Consumer medicine information

Plegridy

Peginterferon beta-1a

BRAND INFORMATION

Brand name

Plegridy

Active ingredient

Peginterferon beta-1a

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Plegridy.

What is in this leaflet

This leaflet answers some common questions about Plegridy.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet.

Speak to your pharmacist or doctor to obtain the most up to date information on this medicine.

You can also download the most up to date leaflet from: www.biogen.com.au/products/plegridy-CMI.pdf

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Plegridy against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Plegridy is used for

Plegridy is a prescription medicine used to treat people with relapsing forms of Multiple Sclerosis (MS). It is not known if Plegridy is safe and effective in people under 18 or over 65 years of age.

The cause of MS is not yet known. MS affects the brain and spinal cord. In MS, the body's immune system reacts against its own myelin (the 'insulation' surrounding nerve fibres). In relapsing forms of MS, people have 'exacerbations' from time to time (e.g. blurred vision, weakness in the legs or arms, or loss of control of bowel or bladder function). They are followed by periods of recovery. Recovery may be complete or incomplete. If it is incomplete there is 'progression of disability'.

Plegridy belongs to a group of medicines called interferons. The active substance in Plegridy is peginterferon beta-1a. Peginterferon beta-1a is a long-acting form of interferon. Interferons exist naturally in the body to help fight viral infections and regulate the body's immunity.

Although the exact mechanism of action of interferons in MS is unknown, it is thought that Plegridy works by decreasing the unwanted immune reaction against myelin.

Ask your doctor if you have any questions about why Plegridy has been prescribed for you. Your doctor may have prescribed it for another reason.

Plegridy is available only with a doctor's prescription.

Use only for the person for whom it has been prescribed.

Before you use Plegridy

When you must not use it

Do not use Plegridy if you have an allergy to:

  • interferon beta or peginterferon
  • any of the other ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not use Plegridy:

  • If you have severe depression or think about committing suicide
  • If you are already pregnant

Do not use Plegridy after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Do not use Plegridy if the medicine is coloured, cloudy, or contains floating particles.

If it has expired or is damaged or looks differently than it should, return it to your pharmacist for disposal.

If you are not sure whether you should use this medicine, talk to your doctor or pharmacist.

Before you use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had:

  • Depression or problems with your moods, or if you have ever considered committing suicide
  • A seizure, fit or convulsion
  • Liver problems
  • Bleeding problems, bruising easily, frequent infections
  • Heart problems
  • Thyroid problems
  • Bone marrow suppression.

Do not start using Plegridy if you are already pregnant. If you could get pregnant, you need to use contraception while you use Plegridy.

Tell your doctor:

  • If you are pregnant or plan to become pregnant
  • If you want to breastfeed

Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start using Plegridy.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Plegridy may interact with some other medicines that are broken down by the liver:

  • medicines to treat epilepsy
  • medicines to treat depression

Ask your doctor, nurse or pharmacist if you have any questions about medicines to be careful with or avoid while using Plegridy.

How to use Plegridy

Follow all directions given to you by your doctor, MS nurse or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to use

Plegridy is only to be injected once every 14 days (two weeks).

Plegridy is injected under the skin (subcutaneously). Try to use Plegridy at the same time on the same day every time you inject.

How to use it

Starting Plegridy
If you are new to Plegridy your doctor or MS nurse may advise you to gradually increase your dose so that you can adjust to the effects of Plegridy before taking the full dose. You will be provided with a Titration Pack containing your first two injections. For further details on use, please follow the instructions provided with the Titration Pack.

The recommended starting dose is a single injection of Plegridy 63 micrograms, followed by a single injection of Plegridy 94 micrograms two weeks later.

Use the record table printed on the inside lid of the Titration Pack to keep a track of your injection dates.

Many people with MS learn to give themselves the injection or have it given by a carer.

Self-injection needs to be taught and practised. It is important that a qualified health care professional supervises your first injection.

Your doctor may teach you to self-inject or arrange for an MS nurse to do so.

After being taught to self-inject, you should refer to the leaflet in the pack for step-by-step instructions about how to prepare and inject Plegridy.

Continuing to use Plegridy
You will be provided with an Administration Dose Pack containing your next injections.

The recommended third dose is a single injection of Plegridy 125 micrograms (full dose), two weeks after the second dose.

Full doses of Plegridy 125 micrograms are then recommended every 14 days (two weeks).

Keep referring to the leaflet for detailed instructions on how to use Plegridy.

How long to use it

The positive effects of Plegridy are not seen immediately. They occur with long-term treatment. It is important to continue treatment with Plegridy unless your doctor tells you to stop.

If you forget to take it

Inject as soon as you remember and then resume your regular dosing schedule. However, never inject more than once in a 7-day period.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist or MS nurse for some hints.

If you take too much (overdose)

Immediately telephone the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764 766), if you think that you or anyone else may have used too much Plegridy. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using Plegridy

Things you must do

If you become pregnant while on treatment with Plegridy, immediately tell your doctor. If you are a female of childbearing age and are sexually active, you should use birth control during treatment with Plegridy.

If you have new or worsening depression or suicidal thoughts, immediately tell your doctor: This could include feeling hopeless or bad about yourself, thoughts of hurting yourself or suicide, irritability (getting upset easily), nervousness, or new or worsening anxiety.

Always talk to your doctor or pharmacist before taking any other medicine while you are using Plegridy. If he or she recommends that you take a medication to reduce symptoms of pain and inflammation, follow their advice carefully. Do not take more than the recommended dose.

Tell any other doctors, dentists and pharmacists who treat you that you are using this medicine.

If you are about to have any blood tests, tell your doctor that you are using Plegridy. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do blood tests before you start treatment and from time to time to monitor your progress and prevent unwanted side effects.

Things you must not do

Do not give Plegridy to anyone else, even if they appear to have the same condition as you.

Do not stop using Plegridy or change the dosage, without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Plegridy.

Plegridy helps most people with MS but it may have unwanted effects in a few people. All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor, MS nurse or pharmacist to answer any questions you may have.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you experience any of the following:

  • Yellowing of your skin or the whites of your eyes (jaundice)
  • Itching all over
  • Feeling sick, being sick (nausea and vomiting), loss of appetite
  • Tiredness, sleepiness, confusion
  • Bleeding more easily than normal, easy bruising of the skin
  • Dark coloured urine, and pale stools
  • Depression, thoughts of hurting yourself or suicide, new mood changes
  • Symptoms of an allergic reaction such as shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Tell your doctor, nurse or pharmacist as soon as possible if you experience any of the following:

  • Seizure (fit)
  • Severe swelling, weakness, shortness of breath, lethargy or confusion

The above list includes signs of possible serious side effects that may require medical attention. Serious side effects are rare.

Flu-like symptoms
The most common side effect is to feel 'flu-like' symptoms, e.g. headache, tiredness, muscle aches, joint pain, shivering and fever. Your doctor or MS nurse may advise you to gradually increase your dose of Plegridy during the first month of treatment to help reduce these symptoms. These side effects generally occur less often as therapy continues.

Three simple ways to help reduce the impact of flu-like symptoms:

  1. Consider the timing of your Plegridy injection. The start and end of flu-like symptoms are different for every patient. On average, flu-like symptoms begin approximately 10 hours after injection and last for about 17 hours.
  2. Take paracetamol or ibuprofen half an hour before your Plegridy injection. Speak to your doctor or pharmacist about how much to take and how long to take it.
  3. If you have a fever, drink plenty of water to keep you hydrated.

Injection site reactions
You may get reactions around the place you inject. These usually get less over time. Reactions such as redness, itching or pain are very common. Swelling, bruising, warmth or rash at the injection site is common.

To reduce injection site reactions, read and follow the advice given in the "Instructions for Use" at the end of the pack insert.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

  • Headache
  • Muscle pain
  • Pain in your joints, arms, legs or neck (arthralgia)
  • Fever, chills, feeling cold
  • Feeling weak and tired (asthenia)
  • Feeling or being sick (nausea or vomiting)
  • Itchy skin (pruritus)
  • Increase in body temperature

The above list includes some of the more common side effects of Plegridy, effects that might be related to your general health or the MS process, or a combination of these.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

Some side effects (such as decreased blood cell counts, or changed liver function) can only be found when your doctor does tests from time to time to check your progress.

After using Plegridy

Storage

Keep your Plegridy in its original pack until it is time to use it.

Keep Plegridy in the refrigerator at 2°C to 8°C. Do not freeze. If necessary, you can keep Plegridy out of the refrigerator for up to 30 days as long as it is kept away from light. If out of the refrigerator, store the carton in a cool dry place where the temperature stays between 2°C to 25°C.

Do not use any Plegridy that has been out of the refrigerator for more than 30 days (refer to Disposal below).

Do not store Plegridy or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car. Heat and dampness can destroy some medicines.

Keep Plegridy where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Please read the package insert carefully for full details, including safe disposal of needles and syringes after use.

If your doctor tells you to stop using Plegridy or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

The Plegridy pre-filled syringe Titration Pack holds 2 ready to use syringes. Each Titration Pack for Plegridy syringe contains a clear, colourless liquid (0.5 mL) containing either 63 or 94 micrograms of peginterferon beta-1a.

The Plegridy pre-filled syringe Administration Dose Pack holds 2 ready to use syringes. Each Administration Dose Pack syringe contains a clear, colourless liquid (0.5 mL) containing 125 micrograms of peginterferon beta-1a.

Every syringe has a pre-attached needle and is ready to inject.

The Plegridy pre-filled pen Titration Pack holds 2 ready to use pens. Each Titration Pack for Plegridy pen contains a clear, colourless liquid (0.5 mL) containing either 63 or 94 micrograms of peginterferon beta-1a.

The Plegridy pre-filled pen Administration Dose Pack holds 2 ready to use pens. Each Administration Dose Pack pen contains a clear, colourless liquid (0.5 mL) containing 125 micrograms of peginterferon beta-1a.

Every pen has a pre-attached needle and is ready to inject.

Ingredients

Plegridy is available in 3 strengths: 63 micrograms, 94 micrograms, and 125 micrograms.

Active Ingredient:

  • peginterferon beta-1a (rch)

It also contains:

  • Sodium acetate trihydrate
  • Glacial acetic acid
  • L-arginine hydrochloride
  • Polysorbate 20
  • Water for injections

Further information

You can obtain more information from your doctor, pharmacist or the MS Society in your State, or by telephoning 1800 852 289 in Australia or 0800 852 289 in NZ.

Supplier

Plegridy is supplied in Australia by:

Biogen Australia Pty Ltd
ABN 30 095 760 115
Level 4
2 Banfield Road
Macquarie Park NSW 2113
Australia

It is supplied in New Zealand by:

Biogen NZ Biopharma Limited Auckland

Australian registration numbers

Plegridy 63 microgram/0.5 mL and 94 microgram/0.5 mL:
AUST R 214198 (pre-filled syringe)
AUST R 214200 (pre-filled pen)

Plegridy 125 microgram/0.5 mL:
AUST R 214199 (pre-filled syringe)
AUST R 214197 (pre-filled pen)

Date of preparation

This leaflet was prepared in June 2021.

PLEGRIDY® is a registered trademark of Biogen MA Inc.

Published by MIMS September 2021

BRAND INFORMATION

Brand name

Plegridy

Active ingredient

Peginterferon beta-1a

Schedule

S4

 

1 Name of Medicine

Peginterferon beta-1a (rch).

2 Qualitative and Quantitative Composition

Pre-filled pen.

A single pre-filled syringe contains 0.5 mL of solution of Plegridy containing 63 micrograms, 94 micrograms, or 125 micrograms of peginterferon beta-1a. The glass syringe is contained within a single-use, disposable, injection device (pre-filled pen).

Pre-filled syringe.

A single pre-filled syringe contains 0.5 mL of solution of Plegridy containing 63 micrograms, 94 micrograms or 125 micrograms of peginterferon beta-1a.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Plegridy is indicated for the treatment of relapsing forms of multiple sclerosis (MS) (see Section 5.1 Pharmacodynamic Properties).

4.2 Dose and Method of Administration

Plegridy is administered subcutaneously using a single use pre-filled pen or single use pre-filled syringe.
The recommended dosage of Plegridy is 125 micrograms injected subcutaneously every 2 weeks.

Treatment initiation.

It is generally recommended that patients start treatment with 63 micrograms at dose 1 (day 0), increasing to 94 micrograms at dose 2 (day 14), reaching the full dose of 125 micrograms by dose 3 (day 28) and continuing with the full dose (125 micrograms) every 14 days (2 weeks) thereafter (see Table 1).
A titration pack is available containing the 63 micrograms (dose 1, orange label) and 94 micrograms (dose 2, blue label) syringes/ pens.
It is recommended that a health care professional trains patients in the proper technique for self administering subcutaneous injections using the pre-filled pen/ syringe. Patients should be advised to rotate sites for subcutaneous injections. The usual sites for subcutaneous injections include abdomen, arm, and thigh.
If a dose of Plegridy 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 Plegridy within 7 days of each other.
Each Plegridy pre-filled pen/ syringe is provided with the needle pre-attached. Pre-filled pens/ syringes are for single use only and should be discarded after use.
Dose titration at the initiation of treatment may help to ameliorate flu-like symptoms that can occur at treatment initiation with interferons. Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during interferon treatment.

Children and adolescents.

The safety and efficacy of Plegridy in patients below 18 years of age has not been studied.

Dosage adjustment in 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 Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Dosage adjustment in hepatic impairment.

Plegridy has not been studied in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Dosage adjustment in the elderly.

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

4.3 Contraindications

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.
The initiation of treatment is contraindicated during pregnancy, and in patients with current severe depression and/or suicidal ideation.

4.4 Special Warnings and Precautions for Use

Hepatic injury.

Hepatic injury, including elevated serum hepatic transaminase levels, hepatitis, and autoimmune hepatitis, and rare cases of severe hepatic failure, has been reported with interferon beta. Elevations in hepatic enzymes, noninfectious hepatitis and hepatic injury have been observed with the use of Plegridy. Patients should be monitored for signs of hepatic injury. Withdrawal of treatment with Plegridy should be considered if hepatic transaminase levels significantly increase or if they are associated with clinical symptoms such as jaundice (see Section 4.8 Adverse Effects (Undesirable Effects)).

Pulmonary arterial hypertension.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including Plegridy. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalisation, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.
Patients who develop unexplained symptoms (e.g. dyspnoea, new or increasing fatigue) should be assessed for PAH. If alternative aetiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.

Depression and suicidal ideation.

Depression and suicidal ideation have been reported to occur with increased frequency in patients receiving interferon beta. Patients treated with Plegridy should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with Plegridy and treated appropriately. If a patient develops depression or other severe psychiatric symptoms, cessation of Plegridy therapy should be considered (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).

Anaphylactic and hypersensitivity reactions.

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

Injection site reactions.

Injection site reactions, including injection site necrosis, have been reported with the use of subcutaneous interferon beta. One patient treated with Plegridy in clinical trials experienced an injection site necrosis. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis (see Section 4.8 Adverse Effects (Undesirable Effects)).

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 Plegridy. Patients should be monitored for symptoms or signs of decreased peripheral blood counts (see Section 4.8 Adverse Effects (Undesirable Effects)).

Thrombotic microangiopathy.

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome have been reported with interferon beta products, including fatal cases. Monitoring of early symptoms in all patients e.g. new onset hypertension, impaired renal function and thrombocytopenia is recommended. Prompt treatment is required and discontinuation of treatment with interferon is recommended.

Nephrotic syndrome.

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 interferon should be considered.

Seizure.

Seizures have been associated with the use of interferon beta. Caution should be exercised when administering Plegridy to patients with pre-existing seizure disorder (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiac disease.

Worsening of cardiac disease has been reported in patients receiving interferon beta. The incidence of cardiovascular events was similar between Plegridy (125 micrograms every 2 weeks) and placebo treatment groups (7% in each group). 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. Plegridy does not have any known direct acting cardiac toxicity; however, symptoms of the flu-like syndrome seen with Plegridy therapy may prove stressful to patients with cardiac conditions.

Endocrine disorders.

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.

Autoimmune disorders.

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.

Immunogenicity.

Immunogenicity to Plegridy was evaluated in relapsing multiple sclerosis patients for a minimum of one year and up to two years. Less than 1% of patients (5/715) developed persistent treatment emergent neutralising antibodies to interferon beta-1a. Persistent treatment emergent antibodies to the PEG moiety were also seen in 3% (18/681) of patients. In general, neutralising antibodies have the potential to reduce clinical efficacy. In the ADVANCE study, the development of antibodies against the interferon or PEG moiety of Plegridy had no discernible impact on the pharmacodynamic response, safety, or clinical efficacy, although the analysis was limited by the low immunogenicity incidence.

Use in hepatic impairment.

It is recommended that liver function tests be undertaken prior to initiation of treatment with Plegridy and monitored periodically thereafter. Caution should be used and close monitoring considered when administering Plegridy 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 drugs or hepatotoxic agents (e.g. alcohol) associated with hepatic injury (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dose adjustment is necessary for Plegridy in patients with mild to severe renal impairment, or end stage renal disease.
The pharmacokinetics of Plegridy were assessed in a single dose study in healthy volunteers and subjects with mild, moderate, and severe renal impairment as well as patients with end stage renal disease. No clinically important differences in pharmacokinetic profiles were identified based on renal function (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

The safety and effectiveness of Plegridy in patients aged 65 and over have not been established.

Paediatric use.

The safety and effectiveness of Plegridy in patients below the age of 18 have not been studied.

Effects on laboratory tests.

Laboratory abnormalities are associated with the use of interferons. Complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during Plegridy therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been conducted with Plegridy. Patients who experienced a relapse in the study could receive standard therapy with corticosteroids. Interferons have been reported to reduce the activity of hepatic cytochrome P450 dependent enzymes in humans and animals. Caution should be exercised when Plegridy 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. antiepileptics and some classes of antidepressants.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The weekly subcutaneous administration of peginterferon beta-1a at 170 times the clinical exposure (based on serum AUC) to sexually mature female rhesus monkeys over the course of one menstrual cycle (up to 5 weeks), resulted in menstrual irregularities, anovulation, and decreased serum progesterone. This is consistent with the effects observed with non-pegylated interferon beta. These effects were reversible after discontinuation of drug. The significance of these non-clinical effects to humans is unknown.
(Category D)
Initiation of treatment is contraindicated during pregnancy (see Section 4.3 Contraindications).
Peginterferon beta-1a has not been tested for reproductive toxicity in pregnant animals. Non-pegylated interferon beta-1a has shown no evidence of teratogenicity in pregnant animals. Similar results have been obtained with other interferons.
Non-pegylated interferon beta-1a was not teratogenic in rhesus monkeys at doses up to 50 micrograms (10 million IU)/kg SC. Abortifacient activity was evident at this dose but not at 1.25 micrograms (0.25 million IU)/kg. Patients should be advised of the abortifacient potential of interferon beta observed in animal studies.
There are no adequate and well-controlled studies in pregnant women. Women of child-bearing potential should take appropriate contraceptive measures during treatment. If a patient becomes or plans to become pregnant whilst on therapy, they should be informed of the potential hazards to the fetus. Plegridy should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
 It is not known whether Plegridy is excreted in human milk. Because of the potential for serious adverse reactions in breastfeeding infants, a decision should be made either to discontinue breastfeeding or Plegridy therapy.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
The most common adverse drug reactions (ADRs; incidence ≥ 10%, and ≥ 2% compared to placebo) for Plegridy 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 events leading to discontinuation in patients treated with Plegridy 125 micrograms subcutaneously every 2 weeks was influenza-like illness (< 1%).

Clinical trials.

In clinical studies (Study 1 and 2/ ADVANCE, ATTAIN), a total of 1468 patients with relapsing multiple sclerosis received Plegridy for up to 278 weeks (65 months), with an overall exposure equivalent to 4217 person-years. A total of 1285 patients received at least 1 year, 1124 patients received at least 2 years, 947 patients received at least 3 years, and 658 patients received at least 4 years of treatment with Plegridy. The experience in the extension study ATTAIN (all patients received Plegridy; treatment was for up to 4 years in ATTAIN) was consistent with the experience in the 1-year placebo-controlled phase of the ADVANCE study.
Table 2 summarises ADRs from 512 patients treated with Plegridy 125 micrograms subcutaneously every 2 weeks and 500 patients who received placebo for up to 48 weeks.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organ class (SOC).
Description of selected adverse events.

Flu-like symptoms.

Influenza-like illness was experienced by 47% of patients receiving Plegridy 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 during 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 Plegridy 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 Plegridy evaluated the onset and duration of prophylactically treated flu-like symptoms. Patients were taking prophylactic and concurrent analgesics and/or antipyretics. Approximately 90% of patients had at least 1 occurrence of flu-like symptoms in the first 8 weeks and approximately 90% of patients reported no new or worsening of flu-like symptoms during the transition with either treatment for the first 8 weeks after switching to Plegridy. Symptoms were generally mild with the median time of onset of 10 hours (interquartile range, 7 to 16 hours) following injection and the median duration was 17 hours (interquartile range, 12 to 22 hours).

Injection site reactions.

Injection site reactions (e.g. injection site erythema, pain, pruritus, or oedema) were reported by 66% of patients who received Plegridy 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 1468 patients who received Plegridy 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 Plegridy 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 Plegridy 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 Plegridy in the clinical trials. Both cases resolved following discontinuation of Plegridy.

Haematological disorders.

Decreases in white blood cell counts of < 3.0 x 109/L were observed in 7% of patients receiving Plegridy and in 1% receiving placebo. Mean white blood cell counts remained within normal limits in patients treated with Plegridy. Decreases in white blood cell 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%), platelet counts (≤ 100 x 109/L) (≤ 1%) was similar in Plegridy-treated patients compared to placebo-treated patients. Two serious cases were reported in patients treated with Plegridy: 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 Plegridy. Compared to placebo, there were no significant differences observed in red blood cell counts in patients treated with Plegridy.

Hypersensitivity reactions.

Hypersensitivity events were reported in 16% of patients treated with Plegridy 125 micrograms every 2 weeks and 14% of patients who received placebo. Less than 1% of Plegridy-treated patients experienced a serious hypersensitivity event (e.g. angioedema, urticaria) and they recovered promptly after treatment with anti-histamines and/or corticosteroids.

Depression and suicidal ideation.

The overall incidence of adverse events related to depression and suicidal ideation was 8% for both Plegridy 125 micrograms every 2 weeks and placebo groups. The incidence of serious events related to depression and suicidal ideation were similar and low (< 1%) in both Plegridy 125 micrograms every 2 weeks and placebo-treated patients.

Seizure.

The incidence of seizure events was low and comparable in patients receiving Plegridy (125 micrograms every 2 weeks) and placebo (< 1% in each group).

Post-marketing experience.

Suspected adverse reactions reported in post-marketing experience that are not already included under Clinical trials are shown in Table 3.

Hepatic injury.

In post marketing experience, noninfectious hepatitis (including serious hepatitis) cases have been reported following Plegridy administration (see Section 4.4 Special Warnings and Precautions for Use).

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
No case of overdose has been reported. In case of overdosage, appropriate supportive treatment should be given.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Plegridy is interferon beta-1a conjugated to a single, linear 20 kDa methoxy poly(ethylene glycol) molecule to 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 to biological and chemical stimuli, and mediate numerous cellular responses that have been classified as antiviral, antiproliferative, and immunomodulatory in nature.
The pharmacological properties of Plegridy are consistent with those of interferon beta-1a and are believed to be mediated by the protein portion of the molecule.
A definitive mechanism of action of Plegridy in multiple sclerosis is not known. However, as the biological effects of Plegridy are consistent with those of non-pegylated interferon beta-1a, the mechanism of action of Plegridy is likely to be similar. Plegridy binds to the type I interferon receptor on the surface of cells and elicits a cascade of intracellular events leading to the regulation of interferon-responsive gene expression. These genes, and their gene products, are believed to mediate the efficacy of Plegridy in multiple sclerosis.
As an interferon beta, Plegridy modulates immune responses that are believed to play a role in the pathogenesis of multiple sclerosis. While the pathogenesis of the disease is complex and multifaceted, Plegridy may act at several levels including up-regulation of anti-inflammatory cytokines (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; however additional mechanisms have been proposed.
Pharmacodynamic responses were evaluated by measuring the induction of interferon-responsive genes including those encoding 2',5'-oligoadenylate synthetase (2',5'-OAS), myxovirus resistance protein A (MxA), and several chemokines and cytokines, as well as the gene product neopterin (D-erythro-1, 2, 3,-trihydroxypropylpterin), a product of the interferon-inducible enzyme, GTP-cyclohydrolase I. Gene induction in healthy human subjects was greater in terms of peak level and exposure (area under the effect curve) for Plegridy compared to non-pegylated interferon beta-1a (IM) when both were given at equivalent doses as measured by in vitro activity in a cytopathic effect assay (6 MIU). The duration of this response was sustained and prolonged for Plegridy, with elevations detected up to 15 days compared to 4 days for non-pegylated interferon beta-1a. Increased concentrations of neopterin were observed in both healthy subjects and multiple sclerosis patients treated with Plegridy, with a sustained and prolonged elevation over 10 days compared to 5 days observed for non-pegylated interferon beta-1a. Neopterin concentrations return to baseline within the two-week dosing interval.

Clinical trials.

The efficacy and safety of Plegridy were assessed from the first year of a 2-year randomised, double-blind, clinical study in patients with relapsing remitting multiple sclerosis (the ADVANCE study). Efficacy results were derived from the placebo-controlled first year of the study. At study entry 1512 patients were randomised and dosed to 125 micrograms Plegridy injected subcutaneously every 2 (n = 512) or 4 (n = 500) weeks versus placebo (n = 500). At the end of the first year, patients who received placebo were randomised to Plegridy every 2 or every 4 weeks while the patients randomised to Plegridy in the first year remained on their original dose assignment.
The study enrolled patients who had experienced at least two relapses within the prior three years including at least one in the year prior to randomisation and had an Expanded Disability Status Scale (EDSS) score ranging from 0 to 5. Neurological evaluations were performed at baseline, every 12 weeks and at time of suspected relapse. Brain MRI evaluations were performed at baseline, weeks 24 and 48. The primary endpoint was the annualised relapse rate (ARR) over one year. Secondary endpoints included the proportion of subjects relapsing, new or newly enlarging T2 hyperintense lesions and time to confirmed disability progression, defined as at least a 1 point increase from baseline EDSS ≥ 1 or 1.5 point increase for patients with baseline EDSS of 0, sustained for 12 weeks.
The mean age of the study population was 37 years, the mean disease duration was 3.6 years and the mean EDSS at baseline was 2.46. The majority of the patients were female (71%). Plegridy had a statistically significant effect on the primary and all secondary endpoints.
Plegridy every two weeks reduced the ARR by 36% compared to placebo (p = 0.0007) at one year (Table 4). There was a consistent reduction of the ARR noted in subgroups defined by demographic and baseline disease characteristics. Plegridy reduced the proportion of subjects who relapsed by 39% (p = 0.0003), the proportion of subjects with sustained disability progression by 38% (p = 0.0383), the number of new or newly enlarging T2 lesions by 67% (p < 0.0001), the number of Gd enhancing lesions by 86% (p < 0.0001) and the number of T1 hypointense lesions by 53% (p < 0.0001). A treatment effect was observed as early as six months, with the Plegridy group demonstrating a 61% reduction (p < 0.0001) in new or newly enlarging T2 lesions as compared with placebo.
Across relapse and MRI endpoints Plegridy 125 micrograms every two weeks showed a numerically greater treatment effect over the Plegridy every four weeks dosing regimen.

ADVANCE, year 2.

Results over 2 years confirmed that efficacy was maintained beyond the placebo-controlled first year of the study. Patients who continued treatment with Plegridy for 2 years (438 of 512, or 85.5% of patients) had an annualised relapse rate of 0.230 (95% CI = 0.183, 0.291) in year 1 and a rate of 0.178 (95% CI = 0.136, 0.233) in year 2. In this population, the proportion of subjects who had 12 week disability progression was 0.061 in year 1 and 0.034 in year 2. In the ATTAIN extension study (continued treatment up to 4 years), efficacy was maintained with long-term treatment.
Results for this study are shown in Table 4 and Figure 1.

5.2 Pharmacokinetic Properties

The serum half-life of Plegridy peginterferon beta-1a is prolonged compared with non-pegylated interferon beta-1a. Serum concentration of peginterferon beta-1a was dose-proportional in the range of 63-188 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 healthy subjects.

Absorption.

Following subcutaneous administration of peginterferon beta-1a in multiple sclerosis patients, the peak concentration was reached between 1-1.5 days post-dose. The observed Cmax (mean ± SE) was 280 ± 79 picogram/mL following repeat dosing of 125 micrograms every two weeks and the AUC over the 14 day dosing interval was 35 ± 6 nanogram.hr/mL.
Subcutaneous peginterferon beta-1a resulted in approximately 4, 9, and 13-fold higher exposure (AUC168 h) values and approximately 2, 3.5 and 5-fold higher Cmax, following single doses of 63 (6 MIU), 125 (12 MIU), and 188 (18 MIU) micrograms respectively, compared to intramuscular administration of 30 (6 MIU) micrograms non-pegylated beta-1a.

Distribution.

Following repeat dosing of 125 microgram doses every two weeks by subcutaneous administration in multiple sclerosis patients, peginterferon beta-1a was widely distributed with a volume of distribution of 479 ± 105 L (mean ± SE).

Biotransformation and elimination.

Clearance mechanisms for Plegridy include catabolism and excretion. The major pathway of elimination of peginterferon beta-1a is renal. Renal elimination is postulated to be a major excretory pathway for the PEG moiety. Other potential minor routes of elimination for the PEG moiety include hepatic metabolism and biliary excretion.
The process of covalently conjugating a PEG moiety to a protein can alter the in vivo properties of the unmodified protein, including decreased renal clearance and decreased proteolysis thus extending the circulating half-life. Accordingly, the half-life (t1/2) of peginterferon beta-1a is approximately 2-fold longer than non-pegylated interferon beta-1a in healthy volunteers. In multiple sclerosis patients, the t1/2 (mean ± SE) of peginterferon beta-1a was 78 ± 15 hours at steady state. The mean steady-state clearance of peginterferon beta-1a was 4.1 ± 0.4 L/hr.

Special populations.

Elderly (> 65 years).

Clinical experience in patients aged above 65 years is limited. However, results from a population pharmacokinetic analysis suggest that age does not impact peginterferon beta-1a clearance.

Gender.

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

Race.

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

Renal impairment.

A single dose study in healthy subjects (creatinine clearance > 80 mL/minute) and subjects with various degree of renal impairment showed a fractional increase in AUC336 h (30%, 40% and 53%) and Cmax (27%, 26% and 42%) in subjects with mild (creatinine clearance 50 to ≤ 80 mL/minute), moderate (creatinine clearance 30 to < 50 mL/minute), and severe (creatinine clearance < 30 mL/minute) renal impairment respectively, compared to subjects with normal renal function (creatinine clearance > 80 mL/minute). Subjects with end stage renal disease requiring haemodialysis 2-3 times weekly showed similar AUC336 h and Cmax as compared to subjects with normal renal function. Each haemodialysis reduced peginterferon beta-1a concentration by approximately 24%, suggesting that haemodialysis partially removes peginterferon beta-1a from systemic circulation.

Hepatic impairment.

The pharmacokinetics of peginterferon beta-1a have not been evaluated in patients with hepatic insufficiency.

5.3 Preclinical Safety Data

Genotoxicity.

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.

Carcinogenicity.

Peginterferon beta-1a has not been tested for carcinogenicity in animals.

Toxicology.

Human interferon beta-1a is pharmacologically active in rhesus monkeys. Due to the immunogenicity of human interferons in rhesus monkeys, the studies were limited to five weeks duration. Exposure to peginterferon beta-1a by subcutaneous administration up to 325 times the clinical exposure, based on serum AUC, produced no signs of toxicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Plegridy also contains sodium acetate trihydrate, glacial acetic acid, L-arginine hydrochloride, and polysorbate 20 in water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in the closed original carton to protect from light until ready for injection. Store in a refrigerator between 2 to 8°C. Do not freeze. Discard if frozen. The formulation is preservative-free.
When no refrigerator is available, Plegridy may be stored protected from light between 2°C to 25°C for a maximum of 30 days in total.
Once removed from the refrigerator, Plegridy should be allowed to warm to room temperature (about 30 minutes) prior to injection. Do not use external heat sources such as hot water to warm Plegridy.
Plegridy can be removed from and returned to the refrigerator if necessary. The total combined time out of refrigeration should not exceed 30 days, at a temperature that does not exceed 2°C to 25°C, protected from light.

6.5 Nature and Contents of Container

Plegridy is produced by recombinant DNA technology and is manufactured in three strengths, 63 micrograms, 94 micrograms, and 125 micrograms. Plegridy is supplied as pre-filled pen and pre-filled syringe.

Pre-filled pen.

Plegridy is formulated as a sterile clear liquid for subcutaneous injection. Each unit of Plegridy is stored in a 1 mL Type I glass syringe with a latex free bromobutyl rubber stopper and thermoplastic and polypropylene rigid needle shield. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe. A single pre-filled syringe contains 0.5 mL of solution of Plegridy containing 63 micrograms, 94 micrograms, or 125 micrograms of peginterferon beta-1a. The glass syringe is contained within a single-use, disposable, injection device (prefilled pen).
The Plegridy pre-filled pen Titration Pack holds 2 ready to use pens. Each Titration Pack for Plegridy pen contains a clear, colourless liquid (0.5 mL) containing either 63 or 94 micrograms of peginterferon beta-1a.
The Plegridy pre-filled pen Administration Dose Pack holds 2 or 6 ready to use pens. Each Administration Dose Pack pen contains a clear, colorless liquid (0.5 mL) containing 125 micrograms of peginterferon beta-1a.

Pre-filled syringe.

Plegridy is formulated as a sterile clear liquid for subcutaneous injection. Each unit of Plegridy is stored in a 1 mL Type I glass syringe with a latex free bromobutyl rubber stopper and thermoplastic and polypropylene rigid needle shield. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe. A single pre-filled syringe contains 0.5 mL of solution of Plegridy containing 63 micrograms, 94 micrograms or 125 micrograms of peginterferon beta-1a.
The Plegridy pre-filled syringe Titration Pack holds 2 ready to use syringes. Each Titration Pack for Plegridy syringe contains a clear, colorless liquid (0.5 mL) containing either 63 or 94 micrograms of peginterferon beta-1a.
The Plegridy pre-filled syringe Administration Dose Pack holds 2 or 6 ready to use syringes. Each Administration Dose Pack syringe contains a clear, colorless liquid (0.5 mL) containing 125 micrograms of peginterferon beta-1a.
Not all pack sizes are being distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Peginterferon beta-1a (rch) is recombinant interferon beta-1a conjugated to 20 kDa methoxy poly(ethylene glycol) using an -O-2-methylpropionaldehyde linker. It is expressed in mammalian cells and has the same sequence as naturally occurring human interferon beta. The 20 kDa mPEG-O-2-methylpropionaldehyde is attached to the a-amino group of the N-terminal amino acid residue using reductive amination chemistry.

CAS number.

The CAS Registry Number is 1211327-92-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes