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Peginterferon alfa 2aPEGASYS® (peginterferon alfa-2a)
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. Each 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 m 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 ± 0.01. Pharmacodynamics Interferons bind to specific receptors on the cell surface initiating intracellular signaling via a complex cascade of protein-protein interactions leading to rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation, and immunomodulation. The clinical relevance of these in vitro activities is not known. PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5’-oligoadenylate synthetase. Pharmacokinetics Maximal serum concentrations (Cmax) occur between 72 to 96 hours post-dose. The Cmax and AUC measurements of PEGASYS increase in a dose-related manner. 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 (8 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 2.0. 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 (ROFERONÒ -A). The mean terminal half-life after sc dosing in patients with chronic hepatitis C was 80 hours (range 50 to 140 hours) compared to 5.1 hours (range 3.7 to 8.5 hours) for ROFERONÒ -A. Special Populations 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 m g PEGASYS, but peak concentrations were similar (9 vs 10 ng/mL) in those older and younger than 62 years. Pediatric Patients The pharmacokinetics of PEGASYS have not been adequately studied in pediatric patients. Renal Dysfunction In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance (see PRECAUTIONS: Renal Impairment). 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 WARNINGS and DOSAGE AND ADMINISTRATION). Effect of Food on Absorption of Ribavirin Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when COPEGUS was taken with a high-fat meal compared with fasting conditions (see DOSAGE AND ADMINISTRATION). DRUG INTERACTIONS Nucleoside Analogues Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased anti-retroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is co-administered with ribavirin (see PRECAUTIONS: Drug Interactions). CLINICAL STUDIES PEGASYS Monotherapy (Studies 1, 2, and 3) 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 patients were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All patients received therapy by sc 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 patients with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%). In study 1 (n=630), patients received either ROFERON-A (interferon alfa-2a) 3 MIU three times/week (tiw), PEGASYS 135m g once each week (qw) or PEGASYS 180m g qw. In study 2 (n=526), patients received either ROFERON-A 6 MIU tiw for 12 weeks followed by 3 MIU tiw for 36 weeks or PEGASYS 180m g qw. In study 3 (n=269), patients received ROFERON-A 3 MIU tiw, PEGASYS 90m g qw or PEGASYS 180m g once each week. In all three studies, treatment with PEGASYS 180m g resulted in significantly more patients who experienced a sustained response (defined as undetectable HCV RNA and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In study 1, response to PEGASYS 135m g was not different from response to 180m g. In study 3, response to PEGASYS 90m g was intermediate between PEGASYS 180m g and ROFERON-A.
Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of patients. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups. Of the patients 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 180m g therapy, 2% (3/156) achieved a sustained virologic response (see DOSAGE AND ADMINISTRATION). Averaged over study 1, study 2, and study 3, response rates to PEGASYS were 23% among patients with viral genotype 1 and 48% in patients with other viral genotypes. The treatment response rates were similar in men and women. PEGASYS/COPEGUS Combination Therapy (Studies 4 and 5) 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 patients 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 patients in both studies had compensated cirrhosis (Child-Pugh class A). In study 4, patients were randomized to receive either PEGASYS 180m g sc once weekly (qw) with an oral placebo, PEGASYS 180m g qw with COPEGUS 1000 mg po (body weight <75 kg) or 1200 mg po (body weight ³ 75 kg) or REBETRONTM (interferon alfa-2b 3 MIU sc tiw plus ribavirin 1000 mg or 1200 mg po). All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. PEGASYS in combination with COPEGUS resulted in a higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table 2). In all treatment arms, patients with viral genotype 1 regardless of viral load, had a lower response rate.
Difference in overall treatment response (PEGASYS/COPEGUS – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3). In study 5, all patients received PEGASYS 180m g sc qw 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 / ³ 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients 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. Genotype 1 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. Genotype non-1 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 3).
Among the 36 patients with genotype 4, response rates were similar to those observed in patients with genotype 1 (data not shown). The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment. Treatment Response in Patient Subgroups Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in patients older than 40 years (50% vs 66%), in patients with cirrhosis (47% vs 59%), in patients weighing over 85 kg (49% vs 60%), and in patients with genotype 1 with high vs low viral load (43% vs 56%). African American patients had lower response rates compared to Caucasians. Paired liver biopsies were performed on approximately 20% of patients 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 at 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response at 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response at 24 weeks, nineteen completed a full course of therapy and none achieved an SVR. 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). There are no safety and efficacy data on treatment for longer than 48 weeks. 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 (see CLINICAL STUDIES). PEGASYS The recommended dose of PEGASYS monotherapy is 180 mg (1.0 mL) once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh. PEGASYS and COPEGUS COMBINATION The recommended dose of PEGASYS when used in combination with ribavirin is 180 mg (1.0 mL) once weekly. The recommended dose of COPEGUS and duration for PEGASYS/COPEGUS therapy is based on viral genotype (see Table 5). 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 (eg, genotype), response to therapy, and tolerability of the regimen. Since COPEGUS absorption increases when administered with a meal, patients are advised to take COPEGUS with food.
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. 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 with particulate matter or discoloration should be returned to the pharmacist. 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 m g (0.75 mL) is generally adequate. However, in some cases, dose reduction to 90 m g (0.5 mL) may be needed. Following improvement of the adverse reaction, re-escalation of the dose may be considered (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS). Hematological
Renal Function In patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 m g PEGASYS is recommended. Signs and symptoms of interferon toxicity should be closely monitored. Liver Function In patients with progressive ALT increases above baseline values, the dose of PEGASYS should be reduced to 135 m g. If ALT increases are progressive despite dose reduction or accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be immediately discontinued. COPEGUS
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 WARNINGS and COPEGUS Package Insert). Single Dose Vial Each PEGASYS (peginterferon alfa-2a) 180 m g single use, clear glass vial provides 1.0 mL containing 180 m g peginterferon alfa-2a for sc injection. Each package contains 1 vial (NDC 0004-0350-09). Monthly Convenience Pack Four vials of PEGASYS (peginterferon alfa-2a), 180 m g single use, in a box with 4 syringes and 8 alcohol swabs (NDC 0004-0350-39). Each syringe is a 1 mL (1 cc) volume syringe supplied with a 27 gauge, ˝ inch needle with needle-stick protection device. Storage Store in the refrigerator at 36° to 46°F (2° to 8°C). Do not freeze or shake. Protect from light. Vials are for single use only. Discard any unused portion. REBETRONTM is a trademark of Schering Corporation. U.S. Govt. Lic. No. 0136 Copyright, 2002 by Hoffmann-La Roche Inc. All rights reserved., Revised: December 2002 Printed in USA PEGASYS alone or in combination with COPEGUS causes a broad variety of serious adverse reactions (see BOXED WARNING and WARNINGS). In all studies, one or more serious adverse reactions occurred in 10% of patients receiving PEGASYS alone or in combination with COPEGUS. 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 occurred at a frequency of <1%. Nearly all patients in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions were psychiatric reactions, including depression, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Overall 11% of patients receiving 48 weeks of therapy with PEGASYS either alone (7%) or in combination with COPEGUS (10%) discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (eg, lethargy, fatigue, headache), dermatologic, and gastrointestinal disorders. The most common reason for dose modification in patients receiving combination therapy was for laboratory abnormalities; neutropenia (20%) and thrombocytopenia (4%) for PEGASYS and anemia (22%) for COPEGUS. 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 12% in patients receiving 800 mg COPEGUS for 24 weeks. 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.
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 <10g/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. The most common serious adverse event (3%) was bacterial infection (eg, 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 (eg, hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis) peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, and cerebral hemorrhage. Laboratory Test Values Hemoglobin The hemoglobin concentration decreased below 12g/dL in 17% (median Hgb drop = 2.2 g/dL) of monotherapy and 52% (median Hgb drop = 3.7 g/dL) of combination therapy patients. Severe anemia (Hgb <10 g/dL) was encountered in 13% of patients receiving combination therapy and 2% of monotherapy recipients. Dose modification for anemia was required in 22% of ribavirin recipients treated for 48 weeks. Hemoglobin decreases in PEGASYS monotherapy were generally mild and did not require dose modification (see DOSAGE AND ADMINISTRATION: Dose Modifications). Neutrophils Decreases in neutrophil count below normal were observed in 95% of patients treated with PEGASYS either alone or in combination with COPEGUS. Severe potentially life-threatening neutropenia (ANC <0.5x109/L) occurred in approximately 5% of patients receiving PEGASYS either alone or in combination with COPEGUS. Seventeen percent of patients receiving PEGASYS monotherapy and 20% to 24% of patients receiving PEGASYS/COPEGUS combination therapy required modification of interferon dosage for neutropenia. Two percent of patients 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. Lymphopenia was observed during both monotherapy (86%) and combination therapy with PEGASYS and COPEGUS (94%). Severe lymphopenia (<0.5x109/L) occurred in approximately 5% of monotherapy patients and 14% of combination PEGASYS and COPEGUS therapy recipients. Dose adjustments were not required by protocol. Median lymphocyte counts return to pre-treatment levels after 4 to 12 weeks of the cessation of therapy. The clinical significance of the lymphopenia is not known. Platelets Platelet counts decreased in 52% of patients treated with PEGASYS alone (median drop 45% from baseline), 33% of patients receiving combination with COPEGUS (median drop 30% from baseline). Median platelet counts return to pretreatment levels 4 weeks after the cessation of therapy. 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 higher ³400 mg/dL were observed in about 20% of patients. ALT Elevations Less than 1% of patients experienced marked elevations (5- to 10-fold above baseline) in ALT levels during treatment. 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). 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. 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 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 of 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 these products may be misleading. 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 PRECAUTIONS). There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. In patients with chronic hepatitis C treated with PEGASYS in combination with COPEGUS, PEGASYS treatment did not affect ribavirin distribution or clearance. Nucleoside Analogues 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). Stavudine and Zidovudine Ribavirin can antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be avoided. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis PEGASYS has not been tested for its carcinogenic potential. Mutagenesis 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. The carcinogenic potential of ribavirin has not been fully determined. In a p53 (+/-) mouse carcinogenicity study at doses up to the maximum tolerated dose of 100 mg/kg/day ribavirin was not oncogenic. However, on a body surface area basis, this dose was 0.5 times maximum recommended human 24-hour dose of ribavirin. A study in rats to assess the carcinogenic potential of ribavirin is ongoing. Mutagenesis (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 sc injections of 600 m g/kg/dose (7200 m g/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 17b -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 100m g/kg (1200m g/m2) PEGASYS (equivalent to approximately 30 times the recommended human dose) had no effects on cycle duration or reproductive hormone status. The effects of PEGASYS on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys treated with non-pegylated interferon alfa-2a for 5 months at doses up to 25 x 106 IU/kg/day (see COPEGUS Package Insert). Pregnancy Pregnancy: Category C 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) 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, WARNINGS, and COPEGUS Package Insert). If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, such cases should be reported to the COPEGUS Pregnancy Registry at 1-800-526-6367. 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. 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). 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 (eg, 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.
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). INFORMATION FOR PATIENTS Patients receiving PEGASYS alone or in combination with COPEGUS should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the PEGASYS and, if applicable, COPEGUS (ribavirin) MEDICATION GUIDES. 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 physician immediately in the event of a pregnancy (see CONTRAINDICATIONS and WARNINGS). Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded; routine monthly pregnancy tests must be performed during this time (see CONTRAINDICATIONS and COPEGUS Package Insert). If pregnancy does occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to COPEGUS, the COPEGUS Pregnancy Registry has been established. Physicians and patients are strongly encouraged to register by calling 1-800-526-6367. Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter (see Laboratory Tests). 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 informed that it is not known if therapy with PEGASYS alone or in combination with COPEGUS will prevent transmission of HCV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HCV infection. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery. 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 MEDICATION GUIDE). Laboratory Tests Before beginning PEGASYS or PEGASYS and COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. 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, and then every 4 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:
PEGASYS treatment was associated with decreases in WBC, ANC, lymphocytes and platelet counts often starting within the first 2 weeks of treatment (see ADVERSE REACTIONS). Dose reduction is recommended in patients with hematologic abnormalities (see DOSAGE AND ADMINISTRATION: Dose Modifications). While fever is commonly caused by PEGASYS therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia (see WARNINGS: Infections). Transient elevations in ALT (2-fold to 5-fold above baseline) were observed in some patients receiving PEGASYS, and were not associated with deterioration of other liver function tests. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, PEGASYS therapy should be discontinued (see DOSAGE AND ADMINISTRATION: Dose Modifications). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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