegIntron before mixing as follows:
- PegIntron REDIPEN single-use pre-filled pens: store in the refrigerator between 36-46°F (2-8°C)
- PegIntron Powder for Solution: store at room temperature between 59-86°F (15-30°C)
Patients should be instructed on the importance of site selection for self-administering the injection, as well as the importance on rotating the injection sites.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis and Mutagenesis
PegIntron has not been tested for its carcinogenic potential. Neither PegIntron nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.
Use with Ribavirin: See ribavirin labeling for additional warnings relevant to PegIntron therapy in combination with ribavirin.
Impairment of Fertility
PegIntron may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 mcg/m² PegIntron alone every other day for 1 month (approximately 345 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of PegIntron treatment. Every other day dosing with 262 mcg/m² (approximately 21 times the weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of PegIntron on male fertility have not been studied.
Use In Specific Populations
Pregnancy Category C: Nonpegylated interferon alfa-2b has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). PegIntron should be assumed to also have abortifacient potential. There are no adequate and well-controlled trials in pregnant women. PegIntron therapy is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Therefore, PegIntron is recommended for use in fertile women only when they are using effective contraception during the treatment period.
Use with Ribavirin
Pregnancy Category X: Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant [see CONTRAINDICATIONSand ribavirin labeling].
A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
It is not known whether the components of PegIntron and/or ribavirin are excreted in human milk. Studies in mice have shown that mouse interferons are excreted in breast milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue the PegIntron and ribavirin treatment, taking into account the importance of the therapy to the mother.
Safety and effectiveness in pediatric patients below the age of 3 years have not been established. Clinical trials in pediatric subjects less than 3 years of age are not considered feasible due to the small proportion of patients in this age group requiring treatment for CHC.
Long-term follow-up data in pediatric subjects indicates that PegIntron in combination with REBETOL may induce a growth inhibition that results in reduced height in some patients [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
In general, younger patients tend to respond better than older patients to interferon-based therapies. Clinical trials of PegIntron alone or in combination with REBETOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Treatment with alpha interferons, including PegIntron, is associated with neuropsychiatric, cardiac, pulmonary, GI, and systemic (flu-like) adverse effects. Because these adverse reactions may be more severe in the elderly, caution should be exercised in the use of PegIntron in this population. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in patients with impaired renal function [see CLINICAL PHARMACOLOGY]. When using PegIntron/ ribavirin therapy, refer also to the ribavirin labeling.
Organ Transplant Recipients
The safety and efficacy of PegIntron alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. In a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center's previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.
HIV Or HBV Co-infection
The safety and efficacy of PegIntron/ ribavirin for the treatment of patients with HCV co-infected with HIV or HBV have not been established.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/1/2015
Additional Peg-Intron Information
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