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peginterferon alfa-2a injection, solution
FULL PRESCRIBING INFORMATION
WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS
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 Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions.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].
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C
PEGASYS, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of adults 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 subjects with clinically stable HIV disease and CD4 count >100 cells/mm3.
The following points should be considered when initiating therapy with PEGASYS and COPEGUS:
2 DOSAGE AND ADMINISTRATION
Pegasys is administered by subcutaneous injection in the abdomen or thigh.
2.1 Chronic Hepatitis C
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.
PEGASYS/COPEGUS 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 (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.
2.2 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.
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.
2.3 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.
2.4 Dose Modifications
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 2, Table 3, and Table 4 provide guidelines for dose modifications and discontinuation of PEGASYS/COPEGUS based on laboratory abnormalities, patient's depression status, and cardiac status.
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 syringes) is recommended. 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 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)].
Once COPEGUS has been withheld due to a laboratory abnormality or clinical adverse event, 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).
2.5 Renal Function
In 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.
Renal function should be evaluated in all patients on COPEGUS. COPEGUS should not be administered to patients with creatinine clearance <50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].
2.6 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 (>5 x 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 >10 times above the upper limit of normal) hepatitis B flares, consideration should be given to discontinuation of treatment.
2.7 Discontinuation of Dosing
Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log10 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 events, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn [see Boxed Warning].
2.8 Preparation and Administration
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 and prefilled syringes with particulate matter or discoloration should be returned to the pharmacist.
Discard unused portion of PEGASYS in single-use vials or prefilled syringes in excess of the labeled volume. Use only one vial or prefilled syringe per dose.
3 DOSAGE FORMS AND STRENGTHS
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 in neonates and infants, which are sometimes fatal.
PEGASYS/COPEGUS combination therapy is additionally contraindicated in:
5 WARNINGS AND PRECAUTIONS
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].
5.1 Use with Ribavirin including COPEGUS
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].
The primary toxicity of COPEGUS is hemolytic anemia. Hemoglobin <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 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 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)].
5.3 Cardiovascular Disorders
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 (5.15) and COPEGUS Package Insert].
5.4 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 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 <1500 cells/mm3, with baseline platelet counts <90,000 cells/mm3 or baseline hemoglobin <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)].
5.5 Autoimmune Disorders
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.
5.6 Endocrine 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.
5.7 Ophthalmologic Disorders
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.
5.8 Cerebrovascular 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.
5.9 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 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 >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)].
5.10 Pulmonary Disorders
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)].
5.15 Peripheral Neuropathy
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 has not been demonstrated.
5.16 Laboratory Tests
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 the 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. 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:
6 ADVERSE REACTIONS
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 <1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects [see Warnings and Precautions (5.9)].
6.1 Clinical Trials Experience
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.
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 event (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 <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 events. 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 5 displays pooled rates of adverse events occurring in > 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 reason for dose modification of PEGASYS in CHC and CHC/HIV subjects was for laboratory abnormalities, 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 events (3% vs. 10%), Hgb <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 events appeared to be similar in the two treatment groups.
CHC with HIV Coinfection
The adverse event profile of coinfected subjects treated with PEGASYS/COPEGUS in Study 6 was generally similar to that shown for monoinfected subjects in Study 4 (Table 5). Events occurring more frequently in coinfected subjects were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).
Chronic Hepatitis B
In clinical trials of 48 week treatment duration, the adverse event profile of PEGASYS in chronic hepatitis B was similar to that seen in CHC PEGASYS monotherapy use, except for exacerbations of hepatitis [see Warnings and Precautions (5.9)]. Six percent of PEGASYS treated subjects in the hepatitis B studies experienced one or more serious adverse events.
The most common or important serious adverse events, all of which occurred at a frequency of ≤ 1%, in the hepatitis B studies were infections (sepsis, appendicitis, tuberculosis, influenza), hepatitis B flares, and thrombotic thrombocytopenic purpura.
One serious adverse event of anaphylactic shock occurred in a dose ranging study of 191 subjects in a subject taking a higher than approved dose of PEGASYS.
The most commonly observed adverse reactions in the PEGASYS and lamivudine groups, respectively, were pyrexia (54% vs. 4%), headache (27% vs. 9%), fatigue (24% vs. 10%), myalgia (26% vs. 4%), alopecia (18% vs. 2%), and anorexia (16% vs. 3%).
Overall 5% of hepatitis B subjects discontinued PEGASYS therapy and 40% of subjects required modification of PEGASYS dose. The most common reason for dose modification in subjects receiving PEGASYS therapy was for laboratory abnormalities including neutropenia (20%), thrombocytopenia (13%), and ALT elevation (11%).
The laboratory test values observed in the hepatitis B trials (except where noted below) were similar to those seen in the PEGASYS monotherapy CHC trials.
In the hepatitis C studies, decreases in neutrophil count below normal were observed in 95% of all subjects treated with PEGASYS either alone or in combination with COPEGUS. Severe potentially life-threatening neutropenia (ANC <0.5 × 109/L) occurred in 5% of CHC subjects and 12% of CHC/HIV subjects receiving PEGASYS either alone or in combination with COPEGUS. Modification of PEGASYS dose for neutropenia occurred in 17% of subjects receiving PEGASYS monotherapy and 22% of subjects receiving PEGASYS/COPEGUS combination therapy. In the CHC/HIV subjects 27% required modification of interferon dosage for neutropenia. Two percent of subjects with CHC and 10% of subjects with CHC/HIV required permanent reductions of PEGASYS dosage and <1% required permanent discontinuation. Median neutrophil counts return to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.5)].
Decreases in lymphocyte count are induced by interferon alpha therapy. PEGASYS plus COPEGUS combination therapy induced decreases in median total lymphocyte counts (56% in CHC and 40% in CHC/HIV, with median decrease of 1170 cells/mm3 in CHC and 800 cells/mm3 in CHC/HIV). In the hepatitis C studies, lymphopenia was observed during both monotherapy (81%) and combination therapy with PEGASYS and COPEGUS (91%). Severe lymphopenia (<0.5 × 109/L) occurred in approximately 5% of all monotherapy subjects and 14% of all combination PEGASYS and COPEGUS therapy recipients. Dose adjustments were not required by protocol. The clinical significance of the lymphopenia is not known.
In CHC with HIV coinfection, CD4 counts decreased by 29% from baseline (median decrease of 137 cells/mm3) and CD8 counts decreased by 44% from baseline (median decrease of 389 cells/mm3) in the PEGASYS plus COPEGUS combination therapy arm. Median lymphocyte CD4 and CD8 counts return to pre-treatment levels after 4 to 12 weeks of the cessation of therapy. CD4% did not decrease during treatment.
In the hepatitis C studies, platelet counts decreased in 52% of CHC subjects and 51% of CHC/HIV subjects treated with PEGASYS alone (respectively median decrease of 41% and 35% from baseline), and in 33% of CHC subjects and 47% of CHC/HIV subjects receiving combination therapy with COPEGUS (median decrease of 30% from baseline). Moderate to severe thrombocytopenia (<50,000/mm3) was observed in 4% of CHC and 8% of CHC/HIV subjects. Median platelet counts return to pre-treatment levels 4 weeks after the cessation of therapy.
In the hepatitis C studies, the hemoglobin concentration decreased below 12 g/dL in 17% (median Hgb reduction of 2.2 g/dL) of monotherapy and 52% (median Hgb reduction of 3.7 g/dL) of combination therapy subjects. Severe anemia (Hgb <10 g/dL) was encountered in 13% of all subjects receiving combination therapy and in 2% of CHC subjects and 8% of CHC/HIV subjects receiving PEGASYS monotherapy. Dose modification for anemia in COPEGUS recipients treated for 48 weeks occurred in 22% of CHC subjects and 16% of CHC/HIV subjects [see Dosage and Administration (2.6)].
Triglyceride levels are elevated in subjects receiving alfa interferon therapy and were elevated in the majority of subjects participating in clinical studies receiving either PEGASYS alone or in combination with COPEGUS. Random levels ≥400 mg/dL were observed in about 20% of CHC subjects. Severe elevations of triglycerides (>1000 mg/dL) occurred in 2% of CHC monoinfected subjects.
In HCV/HIV coinfected subjects, fasting levels ≥400 mg/dL were observed in up to 36% of subjects receiving either PEGASYS alone or in combination with COPEGUS. Severe elevations of triglycerides (>1000 mg/dL) occurred in 7% of coinfected subjects.
Chronic Hepatitis C
One percent of subjects in the hepatitis C trials experienced marked elevations (5- to 10-fold above the upper limit of normal) in ALT levels during treatment and follow-up. These transaminase elevations were on occasion associated with hyperbilirubinemia and were managed by dose reduction or discontinuation of study treatment. Liver function test abnormalities were generally transient. One case was attributed to autoimmune hepatitis, which persisted beyond study medication discontinuation [see Dosage and Administration (2.5)].
Chronic Hepatitis B
Transient ALT elevations are common during hepatitis B therapy with PEGASYS. Twenty-five percent and 27% of subjects experienced elevations of 5 to 10 × ULN and 12% and 18% had elevations of >10 × ULN during treatment of HBeAg negative and HBeAg positive disease, respectively. Flares have been accompanied by elevations of total bilirubin and alkaline phosphatase and less commonly with prolongation of PT and reduced albumin levels. Eleven percent of subjects had dose modifications due to ALT flares and <1% of subjects were withdrawn from treatment [see Warnings and Precautions (5.9) and Dosage and Administration (2.5)].
ALT flares of 5 to 10 × ULN occurred in 13% and 16% of subjects, while ALT flares of >10 × ULN occurred in 7% and 12% of subjects in HBeAg negative and HBeAg positive disease, respectively, after discontinuation of PEGASYS therapy.
PEGASYS alone or in combination with COPEGUS was associated with the development of abnormalities in thyroid laboratory values, some with associated clinical manifestations. In the hepatitis C studies, hypothyroidism or hyperthyroidism requiring treatment, dose modification or discontinuation occurred in 4% and 1% of PEGASYS treated subjects and 4% and 2% of PEGASYS and COPEGUS treated subjects, respectively. Approximately half of the subjects, who developed thyroid abnormalities during PEGASYS treatment, still had abnormalities during the follow-up period [see Warnings and Precautions (5.6)].
Chronic Hepatitis C
Nine percent (71/834) of subjects treated with PEGASYS with or without COPEGUS developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Three percent of subjects (25/835) receiving PEGASYS with or without COPEGUS, developed low-titer neutralizing antibodies (using an assay with a sensitivity of 100 INU/mL).
Chronic Hepatitis B
Twenty-nine percent (42/143) of hepatitis B subjects treated with PEGASYS for 24 weeks developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Thirteen percent of subjects (19/143) receiving PEGASYS developed low-titer neutralizing antibodies (using an assay with a sensitivity of 100 INU/mL).
The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The percentage of subjects whose test results were considered positive for antibodies is highly dependent on the sensitivity and specificity of the assays.
Additionally, the observed incidence of antibody positivity in these assays may be influenced by several factors including sample timing and handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PEGASYS with the incidence of antibodies to other products may be misleading.
6.3 Postmarketing Experience
The following adverse reactions have been identified and reported during post-approval use of PEGASYS therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System disorders
Ear and Labyrinth Disorders
Immune system disorders
Metabolism and Nutrition Disorders
Skin and subcutaneous tissue disorders
7 DRUG INTERACTIONS
7.1 Drugs Metabolized by Cytochrome P450
There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.
Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC.
Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS.
In a PK study of HCV subjects concomitantly receiving methadone, treatment with PEGASYS once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity.
The pharmacokinetics of concomitant administration of methadone and PEGASYS were evaluated in 24 PEGASYS naive chronic hepatitis C (CHC) subjects (15 male, 9 female) who received 180 mcg PEGASYS subcutaneously weekly. All subjects were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving PEGASYS. Mean methadone PK parameters were 10% to 15% higher after 4 weeks of PEGASYS treatment as compared to baseline. Methadone did not significantly alter the PK of PEGASYS as compared to a PK study of 6 chronic hepatitis C subjects not receiving methadone.
7.4 Nucleoside Analogues
In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected subjects.
In Study 6 among the CHC/HIV coinfected cirrhotic subjects receiving NRTIs cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.9)].
Patients receiving PEGASYS/COPEGUS and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening toxicities are observed [see Warnings and Precautions (5.3, 5.9), Dosage and Administration (2.5, 2.6)].
Co-administration of COPEGUS and didanosine is contraindicated. In vitro, Didanosine and its active metabolite (dideoxyadenosine 5'-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4)].
In Study 6, subjects who were administered zidovudine in combination with PEGASYS/COPEGUS developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar subjects not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6).
The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions (5.1)].
Please refer to the Full Prescribing Information for ribavirin for full details on ribavirin's drug interaction potential.
8 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 [see Contraindications (4)].
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. COPEGUS therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant [see Contraindications (4), Warnings and Precautions (5.1), and COPEGUS Package Insert].
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.
8.3 Nursing Mothers
It is not known whether peginterferon or ribavirin or its components are excreted in human milk. The effect of orally ingested peginterferon or ribavirin 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 and COPEGUS treatment.
8.4 Pediatric Use
The safety and effectiveness of PEGASYS, alone or in combination with COPEGUS in patients below the age of 18 years have not been established.
PEGASYS contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal [see Contraindications (4)].
8.5 Geriatric Use
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 and COPEGUS are 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 <50 mL/min and COPEGUS should not be administered to patients with creatinine clearance <50 mL/min.
8.6 Hepatic impairment
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 ≥6) is observed [see Contraindications (4)]. Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation >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.
8.7 Renal impairment
A 25% to 45% higher exposure to PEGASYS is seen in subjects undergoing hemodialysis. In patients with impaired renal function, signs and symptoms of interferon toxicity should be closely monitored. Doses of PEGASYS should be adjusted accordingly. PEGASYS should be used with caution in patients with creatinine clearance <50 mL/min [see Dosage and Administration (2.5)].
It is recommended that renal function be evaluated in all patients on COPEGUS. COPEGUS should not be administered to patients with creatinine clearance <50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].
8.8 Organ Transplant Recipients
The safety and efficacy of PEGASYS and COPEGUS 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, alone or in combination with COPEGUS [see Adverse Reactions (6.3)].
There is limited experience with overdosage. The maximum dose received by any patient was 7 times the intended dose of PEGASYS (180 mcg/day for 7 days). There were no serious reactions attributed to overdosages. Weekly doses of up to 630 mcg have been administered to patients with cancer. Dose-limiting toxicities were fatigue, elevated liver enzymes, neutropenia, and thrombocytopenia. There is no specific antidote for PEGASYS. Hemodialysis and peritoneal dialysis are not effective.
PEGASYS, peginterferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon (approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced using recombinant DNA technology in which a cloned human leukocyte interferon gene is inserted into and expressed in Escherichia coli.
PEGASYS is a sterile, preservative-free, colorless to light yellow injectable solution administered subcutaneously.
180 mcg/1.0 mL Vial: Each vial contains approximately 1.2 mL of solution to deliver 1.0 mL of drug product. Subcutaneous (sc) administration of 1.0 mL of 180 mcg of drug product (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.05 mg), benzyl alcohol (10.0 mg), polysorbate 80 (0.05 mg), sodium acetate trihydrate (2.62 mg), and sodium chloride (8.0 mg) at pH 6.0 ± 0.5.
180 mcg/0.5 mL Prefilled Syringe: Each syringe contains 0.6 mL of solution to deliver 0.5 mL of drug product. Subcutaneous (sc) administration of 0.5 mL delivers 180 mcg of drug product (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.0231 mg), benzyl alcohol (5.0 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4.0 mg) at pH 6.0 ± 0.5.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune response [see Clinical Pharmacology (12.4)].
PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5'-oligoadenylate synthetase.
Maximal serum concentrations (Cmax) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mcg of PEGASYS. Maximal serum concentrations (Cmax) occur between 72 to 96 hours post-dose.
Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON®-A). The mean terminal half-life after subcutaneous dosing in subjects with chronic hepatitis C was 160 hours (range 84 to 353 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A.
Gender and Age
PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng∙h/mL in subjects older than 62 years taking 180 mcg PEGASYS, but peak concentrations were similar (9 vs. 10 ng/mL) in those older and younger than 62 years.
In a population pharmacokinetics study, 14 children 2 to 8 years of age with CHC received PEGASYS based on their body surface area (BSA of the child x 180 mcg/1.73m2). The clearance of PEGASYS in children was nearly 4-fold lower compared to the clearance reported in adults.
Steady-state trough levels in children with the BSA-adjusted dosing were similar to trough levels observed in adults with 180 mcg fixed dosing. Time to reach the steady state in children is approximately 12 weeks, whereas in adults, steady state is reached within 5 to 8 weeks. In these children receiving the BSA adjusted dose, the mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing. The safety and effectiveness of PEGASYS in patients below the age of 18 years have not been established [see Use in Specific Populations (8.4)].
In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance [see Use in Specific Populations (8.7)].
The pharmacokinetics of ribavirin following administration of COPEGUS have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of COPEGUS in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with COPEGUS [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Mechanism of Action
The biological activity of PEGASYS is derived from its recombinant human interferon α-2a moiety. Peginterferon α-2a binds to the human type 1 interferon receptor leading to receptor dimerization. Receptor dimerization activates multiple intracellular signal transduction pathways initially mediated by the JAK/STAT pathway. Given the diversity of cell types that respond to interferon α-2a, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon α-2a is expected to have pleiotropic biological effects in the body.
Antiviral Activity in Cell Culture
In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV RNA replication with an effective concentration (EC) value of 11-21 µm. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC value of 0.1 - 3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.
Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.
Cross-resistance between IFN-α and ribavirin has not been observed.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 Ribavirin: Ribavirin is genotoxic and mutagenic in in vitro and in vivo assays, and therefore, potential carcinogenic risk to humans cannot be excluded. In a p53 (+/-) mouse carcinogenicity study at doses up to 100 mg/kg/day ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2-year carcinogencity study at doses 60 mg/kg/day. On a body surface area basis, these doses were 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin respectively [see COPEGUS Package Insert].
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 × 106 IU/kg/day.
14 CLINICAL STUDIES
14.1 Chronic Hepatitis C Studies 1, 2, and 3: PEGASYS Monotherapy
The safety and effectiveness of PEGASYS for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All subjects were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All subjects received therapy by subcutaneous injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).
In Study 1 (n=630), subjects received either ROFERON-A (interferon alfa-2a) 3 MIU three times a week, PEGASYS 135 mcg once weekly or PEGASYS 180 mcg once weekly. In Study 2 (n=526), subjects received either ROFERON-A 6 MIU three times a week for 12 weeks followed by 3 MIU three times a week for 36 weeks or PEGASYS 180 mcg once weekly. In Study 3 (n=269), subjects received ROFERON-A 3 MIU three times a week, PEGASYS 90 mcg once weekly or PEGASYS 180 mcg once each week.
In all three studies, treatment with PEGASYS 180 mcg resulted in significantly more subjects who experienced a sustained response (defined as undetectable HCV RNA [<50 IU/mL] using the COBAS AMPLICOR® HCV Test, version 2.0 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In Study 1, response to PEGASYS 135 mcg was not different from response to 180 mcg. In Study 3, response to PEGASYS 90 mcg was intermediate between PEGASYS 180 mcg and ROFERON-A.
Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of subjects. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups.
Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2log10 drop in HCV RNA titer from baseline by 12 weeks of PEGASYS 180 mcg therapy, 2% (3/156) achieved a sustained virologic response [see Dosage and Administration (2.2)].
Averaged over Study 1, Study 2, and Study 3, response rates to PEGASYS were 23% among subjects with viral genotype 1 and 48% in subjects with other viral genotypes. The treatment response rates were similar in men and women.
14.2 Chronic Hepatitis C Studies 4 and 5: PEGASYS/COPEGUS Combination Therapy
The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of subjects in both studies had compensated cirrhosis (Child-Pugh class A). Subjects coinfected with HIV were excluded from these studies.
In Study 4, subjects were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS 180 mcg once weekly with COPEGUS 1000 mg by mouth (body weight <75 kg) or 1200 mg by mouth (body weight ≥75 kg) or Rebetron® (interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth). All subjects received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table 7). In all treatment arms, subjects with viral genotype 1, regardless of viral load, had a lower response rate.
In Study 5 (see Table 8), all subjects received PEGASYS 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg / ≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Subjects with genotype 1 and high viral titer (defined as >2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.
HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg COPEGUS.
HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS (see Table 8).
The numbers of subjects with genotype 5 and 6 were too few to allow for meaningful assessment.
Other Treatment Response Predictors
Treatment response rates are lower in subjects with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in subjects older than 40 years (50% vs. 66%), in subjects with cirrhosis (47% vs. 59%), in subjects weighing over 85 kg (49% vs. 60%), and in subjects with genotype 1 with high vs. low viral load (43% vs. 56%). African-American subjects had lower response rates compared to Caucasians.
Paired liver biopsies were performed on approximately 20% of subjects in studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups.
In studies 4 and 5, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of subjects who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of subjects who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.
14.3 Chronic Hepatitis C and Coinfection with HIV (CHC/HIV) Study 6: PEGASYS Monotherapy and PEGASYS/COPEGUS Combination Therapy
In Study 6, subjects with CHC/HIV were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly plus an oral placebo, PEGASYS 180 mcg once weekly plus COPEGUS 800 mg by mouth daily or ROFERON-A (interferon alfa-2a), 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All subjects received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS treatment arms. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Subjects also had CD4+ cell count ≥200 cells/mcL or CD4+ cell count ≥100 cells/mcL but <200 cells/mcL and HIV-1 RNA <5000 copies/mL, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in Table 9.
Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.
Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2log10 reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and COPEGUS combination therapy, 2% (2/85) achieved an SVR.
In CHC subjects with HIV coinfection who received 48 weeks of PEGASYS alone or in combination with COPEGUS treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.
14.4 Chronic Hepatitis B Studies 7 and 8: PEGASYS Monotherapy
The safety and effectiveness of PEGASYS for the treatment of chronic hepatitis B were assessed in controlled clinical trials in HBeAg positive (Study 7) and HBeAg negative (Study 8) subjects with chronic hepatitis B.
Subjects were randomized to PEGASYS 180 mcg subcutaneous once weekly, PEGASYS 180 mcg subcutaneous once weekly combined with lamivudine 100 mg once daily by mouth or lamivudine 100 mg once daily by mouth. All subjects received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of PEGASYS or no PEGASYS was not masked.
All subjects were adults with compensated liver disease, had chronic hepatitis B virus (HBV) infection, and evidence of HBV replication (serum HBV >500,000 copies/mL for Study 7 and >100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR® HBV Assay). All subjects had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic hepatitis.
The results observed in the PEGASYS and lamivudine monotherapy groups are shown in Table 10.
PEGASYS co-administered with lamivudine did not result in any additional sustained response when compared to PEGASYS monotherapy.
Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.
16 HOW SUPPLIED/STORAGE AND HANDLING
Single Use Vial: Each PEGASYS (peginterferon alfa-2a) 180 mcg single use, clear glass vial provides 1.0 mL containing 180 mcg peginterferon alfa-2a for subcutaneous injection. Each package contains 1 vial (NDC 0004-0350-09).
Prefilled Syringes Monthly Convenience Pack: Four prefilled syringes of PEGASYS (peginterferon alfa-2a), 180 mcg single use, graduated, clear glass prefilled syringes, in a box with 4 needles and 4 alcohol swabs (NDC 0004-0352-39). Each syringe is a 0.5 mL (½ cc) volume syringe supplied with a 27-gauge, ½-inch needle with needle-stick protection device.
Storage and Handling
Store in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Vials and prefilled syringes are for single use only. Discard any unused portion.
If home use is prescribed, a puncture-resistant container for the disposal of used needles and syringes should be supplied to the patients. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of any needles and syringes. The full container should be disposed of according to the directions provided by the physician [see FDA Approved Medication Guide].
17 PATIENT COUNSELING INFORMATION
PEGASYS and COPEGUS combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. COPEGUS 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 COPEGUS 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 (4) and Warnings and Precautions (5.1)].
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 (4) and COPEGUS Package Insert].
To monitor maternal and fetal outcomes of pregnant women exposed to COPEGUS, 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 (5.16)]. Patients should be instructed to remain well hydrated, especially during the initial stages of treatment. Patients should be advised to take COPEGUS with food.
Patients should be questioned about prior history of drug abuse before initiating COPEGUS/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 alone or in combination with COPEGUS will prevent transmission of HCV or HBV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HCV or HBV infection. 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 must be instructed on the use of aseptic techniques when administering PEGASYS. Appropriate training for preparation using the vial or syringe must be given by a healthcare provider, including a careful review of the PEGASYS Medication Guide and Medication Guide Appendix: Instructions for Preparing and Giving a Dose with a PEGASYS® Prefilled Syringe and Appendix: Instructions for Use PEGASYS® Solution for Injection Vial.
Patients should be instructed to allow the vial or prefilled syringe to come to room temperature and for condensation on the outside of the syringe to disappear before use. Patients should be advised not to shake the vial or prefilled syringe 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.
Solution for Subcutaneous Injection
Read this Medication Guide before you start taking PEGASYS, and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
If you are taking PEGASYS with COPEGUS, also read the Medication Guide for COPEGUS (ribavirin) Tablets.
Before taking PEGASYS, tell your healthcare provider if you:
Call your healthcare provider right away if you get any of these problems while taking PEGASYS:
During treatment with PEGASYS you will need to see your healthcare provider regularly and have blood tests to make sure that your treatment is working and to check for side effects.
PEGASYS can cause serious side effects. Some of these side effects may cause death. Tell your healthcare provider right away if you have any of these symptoms while taking PEGASYS. Other serious side effects are listed in "What are the possible side effects of PEGASYS?"
What is PEGASYS?
PEGASYS is a prescription medicine that is:
It is not known if PEGASYS is safe and will work in children under 18 years age.
Who should not take PEGASYS?
Do not take PEGASYS if you:
Do not take PEGASYS in combination with COPEGUS if you:
Talk to your healthcare provider before taking PEGASYS if you have any of these conditions.
Do not give PEGASYS to a baby under 1 year of age. PEGASYS contains benzyl alcohol. Benzyl alcohol can cause nervous system problems and other problems which may lead to death.
What should I tell my healthcare provider before taking PEGASYS?
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. PEGASYS and certain other medicines may affect each other and cause side effects.
Especially tell your healthcare provider if you take:
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take PEGASYS?
What should I avoid while taking PEGASYS, or PEGASYS with COPEGUS?
What are the possible side effects of PEGASYS?
PEGASYS can cause serious side effects including:
You may need to have a chest X-ray or other tests if you develop fever, cough, shortness of breath or other symptoms of a lung problem during treatment with PEGASYS.
Tell your healthcare provider right away if you have any of the symptoms listed above.
The most common, but less serious side effects of PEGASYS include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the side effects of PEGASYS. For more information; ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.
How should I store PEGASYS?
Keep PEGASYS vials, prefilled syringes, and all medicines out of the reach of children.
General information about PEGASYS
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PEGASYS for a condition for which it was not prescribed. Do not give PEGASYS to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about PEGASYS. If you would like more information about PEGASYS, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information that is written for health professionals.
What are the ingredients in PEGASYS?
Active ingredient: interferon alfa-2a
Inactive ingredients: acetic acid, benzyl alcohol, polysorbate 80, sodium acetate trihydrate, and sodium chloride
Keep PEGASYS and all medicines out of the reach of children.
This Medication Guide has been approved by the US Food and Drug Administration.
MG Revised: February 2011
Medication Guide Appendix: Instructions for Use
Solution for Injection Prefilled Syringe
Be sure that you read, understand and follow these instructions before injecting PEGASYS. Your healthcare provider should show you how to prepare, measure and inject PEGASYS properly before you use it for the first time. Ask your healthcare provider if you have any questions.
PEGASYS prefilled syringes come in a Monthly Convenience Pack that contains 4 prefilled syringes of PEGASYS in a box with 4 needles and 4 alcohol pads. Each needle has a needle-stick protection device.
Before starting, collect all of the supplies that you will need to use for preparing and injecting PEGASYS. You will need the following supplies:
You will also need a puncture-proof disposable container to throw away used prefilled syringes and needles.
How should I prepare a dose of PEGASYS?
How do I attach the needle to the PEGASYS prefilled syringe?
How should I choose a site for injection?
How do I prepare the PEGASYS prefilled syringe for injection?
How Do I Give the Injection of PEGASYS
Always keep the puncture-proof container out of the reach of children.
How should I store PEGASYS?
MG Appendix: Prefilled Syringe revision date: February 2011
Medication Guide Appendix: Instructions for Use
Be sure that you read, understand and follow these instructions before injecting PEGASYS. Your healthcare provider should show you how to prepare, measure, and inject PEGASYS properly before you use it for the first time. Ask your healthcare provider if you have any questions.
Before starting, collect all of the supplies that you will need to use for preparing and injecting PEGASYS. You will need the following supplies:
You will also need a puncture-proof container to throw away used syringes, needles, and vials.
How should I prepare a dose of PEGASYS?
If you are not sure how much medicine to use or which mark on the syringe to use, stop and call your healthcare provider right away.
How should I choose a site for injection?
How should I give an injection?
How should I store PEGASYS?
MG Appendix: Vial revision date: February 2011
COPEGUS and PEGASYS are trademarks of Hoffmann-La Roche Inc.
PI Revised: February 2011
Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, NJ 07110-1199
(US Govt. Lic. No. 0136)
Genentech USA, Inc.
© 2011 Genentech, Inc. All rights reserved.
Representative sample of labeling (see the HOW SUPPLIED section for complete listing):
PRINCIPAL DISPLAY PANEL - 180 µg/1 mL Vial Carton
180 µg/1 mL
For Subcutaneous Use
ATTENTION PHARMACIST: Each
Vial contains: 180 µg/1 mL
PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Carton
NOT FOR INDIVIDUAL SALE
180 µg/0.5 mL
For Subcutaneous Injection Only
Each Carton Contains:
Each Prefilled Syringe Contains:
PRINCIPAL DISPLAY PANEL - 0.5 mL 4 Syringe Monthly Convenience Pack
180 µg/0.5 mL
For Subcutaneous Injection Only
Prefilled Syringes Monthly Convenience Pack Package Contains:
Each Prefilled Syringe Contains:
ATTENTION PHARMACIST: Each patient is required
Revised: 02/2011 Genentech, Inc.
Reproduced with permission of U.S. National Library of Medicine
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