There are no safety and efficacy data on treatment of chronic hepatitis C or hepatitis B for longer than 48 weeks. For patients with hepatitis C, consideration should be given to discontinuing therapy after 12 to 24 weeks of therapy if the patient has failed to demonstrate an EVR defined as undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of therapy (see CLINICAL STUDIES in the complete product information).
A patient should self-inject PEGASYS only if the physician determines that it is appropriate, the patient agrees to medical follow-up as necessary, and training in proper injection technique has been provided to the patient (see illustrated PEGASYS 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 and prefilled syringes with particulate matter or discoloration should be returned to the pharmacist.
(For complete dosing information, see DOSAGE AND ADMINISTRATION in the complete product information).
Chronic hepatitis C
PEGASYS monotherapy
The recommended dose of PEGASYS monotherapy for chronic hepatitis C is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
PEGASYS and COPEGUS® (Ribavirin, USP) combination therapy
The recommended dose of PEGASYS when used in combination with ribavirin for chronic hepatitis C is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly. The recommended dose of COPEGUS and duration for PEGASYS/COPEGUS therapy is based on viral genotype.
The daily dose of COPEGUS is 800 to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (eg, genotype), response to therapy, and tolerability of the regimen.
Since COPEGUS absorption increases when administered with a meal, patients are advised to take COPEGUS with food.
Chronic hepatitis C with HIV coinfection
PEGASYS monotherapy
The recommended dose of PEGASYS monotherapy for chronic hepatitis C in patients coinfected with HIV is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
PEGASYS/COPEGUS combination therapy
The recommended dose when used in combination with ribavirin is PEGASYS 180 mcg administered subcutaneously in the abdomen or thigh once weekly and COPEGUS
800 mg administered 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.
Chronic hepatitis B
PEGASYS monotherapy
The recommended dose of PEGASYS monotherapy for hepatitis B is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
Dose modifications
If severe adverse reactions or laboratory abnormalities develop during combination COPEGUS/PEGASYS therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, COPEGUS/PEGASYS therapy should be discontinued.
PEGASYS
General
When dose modification is required for moderate to severe 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 syringes) is generally adequate. However, in some cases, dose reduction to 90 mcg (which is 0.5 mL for the vials or adjustment to the corresponding graduation mark for the syringes) may be needed.
Following improvement of the adverse reaction, re-escalation of the dose may be considered (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS in the complete product information).
Hematological
PEGASYS hematological dose modification guidelines
Laboratory Values |
PEGASYS Dose |
Discontinue PEGASYS if: |
ANC >750/mm3
ANC <750/mm3 |
Maintain
180 mcg
Reduce
to 135 mcg |
ANC <500/mm3, treatment should be suspended until ANC values return to >1000/mm3
Reinstitute at 90 mcg and monitor ANC |
Platelet
>50,000/mm3
Platelet <50,000/mm3 |
Maintain
180 mcg
Reduce
to 90 mcg |
Platelet count <25,000/mm3 |
Psychiatric: depression
Guidelines for modification or discontinuation of PEGASYS
and for scheduling visits for patients with depression
Depression Severity |
Initial Management
(4-8 weeks) |
Depression |
|
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 |
Renal function
In patients with end-stage renal disease requiring hemodialysis, PEGASYS dose reduction to 135 mcg is recommended. Signs and symptoms of interferon toxicity should be closely monitored.
PEGASYS should be used with caution in patients with creatinine clearance <50 mL/min. COPEGUS should not be used in patients with creatinine clearance <50 mL/min.
Liver function
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 (>5x 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 patients with persistent, severe (ALT >10x the upper limit of normal) hepatitis B flares, consideration should be given to discontinuation of treatment.
COPEGUS
COPEGUS dose modification guidelines
Laboratory Values
|
Reduce Only COPEGUS Dose to
600 mg/day* if: |
Discontinue
COPEGUS if: |
Hemoglobin in patients with no cardiac disease |
<10 g/dL |
<8.5 g/dL |
Hemoglobin in patients with history of stable cardiac disease |
>2 g/dL decrease in hemoglobin during any 4-week period of treatment |
<12 g/dL despite 4 weeks at reduced dose |
*One 200-mg tablet in the morning and two 200-mg tablets in the evening.
Once COPEGUS has been withheld due to a laboratory abnormality or clinical manifestation, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily depending on the physician’s judgment. However, it is not recommended that COPEGUS be increased to the original dose (1000 or 1200 mg).
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INDICATIONS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that is clinically stable (eg, antiretroviral therapy not required or receiving stable antiretroviral therapy).
PEGASYS is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation.
Boxed WARNINGS and additional IMPORTANT SAFETY INFORMATION
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.
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. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.
CONTRAINDICATIONS
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal.
PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
AVOIDING PREGNANCY
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 during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
WARNINGS
Serious adverse events in hepatitis B and hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema), and peripheral neuropathy (in combination with telbivudine).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include dehydration, hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, infections (bacterial, viral and fungal), and serous retinal detachment, and pure red cell aplasia.
MOST COMMON ADVERSE EVENTS
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65%), headache (43%), pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection-site reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%). The adverse event profile of coinfected patients treated with PEGASYS and COPEGUS was generally similar to that shown for monoinfected patients. Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%) and mood alteration (9%). In clinical trials of 48-week treatment duration, the adverse event profile of PEGASYS in chronic hepatitis B was similar to that seen in chronic hepatitis C PEGASYS monotherapy use, except for exacerbations of hepatitis. The most common adverse events reported for PEGASYS, observed in clinical studies, were pyrexia (54%), headache (27%), myalgia (26%), fatigue (24%), alopecia (18%) and anorexia (16%).
WARNINGS SPECIFIC TO HEPATITIS C PATIENTS
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. During treatment, patients’ clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score >6) is observed. 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.
WARNINGS SPECIFIC TO HEPATITIS B PATIENTS
Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. 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.
Please see full Prescribing Information, including Boxed WARNINGS for additional Important
Safety Information.