PLEGRIDY 125mcg injection for pre-filled pen medication leaflet

Plegridy 63 micrograms solution for injection in pre-filled syringe

Plegridy 94 micrograms solution for injection in pre-filled syringe

Plegridy 125 micrograms solution for injection in pre-filled syringe

Plegridy 63 micrograms solution for injection in pre-filled pen

Plegridy 94 micrograms solution for injection in pre-filled pen

Plegridy 125 micrograms solution for injection in pre-filled pen

Plegridy 63 micrograms solution for injection in pre-filled syringe (for subcutaneous use)

Each pre-filled syringe contains 63 micrograms of peginterferon beta-1a* in 0.5 mL solution forinjection.

Plegridy 94 micrograms solution for injection in pre-filled syringe (for subcutaneous use)

Each pre-filled syringe contains 94 micrograms of peginterferon beta-1a* in 0.5 mL solution forinjection.

Plegridy 125 micrograms solution for injection in pre-filled syringe (for subcutaneous use)

Each pre-filled syringe contains 125 micrograms of peginterferon beta-1a* in 0.5 mL solution forinjection.

Plegridy 125 micrograms solution for injection in pre-filled syringe (for intramuscular use)

Each pre-filled syringe contains 125 micrograms of peginterferon beta-1a* in 0.5 mL solution forinjection.

Plegridy 63 micrograms solution for injection in pre-filled pen (for subcutaneous use)

Each pre-filled pen contains 63 micrograms of peginterferon beta-1a* in 0.5 mL solution for injection.

Plegridy 94 micrograms solution for injection in pre-filled pen (for subcutaneous use)

Each pre-filled pen contains 94 micrograms of peginterferon beta-1a* in 0.5 mL solution for injection.

Plegridy 125 micrograms solution for injection in pre-filled pen (for subcutaneous use)

Each pre-filled pen contains 125 micrograms of peginterferon beta-1a* in 0.5 mL solution forinjection.

The dose indicates the quantity of the interferon beta-1a moiety of peginterferon beta-1a withoutconsideration of the PEG moiety attached.

*The active substance, peginterferon beta-1a, is a covalent conjugate of interferon beta-1a, produced in

Chinese hamster ovary cells, with 20,000 Dalton (20 kDa) methoxy poly(ethyleneglycol) using an

O-2-methylpropionaldehyde linker.

The potency of this medicinal product should not be compared to the one of another pegylated ornon-pegylated protein of the same therapeutic class. For more information see section 5.1.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear and colourless solution with pH 4.5-5.1.

Plegridy is indicated in adult patients for the treatment of relapsing remitting multiple sclerosis (seesection 5.1).

Treatment should be initiated under supervision of a physician experienced in the treatment of multiplesclerosis.

Plegridy may be administered subcutaneously (SC) using a single-use pre-filled pen or pre-filledsyringe or intramuscularly (IM) using a single use pre-filled syringe.

Efficacy of peginterferon beta-1a administered subcutaneously has been demonstrated over placebo.

Direct comparative data for peginterferon beta-1a versus non-pegylated interferon beta or data onefficacy of peginterferon beta-1a after switching from a non-pegylated interferon beta are notavailable. This should be considered when switching patients between pegylated and non-pegylatedinterferons (see section 5.1).

The recommended dose of Plegridy is 125 micrograms injected SC or IM every 2 weeks (14 days).

Treatment initiation

It is generally recommended that patients start SC or IM treatment with 63 micrograms at dose 1 (onday 0), increasing to 94 micrograms at dose 2 (on day 14), reaching the full dose of 125 microgramsby dose 3 (on day 28) and continuing with the full dose (125 micrograms) every 2 weeks (14 days)thereafter (see Table 1a for SC use or Table 1b for IM use).

Subcutaneous route

An initiation pack is available containing the first 2 doses (63 micrograms and 94 micrograms).

Table 1a: Titration schedule at initiation via SC route

Dose Time* Amount (micrograms) Syringe label

Dose 1 Day 0 63 Orange

Dose 2 Day 14 94 Blue

Dose 3 Day 28 125 (full dose) Grey

*Dosed every 2 weeks (14 days)

Intramuscular route

An administration dose pack contains the full 125 microgram dose in 1 pre-filled syringe.

The Plegridy titration clips, designed for use with the pre-filled syringe are intended to limit the dosethat is administered to 63 micrograms (dose 1 (1/2 dose), yellow titration clip) and 94 micrograms(dose 2 (3/4 dose), purple titration clip), for day 0 and day 14 respectively. Each Plegridy titration clipshould be used once, and then discarded along with any remaining medicinal product. Patients shoulduse the full dose of 125 micrograms (no clip required) from day 28 onwards (dosing every 14 days).

Table 1b Titration schedule at initiation via IM route

Dose Time* Amount (micrograms) Titration clip

Dose 1 Day 0 63 Yellow

Dose 2 Day 14 94 Purple

Dose 3 Day 28 125 (full dose) No clips needed

*Dosed every 2 weeks (14 days)

Dose titration at the initiation of treatment may help to ameliorate flu-like symptoms that can occur attreatment initiation with interferons. Prophylactic and concurrent use of anti-inflammatory, analgesicand/or antipyretic treatments may prevent or ameliorate flu-like symptoms sometimes experiencedduring interferon treatment (see section 4.8).

Switching between the SC and IM routes of administration and vice versa has not been studied. Basedupon bioequivalence demonstrated between the two routes of administration it is not expected thatdose titration will be required if switching between SC and IM, or vice versa (see sections 5.1 and 5.2).

If a dose is missed, it should be administered as soon as possible.

- If 7 days or more to the next planned dose: Patients should administer their missed doseimmediately. Treatment can then continue with the next scheduled dose as planned.

- If less than 7 days to the next planned dose: Patients should begin a new 2 week dosing schedulestarting from when they administer their missed dose. A patient should not administer two dosesof peginterferon beta-1a within 7 days of each other.

The safety and efficacy of peginterferon beta-1a in patients over the age of 65 have not beensufficiently studied due to the limited number of such patients included in clinical trials.

No dosage adjustments are necessary in patients with renal impairment based on study data in mild,moderate, and severe renal impairment and end stage renal disease (see sections 4.4 and 5.2).

Peginterferon beta-1a has not been studied in patients with hepatic impairment (see section 4.4).

The safety and efficacy of peginterferon beta-1a in children and adolescents aged 0 to 18 years havenot been established in multiple sclerosis. No data are available.

It is recommended that a healthcare professional trains patients in the proper technique for self—administering SC injections using the SC pre-filled syringe/pre-filled pen or IM injections using the

IM pre-filled syringes as appropriate. Patients should be advised to rotate sites for SC or IM injectionsevery two weeks. The usual sites for subcutaneous injections include abdomen, arm, and thigh. Theusual site for intramuscular injection is the thigh.

Each Plegridy pre-filled pen/syringe for SC is provided with the needle pre-attached. Plegridy prefilledsyringe for IM use is supplied as a prefilled syringe with a separate needle for IM use.

Both IM and SC pre-filled syringes and SC pre-filled pens are for single use only and should be discardedafter use.

Once removed from the refrigerator, Plegridy should be allowed to warm to room temperature (up to25 °C) for about 30 minutes prior to injection. External heat sources such as hot water must not beused to warm the medicinal product

Plegridy pre-filled syringe must not be used if the liquid is coloured, cloudy, or contains floatingparticles. The liquid in the syringe must be clear and colourless.

Plegridy pre-filled pen must not be used unless the green stripes are visible in the pen injection statuswindow. Plegridy pre-filled pen must not be used if the liquid is coloured, cloudy, or contains floatingparticles. The liquid in the medicinal product window must be clear and colourless.

- Hypersensitivity to natural or recombinant interferon beta or peginterferon or to any of theexcipients listed in section 6.1.

- Patients with current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Elevated serum hepatic transaminase levels, hepatitis, autoimmune hepatitis and rare cases of severehepatic failure have been reported with interferon beta medicinal products. Elevations in hepaticenzymes have been observed with the use of peginterferon beta-1a. Patients should be monitored forsigns of hepatic injury (see section 4.8).

Depression

Peginterferon beta-1a should be administered with caution to patients with previous depressivedisorders (see section 4.3). Depression occurs with increased frequency in the multiple sclerosispopulation and in association with interferon use. Patients should be advised to immediately report anysymptoms of depression and/or suicidal ideation to their prescribing physician.

Patients exhibiting depression should be monitored closely during therapy and treated appropriately.

Cessation of therapy with peginterferon beta-1a should be considered (see section 4.8).

Serious hypersensitivity reactions including cases of anaphylaxis have been reported as a rarecomplication of treatment with interferon beta, including peginterferon beta-1a. Patients should beadvised to discontinue treatment with peginterferon beta-1a and seek immediate medical care if theyexperience signs and symptoms of anaphylaxis or severe hypersensitivity. Treatment withpeginterferon beta-1a should not be restarted (see section 4.8).

Injection site reactions, including injection site necrosis, have been reported with the use ofsubcutaneous interferon beta. To minimise the risk of injection site reactions patients should beinstructed in the use of an aseptic injection technique. The procedure for the self-administration by thepatient should be reviewed periodically especially if injection site reactions have occurred. If thepatient experiences any break in the skin, which may be accompanied by swelling or drainage of fluidfrom the injection site, the patient should be advised to speak with their doctor. One patient treatedwith peginterferon beta-1a in clinical trials experienced an injection site necrosis with SCpeginterferon beta-1a. Whether to discontinue therapy following a single site of necrosis is dependenton the extent of necrosis (see section 4.8).

Decreased peripheral blood counts

Decreased peripheral blood counts in all cell lines, including rare pancytopenia and severethrombocytopenia, have been reported in patients receiving interferon beta. Cytopenias, including raresevere neutropenia and thrombocytopenia, have been observed in patients treated with peginterferonbeta-1a. Patients should be monitored for symptoms or signs of decreased peripheral blood counts (seesection 4.8).

Nephrotic syndrome (class effects)

Cases of nephrotic syndrome with different underlying nephropathies including collapsing focalsegmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferativeglomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported duringtreatment with interferon-beta products. Events were reported at various time points during treatmentand may occur after several years of treatment with interferon beta. Periodic monitoring of early signsor symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially inpatients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required anddiscontinuation of treatment with peginterferon beta-1a should be considered.

Caution should be used when administering peginterferon beta-1a to patients with severe renalimpairment.

Thrombotic microangiopathy (TMA) (class effects)

Cases of TMA, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemicsyndrome (HUS), including fatal cases, have been reported with interferon beta products. Events werereported at various time points during treatment and may occur several weeks to several years afterstarting treatment with interferon beta. Early clinical features include thrombocytopenia, new onsethypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renalfunction. Laboratory findings suggestive of TMA include decreased platelet counts, increased serumlactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on ablood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels,serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatmentis required (considering plasma exchange) and immediate discontinuation of peginterferon beta-1a isrecommended.

Laboratory abnormalities are associated with the use of interferons. In addition to those laboratorytests normally required for monitoring patients with multiple sclerosis, complete blood and differentialblood cell counts, platelet counts, and blood chemistries, including liver function tests (e.g. aspartateaminotransferase (AST), alanine aminotransaminase (ALT)), are recommended prior to initiation andat regular intervals following introduction of peginterferon beta-1a therapy and then periodicallythereafter in the absence of clinical symptoms.

Patients with myelosuppression may require more intensive monitoring of complete blood cell counts,with differential and platelet counts.

Hypothyroidism and hyperthyroidism have been observed with the use of interferon beta products.

Regular thyroid function tests are recommended in patients with a history of thyroid dysfunction or asclinically indicated.

Peginterferon beta-1a should be administered with caution to patients with a history of seizures, tothose receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlledwith anti-epileptics (see section 4.8).

Cardiac disease

Worsening of cardiac disease has been reported in patients receiving interferon beta. The incidence ofcardiovascular events was similar between peginterferon beta-1a (125 micrograms every 2 weeks) andplacebo treatment groups (7% in each group). No serious cardiovascular events were reported inpatients who received peginterferon beta-1a in the ADVANCE study. Nevertheless, patients with pre-existing- significant cardiac disease, such as congestive heart failure, coronary artery disease orarrhythmia should be monitored for worsening of their cardiac condition, particularly during initiationof treatment.

Patients may develop antibodies to peginterferon beta-1a. Data from patients treated up to 2 years withpeginterferon beta-1a administered SC suggests that less than 1% (5/715) developed persistentneutralising- antibodies to the interferon beta-1a portion of peginterferon beta-1a. Neutralisingantibodies have the potential to reduce clinical efficacy. However, the development of antibodiesagainst the interferon moiety of peginterferon beta-1a had no discernible impact on safety or clinicalefficacy, although the analysis was limited by the low immunogenicity incidence.

Three percent of patients (18/681) developed persistent antibodies to the PEG moiety of peginterferonbeta-1a. In the clinical study conducted, the development of antibodies against the PEG moiety ofpeginterferon beta-1a had no discernible impact on safety, or clinical efficacy (including annualisedrelapse rate, magnetic resonance imaging (MRI) lesions, and disability progression).

Caution should be used and close monitoring considered when administering peginterferon beta-1a topatients with severe hepatic impairment. Patients should be monitored for signs of hepatic injury andcaution exercised when interferons are used concomitantly with other medicinal products associatedwith hepatic injury (see sections 4.8 and 5.2).

This medicinal product contains less than 1 mmol (23 mg) sodium, that is to say it is essentially“sodium-free”.

No interaction studies have been performed. The clinical studies indicate that multiple sclerosispatients can receive peginterferon beta-1a and corticosteroids during relapses. Interferons have beenreported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans andanimals. Caution should be exercised when peginterferon beta-1a is administered in combination withmedicinal products that have a narrow therapeutic index and are largely dependent on the hepaticcytochrome P450 system for clearance, e.g. some classes of antiepileptics and antidepressants.

A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketingexperience indicates no increased risk of major congenital anomalies after pre-conception exposure tointerferon beta or such exposure during the first trimester of pregnancy. However, the duration ofexposure during the first trimester is uncertain, because data were collected when interferon beta usewas contraindicated during pregnancy, and treatment likely interrupted when pregnancy was detectedand/or confirmed. Experience with exposure during the second and third trimester is very limited.

Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion.

The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately beevaluated based on the currently available data, but the data do not suggest an increased risk so far.

If clinically needed, the use of peginterferon beta-1ay may be considered during pregnancy.

Limited information available on the transfer of interferon beta-1a/peginterferon beta-1a into breastmilk, together with the chemical/physiological characteristics of interferon beta, suggests that levelsof interferon beta-1a/peginterferon beta-1a excreted in human milk are negligible. No harmful effectson the breastfed newborn/infant are anticipated.

Peginterferon beta-1a can be used during breast-feeding.

There are no data on the effects of peginterferon beta-1a on human fertility. In animals, anovulatoryeffects were observed at very high doses (see section 5.3). No information is available on the effectsof peginterferon beta-1a on male fertility in animals.

Peginterferon beta-1a has no or negligible influence on the ability to drive and use machines.

The most common adverse drug reactions (ADR) (at a higher incidence than placebo) for

Peginterferon beta-1a 125 micrograms subcutaneously every 2 weeks were injection site erythema,influenza like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection sitepruritus, and arthralgia.

The most commonly reported adverse reaction leading to discontinuation in patients treated withpeginterferon beta-1a 125 micrograms subcutaneously every 2 weeks was influenza-like illness (<1%).

Tabulated list of adverse reactions via subcutaneous route of administration

In clinical studies, a total of 1,468 patients received peginterferon beta-1a SC for up to 278 weeks withan overall exposure equivalent of 4,217 person -years. 1,285 patients received at least 1 year, 1,124patients have received at least 2 years, 947 patients received at least 3 years, and 658 patients receivedat least 4 years of treatment with peginterferon beta-1a. The experience in the randomised,uncontrolled phase (year 2) of the ADVANCE study and in the extension study ATTAIN (treatmentreceived for up to 4 years) was consistent with the experience in the 1 year placebo-controlled phase ofthe ADVANCE study.

Table 2 summarizes ADRs (incidence above placebo and with a reasonable possibility of causality)from 512 patients treated with peginterferon beta-1a 125 micrograms SC every 2 weeks and500 patients who received placebo for up to 48 weeks and post-marketing data.

The ADRs are presented as MedDRA preferred terms under the MedDRA System Organ Class. Theincidence of the adverse reactions below are expressed according to the following categories:

- Very common (≥1/10)

- Common (≥1/100 to <1/10)

- Uncommon (≥1/1,000 to <1/100)

- Rare (≥1/10,000 to <1/1,000)

- Very rare (<1/10,000)

- Not known (cannot be estimated from the available data)

Table 2 Tabulated summary of adverse drug reactions

MedDRA system organ class Adverse reaction Frequency category

Blood and lymphatic system Thrombocytopenia Uncommondisorders Thrombotic microangiopathy Rareincluding thromboticthrombocytopenicpurpura/haemolytic uraemicsyndrome*

Immune system disorders Angioedema Uncommon

Anaphylaxis1 Not known

Psychiatric disorders Depression Common

Nervous system disorders Headache Very common

Seizure Uncommon

Respiratory, thoracic and Pulmonary arterial Not knownmediastinal disorders hypertension┼

Gastrointestinal disorders Nausea Common

Skin and subcutaneous tissue Alopecia$ Commondisorders Pruritus

Urticaria Uncommon

Musculoskeletal and Myalgia Very commonconnective tissue disorders Arthralgia

Renal and urinary disorders Nephrotic syndrome, Rareglomerulosclerosis

General disorders and Influenza like illness Very commonadministration site conditions Pyrexia

Chills

Injection site erythema

Injection site pain

Injection site pruritus

Asthenia

Hyperthermia Common

Injection site inflammation

Injection site haematoma

Injection site oedema

Injection site rash

Injection site warmth

Injection site discolouration

Injection site necrosis Rare

Investigations Alanine aminotransferase Commonincreased

Aspartate aminotransferaseincreased

Gamma-glutamyltransferaseincreased

White blood cell countdecreased

Haemoglobin decreased

MedDRA system organ class Adverse reaction Frequency category

Body temperature increased

Platelet count decreased Uncommon

*Class label for interferon beta products (see section 4.4).┼ Class label for interferon products, see below Pulmonary arterial hypertension$ Class label for interferon products1 Adverse reactions derived only during post marketing experience

Description of selected adverse reactions via subcutaneous route of administration

Flu-like symptoms

Influenza -like illness was experienced by 47% of patients receiving peginterferon beta-1a125 micrograms every 2 weeks and 13% of patients receiving placebo. The incidence of flu-likesymptoms (e.g. influenza -like illness, chills, hyperpyrexia, musculoskeletal pain, myalgia, pain,pyrexia) was highest at the initiation of treatment and generally decreased over the first 6 months. Ofthe patients who reported flu-like symptoms 90% reported them as mild or moderate in severity. Nonewere considered serious in nature. Less than 1% of patients who received peginterferon beta-1a duringthe placebo-controlled phase of the ADVANCE study discontinued treatment due to flu-likesymptoms. An open -label study in patients switching from interferon beta therapy to peginterferonbeta-1a evaluated the onset and duration of prophylactically treated flu-like symptoms. In patientsexperiencing flu-like symptoms, the median time to onset was 10 hours (interquartile range, 7 to16 hours) after injection, and the median duration was 17 hours (interquartile range, 12 to 22 hours).

Injection site reactions (ISRs)

ISRs (e.g. injection site erythema, pain, pruritus, or oedema) were reported by 66% of patients whoreceived peginterferon beta-1a 125 micrograms every 2 weeks compared to 11% of patients receivingplacebo. Injection site erythema was the most commonly reported injection site reaction. Of thepatients who experienced injection site reactions 95% reported them as mild or moderate in severity.

One patient out of 1,468 patients who received peginterferon beta-1a in clinical studies experienced aninjection site necrosis which resolved with standard medical treatment.

Hepatic transaminase abnormalities

The incidence of hepatic transaminase increases was greater in patients receiving peginterferon beta-1acompared to placebo. The majority of enzyme elevations were <3 times the upper limit of normal(ULN). Elevations of alanine aminotransferase and aspartate aminotransferase (>5 times ULN), werereported in 1% and <1% of placebo-treated patients and 2% and <1% of patients treated withpeginterferon beta-1a respectively. Elevations of serum hepatic transaminases combined with elevatedbilirubin were observed in two patients who had pre-existing liver test abnormalities prior to receivingpeginterferon beta-1a in the clinical trials. Both cases resolved following discontinuation of themedicinal product.

Decreases in white blood cell (WBC) counts of <3.0 x 109/L were observed in 7% of patientsreceiving peginterferon beta-1a and in 1% receiving placebo. Mean WBC counts remained withinnormal limits in patients treated with peginterferon beta-1a. Decreases in WBC counts were notassociated with an increased risk of infections or serious infections. The incidence of potentiallyclinically significant decreases in lymphocyte counts (<0.5 x 109/L) (<1%), neutrophil counts(≤1.0 x 109/L) (<1%) and platelet counts (≤100 x 109/L) (≤1%) was similar in peginterferon beta-1a-treated patients compared to placebo-treated patients. Two serious cases were reported in patientstreated with peginterferon beta-1a: one patient (<1%) experienced severe thrombocytopenia (plateletcount <10 x 109/L), another patient (<1%) experienced severe neutropenia (neutrophil count<0.5 x 109/L). In both patients, cell counts recovered after discontinuation of peginterferon beta-1a.

Slight decreases in mean red blood cell (RBC) counts were observed in peginterferon beta-1atreatedpatients. The incidence of potentially clinically significant decreases in RBC counts (<3.3 x 1012/L)was similar in peginterferon beta-1a treated patients compared to placebo- treated- patients.

Hypersensitivity events were reported in 16% of patients treated with peginterferon beta-1a125 micrograms every 2 weeks and 14% of patients who received placebo. Less than 1% ofpeginterferon beta-1a treated patients experienced a serious hypersensitivity event (e.g. angioedema,urticaria) and they recovered promptly after treatment with anti-histamines and/or corticosteroids. Inpost marketing experience, serious hypersensitivity events including cases of anaphylaxis (frequencynot known) have been reported following peginterferon beta-1a administration.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products.

Events were reported at various time points including up to several years after starting treatment withinterferon beta.

Intramuscular route of administration

An open-label, crossover study enrolled 136 subjects to assess the bioequivalence of single doses of125 micrograms of peginterferon beta-1a administered SC and IM injection in healthy volunteers. Themost commonly reported AEs (with >10% incidence in either arm) across both treatment periods werechills (35.6% in IM vs 26.9% in SC ), pain (22.0% in IM vs 14.2% in SC), injection site pain (11.4%in IM vs 14.9% in SC), injection site erythema (2.3% in IM vs 25.4% in SC ), and headache (35.6% in

IM vs 41.0% in SC). Injection site reactions were reported with a lower frequency in IM (14.4%)compared to SC (32.1%).

Abnormal urine protein was reported in 1/130 (0.8%) for the SC arm and 4/131 (3.1%) in the IMgroup without any associated adverse drug reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of over-dose, patients may be hospitalized for observation and appropriate supportive treatmentshould be given.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, immunostimulants,interferons, ATC code: L03AB13

Peginterferon beta-1a is an interferon beta-1a conjugated with a single, linear molecule of 20,000 Damethoxy poly(ethyleneglycol)-O-2-methylpropionaldehyde (20 kDamPEG-O-2-methylpropionaldehyde) at a degree of substitution of 1 mole of polymer/mole of protein.

The average molecular mass is approximately 44 kDa of which the protein moiety constitutesapproximately 23 kDa.

A definitive mechanism of action of peginterferon beta-1a in multiple sclerosis (MS) is not known.peginterferon beta-1a binds to the type I interferon receptor on the surface of cells and elicits a cascadeof intracellular events leading to the regulation of interferon-responsive gene expression. Biologicaleffects that may be mediated by peginterferon beta-1a include up-regulation of anti-inflammatorycytokines (e.g. IL-4, IL-10, IL-27), down-regulation of pro-inflammatory cytokines (e.g. IL-2, IL-12,

IFN-γ, TNF-α) and inhibiting the migration of activated T cells across the blood brain barrier; howeveradditional mechanisms may be involved. Whether the mechanism of action of peginterferon beta-1a in

MS is mediated by the same pathway(s) as the biological effects described above is not known becausethe pathophysiology of MS is only partially understood.

Peginterferon beta-1a is interferon beta-1a conjugated to a single, linear 20 kDa methoxypoly(ethyleneglycol) molecule at the alpha-amino group of the N-terminal amino acid residue.

Interferons are a family of naturally occurring proteins that are induced by cells in response tobiological and chemical stimuli, and mediate numerous cellular responses that have been classified asantiviral, antiproliferative, and immunomodulatory in nature. The pharmacological properties ofpeginterferon beta-1a are consistent with those of interferon beta-1a and are believed to be mediatedby the protein portion of the molecule.

Pharmacodynamic responses were evaluated by measuring the induction of interferon-responsivegenes including those encoding 2′,5′-oligoadenylate synthetase (2′,5′-OAS), myxovirus resistanceprotein A (MxA), and several chemokines and cytokines, as well as neopterin (D-erythro-1, 2, 3,-trihydroxypropylpterin), a product of the interferon-inducible enzyme, GTP-cyclohydrolase I. Geneinduction in healthy human subjects was greater in terms of peak level and exposure (area under theeffect curve) for peginterferon beta-1a compared to non-pegylated interferon beta-1a (IM) when bothwere given at the same dose by activity (6 MIU). The duration of this response was sustained andprolonged for peginterferon beta-1a, with elevations detected up to 15 days compared to 4 days fornon-pegylated interferon beta-1a. Increased concentrations of neopterin were observed in both healthysubjects and multiple sclerosis patients treated with peginterferon beta-1a, with a sustained andprolonged elevation over 10 days compared to 5 days observed for non-pegylated interferon beta-1a.

Neopterin concentrations return to baseline after the two week dosing interval.

Clinical efficacy and safety via subcutaneous route

The efficacy and safety of peginterferon beta-1a was assessed from the placebo controlled- first year ofa 2 year randomised, double-blind, clinical study in patients with relapsing remitting multiple sclerosis(the ADVANCE study). 1512 patients were randomised to and dosed with 125 microgramspeginterferon beta-1a injected subcutaneously every 2 (n=512) or 4 (n=500) weeks versus placebo(n=500).

The primary endpoint was the annualised relapse rate (ARR) over 1 year. The study design and patientdemographics are presented in Table .3

No data are available from clinical efficacy/safety studies directly comparing pegylated withnon-pegylated interferon beta-1a, or from patients switching between non-pegylated and pegylatedinterferon.

Table 3: Study design

Study design

Disease history Patients with RRMS, with at least 2 relapseswithin the prior 3 years, and 1 relapse in theprior year, with an EDSS score of ≤5.0

Follow-up 1 year

Study population 83% treatment-naïve patients47% ≥2 relapses in prior year38% at least 1 Gd+ lesion at baseline92% ≥9 T2 lesions baseline16% EDSS ≥417% previously treated

Baseline characteristics

Mean age (years) 37

Mean/Median disease duration (years) 3.6/2.0

Mean number of relapses within the past 3 years 2.5

Mean EDSS score at baseline 2.5

RRMS: relapsing remitting multiple sclerosis

EDSS: expanded disability status scale

Gd+: gadolinium-enhancing

Peginterferon beta-1a every 2 weeks significantly reduced the annualized relapse rate (ARR) by 36%compared to placebo (p=0.0007) at one year (Table 4) with consistent reductions of the ARR noted insubgroups defined by demographic and baseline disease characteristics. peginterferon beta-1a alsosignificantly reduced the risk of relapse by 39% (p=0.0003), the risk of sustained disability progressionconfirmed at 12 weeks by 38% (p=0.0383) and at 24 weeks (post-hoc analysis) by 54% (p=0.0069),the number of new or newly enlarging T2 lesions by 67% (p<0.0001), the number of Gd-enhancinglesions by 86% (p<0.0001) and the number of new T1 hypointense lesions compared to placebo by53% (p<0.0001). A treatment effect was observed as early as 6 months, with peginterferon beta-1a125 micrograms every 2 weeks demonstrating a 61% reduction (p<0.0001) in new or newly enlarging

T2 lesions as compared with placebo. Across relapse and MRI endpoints peginterferon beta-1a125 micrograms every two weeks showed a numerically greater treatment effect over the peginterferonbeta-1a every four weeks dosing regimen at year 1.

Results over 2 years confirmed that efficacy was maintained beyond the placebo controlled first yearof the study. Patients exposed to peginterferon beta-1a every 2 weeks showed statistically significantreductions compared to patients exposed to peginterferon beta-1a every 4 weeks over 2 years in apost-hoc analysis for endpoints including ARR (24%, p=0.0209), the risk of relapse (24%, p=0.0212),the risk of disability progression with 24 week confirmation (36%, p=0.0459), and MRI endpoints(new/enlarging T2 60%, Gd+ 71%, and new T1 hypointense lesions 53%; p<0.0001 for all). In the

ATTAIN extension study, long-term efficacy with peginterferon beta-1a was maintained withcontinuous treatment up to 4 years as shown by clinical and MRI measures of MS disease activity. Ofa total of 1,468 patients, 658 patients continued at least 4 years of treatment with peginterferonbeta-1a.

Results for this study are shown in Table 4.

Table 4: Clinical and MRI results

Placebo Peginterferon Peginterferonbeta-1a beta-1a125 micrograms 125 microgramsevery 2 weeks every 4 weeks

Clinical endpoints

N 500 512 500

Annualised relapse rate 0.397 0.256 0.288

Rate ratio 0.64 0.7295% CI 0.50 - 0.83 0.56 - 0.93

P-value p=0.0007 p=0.0114

Proportion of subjects relapsed 0.291 0.187 0.222

HR 0.61 0.7495% CI 0.47 - 0.80 0.57 - 0.95

P-value p=0.0003 p=0.020

Proportion with 12-week confirmed 0.105 0.068 0.068disability progression*

HR 0.62 0.6295% CI 0.40 - 0.97 0.40 - 0.97

P-value p=0.0383 p=0.0380

Proportion with 24-week confirmed 0.084 0.040 0.058disability progression*

HR 0.46 0.6795% CI (0.26 - 0.81) (0.41 - 1.10)

P-value p=0.0069 p=0.1116

MRI endpoints

N 476 457 462

Mean [Median] no. of new or newly 13.3 [6.0] 4.1 [1.0] 9.2 [3.0]enlarging T2 hyperintense lesions (0 - 148) (0 - 69) (0 - 113)(range)

Lesion mean ratio (95% CI) 0.33 (0.27, 0.40) 0.72 (0.60, 0.87)

P-value p≤0.0001 p=0.0008

Mean [Median] no. of Gd-enhancing 1.4^ [0.0] 0.2 [0.0] 0.9 [0.0]lesions (range) (0 - 39) (0 - 13) (0 - 41)% reduction vs placebo 86 36

P-value p<0.0001 p=0.0738

Mean [Median] no. of new T1 3.8 [1.0] 1.8 [0.0] 3.1 [1.0]hypointense lesions (range) (0 - 56) (0 - 39) (0 - 61)% reduction vs placebo 53 18

P-value p<0.0001 0.0815

HR: hazard ratio

CI: confidence interval

* Sustained disability progression was defined as at least a 1 point increase from baseline EDSS ≥ 1 or1.5 point increase for patients with baseline EDSS of 0, sustained for 12/24 weeks.^n=477

Patients who failed previous MS treatment were not included in the study.

Subgroups of patients with higher disease activity were defined by relapse and MRI criteria as reportedbelow, with the following efficacy results:

- For patients with ≥1 relapse in the previous year and ≥9 T2 lesions or ≥1 Gd+ lesion (n=1,401),the annual relapse rate at 1 year was 0.39 for placebo, 0.29 for peginterferon beta-1a every4 weeks and 0.25 for peginterferon beta-1a every 2 weeks.

Results in this subgroup were consistent with those in the overall population.

- For patients with ≥2 relapses in the previous year and at least 1 Gd+ lesion (n=273), the annualrelapse rate at 1 year was 0.47 for placebo, 0.35 for peginterferon beta-1a every 4 weeks, and0.33 for peginterferon beta-1a every 2 weeks.

Results in this subgroup were numerically consistent with those in the overall population but notstatistically significant.

IM and SC bioequivalence study

An -open-label, crossover study enrolled 136 subjects to assess the bioequivalence of single doses of125 micrograms of Plegridy administered SC and IM injection in healthy volunteers.

The serum concentration of neopterin, a marker of interferon beta activity, following administration of125 micrograms peginterferon beta-1a IM and SC was measured for pharmacodynamic (PD) analysis.

The serum neopterin concentration versus time profiles following single doses of 125 microgramspeginterferon beta-1a SC or 125 micrograms peginterferon beta-1a IM were similar, with maximalconcentrations (Epeak) reached at a median ETmax of 40.1 hours and 44.0 hours, respectively. Geometricmean neopterin levels increased from baseline to maximum concentration similarly between the2 injection routes, with the increase from 8.0 to 22.6 nmol/L for SC, and from 8.1 to 23.2 nmol/L for

IM. The overall systemic exposure to neopterin (EAUC0 336h and EAUC0-504h) were also similarbetween the 2 routes of administration.

Since bioequivalence was demonstrated between the IM and SC routes of administration, it is expectedthat IM and SC peginterferon beta-1a will have a similar efficacy profile.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Plegridy in one or more subsets of the paediatric population in treatment of multiple sclerosis (seesection 4.2 for information on paediatric use).

The serum half-life of peginterferon beta-1a is prolonged compared with non-pegylated interferonbeta-1a. Serum concentration of peginterferon beta-1a was dose-proportional in the range of 63 to188 micrograms as observed in a single dose and a multiple dose study in healthy subjects.

Pharmacokinetics observed in multiple sclerosis patients were consistent with those seen in healthysubjects.

Following subcutaneous administration of peginterferon beta-1a in multiple sclerosis patients, the peakconcentration was reached between 1 to 1.5 days post-dose. The observed Cmax (mean±SE) was280 ± 79 pg/mL following repeat dosing of 125 micrograms every two weeks.

Subcutaneous peginterferon beta-1a resulted in approximately 4-, 9-, and 13-fold higher exposure(AUC168h) values and approximately 2-, 3.5- and 5-fold higher Cmax, following single doses of63 (6 MIU), 125 (12 MIU), and 188 (18 MIU) micrograms respectively, compared to intramuscularadministration of 30 (6 MIU) micrograms non-pegylated beta-1a.

Following repeat dosing of 125 micrograms doses every two weeks by subcutaneous administration,the volume of distribution uncorrected for bioavailability (mean±SE) was 481 ± 105 L.

Urinary (renal) clearance is postulated to be a major excretory pathway for peginterferon beta-1a. Theprocess of covalently conjugating a PEG moiety to a protein can alter the in vivo properties of theunmodified protein, including decreased renal clearance and decreased proteolysis thus extending thecirculating half-life. Accordingly, the half-life (t1/2) of peginterferon beta-1a is approximately 2-foldlonger than non-pegylated interferon beta-1a in healthy volunteers. In multiple sclerosis patients, thet1/2 (mean±SE) of peginterferon beta-1a was 78 ± 15 hours at steady state. The mean steady stateclearance of peginterferon beta-1a was 4.1 ± 0.4 L/hr.

Clinical experience in patients aged above 65 years is limited. However, results from a populationpharmacokinetic analysis (in patients up to 65 years) suggest that age does not impact peginterferonbeta-1a clearance.

A single-dose study in healthy subjects and subjects with various degrees of renal impairment (mild,moderate, and severe renal impairment as well as subjects with end state renal disease) showed afractional increase in AUC (13-62%) and Cmax (42-71%) in subjects with mild (estimated glomerularfiltration rate 50 to ≤80 mL/min/1.73m2), moderate (estimated glomerular filtration rate 30 to50 mL/min/1.73m2), and severe (estimated glomerular filtration rate <30 mL/min/1.73m2) renalimpairment, compared to subjects with normal renal function (estimated glomerular filtration rate>80 mL/min/1.73m2). Subjects with end stage renal disease requiring 2-3 times haemodialysis weeklyshowed similar AUC and Cmax as compared to subjects with normal renal function. Eachhaemodialysis reduced peginterferon beta-1a concentration by approximately 24%, suggesting thathaemodialysis partially removes peginterferon beta-1a from systemic circulation.

Hepatic function

The pharmacokinetics of peginterferon beta-1a has not been evaluated in patients with hepaticinsufficiency.

No gender effect on the pharmacokinetics of peginterferon beta-1a was found in a populationpharmacokinetic analysis.

Race had no effect on the pharmacokinetics of peginterferon beta-1a in a population pharmacokineticanalysis.

IM and SC bioequivalence study

The pharmacokinetic (PK) profiles following single doses of 125 micrograms peginterferon beta-1a

IM and 125 micrograms peginterferon beta-1a SC in healthy volunteers were similar, with maximalconcentrations reached at 40.0 hours post-dose (for both SC and IM), and t1/2 values of 97.1 hours and79.1 hours, respectively. Statistical analysis of Cmax and AUC∞ further demonstrated bioequivalencebetween 125 micrograms peginterferon beta-1a IM and SC. The geometric mean ratio (90%confidence interval) of IM versus SC for Cmax was 1.08 (0.98 to 1.20) and 1.09 (1.02 to 1.16) for

AUC∞. These values fall within the designated 0.80 to 1.25 equivalence range.

Toxicity

Following repeated subcutaneous administration of peginterferon beta-1a in rhesus monkeys at dosesup to 400-fold (based on exposure, AUC) the recommended therapeutic dose; no effects other than theknown mild pharmacological responses by rhesus monkeys to interferon beta-1a were observed afterthe first and second weekly dose. Repeated dose toxicology studies were limited to 5 weeks asexposure was greatly diminished from 3 weeks onwards, due to the formation of anti-drug antibodiesby rhesus monkeys to human interferon beta-1a. Therefore, the long-term safety of chronicadministration of peginterferon beta-1a to patients cannot be assessed on the basis of these studies.

Peginterferon beta-1a 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.

Peginterferon beta-1a has not been tested for carcinogenicity in animals. Based on the knownpharmacology of interferon beta-1a and clinical experience with interferon beta, the potential forcarcinogenicity is expected to be low.

Peginterferon beta-1a has not been tested for reproductive toxicity in pregnant animals. Fertility anddevelopmental studies in rhesus monkeys have been carried out with non-pegylated interferon beta-1a.

At very high doses, anovulatory and abortifacient effects were observed in animals. No information isavailable on the potential effects of peginterferon beta-1a on male fertility. Upon repeated dosing withpeginterferon beta-1a of sexually mature female monkeys, effects on menstrual cycle length andprogesterone levels were observed. Reversibility of the effects on menstrual cycle length wasdemonstrated. The validity of extrapolating these non-clinical data to humans is unknown.

Data from studies with other interferon beta compounds did not show teratogenic potential. Theavailable information on the effects of interferon beta-1a in the peri- and postnatal periods is limited.

Sodium acetate trihydrate

Acetic acid, glacial

Arginine hydrochloride

Polysorbate 20

Water for injections

Not applicable.

3 years.

Plegridy for SC or IM administration can be stored at room temperature (up to 25 °C) for up to 30 daysas long as it is stored away from light. If Plegridy is at room temperature for a total of 30 days, itshould be used or discarded. If it is not clear if Plegridy has been stored at room temperature 30 daysor more, it should be discarded.

Store in a refrigerator (2 °C to 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

See section 6.3 for additional information on storage at room temperature.

Pre-filled syringe/pre-filled pen (subcutaneous)1 mL pre-filled syringe made of glass (Type I) with a bromobutyl rubber stopper and thermoplasticand polypropylene rigid needle shield, containing 0.5 mL of solution. A 29 gauge, 0.5 inch stakedneedle is pre-affixed to the syringe.

A pre-filled syringe of Plegridy is contained within a single-use, disposable, spring-powered peninjector called Plegridy Pen. The syringe inside the pen is a 1 mL pre-filled syringe made of glass(Type I) with a bromobutyl rubber stopper and thermoplastic and polypropylene rigid needle shield,containing 0.5 mL of solution. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe.

The Plegridy initiation pack contains 1x 63 micrograms pre-filled syringe (orange labelled syringe, 1stdose) and 1x 94 micrograms pre-filled syringe (blue labelled syringe, 2nd dose) in sealed plastic trays.

The Plegridy Pen initiation pack contains 1x 63 micrograms pre-filled pen (orange labelled pen, 1stdose) and 1x 94 micrograms pre-filled pen (blue labelled pen, 2nd dose) in a protective plastic tray.

Box of two or six 125 microgram pre-filled syringes (grey labelled syringes) in sealed plastic trays.

Box of two 125 microgram pre-filled pens (grey labelled pens) in a protective plastic tray.

Multipacks containing 6 (3 packs of 2) 125 microgram pre-filled pens (grey labelled pens). The packcontains 3 inner cartons. Each inner carton contains 2 pens in a protective plastic tray.

Not all pack sizes may be marketed.

Pre-filled syringe (intramuscular)1 mL pre-filled Luer-Lok syringe made of glass (Type I) with a bromobutyl rubber stopper containing0.5 mL of solution and supplied with a 23 gauge, 1.25 inch needle. A single pre-filled syringe contains0.5 mL of solution of Plegridy containing 125 micrograms of peginterferon beta-1a.

Box of two or six 125 microgram pre-filled syringes in sealed plastic trays.

Not all pack sizes may be marketed.

Plegridy prefilled syringes (for IM and SC administration) and pen (for SC administration) are forsingle-use only.

Before use check the dosage form to be used. It should not have any cracks or damage and thesolution should be clear, colourless and not have any particles in it.

Once removed from the refrigerator, the Plegridy pre-filled syringe or pen to be used should beallowed to warm to room temperature (15°C to 30°C) for about 30 minutes.

Do not use external heat sources such as hot water to warm the Plegridy pre-filled syringe or pen

Titration of Plegridy doses for patients initiating treatment is described in section 4.2.

Pre-filled syringe/pre-filled pen (subcutaneous)

Patients initiating treatment with Plegridy via SC administration should use initiation packs.

Pre-filled syringe (intramuscular)

Patients initiating treatment with Plegridy via IM administration should use Plegridy Titration clipswhich may be attached to the syringe to limit the dose.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/14/934/001

EU/1/14/934/002

EU/1/14/934/003

EU/1/14/934/004

EU/1/14/934/005

EU/1/14/934/006

EU/1/14/934/007

EU/1/14/934/008

Date of first authorisation: 18 July 2014

Date of latest renewal: 25 March 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.