"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"...
Refer to the prescribing information of the other HCV antiviral drugs, including ribavirin, for their WARNINGS AND PRECAUTIONS.
Pregnancy: Use With Ribavirin
Ribavirin may cause birth defects and/or death of the exposed fetus. Patients must avoid pregnancy (female patients or female partners of male patients) while taking PEGASYS and ribavirin combination therapy. Ribavirin therapy should not be started unless a confirmed negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time [see CONTRAINDICATIONS, PATIENT INFORMATION and ribavirin labeling].
Life-threatening or fatal neuropsychiatric reactions may manifest in all patients receiving therapy with PEGASYS and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. These reactions may occur in patients with and without previous psychiatric illness.
PEGASYS should be used with extreme caution in all patients who report a history of depression. Neuropsychiatric adverse events observed with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar disorders, and mania. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Patients should be advised to report any sign or symptom of depression or suicidal ideation to their prescribing physicians. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted [see BOXED WARNING, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].
Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients treated with PEGASYS. PEGASYS should be administered with caution to patients with pre-existing cardiac disease. Because cardiac disease may be worsened by ribavirin-induced anemia, patients with a history of significant or unstable cardiac disease should not receive PEGASYS/ribavirin [see ribavirin prescribing information].
Bone Marrow Suppression
PEGASYS suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including PEGASYS. Very rarely, alpha interferons may be associated with aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy [see ribavirin prescribing information].
PEGASYS/ribavirin should be used with caution in patients with baseline neutrophil counts less than 1,500 cells/mm³, with baseline platelet counts less than 90,000 cells/mm³or baseline hemoglobin less than 10 g/dL. PEGASYS therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts [see DOSAGE AND ADMINISTRATION].
Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PEGASYS, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.
Development or exacerbation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported in patients receiving alpha interferon. PEGASYS should be used with caution in patients with autoimmune disorders [see BOXED WARNING].
PEGASYS causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with PEGASYS. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin PEGASYS therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of PEGASYS 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 are induced or aggravated by treatment with PEGASYS or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing 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. PEGASYS 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 alfabased therapies, including PEGASYS. 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 [see BOXED WARNING].
Hepatic Failure And Hepatitis Exacerbations
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study 7 [see Clinical Studies], among 129 CHC/HIV cirrhotic subjects receiving HAART, 14 (11%) of these subjects across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 subjects were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs for the associated risk. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS/ribavirin treatment should be immediately discontinued in patients with hepatic decompensation [see CONTRAINDICATIONS].
Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation greater than 10-fold higher than the upper limit of normal) during PEGASYS treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive subjects, respectively. Marked transaminase flares while on PEGASYS therapy have been accompanied by other liver test abnormalities. Patients experiencing ALT flares should receive more frequent monitoring of liver function. PEGASYS dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of PEGASYS dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, PEGASYS should be immediately discontinued [see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by PEGASYS or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PEGASYS combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.
While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, or fungal), some fatal, have been reported during treatment with alpha interferons including PEGASYS. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered [see BOXED WARNING].
Ulcerative and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. PEGASYS should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.
Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. PEGASYS/ribavirin should be suspended if symptoms or signs suggestive of pancreatitis are observed. PEGASYS/ribavirin should be discontinued in patients diagnosed with pancreatitis.
Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with PEGASYS/ribavirin should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving PEGASYS with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see ADVERSE REACTIONS].
Impact On Growth In Pediatric Patients
During combination therapy for up to 48 weeks with PEGASYS plus ribavirin growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.
The available longer term data on subjects who were followed up to 6 years post-treatment is too limited to determine the risk of reduced adult height in some patients [see Clinical Trials Experience].
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 PEGASYS as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated.
Before beginning PEGASYS or PEGASYS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with PEGASYS/ribavirin.
After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In a pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of PEGASYS may be considered as a guideline to acceptable baseline values for initiation of treatment:
- Platelet count greater than or equal to 90,000 cells/mm³(as low as 75,000 cells/mm³in HCV subjects with cirrhosis or 70,000 cells/mm³in subjects with CHC and HIV)
- Absolute neutrophil count (ANC) greater than or equal to 1,500 cells/mm³
- Serum creatinine concentration less than 1.5 x upper limit of normal
- TSH and T4 within normal limits or adequately controlled thyroid function
- CD4+ cell count greater than or equal to 200 cells/mm³or CD4+ cell count greater than or equal to 100 cells/mm³but less than 200 cells/mm³and HIV-1 RNA less than 5,000 copies/mL in subjects coinfected with HIV
- Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected subjects
- Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in subjects with CHC and HIV
Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)
Patients receiving PEGASYS alone or in combination with an approved HCV antiviral drug should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to FDA-approved patient labeling (Medication Guideand Instructions for Use).
Patients must be informed that ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin therapy and for 6 months post-therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has been stopped; routine monthly pregnancy tests must be performed during this time [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations, and ribavirin prescribing information].
To monitor maternal and fetal outcomes of pregnant women exposed to ribavirin, the Ribavirin Pregnancy Registry has been established. Patients should be encouraged to register by calling 1-800-593-2214.
Laboratory Evaluations and Hydration
Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS]. Patients should be instructed to remain well hydrated, especially during the initial stages of treatment.
Patients should be questioned about prior history of drug abuse before initiating PEGASYS; as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.
Patients should be informed that it is not known if therapy with PEGASYS will prevent transmission of HBV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HBV infection.
Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken.
Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.
Patients should be advised to avoid drinking alcohol to reduce the chance of further injury to the liver.
Patients should not switch to another brand of interferon without consulting their healthcare provider.
Patients should be advised to take their prescribed dose of PEGASYS on the same day and approximately same time each week. Patients should also be advised that if they miss a dose, but remember within 2 days, to take their missed dose as soon as they remember and then to take their next dose on the day they normally do. If they remember when more than 2 days have passed, patients should be advised to consult their healthcare provider. Patients should also be advised to consult their healthcare provider if the full dose is not received (e.g., leakage around the injection site).
Patients must be instructed on the use of aseptic techniques when administering PEGASYS. Appropriate training for preparation using the vial, prefilled syringe or autoinjector must be given by a healthcare provider, including a careful review of the PEGASYS Medication Guide and Instructions for Use for the vial, prefilled syringe and autoinjector.
Patients should be instructed to allow the vial, prefilled syringe or autoinjector to come to room temperature and for condensation on the outside of the prefilled syringe or autoinjector to disappear before use. The following instructions should be given:
- Vial: warm the refrigerated medicine by gently rolling in the palms of the hands for about one minute.
- Pre-filled syringe: lay the syringe on a flat clean surface and wait a few minutes until it reaches room temperature. If condensation water is observed on the outside of the syringe, wait another few minutes until it disappears.
- Disposable autoinjector: place the autoinjector on a clean flat surface. Do not remove the cap at this time. Allow the autoinjector to come to room temperature for about 20 minutes to warm up. Do not warm up the autoinjector in any other way.
Patients should be advised not to shake the vial, prefilled syringe or autoinjector as foaming may occur.
Patients should be advised to choose a different place on either the thigh or abdomen each time an injection is made.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
PEGASYS has not been tested for its carcinogenic potential.
Use with other HCV antiviral drugs: Refer to the prescribing information for specific antiviral drugs used in combination with PEGASYS for additional warnings
PEGASYS did not cause DNA damage when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes, either in the presence or absence of metabolic activation.
Use with other HCV antiviral drugs: Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for additional warnings.
Impairment of Fertility
PEGASYS may impair fertility in women. Prolonged menstrual cycles and/or amenorrhea were observed in female cynomolgus monkeys given subcutaneous injections of 600 mcg/kg/dose (7200 mcg/m²/dose) of PEGASYS every other day for one month, at approximately 180 times the recommended weekly human dose for a 60 kg person (based on body surface area). Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17β-estradiol and progesterone levels following administration of PEGASYS to female monkeys. A return to normal menstrual rhythm followed cessation of treatment. Every other day dosing with 100 mcg/kg (1200 mcg/m²) PEGASYS (equivalent to approximately 30 times the recommended human dose) had no effects on cycle duration or reproductive hormone status.
The effects of PEGASYS on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys treated with non-pegylated interferon alfa-2a for 5 months at doses up to 25 x 106 IU/kg/day.
Use with other HCV antiviral drugs: Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for additional warnings.
Use In Specific Populations
Pregnancy Category C: PEGASYS Monotherapy
PEGASYS has not been studied for its teratogenic effect. Non-pegylated interferon alfa-2a treatment of pregnant Rhesus monkeys at approximately 20 to 500 times the human weekly dose resulted in a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. PEGASYS should be assumed to have abortifacient potential. There are no adequate and well-controlled studies of PEGASYS in pregnant women. PEGASYS is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. PEGASYS is recommended for use in women of childbearing potential only when they are using effective contraception during therapy.
Pregnancy Category X: Use with Ribavirin
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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ribavirin labeling].
Ribavirin Pregnancy Registry
A Ribavirin Pregnancy Registry has been established to monitor maternal and fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.
It is not known whether peginterferon or its components are excreted in human milk. The effect of orally ingested peginterferon from breast milk on the nursing infant has not been evaluated. Because of the potential for adverse reactions from the drugs in nursing infants, a decision must be made whether to discontinue nursing or discontinue PEGASYS.
The safety and effectiveness of PEGASYS, in patients below the age of 5 years have not been established.
PEGASYS contains benzyl alcohol. In neonates and infants, benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications which are sometimes fatal in neonates and infants [see CONTRAINDICATIONS].
Younger patients have higher virologic response rates than older patients. Clinical studies of PEGASYS alone or in combination with COPEGUS did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (e.g., flu-like) effects may be more severe in the elderly and caution should be exercised in the use of PEGASYS in this population. PEGASYS is excreted by the kidney, and the risk of toxic reactions to this therapy may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. PEGASYS should be used with caution in patients with creatinine clearance less than or equal to 50 mL/min. The dose of PEGASYS should be reduced for patients with creatinine clearance less than 30 mL/min [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score greater than or equal to 6) is observed [see CONTRAINDICATIONS]. Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation greater than 10-fold higher than the upper limit of normal) during PEGASYS treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive subjects, respectively.
Renal function should be evaluated in all patients prior to initiation of PEGASYS by estimating the patient's creatinine clearance.
A clinical trial evaluated treatment with PEGASYS and COPEGUS in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, PEGASYS was administered at a dose of 135 mcg once weekly. Dose reductions and temporary interruptions of PEGASYS (due to PEGASYS-related adverse reactions, mainly anemia) were observed in up to 22% ESRD/HD subjects during treatment; and 17% of these subjects discontinued PEGASYS due to PEGASYS-related adverse reactions. Only one-third of ESRD/HD subjects received PEGASYS for 48 weeks. Subjects with severe (n=14) or moderate (n=17) renal impairment received PEGASYS 180 mcg once weekly. PEGASYS discontinuation rates were 36% and 0% in subjects with severe and moderate renal impairment, respectively, compared to 0% discontinuation rate in subjects with normal renal function.
Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than 30 mL/min should receive a reduced dose of PEGASYS. In addition, patients with any degree of renal impairment should be carefully monitored for laboratory abnormalities (especially decreased hemoglobin) and adverse reactions, and should undergo careful monitoring of creatinine clearance. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]. Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for information on use in patients with renal impairment.
Organ Transplant Recipients
The safety and efficacy of PEGASYS treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on PEGASYS.
Chronic Hepatitis B
The safety and efficacy of PEGASYS have not been established in:
- Hepatitis B patients coinfected with HCV or HIV
- Hepatitis C patients coinfected with HBV or coinfected with HIV with a CD4+ cell count less than 100 cells/mm³
Last reviewed on RxList: 3/30/2015
Additional Pegasys Information
Pegasys - User Reviews
Pegasys User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find the secrets to longer life.