4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

Plegridy may be administered subcutaneously (SC) using a single-use pre-filled pen or pre-filled syringe 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 on efficacy of peginterferon beta-1a after switching from a non-pegylated interferon beta are not available. This should be considered when switching patients between pegylated and non-pegylated interferons (see section 5.1).

Posology

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 (on day 0), increasing to 94 micrograms at dose 2 (on day 14), reaching the full dose of 125 micrograms by 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 dose that 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 clip should be used once, and then discarded along with any remaining medicinal product. Patients should use 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 at treatment initiation with interferons. Prophylactic and concurrent use of anti-inflammatory, analgesic and/or antipyretic treatments may prevent or ameliorate flu-like symptoms sometimes experienced during interferon treatment (see section 4.8).

Switching between the SC and IM routes of administration and vice versa has not been studied. Based upon bioequivalence demonstrated between the two routes of administration it is not expected that dose 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 dose immediately. 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 schedule starting from when they administer their missed dose. A patient should not administer two doses of peginterferon beta-1a within 7 days of each other.

Special populations

Elderly population

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

Renal impairment

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).

Hepatic impairment

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

Paediatric population

The safety and efficacy of peginterferon beta-1a in children and adolescents aged 10 to less than 18 years have not been established in multiple sclerosis. Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

The safety and efficacy of peginterferon beta-1a in children below 10 years of age have not been established. No data are available.

Method of administration

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 injections every two weeks. The usual sites for subcutaneous injections include abdomen, arm, and thigh. The usual site for intramuscular injection is the thigh.

Each Plegridy pre-filled pen/syringe for SC is provided with the needle pre-attached. Plegridy prefilled syringe 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 discarded after use.

Precautions to be taken before handling or administering the medicinal product

Once removed from the refrigerator, Plegridy should be allowed to warm to room temperature (up to 25 oC) for about 30 minutes prior to injection. External heat sources such as hot water must not be used to warm the medicinal product.

Plegridy pre-filled syringe must not be used if the liquid is coloured, cloudy, or contains floating particles. 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 status window. Plegridy pre-filled pen must not be used if the liquid is coloured, cloudy, or contains floating particles. The liquid in the medicinal product window must be clear and colourless.

4.3. Contraindications

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

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

4.4. Special warnings and precautions for use

Traceability

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

Hepatic injury

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

Depression

Peginterferon beta-1a should be administered with caution to patients with previous depressive disorders (see section 4.3). Depression occurs with increased frequency in the multiple sclerosis population and in association with interferon use. Patients should be advised to immediately report any symptoms 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).

Hypersensitivity reactions

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

Injection site reactions

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

Decreased peripheral blood counts

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

Renal and urinary disorders

Nephrotic syndrome (class effects)

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

Severe renal impairment

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

Thrombotic microangiopathy (TMA) (class effects)

Cases of TMA, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood 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 treatment is required (considering plasma exchange) and immediate discontinuation of peginterferon beta-1a is recommended.

Laboratory abnormalities

Laboratory abnormalities are associated with the use of interferons. In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential blood cell counts, platelet counts, and blood chemistries, including liver function tests (e.g. aspartate aminotransferase (AST), alanine aminotransaminase (ALT)), are recommended prior to initiation and at regular intervals following introduction of peginterferon beta-1a therapy and then periodically thereafter 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 as clinically indicated.

Seizure

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

Cardiac disease

Worsening of cardiac disease has been reported in patients receiving interferon beta. The incidence of cardiovascular events was similar between peginterferon beta-1a (125 micrograms every 2 weeks) and placebo treatment groups (7% in each group). No serious cardiovascular events were reported in patients 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 or arrhythmia should be monitored for worsening of their cardiac condition, particularly during initiation of treatment.

Immunogenicity

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

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

Hepatic impairment

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

Sodium content

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

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing experience indicates no increased risk of major congenital anomalies after pre-conception exposure to interferon beta or such exposure during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, because data were collected when interferon beta use was contraindicated during pregnancy, and treatment likely interrupted when pregnancy was detected and/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 be evaluated 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.

Breast-feeding

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

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

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 site pruritus, and arthralgia.

The most commonly reported adverse reaction leading to discontinuation in patients treated with peginterferon 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 with an overall exposure equivalent of 4,217 person -years. 1,285 patients received at least 1 year, 1,124 patients have received at least 2 years, 947 patients received at least 3 years, and 658 patients received at 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 (treatment received for up to 4 years) was consistent with the experience in the 1 year placebo-controlled phase of the 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 and 500 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. The incidence 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 disorders

Thrombocytopenia

Uncommon

Thrombotic microangiopathy including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome*

Rare

Immune system disorders

Angioedema

Uncommon

Hypersensitivity

Anaphylaxis1

Not known

Psychiatric disorders

Depression

Common

Nervous system disorders

Headache

Very common

Seizure

Uncommon

Respiratory, thoracic and mediastinal disorders

Pulmonary arterial hypertension┼

Not known

Gastrointestinal disorders

Nausea

Common

Vomiting

Skin and subcutaneous tissue disorders

Alopecia$

Common

Pruritus

Urticaria

Uncommon

Musculoskeletal and connective tissue disorders

Myalgia

Very common

Arthralgia

Renal and urinary disorders

Nephrotic syndrome, glomerulosclerosis

Rare

General disorders and administration site conditions

Influenza like illness

Very common

Pyrexia

Chills

Injection site erythema

Injection site pain

Injection site pruritus

Asthenia

Hyperthermia

Common

Injection site inflammation

Pain

Injection site haematoma

Injection site swelling

Injection site oedema

Injection site rash

Injection site warmth

Injection site discolouration

Injection site necrosis

Rare

Investigations

Alanine aminotransferase increased

Common

Aspartate aminotransferase increased

Gamma-glutamyltransferase increased

White blood cell count decreased

Haemoglobin decreased

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 products

1 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-1a 125 micrograms every 2 weeks and 13% of patients receiving placebo. The incidence of flu-like symptoms (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. Of the patients who reported flu-like symptoms 90% reported them as mild or moderate in severity. None were considered serious in nature. Less than 1% of patients who received peginterferon beta-1a during the placebo-controlled phase of the ADVANCE study discontinued treatment due to flu-like symptoms. An open -label study in patients switching from interferon beta therapy to peginterferon beta-1a evaluated the onset and duration of prophylactically treated flu-like symptoms. In patients experiencing flu-like symptoms, the median time to onset was 10 hours (interquartile range, 7 to 16 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 who received peginterferon beta-1a 125 micrograms every 2 weeks compared to 11% of patients receiving placebo. Injection site erythema was the most commonly reported injection site reaction. Of the patients 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 an injection site necrosis which resolved with standard medical treatment.

Hepatic transaminase abnormalities

The incidence of hepatic transaminase increases was greater in patients receiving peginterferon beta-1a compared 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), were reported in 1% and <1% of placebo-treated patients and 2% and <1% of patients treated with peginterferon beta-1a respectively. Elevations of serum hepatic transaminases combined with elevated bilirubin were observed in two patients who had pre-existing liver test abnormalities prior to receiving peginterferon beta-1a in the clinical trials. Both cases resolved following discontinuation of the medicinal product.

Haematological disorders

Decreases in white blood cell (WBC) counts of <3.0 x 109/L were observed in 7% of patients receiving peginterferon beta-1a and in 1% receiving placebo. Mean WBC counts remained within normal limits in patients treated with peginterferon beta-1a. Decreases in WBC counts were not associated with an increased risk of infections or serious infections. The incidence of potentially clinically 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 patients treated with peginterferon beta-1a: one patient (<1%) experienced severe thrombocytopenia (platelet count <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-1atreated patients. 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 reactions

Hypersensitivity events were reported in 16% of patients treated with peginterferon beta-1a 125 micrograms every 2 weeks and 14% of patients who received placebo. Less than 1% of peginterferon 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. In post marketing experience, serious hypersensitivity events including cases of anaphylaxis (frequency not known) have been reported following peginterferon beta-1a administration.

Pulmonary arterial hypertension

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 with interferon beta.

Intramuscular route of administration

An open-label, crossover study enrolled 136 subjects to assess the bioequivalence of single doses of 125 micrograms of peginterferon beta-1a administered SC and IM injection in healthy volunteers. The most commonly reported AEs (with >10% incidence in either arm) across both treatment periods were chills (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 IM group without any associated adverse drug reactions.

Paediatric population

The safety of peginterferon beta-1a in paediatric patients aged 10 to less than 18 years was studied in an open-label randomized active controlled paediatric trial with 152 paediatric patients with RRMS (peginterferon beta-1a n=75; interferon beta-1a n=77). 66 patients in the peginterferon beta-1a group completed 48 weeks of this study. The following adverse events which are very common in the adult population were also reported as very common in the paediatric population: injection site erythema, influenza-like illness, headache and pyrexia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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