PLEGRIDY

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.

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.

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.

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.

Angor History of epilepsy History of depression Cardiac aplasia Arrhythmia Cardiopathies Epilepsy Pregnancy Hypothyroidism, history (d) Congestive heart failure Severe hepatic impairment Severe renal impairment Elderly Subject under 18.

Mechanism of Action The mechanism by which PLEGRIDY exerts its effects in patients with multiple sclerosis is unknown. 12.2 Pharmacodynamics There is no biochemical or physiologic effect known to relate directly to the clinical effect of PLEGRIDY. 12.3 Pharmacokinetics After single-dose or multiple-dose subcutaneous administration of PLEGRIDY to healthy subjects, serum PLEGRIDY peak concentration (C max ) and total exposure over time (area under the curve, or AUC) increased in proportion to doses from to 188 micrograms.

PLEGRIDY did not accumulate in the serum after multiple doses of 125 micrograms every 14 days.

Pharmacokinetic parameters for

PLEGRIDY, including C max and AUC, did not differ significantly between healthy volunteers and multiple sclerosis patients or between single-dose and multiple-dose administrations.

However, the coefficient of variation between individual patients for AUC, C max, and half-life was high (41% to 68%, 74% to 89%, and 45% to 93%, respectively).

After 125 microgram subcutaneous doses of PLEGRIDY in multiple sclerosis patients, the maximum concentration occurred between and 1.5 days, the mean C max was 280 pg/mL, and the AUC over the 14 day dosing interval was 34.8 ng.hr/mL.

In multiple sclerosis patients taking 125 microgram subcutaneous doses of PLEGRIDY every 14 days, the estimated volume of distribution was 481 liters.

Metabolism and Elimination Clearance mechanisms for

PLEGRIDY include catabolism and excretion.

The major pathway of elimination is renal.

The half-life is approximately 78 hours in multiple sclerosis patients.

The mean steady state clearance of

PLEGRIDY is approximately 4.1 L/hr. PLEGRIDY is not extensively metabolized in the liver.

The pharmacokinetics of 125 μg single dose of PLEGRIDY administered subcutaneously and intramuscularly were similar.

Body weight, gender, and age do not require dosage adjustment.

Renal impairment can increase the C max and AUC for PLEGRIDY.

Results of a pharmacokinetic study in patients with mild, moderate, and severe renal impairment (creatinine clearance to 80, 30 to 50, and less than 30 mL/minute, respectively) showed increases above normal for C max of 27%, 26%, and 42%, and for AUC, increases of 30%, 40%, and 53%.

The half-life was 53, 49, and 82 hours in patients with mild, moderate, and severe renal impairment, respectively, compared to 54 hours in normal subjects.

In the same study, subjects with end stage renal disease requiring hemodialysis two or three times weekly had AUC and C max of PLEGRIDY values that were similar to those of normal controls.

Each hemodialysis session removed approximately 24% of circulating PLEGRIDY from the systemic circulation.

The enzyme-reactive enzyme is a biologically active enzyme that is a biologically active enzyme.

The enzyme-reactive enzyme is a biologically active enzyme that is a natural-sourced protein family, produced by eukaryote cells in response to viral infection and other biological inducers.

Interferons are mediating cytokines of antiviral, antiproliferative and immunomodulatory activities.

Three major forms of interferons can be distinguished: alpha, beta and gamma interferons.

Alpha and beta interferons are classified as type I and gamma interferons as type II.

These interferons have overlapping and clearly identifiable biological activities, and can be distinguished by their cellular synthesis sites.

The beta interferon is produced by various cell types, including fibroblasts and macrophages.

• (increase) (Common)
• Blood globinaemia (decrease) (Common)
• Gamma GT (increase) (Common)
• ALT (increase) (Common)
• Body temperature increase (Common)
• White Globules decreased (Common)
• Urinary proteins present Pruritus (Common)
• Urticaria (Uncommon)
• Alopecia (Common)
• Frisher (Very common)
• Asthenia (Very common)
• Irflu pseudo-influenza syndrome (Very common)
• Pain (Common)
• Fever (Very common)
• Hyperthermia (Common)
• Thrombocytopenia (Uncommon)
• Thrombotic thrombocytopenic purpura Oedema of Quincke (Uncommon)
• Hypersensitivity (Uncommon)
• Anaphylactic reaction Pain at injection site (Very common)
• Heat sensation at the injection site (Common)
• Skin rash at injection site (Common)
• Skin colour at injection site (change) (Common)
• Injection site edema (Common)
• Hematoma at the injection site (Common)
• Inflammation at the injection site (Common)
• Pruritus at the injection site (Very common)
• Erythema at the injection site (Very common)
• Necrosis at the injection site (Rare)
• Depression (Common)
• Thrombotic microangiopathy (Rare)
• Nausea (Common)
• Vomiting (Common)
• Muscle pain (Very common)
• Joint pain (Very common)
• Headache (Very common)
• Epilepsy (crisis) (Uncommon)
• Pulmonary hypertension Glomerulosclerosis (Rare)
• Nephrotic syndrome (Rare)
• Hemolytic and uremic syndrome.

is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY.

History of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY.

For subcutaneous or intramuscular use only

Recommended dose: 125 micrograms every 14 days 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 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 Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms 2.1 Dosing Information PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM).

After initial titration, 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.

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.

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 On day 1 63 Orange Dose On day 15 94 Blue Dose On day 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.

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).

Table 2: Schedule for Intramuscular Dose Titration Dose Time a Amount (micrograms) Titration Clip a Dosed every 14 days Dose On day 1 63 Yellow Dose On day 15 94 Purple Dose On day 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 injection site reactions, including necrosis or localized infection.

Once removed from the refrigerator, PLEGRIDY should be allowed to warm to room temperature (about 30 minutes) prior to injection.

Do not use external heat sources such as hot water to warm PLEGRIDY.

PLEGRIDY pen and syringe for subcutaneous injection is provided with the needle pre-attached.

PLEGRIDY prefilled syringe for intramuscular injection is supplied as a prefilled syringe with a separate needle.

Both intramuscular and subcutaneous prefilled syringes and subcutaneously administered prefilled pens are for one-time use in one patient only and should be discarded after use. 2.3 Premedication for Flu-like Symptoms Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during treatment with PLEGRIDY.

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.

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).

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).

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).

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).

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.

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.

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.

In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion.

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.

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.

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 to 5 doses.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of

PLEGRIDY did not include sufficient numbers of subjects aged 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 patients.