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These highlights do not include all the information needed to use PEGASYS safely and effectively. See full prescribing information for PEGASYS. PEGASYS® (peginterferon alfa-2a)Injection for Subcutaneous UseInitial U.S. Approval: 2002 | Pegasys

05:38 EDT 27th August 2014 | BioPortfolio
Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Alpha interferons, including PEGASYS (peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy [see Warnings and Precautions (5.2, 5.5, 5.8, 5.11, 5.14, 5.16), Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)].

Use with Ribavirin

Ribavirin, including COPEGUS, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. [See COPEGUS Package Insert for additional information and other WARNINGS.]

PEGASYS, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Efficacy has been demonstrated in subjects with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and in adult subjects with clinically stable HIV disease and CD4 count greater than 100 cells/mm.

The following points should be considered when initiating therapy with PEGASYS and COPEGUS:

PEGASYS is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B infection who have compensated liver disease and evidence of viral replication and liver inflammation.

PEGASYS is administered by subcutaneous injection in the abdomen or thigh. See COPEGUS Package Insert for all instructions regarding COPEGUS dosing and administration.

Adult Patients

PEGASYS Monotherapy:

The recommended dose of PEGASYS monotherapy for chronic hepatitis C is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly for 48 weeks.

PEGASYS/COPEGUS Combination Therapy:

The recommended dose of PEGASYS when used in combination with ribavirin for chronic hepatitis C is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly. The recommended dose of COPEGUS and duration for PEGASYS/COPEGUS therapy is based on viral genotype (see Table 1 ).

The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses.

COPEGUS should be taken with food.

Table 1 PEGASYS and COPEGUS Dosing Recommendations
Hepatitis C virus Genotype PEGASYS Dose
(once weekly)
COPEGUS Dose
(daily)
Duration
Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 13 ).
Data on genotypes 5 and 6 are insufficient for dosing recommendations.
Genotypes 1, 4 180 mcg <75 kg = 1000 mg
≥75 kg = 1200 mg
48 weeks
48 weeks
Genotypes 2, 3 180 mcg 800 mg 24 weeks

Pediatric Patients

PEGASYS/COPEGUS Combination Therapy:

PEGASYS is administered as 180 mcg/1.73 m × BSA subcutaneously once weekly, to a maximum dose of 180 mcg, and should be given in combination with COPEGUS. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

COPEGUS is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. COPEGUS should be administered with food. The recommended doses for COPEGUS are provided in Table 2 . Patients who initiate treatment prior to their 18 birthday should maintain pediatric dosing through the completion of therapy.

Table 2 COPEGUS Dosing Recommendations for Pediatric Patients
Body Weight in kilograms (kg) COPEGUS Daily Doseapproximately 15 mg/kg/day COPEGUS Number of Tablets
23 – 33 400 mg/day 1 × 200 mg tablet A.M.
1 × 200 mg tablet P.M.
34 – 46 600 mg/day 1 × 200 mg tablet A.M.
2 × 200 mg tablets P.M.
47 – 59 800 mg/day 2 × 200 mg tablets A.M.
2 × 200 mg tablets P.M.
60 – 74 1000 mg/day 2 × 200 mg tablets A.M.
3 × 200 mg tablets P.M.
≥75 1200 mg/day 3 × 200 mg tablets A.M.
3 × 200 mg tablets P.M.

Adult Patients

PEGASYS Monotherapy:

The recommended dose of PEGASYS monotherapy for chronic hepatitis C in patients coinfected with HIV is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly for 48 weeks.

PEGASYS/COPEGUS Combination Therapy:

The recommended dose when used in combination with ribavirin is PEGASYS 180 mcg once weekly and COPEGUS 800 mg orally daily given in two divided doses for a total of 48 weeks, regardless of genotype.

Since COPEGUS absorption increases when administered with a meal, patients are advised to take COPEGUS with food.

Adult Patients

PEGASYS Monotherapy:

The recommended dose of PEGASYS monotherapy for hepatitis B is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly for 48 weeks.

If severe adverse reactions or laboratory abnormalities develop during combination PEGASYS/COPEGUS therapy, the dose should be modified until the adverse reactions abate. If intolerance persists after dose adjustment, PEGASYS/COPEGUS therapy should be discontinued. Table 3, Table 4, Table 5, and Table 6 provide guidelines for dose modifications and discontinuation of PEGASYS/COPEGUS based on laboratory abnormalities, patient's depression status, and cardiac status.

Adult Patients

When dose modification of PEGASYS is required for adverse reactions (clinical and/or laboratory), initial dose reduction to 135 mcg (which is 0.75 mL for the vials or adjustment to the corresponding graduation mark for the prefilled syringes) is recommended. Dose modification to 135 mcg per week can also be achieved by using a 135 mcg/0.5 mL strength disposable autoinjector. Dose reduction to 90 mcg (which is 0.5 mL for the vials or adjustment to the corresponding graduation mark for the prefilled syringes) may be needed if the adverse reaction persists or recurs. Following improvement of the adverse reaction, re-escalation of the dose may be considered [see Warnings and Precautions (5) and Adverse Reactions (6)].

Table 3 PEGASYS Hematological Dose Modification Guidelines
Laboratory Values Recommended Dose
ANC <750 cells/mm3 Reduce to 135 mcg
ANC <500 cells/mm3 Discontinue treatment until ANC values return to more than 1000 cells/mm3. Reinstitute at 90 mcg and monitor ANC.
Platelet <50,000 cells/mm3 Reduce to 90 mcg
Platelet <25,000 cells/mm3 Discontinue treatment
Table 4 Guidelines for Modification or Discontinuation of PEGASYS and for Scheduling Visits for Adult Patients with Depression
Depression Severity Initial Management
(4-8 weeks)
Depression Status
Dose modification Visit schedule Remains stable Improves Worsens
Mild No change Evaluate once weekly by visit and/or phone Continue weekly visit schedule Resume normal visit schedule (See moderate or severe depression)
Moderate Decrease PEGASYS dose to 135 mcg (in some cases dose reduction to 90 mcg may be needed) Evaluate once weekly (office visit at least every other week) Consider psychiatric consultation. Continue reduced dosing If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced dosing or return to normal dose (See severe depression)
Severe Discontinue PEGASYS permanently Obtain immediate psychiatric consultation Psychiatric therapy necessary

Pediatric Patients

If toxicities occur which may be related to PEGASYS or COPEGUS administration, the dose of one or both drugs can be modified. Additionally, COPEGUS or PEGASYS plus COPEGUS combination therapy can be discontinued. COPEGUS should never be given as monotherapy. Recommendations for dose modifications in pediatric patients for toxicities associated with PEGASYS administration are presented in Table 5 .

When dose modification is required for moderate to severe adverse reactions (clinical or laboratory), modification to 135 mcg/1.73 m × BSA is generally adequate. However, in some cases, dose modification to 90 mcg/1.73 m × BSA or 45 mcg/1.73 m × BSA may be needed. Up to 3 dose modifications for toxicity can be made before discontinuation is considered. These modifications apply to pediatric patients with depression, who can be managed similar to the algorithm for adult patients outlined in Table 4 .

Guidelines for dose modification based on neutropenia, increased ALT levels, and decreased platelet counts for pediatric patients are provided in Table 5.

Table 5 PEGASYS Dose Modification for Neutropenia, Increased ALT and Decreased Platelets in Pediatric Patients
PEGASYS Dose Modification
Neutropenia 750-999 cells/mm3: Week 1-2 — immediate modification to 135 mcg/1.73 m2 × BSA; Week 3-48: no modification.
500-749 cells/mm3: Week 1-2 — delay or hold dose until >750 cells/mm3 then resume dose with a modification to 135 mcg/1.73 m2 × BSA, assess weekly × 3 to verify WBC's >750 cells/mm3; Week 3-48 — immediate modification to 135 mcg/1.73 m2 × BSA.
250-499 cells/mm3: Week 1-2 — delay or hold dose until >750 cells/mm3 then resume dose with a modification to 90 mcg/1.73 m2 × BSA; Week 3-48 — delay or hold dose until >750 cells/mm3 then resume dose with a modification to 135 mcg/1.73 m2 × BSA.
<250 cells/mm3 (or febrile neutropenia): discontinue treatment.
Increased alanine transaminase (ALT) For persistent or increasing elevations ≥5 but <10 × ULN, modify dose with a modification to 135 mcg/1.73 m2 × BSA. Monitor weekly, further modifying dose if necessary, until stable or ALT level decreases.
For persistent ALT values ≥10 × ULN discontinue treatment.
Decreased platelet count Platelet <50,000 cells/mm3: Modify dose to 90 mcg/1.73 m2 × BSA.

COPEGUS Dose Modifications

See COPEGUS Package Insert for all instructions regarding COPEGUS dosing and administration.

Adult and Pediatric Patients

The guidelines for COPEGUS dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Table 6 COPEGUS Dose Modification Guidelines for Adults and Pediatric Patients
Body weight in
kilograms (kg)
Laboratory Values
Hemoglobin <10 g/dL in patients with no cardiac disease, or
 
Decrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease
Hemoglobin <8.5 g/dL in patients with no cardiac disease, or
 
Hemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease
Adult Patients older than 18 years of age
Any weight 1 × 200 mg tablet A.M.
2 × 200 mg tablets P.M.
Discontinue COPEGUS
Pediatric Patients 5 to 18 years of age
23 – 33 kg 1 × 200 mg tablet A.M. Discontinue COPEGUS
34 – 46 kg 1 × 200 mg tablet A.M.
1 × 200 mg tablet P.M.
47 – 59 kg 1 × 200 mg tablet A.M.
1 × 200 mg tablet P.M.
60 – 74 kg 1 × 200 mg tablet A.M.
2 × 200 mg tablets P.M.
≥75 kg 1 × 200 mg tablet A.M.
2 × 200 mg tablets P.M.

Adult Patients

Once COPEGUS has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that COPEGUS be increased to the original dose (1000 mg or 1200 mg).

Pediatric Patients

Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in COPEGUS dose to the original dose may be attempted depending upon the physician's judgment. If COPEGUS has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at one-half the full dose.

In patients with CrCL less than 30 mL/min, including patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 mcg PEGASYS is recommended. Signs and symptoms of interferon toxicity should be closely monitored. If severe adverse reactions or laboratory abnormalities develop, the dose of PEGASYS may be reduced to 90 mcg until the adverse reactions abate. If intolerance persists after dose adjustment, PEGASYS/COPEGUS therapy should be discontinued.

Renal function should be evaluated in all patients on COPEGUS. The dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal to 50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].

No data are available for pediatric subjects with renal impairment.

Table 7 Dose Modification for Renal Impairment
Creatinine Clearance PEGASYS Dose
(once weekly)
COPEGUS Dose
(daily)
30 to 50 mL/min 180 mcg Alternating doses, 200 mg and 400 mg every other day
< 30 mL/min 135 mcg 200 mg daily
Hemodialysis 135 mcg 200 mg daily

Adult Patients

If ALT increases are progressive despite dose reduction or accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be immediately discontinued.

In chronic hepatitis C patients with progressive ALT increases above baseline values, the dose of PEGASYS should be reduced to 135 mcg and more frequent monitoring of liver function should be performed. After PEGASYS dose reduction or withholding, therapy can be resumed after ALT flares subside.

In chronic hepatitis B patients with elevations in ALT (greater than 5 × ULN), more frequent monitoring of liver function should be performed and consideration should be given to either reducing the dose of PEGASYS to 135 mcg or temporarily discontinuing treatment. After PEGASYS dose reduction or withholding, therapy can be resumed after ALT flares subside.

In adult patients with persistent, severe (ALT greater than 10 times above the upper limit of normal) hepatitis B flares, consideration should be given to discontinuation of treatment.

Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log reduction from baseline in HCV RNA titer by 12 weeks of therapy or undetectable HCV RNA after 24 weeks of therapy [see Clinical Studies (14)].

During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation is observed [see Contraindications (4)].

Patients should be monitored for serious adverse reactions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn [see Boxed Warning].

A patient should self-inject PEGASYS only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and has been trained in proper injection technique [see illustrated FDA Approved Medication Guide for directions on injection site preparation and injection instructions].

PEGASYS should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Vials, prefilled syringes, and disposable autoinjectors with particulate matter or discoloration should be returned to the pharmacist.

Discard the unused portion of PEGASYS in single-use vials or prefilled syringes in excess of the labeled volume. Use only one vial or prefilled syringe or disposable autoinjector per dose.

PEGASYS is contraindicated in patients with:

PEGASYS is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants.

PEGASYS/COPEGUS combination therapy is additionally contraindicated in:

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 have their therapy withdrawn [see Boxed Warning].

Pregnancy

COPEGUS may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking PEGASYS and COPEGUS combination therapy. COPEGUS therapy should not be started unless a report of a 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 Boxed Warning, Contraindications (4), Patient Counseling Information (17) and COPEGUS Package Insert].

Anemia

The primary toxicity of COPEGUS is hemolytic anemia. Hemoglobin less than 10 g/dL was observed in approximately 13% of COPEGUS and PEGASYS treated subjects in chronic hepatitis C clinical trials. The anemia associated with COPEGUS occurs within 1 to 2 weeks of initiation of therapy with maximum drop in hemoglobin observed during the first eight weeks. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pre-treatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by COPEGUS. Patients should be assessed for underlying cardiac disease before initiation of COPEGUS therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.6)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS [see COPEGUS Package Insert].

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 Adverse Reactions (6.1) and Dosage and Administration (2.5)].

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/COPEGUS [see Warnings and Precautions (5.1) and COPEGUS Package Insert].

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 pre-treatment and monitored routinely during therapy [see Warnings and Precautions (5.1)].

PEGASYS/COPEGUS should be used with caution in patients with baseline neutrophil counts less than 1,500 cells/mm, with baseline platelet counts less than 90,000 cells/mm or 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 (2.6)].

Severe neutropenia and thrombocytopenia occur with a greater incidence in HIV coinfected patients than monoinfected patients and may result in serious infections or bleeding [see Adverse Reactions (6.1)].

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, COPEGUS, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7)].

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.

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 alfa-based 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.

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 6 [see Clinical Studies (14.3)], 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/COPEGUS treatment should be immediately discontinued in patients with hepatic decompensation [see Contraindications (4)].

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 (6.1) and Dosage and Administration (2.5)].

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.

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/COPEGUS should be suspended if symptoms or signs suggestive of pancreatitis are observed. PEGASYS/COPEGUS 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/COPEGUS 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 (6.2)].

Pediatric subjects treated with PEGASYS plus COPEGUS combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

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/COPEGUS 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/COPEGUS.

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:

In clinical trials, a broad variety of serious adverse reactions were observed in 1,010 subjects who received PEGASYS at doses of 180 mcg for 48 weeks, alone or in combination with COPEGUS [see Boxed Warning and Warnings and Precautions (5)]. The most common life-threatening or fatal events induced or aggravated by PEGASYS and COPEGUS include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects [see Warnings and Precautions (5.9)].

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in 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.

Adult Subjects

In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in combination with COPEGUS. The most common serious adverse reactions (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of less than 1% and included: suicide, suicidal ideation, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

In clinical trials, 98 to 99 percent of subjects experienced one or more adverse reactions. For hepatitis C subjects, the most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 8 displays pooled rates of adverse reactions occurring in greater than 5% of subjects in the PEGASYS monotherapy and PEGASYS/COPEGUS combination therapy clinical trials.

Overall 11% of CHC monoinfected subjects receiving 48 weeks of therapy with PEGASYS either alone or in combination with COPEGUS discontinued therapy; 16% of CHC/HIV coinfected subjects discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders, and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of subjects with CHC or CHC/HIV required modification of PEGASYS and/or COPEGUS therapy. The most common reasons for dose modification of PEGASYS in CHC and CHC/HIV subjects was for neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of COPEGUS in CHC and CHC/HIV subjects was anemia (22% and 16%, respectively). PEGASYS dose was reduced in 12% of subjects receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 7% of subjects receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of subjects receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 12% of subjects receiving 800 mg COPEGUS for 24 weeks.

Chronic hepatitis C monoinfected subjects treated for 24 weeks with PEGASYS and 800 mg COPEGUS were observed to have lower incidence of serious adverse reactions (3% vs. 10%), Hgb less than 10 g/dL (3% vs. 15%), dose modification of PEGASYS (30% vs. 36%) and COPEGUS (19% vs. 38%) and of withdrawal from treatment (5% vs. 15%) compared to subjects treated for 48 weeks with PEGASYS and 1000 mg or 1200 mg COPEGUS. The overall incidence of adverse reactions appeared to be similar in the two treatment groups.

Table 8 Adverse Reactions Occurring in Greater Than or Equal to 5% of Subjects in Chronic Hepatitis C Clinical Trials (Pooled Studies 1, 2, 3, and Study 4)
CHC Monotherapy (Pooled Studies 1-3) CHC Combination Therapy (Study 4)
Body System PEGASYS 180 mcg
48 weekPooled studies 1, 2, and 3
ROFERON-A Either 3 MIUAn induction dose of 6 million international units (MIU) three times a week for the first 12 weeks followed by 3 million international units three times a week for 36 weeks given subcutaneously. or 6/3 MIU of ROFERON-A
48 week
PEGASYS 180 mcg + 1000 mg or 1200 mg COPEGUS
48 weekStudy 4
Intron® A + 1000 mg or 1200 mg Rebetol ®
48 week
N=559 N=554 N=451 N=443
% % % %
Application Site Disorders
Injection site reaction 22 18 23 16
Endocrine Disorders
Hypothyroidism 3 2 4 5
Flu-like Symptoms and Signs
Fatigue/Asthenia 56 57 65 68
Pyrexia 37 41 41 55
Rigors 35 44 25 37
Pain 11 12 10 9
Gastrointestinal
Nausea/Vomiting 24 33 25 29
Manufacturer

Genentech, Inc.

Active Ingredients

Source

Drugs and Medications [3 Associated Drugs and Medications listed on BioPortfolio]

Copegus [Genentech, Inc.]

These highlights do not include all the information needed to use COPEGUS safely and effectively. See full prescribing information for COPEGUS. COPEGUS (ribavirin) Tablets Initial U.S. Approval: 2002

Rebetol [Schering Corporation]

These highlights do not include all the information needed to use REBETOL safely and effectively. See full prescribing information for REBETOL.REBETOL (ribavirin, USP) Capsules, Oral SolutionInitial U...

Pegintron [Schering Corporation]

These highlights do not include all the information needed to use PegIntron safely and effectively. See full prescribing information for PegIntron. PegIntron (Peginterferon alfa-2b) Injection, Powder ...

Clinical Trials [130 Associated Clinical Trials listed on BioPortfolio]

A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) in Patients With HBeAg Positive Chronic Hepatitis B (CHB).

This 4 arm study will compare the efficacy and safety of PEGASYS given for 24 or 48 weeks, and at doses of 90 or 180 micrograms weekly, in the treatment of HBeAg positive patients with chr...

A Study of RO5024048 in Combination With Pegasys and Copegus in Treatment-Naive Patients With Chronic Hepatitis C, Genotype 1 or 4

This 6-arm study will assess the efficacy and safety of RO5024048 (R7128) in co mbination with the approved doses of Pegasys (180micrograms sc weekly) + Copegus (1000/1200mg po daily) (SO...

A Study of Early Immunologic Response in Asian Patients With Chronic Hepatitis B, Treated With Pegasys (Peginterferon Alfa-2a (40KD)), Nucleoside Analogues, or Both

This open-label, randomized, parallel-arm study will assess the early immunologi c response in treatment-naïve Asian male patients with chronic hepatitis B after initiation of treatment w...

Trial of Pegasys® in Patients With Chronic Hepatitis C

The purpose of this study is to investigate the efficacy and safety of Pegasys® 180μg for subcutaneous (s.c.) injection in interferon (IFN)-treated or IFN-untreated chronic hepatitis C p...

IMPROVE Study(The Individualized Management With PEGASYS and Ribavirin Offering Viral Eradication): A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) Plus Copegus (Ribavirin) in Patients With Chronic Hepatitis C (CHC) Non-Genotype 2/3.

This study will compare the efficacy and safety of 48 weeks and 72 weeks treatme nt with PEGASYS plus ribavirin in patients with non-genotype 2/3 chronic hepatit is C who, after 12 weeks o...

PubMed Articles [1 Associated PubMed Articles listed on BioPortfolio]

PROSPECTIVE OBSERVATIONAL COHORT STUDY OF PREDICTORS OF THE EFFECTIVENESS OF PEGYLATED INTERFERON IN PATIENTS WITH HEPATITIS C IN GEORGIA.

The main objective of the study was to evaluate the predictive values of virological response at 4th and 12th weeks after treatment initiation on sustained virological response by HCV genotype in pati...

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