Peginterferon alfa-2a
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 Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions.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 ADVERSE REACTIONS).
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 (see COPEGUS Package Insert for additional information and other WARNINGS).
DRUG DESCRIPTION
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 supplied as an injectable solution in vials and prefilled syringes.
180 ?g/1.0 mL Vial: A vial contains approximately 1.2 mL of solution to deliver 1.0 mL of drug product. Subcutaneous (sc) administration of 1.0 mL delivers 180 ?g of drug product (expressed as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.05 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ±0.5.
180 ?g/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 ?g of drug product (expressed as the amount of interferon alfa-2a), 4.0 mg sodium chloride, 0.025 mg polysorbate 80, 5.0 mg benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ±0.5.
INDICATIONS
PEGASYS, peginterferon alfa-2a, 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 (e.g., 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.
DOSAGE AND ADMINISTRATION
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 early virologic response defined as undetectable HCV RNA or at least a 2log10 reduction from baseline in HCV RNA titer by 12 weeks of therapy (see Clinical Studies).
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 training in proper injection technique has been provided to him/her (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.
Chronic Hepatitis C
PEGASYS Monotherapy
The recommended dose of PEGASYS monotherapy for chronic hepatitis C is 180 ?g (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 Combination Therapy
The recommended dose of PEGASYS when used in combination with ribavirin for chronic hepatitis C is 180 ?g (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 7).
The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., 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.
Table 7: PEGASYS and COPEGUS Dosing RecommendationsGenotype PEGASYS Dose COPEGUS Dose Duration
Genotypes 1, 4 180? < 75 kg = 1000 mg 48 weeks
? 75 kg = 1200 mg 48 weeks
Genotypes 2, 3 180? g 800 mg 24 weeks
Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 3).
Data on genotypes 5 and 6 are insufficient for dosing recommendations.
CHC with HIV Coinfection
PEGASYS Monotherapy
The recommended dose of PEGASYS monotherapy for chronic hepatitis C in patients coinfected with HIV is 180 ?g (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 ?g sc once weekly and COPEGUS 800 mg po 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 ?g (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 ?g (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 ?g (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).
Hematological
Table 8: PEGASYS Hematological Dose Modification GuidelinesLaboratory Values Reduce PEGASYS Dose to: Discontinue PEGASYS if:
ANC ? 750/mm³
ANC < 750/mm³ Maintain 180?g
Reduce to 135?g ANC < 500/mm³, treatment should be suspended until ANC values return to more than 1000/mm³
Reinstitute at 90 g and monitor ANC
Platelet ? 50,000/mm³
Platelet < 50,000/mm³ Maintain 180?g
Reduce to 90?g Platelet count < 25,000/mm³
Psychiatric: Depression
Table 9: 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 ?g (in some cases dose reduction to 90?g 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, dose reduction to 135 ?g PEGASYS is recommended. Signs and symptoms of interferon toxicity should be closely monitored.
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 ?g 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 ?g 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.
COPEGUS
Table 10: COPEGUS Dosage Modification GuidelinesLaboratory 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 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 upon the physician's judgment. However, it is not recommended that COPEGUS be increased to the original dose (1000 mg or 1200 mg).
Renal Impairment
COPEGUS should not be used in patients with creatinine clearance < 50 mL/min (see CLINICAL PHARMACOLOGY, WARNINGS and COPEGUS Package Insert).
SIDE EFFECTS
PEGASYS alone or in combination with COPEGUS causes a broad variety of serious adverse reactions (see BOXED WARNING and WARNINGS). The most common life-threatening or fatal events induced or aggravated by PEGASYS and COPEGUS were 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 patients (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations).
In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients and in 19% of CHC/HIV patients 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, psychosis, 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.
Nearly all patients in clinical trials experienced one or more adverse events. For hepatitis C patients, 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.
Overall 11% of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS either alone or in combination with COPEGUS discontinued therapy; 16% of CHC/HIV coinfected patients 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 patients 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 patients 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 patients was anemia (22% and 16%, respectively).
PEGASYS dose was reduced in 12% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 7% of patients receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 12% of patients receiving 800 mg COPEGUS for 24 weeks.
Chronic hepatitis C monoinfected patients 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 patients treated for 48 weeks with PEGASYS and 1000 mg or 1200 mg COPEGUS. On the other hand the overall incidence of adverse events appeared to be similar in the two treatment groups.
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. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice.
Table 6: Adverse Reactions Occurring in ? 5% of Patients in Chronic Hepatitis C Clinical Trials (Pooled Studies 1, 2, 3, and Study 4)Body System CHC Monotherapy (Pooled Studies1-3) CHC Combination Therapy Study 4
PEGASYS
180 ?g
48 week† ROFERON-A*† PEGASYS
180 ?g
+ 1000 mg or 1200 mg
COPEGUS
48 week** Intron A +
mg or 1200 mg
REBETOL
48week**
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
Diarrhea 16 16 11 10
Abdominal pain 15 15 8 9
Dry mouth 6 3 4 7
Dyspepsia < 1 1 6 5
Hematologic‡
Lymphopenia 3 5 14 12
Anemia 2 1 11 11
Neutropenia 21 8 27 8
Thrombocytopenia 5 2 5 < 1
Metabolic and Nutritional
Anorexia 17 17 24 26
Weight decrease 4 3 10 10
Musculoskeletal,Connective Tissue and Bone
Myalgia 37 38 40 49
Arthralgia 28 29 22 23
Back pain 9 10 5 5
Neurological
Headache 54 58 43 49
Dizziness (excluding vertigo) 16 12 14 14
Memory impairment 5 4 6 5
Resistance Mechanism Disorders
Overall 10 6 12 10
Psychiatric
Irritability/Anxiety/ 19 22 33 38
Nervousness
Insomnia 19 23 30 37
Depression 18 19 20 28
Concentration impairment 8 10 10 13
Mood alteration 3 2 5 6
Respiratory, Thoracic and Mediastinal
Dyspnea 4 2 13 14
Cough 4 3 10 7
Dyspnea exertional < 1 < 1 4 7
Skin and Subcutaneous Tissue
Alopecia 23 30 28 33
Pruritus 12 8 19 18
Dermatitis 8 3 16 13
Dry skin 4 3 10 13
Rash 5 4 8 5
Sweating increased 6 7 6 5
Eczema 1 1 5 4
Visual Disorders
Vision blurred 4 2 5 2
† Pooled studies 1, 2, and 3
* Either 3 MIU or 6/3 MIU of ROFERON-A
**Study 4
‡ Severe hematologic abnormalities (lymphocyte < 0.5 x 109/L; hemoglobin < 10 g/dL; neutrophil < 0.75 x 109/L; platelet < 50 x 109/L).
CHC With HIV Coinfection
The adverse event profile of coinfected patients treated with PEGASYS and COPEGUS in Study 6 was generally similar to that shown for monoinfected patients in Study 4 (Table 6). Events occurring more frequently in coinfected patients 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 chronic hepatitis C PEGASYS monotherapy use, except for exacerbations of hepatitis (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations). Six percent of PEGASYS treated patients in the hepatitis B studies experienced one or more serious adverse events.
The most common or important serious adverse events in the hepatitis B studies were infections (sepsis, appendicitis, tuberculosis, influenza), hepatitis B flares, anaphylactic shock, thrombotic thrombocytopenic purpura.
The most commonly observed adverse reactions 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%) in the PEGASYS and lamivudine groups respectively.
Overall 5% of hepatitis B patients discontinued PEGASYS therapy and 40% of patients required modification of PEGASYS dose. The most common reason for dose modification in patients receiving PEGASYS therapy was for laboratory abnormalities including neutropenia (20%), thrombocytopenia (13%), and ALT disorders (11%).
Laboratory Test Values
The laboratory test values observed in the hepatitis B trials (except where noted below) were similar to those seen in the PEGASYS monotherapy hepatitis C trials.
Neutrophils
In the hepatitis C studies, decreases in neutrophil count below normal were observed in 95% of all patients treated with PEGASYS either alone or in combination with COPEGUS. Severe potentially life-threatening neutropenia (ANC < 0.5 x 109/L) occurred in 5% of CHC patients and 12% of CHC/HIV patients receiving PEGASYS either alone or in combination with COPEGUS. Modification of PEGASYS dose for neutropenia occurred in 17% of patients receiving PEGASYS monotherapy and 22% of patients receiving PEGASYS/COPEGUS combination therapy. In the CHC/HIV patients 27% required modification of interferon dosage for neutropenia. Two percent of patients with CHC and 10% of patients 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: Dose Modifications).
Lymphocytes
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 x 109/L) occurred in approximately 5% of all monotherapy patients 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.
Platelets
In the hepatitis C studies, platelet counts decreased in 52% of CHC patients and 51% of CHC/HIV patients treated with PEGASYS alone (respectively median decrease of 41% and 35% from baseline), and in 33% of CHC patients and 47% of CHC/HIV patients 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 patients. Median platelet counts return to pre-treatment levels 4 weeks after the cessation of therapy.
Hemoglobin
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 patients. Severe anemia (Hgb < 10 g/dL) was encountered in 13% of all patients receiving combination therapy and in 2% of CHC patients and 8% of CHC/HIV patients receiving PEGASYS monotherapy. Dose modification for anemia in COPEGUS recipients treated for 48 weeks occurred in 22% of CHC patients and 16% of CHC/HIV patients (see DOSAGE AND ADMINISTRATION: Dose Modifications).
Triglycerides
Triglyceride levels are elevated in patients receiving alfa interferon therapy and were elevated in the majority of patients 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 patients. Severe elevations of triglycerides ( > 1000 mg/dL) occurred in 2% of CHC monoinfected patients. In HCV/HIV coinfected patients, fasting levels ? 400 mg/dL were observed in up to 36% of patients receiving either PEGASYS alone or in combination with COPEGUS. Severe elevations of triglycerides ( > 1000 mg/dL) occurred in 7% of coinfected patients.
ALT Elevations
Chronic Hepatitis C
One percent of patients 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: Dose Modifications).
Chronic Hepatitis B
Transient ALT elevations are common during hepatitis B therapy with PEGASYS. Twenty-five percent and 27% of patients experienced elevations of 5 to 10 x ULN and 12% and 18% had elevations of > 10 x 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 patients had dose modifications due to ALT flares and < 1% of patients were withdrawn from treatment (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations and DOSAGE AND ADMINISTRATION: Dose Modifications).
ALT flares of 5 to 10 x ULN occurred in 13% and 16% of patients, while ALT flares of > 10 x ULN occurred in 7% and 12% of patients in HBeAg negative and HBeAg positive disease, respectively, after discontinuation of PEGASYS therapy.
Thyroid Function
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 patients and 4% and 2% of PEGASYS and COPEGUS treated patients, respectively. Approximately half of the patients, who developed thyroid abnormalities during PEGASYS treatment, still had abnormalities during the follow-up period (see PRECAUTIONS: Laboratory Tests).
Immunogenicity
Chronic Hepatitis C
Nine percent (71/834) of patients treated with PEGASYS with or without COPEGUS developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Three percent of patients (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 patients treated with PEGASYS for 24 weeks developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Thirteen percent of patients (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 patients 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.
Postmarketing Experience
The following adverse reactions have been identified and reported during post-approval use of PEGASYS therapy: dehydration, hearing impairment, hearing loss, and serious skin reactions (see WARNINGS: Hypersensitivity). 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting or (3) strength of causal connection to PEGASYS.
DRUG INTERACTIONS
Theophylline
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 (see CLINICAL PHARMACOLOGY: Drug Interactions).
Methadone
In a PK study of HCV patients 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 (see CLINICAL PHARMACOLOGY: Drug Interactions). The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity.
Nucleoside Analogues
NRTIs
In Study 6 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations).
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, PRECAUTIONS, DOSAGE AND ADMINISTRATION: Dose Modifications).
Didanosine
Co-administration of COPEGUS and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions).
Zidovudine
In Study 6, patients 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 patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%).
Lamivudine, Stavudine, and Zidovudine
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs such as lamivudine, stavudine, and zidovudine. No evidence of a pharmacokinetic or pharmacodynamic interaction was seen when ribavirin was co-administered with lamivudine, stavudine, and/or zidovudine in HIV/HCV coinfected patients (see CLINICAL PHARMACOLOGY: Drug Interactions).
WARNINGS
General
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).
Neuropsychiatric
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 and DOSAGE AND ADMINISTRATION).
Infections
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, 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.
Bone Marrow Toxicity
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 PRECAUTIONS: Laboratory Tests).
PEGASYS and 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: Dose Modifications).
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).
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 use COPEGUS (see WARNINGS: Anemia and COPEGUS Package Insert).
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.
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, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients 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 treatment should be immediately discontinued if decompensation (Child-Pugh score ? 6) is observed (see CONTRAINDICATIONS).
Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B patients 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 patients, 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: Chronic Hepatitis B and DOSAGE AND ADMINISTRATION: Dose Modifications).
Hypersensitivity
Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with PEGASYS and 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 rarely reported in patients receiving PEGASYS with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy (see ADVERSE REACTIONS: Postmarketing Experience).
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.
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.
Pulmonary Disorders
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by PEGASYS or alpha interferon therapy. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with PEGASYS.
Colitis
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
Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. PEGASYS and COPEGUS should be suspended if symptoms or signs suggestive of pancreatitis are observed. PEGASYS and COPEGUS should be discontinued in patients diagnosed with pancreatitis.
Ophthalmologic Disorders
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema 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.
Pregnancy: Use with Ribavirin (also, see COPEGUS Package Insert)
Ribavirin 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, PRECAUTIONS: INFORMATION FOR PATIENTS, and COPEGUS Package Insert).
Anemia
The primary toxicity of ribavirin is hemolytic anemia. Hemoglobin < 10 g/dL was observed in approximately 13% of COPEGUS and PEGASYS treated patients in chronic hepatitis C clinical trials (see PRECAUTIONS: Laboratory Tests). 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. Patients should then be followed as clinically appropriate.
Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin 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: COPEGUS Dosage Modification Guidelines). 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).
Renal
It is recommended that renal function be evaluated in all patients started on COPEGUS. COPEGUS should not be administered to patients with creatinine clearance < 50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).
PRECAUTIONS
General
The safety and efficacy of PEGASYS alone or in combination with COPEGUS have not been established in:
Patients who have failed alpha interferon treatment with or without ribavirin
Liver or other organ transplant recipients
Hepatitis B patients coinfected with HCV or HIV
Hepatitis C patients coinfected with HBV or coinfected with HIV with a CD4+ cell count < 100 cells/?L
Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).
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: Dose Modifications).
COPEGUS should not be used in patients with creatinine clearance < 50 mL/min (see COPEGUS Package Insert).