Plegridy

Warnings and Precautions ( 5.8 ) 7/2023

1 INDICATIONS AND USAGE PLEGRIDY is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. PLEGRIDY is an interferon beta indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults ( 1 )

2 DOSAGE AND ADMINISTRATION For subcutaneous or intramuscular use only ( 2.1 ) Recommended dose: 125 micrograms every 14 days ( 2.1 ) PLEGRIDY dose should be titrated, starting with 63 micrograms on day 1, 94 micrograms on day 15, and 125 micrograms (full dose) on day 29 ( 2.1 ) A healthcare professional should train patients in the proper technique for self-administering subcutaneous injections using the prefilled pen or syringe or intramuscular injections using the prefilled syringe ( 2.2 ) Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms ( 2.3 ) 2.1 Dosing Information PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM). Recommended Maintenance Dosage After initial titration (see Table 1 and Table 2 ), the recommended dosage of PLEGRIDY is 125 micrograms injected every 14 days. For subcutaneous injection: Patients may rotate injection sites between the abdomen, back of the upper arm, or thigh. For intramuscular injection: Patients may rotate injection sites between the left and right thighs. Treatment Initiation Dose titration at the initiation of treatment may help to ameliorate flu-like symptoms that can occur at treatment initiation with interferons. Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during treatment with PLEGRIDY. Switching between the subcutaneous and intramuscular routes of administration and vice versa has not been studied. It is not expected that dose titration should be repeated to ameliorate flu-like symptoms if switching between subcutaneous and intramuscular routes of administration, or vice versa based upon bioequivalence demonstrated between the two routes of administration. Subcutaneous Administration of PLEGRIDY Patients using PLEGRIDY for the first time should start treatment with 63 micrograms on day 1. On day 15 (14 days later), the dose is increased to 94 micrograms, reaching the full dose of 125 micrograms on day 29 (after another 14 days). Patients continue with the full dose (125 micrograms) every 14 days thereafter (see Table 1 ). A PLEGRIDY Starter Pack is available containing two prefilled pens or syringes: 63 micrograms (dose 1) and 94 micrograms (dose 2). Table 1: Schedule for Subcutaneous Dose Titration Dose Time a Amount (micrograms) Color of Pen or Syringe Label a Dosed every 14 days Dose 1 On day 1 63 Orange Dose 2 On day 15 94 Blue Dose 3 On day 29 and every 14 days thereafter 125 (full dose) Grey Intramuscular Administration of PLEGRIDY For patients using PLEGRIDY injected intramuscularly for the first time, PLEGRIDY should be titrated using the PLEGRIDY Titration Kit designed for use with the prefilled syringe. The PLEGRIDY Titration Kit is supplied separately and contains two titration devices to be used only with PLEGRIDY prefilled syringes for intramuscular use. Patients should start treatment with 63 micrograms (yellow clip) on day 1. On day 15 (14 days later), the dose is increased to 94 micrograms (purple clip), reaching the full dose of 125 micrograms on day 29 (after another 14 days). Patients continue with the full dose (125 micrograms) every 14 days thereafter (see Table 2 ). Table 2: Schedule for Intramuscular Dose Titration Dose Time a Amount (micrograms) Titration Clip a Dosed every 14 days Dose 1 On day 1 63 Yellow Dose 2 On day 15 94 Purple Dose 3 On day 29 and every 14 days thereafter 125 (full dose) No Clips Needed 2.2 Important Administration Instructions (All Dosage Forms) Healthcare professionals should train patients in the proper technique for self-administering subcutaneous injections using the prefilled pen or syringe or intramuscular injections using the prefilled syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Advise patients and caregivers to rotate injection sites with each administration to minimize the likelihood of severe …

3 DOSAGE FORMS AND STRENGTHS PLEGRIDY is a clear to slightly opalescent and colorless to slightly yellow solution. Subcutaneous Administration: Injection: 125 mcg/0.5 mL in a single-dose prefilled pen or single-dose prefilled syringe ( 3 ) Injection: 63 mcg/0.5 mL in a single-dose prefilled pen or single-dose prefilled syringe ( 3 ) Injection: 94 mcg/0.5 mL in a single-dose prefilled pen or single-dose prefilled syringe ( 3 ) Intramuscular Administration: Injection: 125 mcg/0.5 mL solution in a single-dose prefilled syringe ( 3 ) Subcutaneous Administration: Injection: 125 mcg/0.5 mL in a single-dose prefilled pen or single-dose prefilled syringe Injection: 63 mcg/0.5 mL in a single-dose prefilled pen or a single-dose prefilled syringe Injection: 94 mcg/0.5 mL in a single-dose prefilled pen or a single-dose prefilled syringe Intramuscular Administration: Injection: 125 mcg/0.5 mL in a single-dose prefilled syringe

4 CONTRAINDICATIONS PLEGRIDY is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY [see Warnings and Precautions ( 5.3 )] . History of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of labeling: Hepatic Injury [see Warnings and Precautions ( 5.1 )] Depression and Suicide [see Warnings and Precautions ( 5.2 )] Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions ( 5.3 )] Injection Site Reactions Including Necrosis [see Warnings and Precautions ( 5.4 )] Congestive Heart Failure [see Warnings and Precautions (Section 5.5 )] Decreased Peripheral Blood Counts [see Warnings and Precautions ( 5.6 )] Thrombotic Microangiopathy [see Warnings and Precautions ( 5.7 )] Pulmonary Arterial Hypertension [see Warnings and Precautions ( 5.8 )] Autoimmune Disorders [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] The most common adverse reactions in clinical trials of subcutaneous PLEGRIDY (incidence ≥10% and at least 2% more frequent on PLEGRIDY than on placebo) were injection site erythema, influenza-like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of PLEGRIDY cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. PLEGRIDY Via Subcutaneous Administration In clinical studies (Study 1 and Study 2), a total of 1468 patients with relapsing multiple sclerosis received PLEGRIDY by subcutaneous injection for up to 177 weeks (41 months), with an overall exposure equivalent to 1932 person-years. A total of 1093 patients received at least 1 year, and 415 patients at least 2 years of treatment with PLEGRIDY. A total of 512 and 500 patients, respectively, received PLEGRIDY 125 micrograms every 14 days or every 28 days during the placebo-controlled phase of Study 1 (year 1). The experience in year 2 of Study 1 and in the 2-year safety extension study (Study 2) was consistent with the experience in the 1-year placebo-controlled phase of Study 1. In the placebo-controlled phase of Study 1, the most common adverse drug reactions for PLEGRIDY 125 micrograms subcutaneously every 14 days were injection site erythema, influenza-like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia (all had incidence more than 10% and at least 2% more than placebo). The most commonly reported adverse event leading to discontinuation in patients treated with PLEGRIDY 125 micrograms subcutaneously every 14 days was influenza-like illness (in less than 1% of patients). Table 3 summarizes adverse reactions reported over 48 weeks from patients treated in the placebo-controlled phase of Study 1 who received subcutaneous PLEGRIDY 125 micrograms (n=512), or placebo (n=500), every 14 days. Table 3: Adverse Reactions in the 48-Week Placebo-Controlled Phase of Study 1 with an Incidence 2% Higher for PLEGRIDY Than for Placebo PLEGRIDY (N=512) % Placebo (N=500) % Nervous System Disorders Headache 44 33 Gastrointestinal Disorders Nausea 9 6 Vomiting 5 2 Musculoskeletal and Connective Tissue Disorders Myalgia 19 6 Arthralgia 11 7 General Disorders and Administration Site Conditions Injection site erythema 62 7 Influenza like illness 47 13 Pyrexia 45 15 Chills 17 5 Injection site pain 15 3 Asthenia 13 8 Injection site pruritus 13 1 Hyperthermia 4 1 Pain 5 3 Injection site edema 3 0 Injection site warmth 3 0 Injection site hematoma 3 1 Injection site rash 2 0 Investigations Body temperature increased 6 3 Alanine aminotransferase increased 6 3 Aspartate aminotransferase increased 4 2 Gamma-glutamyl-transferase increased 3 1 Skin and Subcutaneous Tissue Disorder Pruritus 4 1 Flu-Like Symptoms Influenza-like illness was exper …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Epidemiological data do not suggest a clear relationship between interferon beta use and major congenital malformations, but interferon beta may cause fetal harm based on animal data ( 8.1 ) Severe Renal Impairment: monitor for adverse reactions ( 8.6 ) 8.1 Pregnancy Risk Summary Data from a large population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with the use of interferon beta products during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta products in pregnancy have been inconsistent (see Data ). In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Human Data The majority of observational studies reporting on pregnancies exposed to interferon beta products did not identify an association between the use of interferon beta products during early pregnancy and an increased risk of major birth defects. In a population-based cohort study conducted in Finland and Sweden, data were collected from 1996--2014 in Finland and 2005--2014 in Sweden on 2,831 pregnancy outcomes from women with MS. 797 pregnancies were in women exposed to interferon beta only. No evidence was found of an increased risk of major birth defects among women with MS exposed to interferon beta products compared to women with MS that were unexposed to any non-steroid therapy for MS (n=1,647) within the study. No increased risks were observed for miscarriages and ectopic pregnancies, though there were limitations in obtaining complete data capture for these outcomes, making the interpretation of the findings more difficult. Two small cohort studies that examined pregnancies exposed to interferon beta products (without differentiating between subtypes of interferon beta products) suggested that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies observed an increased prevalence of miscarriage, although the finding was only statistically significant in one study. Most studies enrolled patients later in pregnancy, which made it difficult to ascertain the true percentage of miscarriages. In one small cohort study, a significantly increased risk of preterm birth following interferon beta exposure during pregnancy was observed. Animal Data PLEGRIDY has not been tested for developmental toxicity in pregnant animals. In monkeys given interferon beta by subcutaneous injection every other day during early pregnancy, no adverse effects on embryofetal development were observed. Abortifacient activity was evident following 3 to 5 doses. 8.2 Lactation Risk Summary Limited published literature has described the presence of interferon beta-1a products in human milk at low levels. There are no data on the effects of interferon beta-1a on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PLEGRIDY and any potential adverse effects on the breastfed infant from PLEGRIDY or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of PLEGRIDY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patie …

12.1 Mechanism of Action The mechanism by which PLEGRIDY exerts its effects in patients with multiple sclerosis is unknown.

11 DESCRIPTION Peginterferon beta-1a is a covalent conjugate of recombinant interferon beta-1a (approximate molecular weight [MW] 20,000 daltons) with a single, linear methoxy poly(ethyleneglycol)-O-2-methylpropionaldehyde molecule (approximate MW 20,000 daltons). Interferon beta-1a is produced as a glycosylated protein using genetically-engineered Chinese hamster ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of recombinant interferon beta-1a is identical to that of the human interferon beta counterpart. The molecular weight of peginterferon beta-1a is approximately 44,000 daltons, consistent with the mass of the protein, the carbohydrate moieties (approximately 2,500 daltons), and the attached poly(ethylene glycol). Peginterferon beta-1a 125 mcg contains 125 mcg of interferon beta-1a plus 125 mcg of poly(ethylene glycol). Using the World Health Organization International Standard for interferon beta, peginterferon beta-1a has a specific antiviral activity of approximately 100 million International Units (MIU) per mg of protein as determined using an in vitro cytopathic effect assay. Peginterferon beta-1a 125 mcg contains approximately 12 MIU of antiviral activity. Subcutaneous Administration PLEGRIDY (peginterferon beta-1a) injection is a sterile, preservative-free solution in a single-dose prefilled pen or single-dose prefilled syringe with a 29-gauge, 0.5-inch needle for subcutaneous use. Each prefilled pen or prefilled syringe delivers 0.5 mL. Each 0.5 mL contains 63 mcg, 94 mcg, or 125 mcg of peginterferon beta-1a, and L-arginine HCl (15.8 mg), glacial acetic acid (0.25 mg), polysorbate 20 (0.025 mg), and sodium acetate trihydrate (0.79 mg) in Water for Injection, USP. The pH is approximately 4.8. Intramuscular Administration PLEGRIDY (peginterferon beta-1a) injection is a sterile, preservative-free solution in a single-dose prefilled syringe with a 23-gauge, 1.25-inch needle for intramuscular use. Each prefilled syringe delivers 0.5 mL. Each 0.5 mL contains 125 mcg of peginterferon beta-1a, and L-arginine HCl (15.8 mg), glacial acetic acid (0.25 mg), polysorbate 20 (0.025 mg), and sodium acetate trihydrate (0.79 mg) in Water for Injection, USP. The pH is approximately 4.8.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PLEGRIDY (peginterferon beta-1a) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution supplied as a 0.5 mL single-dose prefilled pen or a 0.5 mL single-dose prefilled syringe. Subcutaneous Administration PLEGRIDY (peginterferon beta-1a) injection for subcutaneous use is supplied as a single-dose prefilled pen or single-dose prefilled syringe with a rubber stopper and a 29-gauge, 0.5-inch staked needle with a rigid needle shield in the following packaging configurations: Carton containing two-125 mcg/0.5 mL single-dose prefilled pens of PLEGRIDY (NDC 64406-011-01). Starter Pack carton containing two single-dose prefilled pens; dose 1 provides 63 mcg/0.5 mL of PLEGRIDY and dose 2 provides 94 mcg/0.5 mL of PLEGRIDY (NDC 64406-012-01). Carton containing two-125 mcg/0.5 mL single-dose prefilled syringes of PLEGRIDY (NDC 64406-015-01). Starter Pack carton containing two single-dose prefilled syringes; dose 1 provides 63 mcg/0.5 mL of PLEGRIDY, and dose 2 provides 94 mcg/0.5 mL of PLEGRIDY (NDC 64406-016-01). Intramuscular Administration PLEGRIDY (peginterferon beta-1a) injection for intramuscular use is supplied as a single-dose prefilled syringe with a rubber stopper and a 23-gauge, 1.25-inch staked needle provided separately with the syringe in the following packaging configurations: Carton containing two-125 mcg/0.5 mL single-dose prefilled syringes of PLEGRIDY (NDC 64406-017-01). The PLEGRIDY Titration Kit must be prescribed and dispensed separately for treatment initiation. The Titration Kit contains two titration clips: The yellow clip (for dose 1) allows a delivered dose of 63 mcg of PLEGRIDY, and the purple clip (for dose 2) allows a delivered dose of 94 mcg of PLEGRIDY. 16.2 Storage and Handling Store PLEGRIDY prefilled pens and prefilled syringes in a refrigerator between 2°C to 8°C (36°F to 46°F) in the closed original carton to protect from light until ready for injection. Do not freeze. Discard if frozen. If refrigeration is unavailable, PLEGRIDY may be stored at room temperature up to 25°C (77°F) for a period up to 30 days, protected from light. PLEGRIDY can be removed from, and returned to, a refrigerator if necessary. The total combined time out of refrigeration should not exceed 30 days. PLEGRIDY prefilled syringe for intramuscular administration contains natural rubber latex which may cause allergic reactions. Dispose in a sharps-bin container or other hard plastic or metal sealable container. Always follow local regulations for disposal.