HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`PLEGRIDY™ safely and effectively. See full prescribing information for
`PLEGRIDY.
`
`PLEGRIDY (peginterferon beta-1a) injection, for subcutaneous injection
`Initial U.S. Approval: 2014
`
`
`__________________ INDICATIONS AND USAGE
` _________________
`PLEGRIDY is an interferon beta indicated for the treatment of patients with
`relapsing forms of multiple sclerosis (1)
`
`_______________
`DOSAGE AND ADMINISTRATION
`
`
`For subcutaneous 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 (2.2)
`Analgesics and/or antipyretics on treatment days may help ameliorate
`
`
`flu-like symptoms (2.3)
`
`
`______________ DOSAGE FORMS AND STRENGTHS
`_____________
`
`Injection: 125 micrograms per 0.5 mL solution in a single-dose prefilled
`
`pen (3)
`Injection Starter Pack: 63 micrograms per 0.5 mL solution in a single-
`dose prefilled pen and 94 micrograms per 0.5 mL solution in a single-
`dose prefilled pen (3)
`Injection: 125 micrograms per 0.5 mL solution in a single-dose prefilled
`syringe (3)
`Injection Starter Pack: 63 micrograms per 0.5 mL solution in a single-
`dose prefilled syringe and 94 micrograms per 0.5 mL solution in a
`single-dose prefilled syringe (3)
`
`___________________
`____________________
`CONTRAINDICATIONS
`History of hypersensitivity to natural or recombinant interferon beta or
`peginterferon, or any other component of the formulation (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________ WARNINGS AND PRECAUTIONS _______________
`
`
`Hepatic injury: monitor liver function tests; monitor patients for signs
`
`
`and symptoms of hepatic injury; consider discontinuation of
`PLEGRIDY if hepatic injury occurs (5.1)
`Depression and suicide: advise patients to report immediately any
`symptom of depression or suicidal ideation to their healthcare provider;
`
`consider discontinuation of PLEGRIDY if depression occurs (5.2)
`Seizure: Seizures are associated with the use of interferon beta. Exercise
`caution when administering PLEGRIDY to patients with a seizure
`disorder (5.3)
`
`Anaphylaxis and other allergic reactions: serious allergic reactions have
`been reported as a rare complication of treatment with interferon beta.
`
`Discontinue PLEGRIDY if a serious allergic reaction occurs (5.4)
`
`Injection site reactions: change injection site or consider discontinuation
`
`of PLEGRIDY if there is necrosis (5.5)
`Congestive heart failure: monitor patients with pre-existing significant
`cardiac disease for worsening of cardiac symptoms (5.6)
`
`Decreased peripheral blood counts: monitor complete blood counts (5.7)
`Autoimmune disorders: consider discontinuation of PLEGRIDY if a
`
`new autoimmune disorder occurs (5.8)
`
`____________________ADVERSE REACTIONS____________________
`
`The most common adverse reactions (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 Idec at
`
`1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
` _______________ USE IN SPECIFIC POPULATIONS _______________
`
`
`Pregnancy: based on animal data, may cause fetal harm (8.1)
`
`
`
`
`Severe Renal Impairment: monitor for adverse reactions (8.6)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`Revised: 08/2014
`
`
`
`
`
`
`
`
`
`______________
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 
`12
`
` 
`11
`
` 
` 
`8.5 Geriatric Use
` 
` 
`8.6 Renal Impairment
` 
`DESCRIPTION
` 
` 
`11.1 PLEGRIDY PEN Single-Dose Prefilled Pen
`
` 
` 
`11.2 PLEGRIDY Single-Dose Prefilled Syringe
` 
`CLINICAL PHARMACOLOGY
` 
` 
`12.1 Mechanism of Action
` 
` 
`12.2 Pharmacodynamics
` 
` 
`12.3 Pharmacokinetics
` 
` 
`13
`NONCLINICAL TOXICOLOGY
` 
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
` 
`14
`CLINICAL STUDIES
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`16.1 PLEGRIDY PEN Single-Dose Prefilled Pen
`
` 
` 
`16.2 PLEGRIDY Single-Dose Prefilled Syringe
` 
` 
`16.3 Storage and Handling
` 
` 
`16.4
`Instructions for Disposal
` 
` 
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`2
`DOSAGE AND ADMINISTRATION
` 
` 
`2.1 Dosing Information
` 
` 
`Important Administration Instructions (All Dosage Forms)
`2.2
` 
` 
`2.3
`Premedication for Flu-like Symptoms
` 
` 
`DOSAGE FORMS AND STRENGTHS
`3
` 
` 
`CONTRAINDICATIONS
`4
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
` 
`5.1 Hepatic Injury
` 
` 
`5.2 Depression and Suicide
` 
` 
`5.3
`Seizures
` 
` 
`5.4 Anaphylaxis and Other Allergic Reactions
` 
` 
`5.5
`Injection Site Reactions
` 
` 
`5.6 Congestive Heart Failure
` 
` 
`5.7 Decreased Peripheral Blood Counts
` 
` 
`5.8 Autoimmune Disorders
` 
`ADVERSE REACTIONS
` 
` 
`6.1
` Clinical Trials Experience
` 
`USE IN SPECIFIC POPULATIONS
` 
` 
`8.1
`Pregnancy
` 
` 
`8.3 Nursing Mothers
` 
` 
`8.4
`Pediatric Use
`
` 
`6
` 
`8
`
`
`
`
`
`
`Reference ID: 3608472
`
`1
`
`Biogen Exhibits 2154
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 24
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`PLEGRIDY (peginterferon beta-1a) is indicated for the treatment of patients with relapsing
`
` forms of multiple sclerosis.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Dosing Information
`2.1
`PLEGRIDY is administered subcutaneously.
`The recommended dosage of PLEGRIDY is 125 micrograms injected subcutaneously every 14
`days.
` Treatment initiation
`
`Patients 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 Dose Titration
`Dose
`
` Time*
`
`Amount (micrograms)
`
`Dose 1
`Dose 2
`Dose 3
`
`
`On day 1
`
`On day 15
`On day 29 and every 14
`days thereafter
`
`
`63
`
`94
`125 (full dose)
`
`
`
`
` *Dosed every 14 days
`
`
`
`
`Color of Pen or
`Syringe Label
`Orange
`Blue
`Grey
`
`Important Administration Instructions (All Dosage Forms)
`2.2
`Healthcare professionals should train patients in the proper technique for self-administering
`subcutaneous injections using the prefilled pen or syringe. Patients should be advised to rotate
`sites for subcutaneous injections. The usual sites for subcutaneous injections are abdomen, back
`of the upper arm, and thigh.
`Each PLEGRIDY pen and syringe is provided with the needle pre-attached. Prefilled pens and
`syringes are for a single dose only and should be discarded after use.
`
`Reference ID: 3608472
`
`2
`
`Page 2 of 24
`
`
`
`

`

`Premedication for Flu-like Symptoms
`2.3
`Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-
`like symptoms sometimes experienced during treatment with PLEGRIDY.
`
`DOSAGE FORMS AND STRENGTHS
`
`3
`Pen
`
`Injection: 125 micrograms of PLEGRIDY per 0.5 mL of solution in a single-dose prefilled
`
`pen
`
`Injection: Starter Pack containing 63 micrograms per 0.5 mL of solution in a single-dose
`
`prefilled pen and 94 micrograms per 0.5 mL solution in a single-dose prefilled pen
`
`
`
`
`
`Prefilled Syringe
`
`Injection: 125 micrograms of PLEGRIDY per 0.5 mL of solution in a single-dose prefilled
`
`syringe
`
`Injection: Starter Pack containing 63 micrograms per 0.5 mL of solution in a single-dose
`prefilled syringe and 94 micrograms per 0.5 mL of solution in a single-dose prefilled syringe
`
`
`
`
`
`
` CONTRAINDICATIONS
`4
`
`PLEGRIDY is contraindicated in patients with a history of hypersensitivity to natural or
` recombinant interferon beta or peginterferon, or any other component of the formulation [see
`
` Warnings & Precautions (5.4)].
`
`
`
`5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`Hepatic Injury
`5.1
`Severe hepatic injury, including hepatitis, autoimmune hepatitis, and rare cases of severe hepatic
`failure, have been reported with interferon beta. Asymptomatic elevation of hepatic
`transaminases has also been reported, and in some patients has recurred upon rechallenge with
`
` interferon beta.
`Elevations in hepatic enzymes and hepatic injury have been observed with the use of
`PLEGRIDY in clinical studies. The incidence of increases in hepatic transaminases was greater
`in patients taking PLEGRIDY than in those taking placebo. The incidence of elevations of
`alanine aminotransferase above 5 times the upper limit of normal was 1% in placebo-treated
`patients and 2% in PLEGRIDY-treated patients. The incidence of elevations of aspartate
`aminotransferase above 5 times the upper limit of normal was less than 1% in placebo-treated
`patients and less than 1% in PLEGRIDY-treated patients. Elevations of serum hepatic
`
`Reference ID: 3608472
`
`3
`
`Page 3 of 24
`
`
`
`

`

`transaminases combined with elevated bilirubin occurred in 2 patients. Both cases resolved
`following discontinuation of PLEGRIDY.
`Monitor patients for signs and symptoms of hepatic injury.
`
`Depression and Suicide
`5.2
`Depression, suicidal ideation, and suicide occur more frequently in patients receiving interferon
`beta than in patients receiving placebo.
`In clinical studies, the overall incidence of adverse events related to depression and suicidal
`ideation in multiple sclerosis patients was 8% in both the PLEGRIDY and placebo groups. The
`incidence of serious events related to depression and suicidal ideation was similar and less than
`1% in both groups.
`Advise patients to report immediately any symptom of depression or suicidal ideation to their
`healthcare provider. If a patient develops depression or other severe psychiatric symptoms,
`consider stopping treatment with PLEGRIDY.
`
`Seizures
`5.3
`Seizures are associated with the use of interferon beta.
`
`The incidence of seizures in multiple sclerosis clinical studies was less than 1% in patients
`
`receiving PLEGRIDY and placebo.
`
`
`Exercise caution when administering PLEGRIDY to patients with a seizure disorder.
`
`
`Anaphylaxis and Other Allergic Reactions
`5.4
`Anaphylaxis and other serious allergic reactions are rare complications of treatment with
`interferon beta.
`Less than 1% of PLEGRIDY-treated patients experienced a serious allergic reaction such as
`angioedema or urticaria. Those who did have serious allergic reactions recovered promptly after
`treatment with antihistamines or corticosteroids.
`
`Discontinue PLEGRIDY if a serious allergic reaction occurs.
`
`Injection Site Reactions
`5.5
`Injection site reactions, including injection site necrosis, can occur with the use of subcutaneous
`interferon beta.
`In clinical studies, the incidence of injection site reactions (e.g., injection site erythema, pain,
`pruritus, or edema) was 66% in the PLEGRIDY group and 11% in the placebo group; the
`incidence of severe injection site reactions was 3% in the PLEGRIDY group and 0% in the
`placebo group. One patient out of 1468 patients who received PLEGRIDY in clinical studies
`experienced injection site necrosis. The injury resolved with standard medical treatment.
`Decisions to discontinue therapy following necrosis at a single injection site should be based on
`the extent of the necrosis. For patients who continue therapy with PLEGRIDY after injection
`
`Reference ID: 3608472
`
`4
`
`Page 4 of 24
`
`
`
`

`

`site necrosis has occurred, avoid administration of PLEGRIDY near the affected area until it is
`
` fully healed. If multiple lesions occur, discontinue PLEGRIDY until healing occurs.
`
`Congestive Heart Failure
`5.6
`Congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure
`occur in patients receiving interferon beta.
`In clinical studies, the incidence of cardiovascular events was 7% in both PLEGRIDY and
`placebo treatment groups. No serious cardiovascular events were reported in the PLEGRIDY
`group.
`Monitor patients with significant cardiac disease for worsening of their cardiac condition during
`initiation and continuation of treatment with PLEGRIDY.
`
`Decreased Peripheral Blood Counts
`5.7
`Interferon beta can cause decreased peripheral blood counts in all cell lines, including rare
`instances of pancytopenia and severe thrombocytopenia.
`In clinical studies, decreases in white blood cell counts below 3.0 x 109/L occurred in 7% of
`patients receiving PLEGRIDY and in 1% receiving placebo. There is no apparent association
`between decreases in white blood cell counts and an increased risk of infections or serious
`infections. The incidence of clinically significant decreases in lymphocyte counts (below 0.5 x
`109/L), neutrophil counts (below 1.0 x 109/L), and platelet counts (below 100 x 109/L) were all
`less than 1% and similar in both placebo and PLEGRIDY groups. Two serious cases were
`reported in patients treated with PLEGRIDY: one patient (less than 1%) experienced severe
`thrombocytopenia (defined as a platelet count less than or equal to 10 x 109/L), and another
`patient (less than 1%) experienced severe neutropenia (defined as a neutrophil count less than or
`equal to 0.5 x 109/L). In both patients, cell counts recovered after discontinuation of
`PLEGRIDY. Compared to placebo, there were no significant differences in red blood cell counts
`in patients treated with PLEGRIDY.
`Monitor patients for infections, bleeding, and symptoms of anemia. Monitor complete blood cell
`counts, differential white blood cell counts, and platelet counts during treatment with
`PLEGRIDY. Patients with myelosuppression may require more intensive monitoring of blood
`cell counts.
`
`Autoimmune Disorders
`5.8
`Autoimmune disorders of multiple target organs including idiopathic thrombocytopenia, hyper-
`and hypothyroidism, and autoimmune hepatitis have been reported with interferon beta.
`In clinical studies, the incidence of autoimmune disorders was less than 1% in both PLEGRIDY
`and placebo treatment groups.
`If patients develop a new autoimmune disorder, consider stopping PLEGRIDY.
`
`Reference ID: 3608472
`
`5
`
`Page 5 of 24
`
`
`
`

`

` ADVERSE REACTIONS
`6
`
`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)]
`
`
` Seizures [see Warnings and Precautions (5.3)]
`
`
` Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.4)]
`
`
`Injection Site Reactions [see Warnings and Precautions (5.5)]
`
`
`
` Congestive Heart Failure [see Warnings and Precautions (5.6)]
`
`
` Decreased Peripheral Blood Counts [see Warnings and Precautions (5.7)]
`
`
` Autoimmune Disorders [see Warnings and Precautions (5.8)]
`
`
`
`Clinical Trials Experience
`6.1
`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.
`In clinical studies (Study 1 and Study 2), a total of 1468 patients with relapsing multiple sclerosis
`received PLEGRIDY 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 2 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.
`
`Reference ID: 3608472
`
`6
`
`Page 6 of 24
`
`
`
`

`

`Table 2:
`
`
`
`Nervous System Disorders
`
`Headache
`Gastrointestinal Disorders
`Nausea
`Vomiting
`Musculoskeletal and Connective Tissue
`Disorders
`
`Myalgia
`Arthralgia
`General Disorders and Administration Site
`Conditions
`Injection site erythema
`
`Influenza like illness
`Pyrexia
`Chills
`Injection site pain
`Asthenia
`Injection site pruritus
`
`Hyperthermia
`Pain
`Injection site edema
`
`Injection site warmth
`Injection site hematoma
`Injection site rash
`Investigations
`
`Body temperature increased
`Alanine aminotransferase increased
`
`Aspartate aminotransferase increased
`
`Gamma-glutamyl-transferase increased
`Skin and Subcutaneous Tissue Disorder
`Pruritus
`
`
`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)
`%
`
`44
`
`
`9
`5
`
`
`Placebo
`(N=500)
`%
`
`33
`
`
`6
`2
`
`
`19
`
`11
`
`
`62
`
`47
`45
`
`17
`15
`
`13
`13
`
`4
`5
`3
`3
`3
`2
`
`6
`6
`4
`3
`
`4
`
`6
`7
`
`
`7
`13
`15
`
`5
`3
`8
`1
`1
`3
`0
`0
`1
`0
`
`3
`3
`2
`1
`
`1
`
`Reference ID: 3608472
`
`7
`
`Page 7 of 24
`
`

`

`Immunogenicity
`For therapeutic proteins, there is a potential for immunogenicity. In Study 1, fewer than 1% of
`patients treated with PLEGRIDY every 14 days for 1 year developed neutralizing antibodies.
`Approximately 7% of PLEGRIDY-treated patients developed antibodies to PEG.
`The detection of antibody formation is highly dependent on the sensitivity and specificity of the
`assay. Additionally, the observed incidence of antibody (including neutralizing antibody)
`positivity in an assay may be influenced by several factors including assay methodology, sample
`handling, timing of sample collection, concomitant medications, and underlying disease. For
`these reasons, comparison of the incidence of antibodies to PLEGRIDY with the incidence of
`antibodies to other products may be misleading.
`Flu-Like Symptoms
`Influenza-like illness was experienced by 47% of patients receiving PLEGRIDY 125
`
` micrograms every 14 days and 13% of patients receiving placebo. Fewer than 1% of
`PLEGRIDY-treated patients in Study 1 discontinued treatment due to flu-like symptoms.
`
`8
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`
` Pregnancy Category C
`There are no adequate and well-controlled studies in pregnant women. PLEGRIDY should be
`used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`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
`teratogenic or other adverse effects on fetal development were observed. Abortifacient activity
`was evident following 3 to 5 doses.
`
`Nursing Mothers
`8.3
`It is not known whether this drug is excreted in human milk. Because many drugs are excreted
`in human milk, caution should be exercised when PLEGRIDY is administered to a nursing
`woman.
`
`Pediatric Use
`8.4
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`Safety and effectiveness in geriatric patients have not been established.
`
`Renal Impairment
`8.6
`Monitor for adverse reactions due to increased drug exposure in patients with severe renal
`impairment [see Clinical Pharmacology (12.3)].
`
`
`Reference ID: 3608472
`
`8
`
`Page 8 of 24
`
`
`
`

`

`DESCRIPTION
`11
`PLEGRIDY (peginterferon beta-1a) is an interferon beta-1a to which a single, linear 20,000
`dalton (Da) methoxy poly(ethyleneglycol)-O-2-methylpropionaldehyde molecule is covalently
`attached to the alpha amino group of the N-terminal amino acid residue.
`The interferon beta-1a portion of PLEGRIDY 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 the recombinant interferon beta-1a is identical
`to that of the human interferon beta counterpart. The molecular mass of PLEGRIDY is
`approximately 44,000 Da, consistent with the mass of the protein (approximately 20,000 Da), the
`carbohydrate moieties (approximately 2,500 Da), and the attached poly(ethylene glycol).
`However, because of the extended and flexible nature of the attached poly(ethylene glycol)
`chain, the apparent mass of PLEGRIDY in solution is greater than 300,000 Da. The more than
`10-fold increase in apparent mass of PLEGRIDY compared to interferon beta-1a has been shown
`to contribute to the reduced clearance in vivo.
`PLEGRIDY 125 micrograms contains 125 micrograms of interferon beta-1a plus 125
`micrograms of poly(ethylene glycol). Using the World Health Organization International
`Standard for interferon beta, PLEGRIDY 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. PLEGRIDY 125 micrograms contains approximately 12 MIU of antiviral activity.
`PLEGRIDY contains no preservative.
`
`PLEGRIDY PEN Single-Dose Prefilled Pen
`11.1
`PLEGRIDY PEN is composed of an autoinjector that surrounds a prefilled glass syringe
`containing 0.5 mL of a sterile solution in water for injection of 63, 94, or 125 micrograms of
`
`peginterferon beta-1a, 15.8 mg of L-arginine HCl, 0.79 mg of sodium acetate trihydrate, 0.25 mg
`of glacial acetic acid, and 0.025 mg of polysorbate 20. The pH is approximately 4.8.
`
`PLEGRIDY Single-Dose Prefilled Syringe
`11.2
`A prefilled syringe of PLEGRIDY for subcutaneous injection contains 0.5 mL of a sterile
`solution in water for injection of 63, 94, or 125 micrograms of peginterferon beta-1a, 15.8 mg of
`L-arginine HCl, 0.79 mg of sodium acetate trihydrate, 0.25 mg of glacial acetic acid, and 0.025
`mg of polysorbate 20. The pH is approximately 4.8.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`The mechanism by which PLEGRIDY exerts its effects in patients with multiple sclerosis is
`unknown.
`
` Pharmacodynamics
`12.2
`
`There is no biochemical or physiologic effect known to relate directly to the clinical effect of
`PLEGRIDY.
`
`Reference ID: 3608472
`
`9
`
`Page 9 of 24
`
`
`
`

`

`Pharmacokinetics
`12.3
`After single-dose or multiple-dose subcutaneous administration of PLEGRIDY to healthy
`subjects, serum PLEGRIDY peak concentration (Cmax) and total exposure over time (area under
`the curve, or AUC) increased in proportion to doses from 63 to 188 micrograms. PLEGRIDY
`did not accumulate in the serum after multiple doses of 125 micrograms every 14 days.
`Pharmacokinetic parameters for PLEGRIDY, including Cmax 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, Cmax, and half-life was high (41% to 68%, 74% to 89%, and 45% to 93%,
`respectively).
`
` Absorption
`After 125 microgram subcutaneous doses of PLEGRIDY in multiple sclerosis patients, the
`maximum concentration occurred between 1 and 1.5 days, the mean Cmax was 280 pg/mL, and
`the AUC over the 14 day dosing interval was 34.8 ng.hr/mL.
`Distribution
`
`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.
`Specific Populations
`Body weight, gender, and age do not require dosage adjustment.
`Renal impairment can increase the Cmax and AUC for PLEGRIDY. Results of a pharmacokinetic
`study in patients with mild, moderate, and severe renal impairment (creatinine clearance 50 to
`
`80, 30 to 50, and less than 30 mL/minute, respectively) showed increases above normal for Cmax
`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 Cmax of PLEGRIDY values that were similar to those of normal
`controls. Each hemodialysis session removed approximately 24% of circulating PLEGRIDY
`from the systemic circulation [see Use in Specific Populations (8.6)].
`
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Carcinogenesis
`
`Reference ID: 3608472
`
`10
`
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`

`The carcinogenic potential of PLEGRIDY has not been tested in animals.
`Mutagenesis
`PLEGRIDY was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) test
`and was not clastogenic in an in vitro assay in human lymphocytes.
`
`Impairment of Fertility
`In monkeys administered interferon beta by subcutaneous injection over the course of one
`menstrual cycle, menstrual irregularities, anovulation, and decreased serum progesterone levels
`were observed. These effects were reversible after discontinuation of drug.
`
`CLINICAL STUDIES
`14
`The efficacy of PLEGRIDY was demonstrated in the randomized, double-blind, and placebo-
`controlled phase (year 1) of Study 1. The trial compared clinical and MRI outcomes at 48 weeks
`in patients who received PLEGRIDY 125 micrograms (n=512) or placebo (n=500) by the
`subcutaneous route, once every 14 days.
`Study 1 enrolled patients who had a baseline Expanded Disability Status Scale (EDSS) score
`from 0 to 5, who had experienced at least 2 relapses within the previous three years, and had
`experienced at least 1 relapse in the previous year. The trial excluded patients with progressive
`forms of multiple sclerosis. The mean age of the study population was 37 years, the mean
`disease duration was 3.6 years, and the mean EDSS score at baseline was 2.46. The majority of
`the patients were women (71%).
`The trial scheduled neurological evaluations at baseline, every 12 weeks, and at the time of a
`suspected relapse. Brain MRI evaluations were scheduled at baseline, week 24, and week 48.
`The primary outcome was the annualized relapse rate over 1 year. Secondary outcomes included
`the proportion of patients relapsing, number of new or newly enlarging T2 hyperintense lesions,
`and time to confirmed disability progression. Confirmed disability progression was defined as
`follows: if the baseline EDSS score was 0, a sustained 12-week increase in EDSS score of 1.5
`points was required; if the baseline EDSS score was greater than 0, a sustained 12-week increase
`in EDSS score of 1 point was required. Table 3 and Figure 1 show the results of Study 1.
`
`
`Reference ID: 3608472
`
`11
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`

`

`Table 3: Clinical and MRI Results of Study 1
`Endpoint
`
`Clinical outcomes at 48 weeks
`
`Annualized relapse rate
`Relative reduction
`Proportion of patients with relapses
`Relative risk reduction
`Proportion of patients with disability progression
`Relative risk reduction
`MRI outcomes at 48 weeks
`Mean number of new or newly enlarging T2
`hyperintense lesions
`Relative reduction
`
`Mean number of Gd enhancing lesions
`Relative reduction
`
`PLEGRIDY
`125 micrograms
`every 14 days
`N=512
`
`
`0.26
`36%
`0.19
`
`39%
`0.07
`38%
`N=457
`3.6
`
`67%
`
`0.2
`
`86%
`
`Placebo
`
`p-value
`
`N=500
`
`0.40
`
`0.29
`
`
`0.11
`
`N=476
`10.9
`
`
`
`1.4
`
`
`
`
`
`0.0007
`
`
`0.0003
`
`
`0.0383
`
`
`
`
`<0.0001
`
`
`
`<0.0001
`
`
`
`
`
`
`
`Reference ID: 3608472
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`

`

`Figure 1:
`
`Time to first relapse
`
`30
`
`NO
`
`_\ 01
`
`UI 0
`PercentageofPatientswithRelapses 8
`
`(29.1%)
`
`Placebo
`
`(18.7%)
`
`PLEGRIDY
`
`Baseline
`
`12
`
`24
`
`36
`
`48
`
`Time on Study (Weeks)
`
`Number of Subjects at Risk
`
`Placebo
`
`PLEGRIDY
`
`500
`
`512
`
`448
`
`458
`
`398
`
`414
`
`363
`
`389
`
`280
`
`318
`
`PLEGRIDY 125 mcg every 14 days (n=512) versus placebo (n=500) Haard Ratio (95% C|)=0.61(0.47, 0.80),
`p=0.0003
`
`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PLEGRIDY is supplied as a sterile, clear liquid for subcutaneous injection in two presentations,
`a prefilled pen and a prefilled syringe.
`
`16.1
`
`PLEGRIDY PEN Single-Dose Prefilled Pen
`
`Each dose of PLEGRIDY is stored in a 1 mL capacity glass syringe with a rubber stopper and
`rigid needle shield. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe. A single
`prefilled syringe contains 0.5 mL of solution of PLEGRIDY containing 63 micrograms, 94
`micrograms, or 125 micrograms of peginterferon beta-la. The glass syringe is contained within
`
`Page 13 of 24
`Reference ID: 3608472
`
`13
`
`

`

`a single-dose, disposable, injection device (prefilled pen). The following packaging
`configurations are available:
`
` A carton containing two single-dose prefilled pens, each providing 125 micrograms of
`PLEGRIDY. The NDC is 64406-011-01.
`
` A Starter Pack carton containing two single-dose prefilled pens; dose 1 provides 63
`micrograms of PLEGRIDY, and dose 2 provides 94 micrograms of PLEGRIDY. The NDC
`is 64406-012-01.
`
`
`
`PLEGRIDY Single-Dose Prefilled Syringe
`16.2
`Each dose of PLEGRIDY is stored in a 1 mL capacity glass syringe with a rubber stopper and
`rigid needle shield. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe. A single
`prefilled syringe contains 0.5 mL of solution of PLEGRIDY containing 63 micrograms, 94
`micrograms, or 125 micrograms of peginterferon beta-1a. The following packaging
`configurations are available:
`
` A carton containing two single-dose prefilled syringes, each providing 125 micrograms of
`PLEGRIDY. The NDC is 64406-015-01.
`
` A Starter Pack carton containing two single-dose prefilled syringes; dose 1 provides 63
`micrograms of PLEGRIDY, and dose 2 provides 94 micrograms of PLEGRIDY. The NDC
`is 64406-016-01.
`
`
`
`Storage and Handling
`16.3
`Store in the closed original carton to protect from light until ready for injection.
`Store in a refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze. Discard if frozen.
`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.
`If refrigeration is unavailable, PLEGRIDY may be stored between 2°C to 25°C (36°F to 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, within a temperature
`range of 2°C to 25°C (36°F to 77°F), should not exceed 30 days.
`
` Instructions for Disposal
`16.4
`
`Dispose in a sharps-bin container or other hard plastic or metal sealable container. Always
`follow local regulations for disposal.
`
`Reference ID: 3608472
`
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`Page 14 of 24
`
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`

`

`PATIENT COUNSELING INFORMATION
`17
`See FDA-approved patient labeling (Medication Guide and Instructions for Use).
`Instruct patients to carefully read the supplied PLEGRIDY Medication Guide and Instructions
`for Use, and caution patients not to change the PLEGRIDY dose or schedule of administration
`without medical consultation.
`Instructions for Self-Injection Technique and Procedures
`Provide appropriate instruction for methods of self-injection, including careful review of the
`PLEGRIDY Medication Guide and Instructions for Use. Instruct patients in the use of aseptic
`technique when administering PLEGRID