Pegasys

Warnings and Precautions, Impact on Growth in Pediatric Patients (5.15) 12/2023

1 INDICATIONS AND USAGE PEGASYS is an inducer of the innate immune response indicated for the treatment of Chronic Hepatitis C (CHC) ( 1.1 ) Adult Patients: In combination therapy with other hepatitis C virus drugs for adults with compensated liver disease. PEGASYS monotherapy is indicated only if patient has contraindication or significant intolerance to other HCV drugs. Pediatric Patients: In combination with ribavirin for pediatric patients 5 years of age and older with compensated liver disease Chronic Hepatitis B (CHB) ( 1.2 ) Adult Patients: Treatment of adults with HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) infection who have compensated liver disease and evidence of viral replication and liver inflammation Pediatric Patients: Treatment of non-cirrhotic pediatric patients 3 years of age and older with HBeAg-positive CHB and evidence of viral replication and elevations in serum alanine aminotransferase (ALT) 1.1 Chronic Hepatitis C (CHC) Adult Patients: PEGASYS, as part of a combination regimen with other hepatitis C virus (HCV) antiviral drugs, is indicated for the treatment of adults with CHC and compensated liver disease. For information about the safe and effective use of other HCV antiviral drugs to be used in combination with PEGASYS, refer to their prescribing information. PEGASYS monotherapy is only indicated for the treatment of patients with CHC and compensated liver disease if there are contraindications or significant intolerance to other HCV antiviral drugs. Pediatric Patients: PEGASYS in combination with ribavirin is indicated for the treatment of pediatric patients 5 years of age and older with CHC and compensated liver disease. Limitations of Use : PEGASYS alone or in combination with ribavirin without additional HCV antiviral drugs is not recommended for treatment of patients with CHC who previously failed therapy with an interferon-alfa. PEGASYS is not recommended for treatment of patients with CHC who have had solid organ transplantation [see Use in Specific Populations (8.8) ] . 1.2 Chronic Hepatitis B (CHB) Adult Patients: PEGASYS is indicated for the treatment of adults with HBeAg-positive and HBeAg-negative CHB infection who have compensated liver disease and evidence of viral replication and liver inflammation. Pediatric Patients: PEGASYS is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic pediatric patients 3 years of age and older with evidence of viral replication and elevations in serum alanine aminotransferase (ALT).

2 DOSAGE AND ADMINISTRATION PEGASYS is administered by subcutaneous injection ( 2 ) In adult patients with CHC, PEGASYS is dosed as 180 mcg per week and the duration of treatment depends on indication, genotype, and whether it is administered with other HCV antiviral drugs ( 2.2 ). In adult patients with CHB, PEGASYS is dosed as 180 mcg per week for 48 weeks ( 2.4 ). In pediatric patients with CHC, PEGASYS is dosed as 180 mcg/1.73 m 2 × BSA per week, in combination with ribavirin, and the duration of treatment depends on genotype ( 2.3 ) In pediatric patients with CHB, PEGASYS is dosed as 180 mcg/1.73 m 2 × BSA per week for 48 weeks ( 2.5 ): Dosage modification is recommended in patients experiencing certain laboratory abnormalities, adverse reactions or renal impairment ( 2.6 , 12.3 ) 2.1 Dosage Overview Administer PEGASYS by subcutaneous injection once weekly in the abdomen or thigh for the treatment of: Adult patients with CHC without or with HIV coinfection [see Dosage and Administration (2.2) ]; Pediatric patients with CHC [see Dosage and Administration (2.3) ] ; Adult patients with CHB [see Dosage and Administration (2.4) ] ; and Pediatric patients with CHB [see Dosage and Administration (2.5) ]. For treatment of CHC, use PEGASYS in combination with other HCV antiviral drugs. For information about the recommended dosage and administration and the safe and effective use of these other HCV antiviral drugs, refer to their prescribing information. PEGASYS monotherapy is only indicated in the treatment of CHC if there are contraindications to or significant intolerance to other HCV antiviral drugs. For dosage modifications in patients with CHC or CHB: Due to neutropenia, thrombocytopenia, ALT elevation, and depression [see Dosage and Administration (2.6) ] . In patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and in patients with creatinine clearance between 30 and 50 mL/minute [see Dosage and Administration (2.6) ] . For important administration instructions for all the PEGASYS injection presentations (i.e., vial and prefilled syringe) [ see Dosage and Administration (2.7) ]. 2.2 Recommended Dosage for Adults with CHC Dosage in Adults with CHC without HIV Coinfection Table 1 displays the recommended dosage and duration of PEGASYS and other HCV antiviral drugs in adults with CHC (without HIV coinfection) based on HCV genotype. For treatment of HCV genotype 1 with PEGASYS in combination with ribavirin or alone, discontinuation of treatment is recommended if at least a 2 log 10 reduction from baseline in HCV RNA has not been demonstrated by 12 weeks of therapy or if undetectable HCV RNA has not been achieved after 24 weeks of therapy [see Clinical Studies (14) ] . Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for information on stopping therapy based on treatment response. Immediately discontinue PEGASYS for hepatic decompensation (Child-Pugh score greater than 6 [class B and C]). Table 1 Recommended Dosage for PEGASYS for Adults with CHC Infection If PEGASYS is used in combination with other antiviral drugs for CHC, refer to the prescribing information of the other HCV antiviral drugs for the recommended dosage of the other HCV antiviral drugs and duration of the entire treatment regimen. Hepatitis C Virus Genotype PEGASYS Dosage PEGASYS Duration Genotypes 1, 4 If PEGASYS and ribavirin are used without other HCV antiviral drugs the recommended duration of therapy is 48 weeks. 180 mcg subcutaneous injection in thigh or abdomen once weekly Refer to the prescribing information of HCV antiviral drugs. Genotypes 2, 3 If PEGASYS and ribavirin are used without other HCV antiviral drugs the recommended duration of therapy is 24 weeks. Genotypes 5, 6 There are insufficient data for dosage recommendations If PEGASYS monotherapy is used for treatment of CHC, the recommended PEGASYS dosage is 180 mcg via subcutaneous injection in thigh or abdomen o …

3 DOSAGE FORMS AND STRENGTHS PEGASYS is a colorless to slightly yellowish solution available as: Injection: 180 mcg/mL in a single-dose vial Injection: 180 mcg/0.5 mL in a single-dose prefilled syringe Injection: 180 mcg/mL solution in a single-dose vial ( 3 ) 180 mcg/0.5 mL solution in a single-dose prefilled syringe ( 3 )

4 CONTRAINDICATIONS PEGASYS is contraindicated in patients with: Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome to alpha interferons, including PEGASYS, or any of its components. Autoimmune hepatitis Hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before treatment Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before treatment PEGASYS is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants. When PEGASYS is used in combination with other HCV antiviral drugs, the contraindications applicable to those agents are applicable to combination therapies. PEGASYS combination treatment with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant [See Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Refer to the prescribing information of the other HCV antiviral drugs, including ribavirin, for a list of their contraindications. Autoimmune hepatitis ( 4 ) Hepatic decompensation in patients with cirrhosis ( 4 ) Use in neonates/infants ( 4 ) Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction and anaphylaxis to alpha interferons or any component of the product ( 4 ) Additional contraindications for use with other HCV antiviral drugs: When used in combination with other HCV antiviral drugs, all contraindications also apply to PEGASYS combination therapy ( 4 ) Ribavirin is contraindicated in pregnant women and men whose female partners are pregnant ( 4 , 8.1 )

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 ribavirin [see Boxed Warning and Warnings and Precautions (5) ] . The most common life-threatening or fatal events induced or aggravated by PEGASYS and ribavirin include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects [see Warnings and Precautions (5.9) ] . Adult subjects: The most common adverse reactions (incidence greater than 40%) are fatigue/asthenia, pyrexia, myalgia, and headache ( 6.1 ) Pediatric subjects: The most common adverse reactions are similar to those seen in adults ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact pharma& agent at 1-888-814-7734 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Chronic Hepatitis C Adult Subjects In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in combination with ribavirin. The most common serious adverse reactions (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of less than 1% and included: suicide, suicidal ideation, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination. In clinical trials, 98 to 99 percent of subjects experienced one or more adverse reactions. For hepatitis C subjects, the most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 7 displays pooled rates of adverse reactions occurring in greater than 5% of subjects in the PEGASYS monotherapy and PEGASYS/ribavirin combination therapy clinical trials. Overall, 11% of CHC monoinfected subjects receiving 48 weeks of therapy with PEGASYS either alone or in combination with ribavirin 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 ribavirin therapy. The most common reasons for dose modification of PEGASYS in CHC and CHC/HIV subjects was for neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of ribavirin 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 ribavirin for 48 weeks and in 7% of subjects receiving 800 mg ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of su …

7 DRUG INTERACTIONS Drugs metabolized by CYP1A2: monitor for increased serum levels of theophylline and adjust dose accordingly ( 7.2 ) Methadone: monitor for signs and symptoms of methadone toxicity ( 7.3 ) Nucleoside analogues: closely monitor for toxicities. Reduce or discontinue the dose of PEGASYS or ribavirin or both should the events worsen ( 7.4 ) Zidovudine: monitor for worsening neutropenia and/or anemia with PEGASYS and/or ribavirin ( 7.4 ) 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. 7.2 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. 7.3 Methadone 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 naïve 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 NRTIs In Study 7 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/ribavirin in combination with other HCV antiviral drugs and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for other HCV antiviral drugs and the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, ribavirin or both, should also be considered if worsening toxicities are observed [see Warnings and Precautions (5.3 , 5.9) and Dosage and Administration (2.6) ] . Zidovudine In Study 7, subjects who were administered zidovudine in combination with PEGASYS/ribavirin developed severe neutropenia (ANC less than 500 cells/mm 3 ) and severe anemia (hemoglobin less than 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, ribavirin or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for information on drug interaction potential.

8 USE IN SPECIFIC POPULATIONS Pediatric patients: Safety and efficacy in CHC pediatric patients less than 5 years old and CHB pediatric patients less than 3 years old have not been established ( 8.4 ) Geriatric patients: Neuropsychiatric, cardiac, and systemic (flu-like) adverse reactions may be more severe ( 8.5 ) Patients with hepatic impairment: Clinical status and hepatic function should be closely monitored and treatment should be immediately discontinued if decompensation occurs ( 8.6 ) Patients with renal impairment: PEGASYS dose should be reduced in patients with creatinine clearance less than 30 mL/min ( 2.6 , 8.7 ) CHB: Safety and efficacy have not been established in hepatitis B patients coinfected with HCV or HIV ( 8.9 ) 8.1 Pregnancy Pregnancy Exposure Registry – Use with ribavirin 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 pregnancy or who become pregnant within 6 months following cessation of treatment with ribavirin. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214. Risk Summary There are no adequate and well-controlled studies of PEGASYS in pregnant women to inform a drug-associated risk. Based on animal reproduction studies, PEGASYS can cause fetal harm and should be assumed to have abortifacient potential. Non-pegylated interferon alfa-2a treatment caused abortion when given to pregnant rhesus monkeys (see Data ). The background risk of major birth defects and miscarriage in the indicated population is 3% and 4-22%, respectively. In the U.S. general population, the estimated background risk for major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively. PEGASYS combination treatment with ribavirin 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 ribavirin labeling] . Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin [see ribavirin labeling]. Data Animal Data – Groups of 8 or 9 pregnant rhesus monkeys were given non-pegylated interferon alfa-2a by daily intramuscular injection over days 22 to 70 of gestation at doses of 1, 5 and 25 million IU/day. Two, 3 and 6 monkeys aborted in the low, mid and high dose groups compared with 1 in the control group. Maternal toxicity, characterized by transient body weight loss, was seen at all dose levels. There were too few remaining pregnancies to assess teratogenic potential but no developmental abnormalities were observed in surviving fetuses. 8.2 Lactation There is no information regarding the presence of peginterferon alfa-2a in human milk, the effects on the breastfed infant, or the effects on milk production. 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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PEGASYS and any potential adverse effects on the breastfed child from PEGASYS or from the underlying maternal condition. The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential transmission of HIV; therefore, CHC- and CHB-infected mothers coinfected with HIV should not breastfeed their infants. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Females of reproductive potential must undergo pregnancy testing before initiation of treatment with PEGASYS or with PEGASYS in combination with ribavirin or with other HCV drugs [see Warnings and Precautions (5.17) ] . Females of reproductive potential receiving PEGASYS in combination with ribavirin must have a routine pregnancy test perform …

12.1 Mechanism of Action Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune response [see Microbiology (12.4) ] .

11 DESCRIPTION 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 slightly yellowish solution available as an injection and is administered subcutaneously. Each vial of 180 mcg/mL peginterferon alfa-2a (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.05 mg), benzyl alcohol (10 mg), polysorbate 80 (0.05 mg), sodium acetate trihydrate (2.62 mg), and sodium chloride (8 mg) at pH 6 ± 0.5. Each prefilled syringe of 180 mcg/0.5 mL peginterferon alfa-2a (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.0231 mg), benzyl alcohol (5 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4 mg) at pH 6 ± 0.5.

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING PEGASYS (peginterferon alfa-2a) injection is a sterile, preservative-free, colorless to slightly yellowish solution administered subcutaneously. Each PEGASYS Single-Dose Vial Package Contains: A box containing 180 mcg per 1 mL solution in a single-dose vial. (NDC 82154-0449-1) Each PEGASYS Prefilled Syringe Monthly Convenience Pack Contains: A box containing four 180 mcg per 0.5 mL (1⁄2 cc) single-dose prefilled syringes with 4 needles. Each prefilled syringe is supplied with a 27-gauge, 1⁄2-inch needle with a needle-stick protection device. (NDC 82154-0451-4) Storage and Handling Store in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not leave PEGASYS out of the refrigerator for more than 24 hours. Do not freeze or shake. Protect from light. Vials and prefilled syringes are for single use only. Discard any unused portion remaining in the vial, prefilled syringe. Disposal Instructions 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 ] .