Consumer medicine information

Betaferon

Interferon beta-1b

BRAND INFORMATION

Brand name

Betaferon

Active ingredient

Interferon beta-1b

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Betaferon.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Betaferon.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Betaferon against the benefits it will have for you.

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

Keep this leaflet with your medicine. You may need to read it again.

WHAT BETAFERON IS USED FOR

Betaferon belongs to a class of medicines known as interferons. Interferons are naturally occurring proteins, produced by the body that help fight against attacks on the immune system such as viral infections.

The active substance of Betaferon is interferon beta-1b, a recombinant human interferon beta produced from a strain of Escherichia coli.

How it works

Multiple sclerosis (MS) is a long term condition that affects the central nervous system (CNS) i.e. brain and spinal cord. The exact cause of MS is unknown. An abnormal response by the body’s immune system is thought to play an important part in the process which damages the CNS.

Betaferon has been shown to change the response of the immune system and to help reduce disease activity.

Single clinical event indicating high risk of developing MS: Betaferon is for use in patients who for the first time have experienced symptoms which indicate a high risk for development of multiple sclerosis. Your doctor will rule out any other reasons which could explain these symptoms before you are treated.

Relapsing-remitting MS: Betaferon is for use in patients who have occasional attacks or relapses during which symptoms become noticeably worse (at least two relapses within the last two years). This is the form of multiple sclerosis where patients experience attacks of CNS problems (for example of visual disturbances, arm/leg weakness, loss of bowel/bladder control) separated by periods of complete or incomplete recovery.

Betaferon has been shown to cut down the number of attacks and make them less severe. It reduces the number of hospital stays due to the disease and prolongs the time without relapses.

Secondary progressive MS: Betaferon is also for use in patients whose symptoms progress to another form of MS called secondary progressive MS. With this, patients become increasingly impaired, whether or not they have relapses. Betaferon can reduce the number and severity of the attacks, and slow the progression of disability.

Betaferon has been shown to have a marked effect on those physical changes in the brain that can be detected by a special kind of brain scan.

This medicine is available only with a doctor's prescription.

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

BEFORE YOU USE BETAFERON

When you must not use it

Do not use Betaferon if you have an allergy to:

  • any medicine containing interferon beta-1b (rbe), mannitol or human albumin
  • any of the 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 this medicine if you have liver failure.

Do not use this medicine if you suffer from epilepsy (fits or seizures) which is not controlled by other medicines.

Do not use this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 2018 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not use this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to 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 any of the following medical conditions:

  • seizures (fits or convulsions)
  • severe depression (feeling of severe sadness and unworthiness) or thoughts of suicide
  • heart disorders
  • kidney disease
  • liver disease
  • blood disorder (e.g. low counts of platelets, red and white blood cells)
  • thyroid disease
  • pancreatitis
  • an increase of certain type of blood fats (triglycerides)
  • allergy to any other medicines, foods, dyes or preservatives
  • bone marrow disorder
  • monoclonal gammopathy (disorder of immune system where abnormal proteins are found in the blood).

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. It is not known whether Betaferon can affect your developing baby if you take it during pregnancy. Women of childbearing age should take appropriate contraceptive measures while using Betaferon.

If you become pregnant while using Betaferon, consider stopping your treatment and contact your doctor immediately. Your doctor can discuss with you the risks and benefits involved.

It is not known whether Betaferon passes into breast milk. If you want to breastfeed while using Betaferon, discuss this with your doctor. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking Betaferon.

Taking other medicines

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

Care must be taken when Betaferon is used with some medicines, including some used to treat fever and pain.

The following medicines commonly used by people with MS have been well tolerated whilst using Betaferon:

  • corticosteroids such as hydrocortisone, prednisone or prednisolone
  • ACTH (adrenocorticotrophic hormone)

Some medicines that are broken down by the liver and Betaferon may interfere with each other. These include:

  • medicine to treat epilepsy
  • medicine used for sedation or to treat anxiety
  • medicine to treat depression

Your doctor may have to adjust the dose of your other medicines while you are using Betaferon. It is therefore important that you tell your doctor about all the medicines that you are taking.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

What else you should know

  • This product contains human albumin and hence carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jacob Disease (CJD) is also considered extremely remote.
  • It is not known if Betaferon can decrease your ability to have children in the future.
  • During treatment with Betaferon, your body may produce substances called neutralising antibodies, which may react with Betaferon. It is not yet clear if these reduce the effectiveness of the treatment. Neutralising antibodies are not produced in all patients.

Betaferon is not recommended for use in children under 18 years of age with MS as there is no clinical experience in this age group.

HOW BETAFERON IS USED

If you do not understand the instructions provided, ask your doctor, MS education nurse or pharmacist for help.

Follow all directions given to you carefully. They may differ from the information contained in this leaflet.

Betaferon is given as a subcutaneous (under the skin) injection after reconstitution every other day.

Treatment with Betaferon should be started under the supervision of a specialist doctor experienced in the treatment of MS.

It is recommended that new users of Betaferon contact the MS immunotherapy nurse to assist with training. A list of contact numbers is included under Further Information. The service is available at no cost.

Before administration, the Betaferon solution for injection has to be prepared from a vial of Betaferon and the 1.2 mL of diluent from the pre-filled syringe.

Each mL of reconstituted solution for injection contains 8 million IU (international units) or 0.25 mg interferon beta-1b (rbe).

The usual dose is 1 mL of the prepared Betaferon solution for injection is injected subcutaneously (under the skin) every other day.

Betaferon should not be injected directly into the veins.

The instructions included in this leaflet are for manual self injection. Auto-injectors are also available for use with Betaferon. If an auto-injector is used, please follow instructions enclosed with your auto-injector.

How much is given

In general, treatment should be started at a low dose of 0.25 mL (0.0625 mg). The dose will then be increased gradually to the full dose of 1.0 mL (0.25 mg) which is equivalent to 8 million IU.

The dose should be increased at every fourth injection in four steps (0.25 mL, 0.5 mL, 0.75 mL, 1.0 mL). Your doctor may decide together with you to change the time interval for the dose increase depending on side effects you may experience at the start of treatment.

Administration will either be done by your doctor or his/her assistant or by yourself after you have been carefully and sufficiently instructed and trained. To assist you in subcutaneous self-administration of Betaferon, detailed instructions for self-injection are set out below. These instructions also tell you how to prepare the Betaferon solution for injection.

To reduce the risk of the injection solution becoming contaminated it should be used as soon as possible after it is prepared. If required, the reconstituted solution for injection may be stored in the refrigerator (not freezer) at 2°C to 8°C and used within 3 hours of preparation.

How to inject

Betaferon is intended to be injected by yourself by subcutaneous (under the skin) injection. The following instructions and pictures explain how to prepare Betaferon for injection and how to inject Betaferon yourself.

Please read the instructions carefully and follow them step by step. Your doctor or their assistant will help you to learn the process of self-administration. Do not attempt to inject yourself until you are sure that you understand how to prepare the injection solution and give the injection to yourself.

The instructions include the following main steps:

A. General advice

B. Getting ready to inject

C. Reconstituting the solution, step by step

D. Drawing up the injection

E. Giving the injection

F. Quick review of the process

A. General advice

  • Be consistent, use Betaferon as described under “How Betaferon is used” within this leaflet.
  • Keep your syringes and syringe disposal unit out of reach of children; lock the supplies away if possible.
  • Never re-use syringes or needles.
  • Always use a sterile (aseptic) technique as described here. If in any doubt, discard needles, syringes or solution and start again.
  • Always place the used syringes in the proper disposal unit.

B. Getting ready to inject

Choosing an injection site
Before preparing your injection, decide where you are going to inject. You should inject Betaferon into the fatty layer between the skin and muscle (that is, subcutaneously, about 8 to 12 mm under the skin). The best places for injections are where the skin is loose and soft, and away from joints, nerves, or bones, for example the abdomen, arm, thigh, or buttocks. Try to avoid the panty or belt line at the waist and the seat portion of the buttocks as daily activity may irritate these areas.

Important: Do not use any area where you can feel lumps, bumps, firm knots, pain or an area that is discoloured, indented, scabbed, or where skin is broken. Talk to your doctor or healthcare professional about these or any other unusual conditions you may find.

You should rotate the injection site at every injection. If some areas are too difficult for you to reach, you may need to ask your support person (or someone who has been trained to give injections) to help you with these injections. Follow the sequence described in the schedule at the end of this leaflet (see “Rotating injection sites”) and you will come back to your first injection site area after 8 injections (16 days). This will give each injection site a chance to fully recover before receiving another injection.

Please refer to the rotation schedule at the end of this leaflet to learn how to choose an injection site. An example of a medication record is also included. This should give you an idea of how you can keep track of your injection sites and dates.

Checking the content of the pack

You will find in the Betaferon pack:

  • 1 Betaferon vial (with powder for solution for injection)
  • 1 pre-filled syringe of diluent for Betaferon (sodium chloride solution 5.4 mg/mL (0.54%)).
    (Be sure that the tip cap is firmly attached to the solvent syringe!)
  • 1 vial adapter with a pre-attached needle
  • 2 alcohol swabs for skin and vial cleaning.

In addition you will need a disposal unit for used syringes and needles.

For skin disinfection use an appropriate disinfectant.

C. Reconstituting the solution, step by step

1 – Wash your hands thoroughly with soap and water before beginning this process.

2 – Open the Betaferon vial and put it on the table. It is best to use your thumb rather than your nail as it could break.

3 – Clean the top of the vial with an alcohol wipe, moving the wipe in one direction only. Leave the wipe on top of the vial.

4 – Open the blister pack containing the vial adapter, but leave the vial adapter inside.

Do not remove the vial adapter from the blister pack at this stage.

Do not touch the vial adapter. This is to keep it sterile.

5 – Rest the vial on a flat surface while attaching the adapter.

6 – Remove the alcohol wipe from the top of the Betaferon vial. Place the blister pack containing the vial adapter on top of the vial. Push it down with your thumb and forefinger or the palm of your hand until you feel it snap into place.

7 – Remove the blister pack from the vial adapter, holding the blister edges. Now you are ready to attach the pre-filled diluent syringe to the vial adapter.

8 – Pick up the syringe. Remove the orange tip cap, using a ‘twist-and-pull’ motion. Throw away the tip cap.

9 – Connect the syringe to the opening on the side of the vial adapter by inserting the end of the syringe and tightening carefully with a clockwise “push-and-twist” motion (see arrow). This will form the syringe assembly.

10 – Hold the syringe assembly at the bottom of the vial. Slowly push the plunger of the syringe in all the way to transfer all of the diluent into the vial. Release the plunger. The plunger may go back to its original position.

11 – With the syringe assembly still attached, swirl the vial around gently to completely dissolve the dry Betaferon powder.

Do not shake the vial.

12 – Examine the solution carefully. It should be clear and contain no particles. If the solution is discoloured or contains particles, discard it and start again with a new single pack of supplies. If foam is present – which can happen if the vial is shaken or swirled too much – let the vial sit undisturbed until the foam settles.

13 – If the plunger has moved back to its original position push it in again and hold it in place. To prepare your injection, turn the assembly over so that the vial is on top, cap side pointing down. Doing this allows the solution to flow down into the syringe.

D. Drawing up the injection

Keep the syringe horizontal. Slowly pull the plunger back to withdraw all the solution out of the vial and into the syringe.

14 – Turn the syringe assembly so that the needle is pointing up. This allows any air bubbles to rise to the top of the solution.

15 – Remove any air bubbles by gently tapping the syringe and pushing the plunger to the 1ml mark, or to the volume prescribed by your doctor.

If too much solution goes into the vial along with the air bubbles, pull the plunger back a little to withdraw the solution back from the vial into the syringe. Do this until all the air is gone and there is 1 ml of reconstituted solution in the syringe.

Important: You will need to hold the syringe assembly to a horizontal position with the vial on top when withdrawing solution again.

16 – Next, hold the blue vial adapter with the attached vial and remove it from the syringe by twisting it and then pulling it down, away from the syringe.

Only hold the blue plastic adapter when removing. Keep the syringe in a horizontal position and the vial below the syringe.

17 – Removing the vial and adapter from the syringe (using the twist and pull motion) ensures that the solution will flow out from the needle when injected.

18 – Dispose of the vial and any unused portion of the solution in the disposal unit.

You are now ready to inject.

If, for some reason, you are not able to inject the Betaferon immediately, you can keep the reconstituted solution in the syringe in a refrigerator for up to 3 hours before using. Do not freeze the solution, and do not wait longer than 3 hours to inject it. If more than 3 hours pass, discard the reconstituted Betaferon solution and prepare a new injection. When you use the solution, warm it up in your hands before injecting to avoid pain.

E. Giving the injection subcutaneously (under the skin)

1 – Choose an area for the injection (see advice at the start and diagrams at the end of this leaflet), and make a note of it in your medication record.

2 – Use an alcohol swab to clean the skin at the injection site. Let the skin air-dry. Throw the swab away.

For skin disinfection use an appropriate disinfectant.

3 – Remove the cap from the needle. Pull the cap, do not twist it.

4 – Gently pinch the skin together around the disinfected injection site (to raise it up a little).

Please follow manufacturer’s instructions for use with an auto-injector. Alternatively, for manual injection:

5 – Holding the syringe like a pencil or a dart, push the needle straight into the skin at a 90° angle with a quick, firm motion.

6 – Inject the medicine using a slow, steady push on the plunger. (Push the plunger all the way in until the syringe is empty.)

7 – Discard the syringe in the disposal unit.

F. Quick review of the process

  • Take out the contents of the pack
  • Attach vial adapter to the vial
  • Connect the syringe to the vial adapter
  • Push syringe plunger to transfer diluent into the vial
  • Turn the syringe assembly over, then pull out the plunger
  • Remove vial from syringe –– you are now ready to inject

NOTE: The injection should be administered immediately after mixing (if the injection is delayed, refrigerate the solution and inject it within 3 hours). Do not freeze.

Rotating injection sites
You need to choose a new site for each injection to allow the area time to recover and help prevent infection. Advice on which areas to choose is given in the first part of this leaflet. It is a good idea to know where you plan to inject before you prepare your syringe. The schedule shown in the diagram below will help you to vary the sites appropriately. For example, give the first injection into the right side of the abdomen, choose the left side for the second injection, then move to the right thigh for the third, and so on through the diagram until all suitable areas of the body have been used. Keep a record of where and when you last gave yourself an injection. One way to do that is to note the injection site on the enclosed medication record card.

By following this schedule, you will come back to your first area (e.g. the right side of the abdomen) after 8 injections (16 days). This is called a Rotation Cycle. On our example schedule each area is split again into 6 injection sites (which adds up to 48 injection sites all together), left, right, upper, middle and lower part of each area. If you come back to an area after one Rotation Cycle, choose the most distant injection site within this area. If an area becomes sore, talk to your doctor or nurse about choosing other injection sites.

Rotation Schedule:

To help you rotate the injection sites appropriately we recommend that you keep a record of the date and location of your injection. You can use the following rotation schedule.

Work through each rotation cycle in turn. Each cycle will be 8 injections (16 days), given in an area 1 through to area 8 in turn. By following this sequence, you will give each area a chance to recover before receiving another injection.

Rotation Cycle 1: Upper left section of each area.

Rotation Cycle 2: Lower right section of each area.

Rotation Cycle 3: Middle left section of each area.

Rotation Cycle 4: Upper right section of each area

BETAFERON Medication record

Instructions for keeping track of your injection sites and dates

  • Start with your first injection (or your last injection if you are not a new Betaferon user).
  • Select an injection site. If you have already been using Betaferon, start with the area that has not been used during the last rotation cycle, i.e. the past 16 weeks.)
  • After your injection, fill in the used injection site and date on the table in your injection record (see the example: Keeping track of your injection sites and dates).

How long to take it

The length of treatment will be decided by you and your doctor.

If you forget to use it

If you have forgotten to give yourself an injection at the right time, do it as soon as you remember and then follow on with the next one 48 hours later. Do not take a double dose to make up for the forgotten single dose.

Ask your doctor if you are not sure what to do or have trouble remembering to inject your medicine.

If you stop using Betaferon

Talk to your doctor if you stop or wish to stop treatment. Stopping Betaferon is not known to lead to acute withdrawal symptoms.

If you inject too much (overdose)

Administration of many times the dose of Betaferon recommended for treatment of multiple sclerosis has not led to life-threatening situations. In case of accidental overdose (e.g. one injection every 24 hours instead of every 48 hours), contact your doctor or the Poisons Information Centre (In Australia telephone 131 126, in New Zealand telephone 0800 764 766) for recommendations on the management and treatment of overdosage.

WHILE YOU ARE USING BETAFERON

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Betaferon.

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

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor may also take blood tests prior to commencing and regularly during treatment with Betaferon to test for changes in your blood count, liver function and thyroid function.

Tell your doctor immediately if you:

  • experience depression or suicide thoughts
  • experience symptoms such as itching, swelling of face and/or your tongue or sudden shortness of breath. These may be symptoms of a serious allergic reaction (hypersensitivity) that may become life threatening.
  • experience irregularity of your heart beats or fluid retention (swelling) in the lower parts of your body (e.g. ankles, legs) or shortness of breath. These may be symptoms of a disease of the heart muscle which has been reported in rare cases during treatment with Betaferon

Tell your doctor if you:

  • suffer from signs of frequent infections such as fever or sore throat; notice unusual bruising or excessive bleeding after injury.
  • notice a yellowish colouration of your skin or eyes (jaundice), loss of appetite, or fatigue.

Injection site skin breakdown and tissue destruction can be extensive and may involve scar formation. If you have multiple lesions, Betaferon must be discontinued until healing has taken place. Patients with single lesions may continue on Betaferon provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis while on Betaferon.

To minimise the risk of injection site necrosis you must:

  • use an aseptic technique
  • rotate the injection sites with each dose

The procedure of self-administration must be reviewed periodically by your doctor, especially if injection site reactions have occurred.

Things you must not do

Do not use Betaferon to treat any other complaints.

Do not stop using Betaferon, or change the dose, without first checking with your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.

Things to be careful of

The effects of the disease or of Betaferon treatment may influence your ability to drive a car or operate machinery. You should discuss this with your doctor if you are concerned.

SIDE EFFECTS

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

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

Do not be alarmed by this list of possible side effects. You may not experience any of them.

At the beginning of treatment, side effects are common but in general they become less with further treatment.

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

Tell your doctor if you notice any of the following and they worry you.

This list contains the more common side effects of your medicine:

  • Injection site reactions including redness, swelling bruising, pain or itching. These may be reduced by administration with an autoinjector. Please consult your doctor for further information.
  • Flu-like symptoms including fever, chills, muscular pain, headache, tiredness, painful joints, general feeling of being unwell, or sweating. These may be relieved if paracetamol or ibuprofen is taken when the injection is given.

This list contains the other common side effects of your medicine:

  • Redness, swelling, discolouration, pain, allergy, skin cell-death where the injection was given. These tend to be worst at the start of treatment and become less of a problem over time. If you experience multiple skin sores, very severe sores or breakage of the skin associated with swelling or drainage of fluid from the injection site you should discuss this with your doctor. It may be necessary to stop using Betaferon until these are healed.
  • Rash, itchiness, urticaria (hives), skin discolouration, sweating.
  • Nausea, vomiting, diarrhoea, constipation, abdominal pain
  • Dizziness, anxiety, nervousness
  • Infected sinus
  • Conjunctivitis.

If any of the side effects get serious, tell your doctor or pharmacist.

The list below includes the less common side effects of your medicine:

  • Migraine
  • Palpitations
  • High blood pressure
  • Menstrual period upsets
  • Depression, emotional instability, convulsions (fits), suicide attempts, and confusion
  • Blood disorders
  • Muscle pain and stiffness
  • Muscle weakness
  • Shortness of breath, wheeze
  • Chest pain
  • Pelvic pain
  • Abnormal vision
  • Back pain
  • Fast heart beat
  • Kidney problems

The following list includes the very rare side effects of your medicine:

  • Disease of the heart muscle
  • When Betaferon has been given to patients who have a very rare disease where abnormal proteins are found in the blood there have been problems with small blood vessels leading to collapse and even death
  • Loss of scalp hair
  • Serious allergic reactions
  • Disturbances of the thyroid gland
  • Hepatitis, liver failure
  • Cystitis
  • Breast pain
  • Joint pain
  • Menorrhagia (heavy menstruation)
  • Infection
  • Insomnia
  • Urinary disorders
  • Anorexia
  • Convulsion
  • Changes in weight

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body
  • shortness of breath, wheezing or trouble breathing
  • yellowing of the skin and/or eyes (jaundice)

These are rare but very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER USING BETAFERON

Storage

Keep Betaferon in the original pack until it is time for it to be used/given.

Keep Betaferon in a cool dry place where the temperature stays below 25°C before reconstitution.

Do not freeze.

Keep it 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.

After preparing the solution, you should use it immediately. However, if you are not able to do so, you can store the reconstituted solution in the refrigerator between 2 to 8°C for up to 3 hours. (Refrigerate. Do Not Freeze).

When you use the solution, warm it up in your hands before injecting to avoid pain. Do not use Betaferon if you notice it contains particles or if it is discoloured.

Once you have administered the injection, you should throw any unused portion away.

Disposal

Betaferon should be used once only. After injecting, you should discard the syringe even if you have not injected all its contents. Syringes should be discarded in an appropriate disposal unit.

If your doctor tells you to stop using Betaferon or if it has passed its expiry date, ask your doctor or pharmacist what to do with any syringes that are left over.

PRODUCT DESCRIPTION

What it looks like

Betaferon is a sterile white to off-white powder for solution for injection.

Betaferon is available in a carton containing 15 single use packs.

Each single use pack contains

  • 1 Betaferon vial with powder for injection
  • 1 pre-filled syringe containing diluent
  • 1 vial adapter with needle and
  • 2 alcohol swabs.

Ingredients

Active ingredients:

  • Betaferon – 0.25 mg interferon beta-1b (rbe) per mL

Inactive ingredients:

  • mannitol
  • human albumin
  • 0.54 % sodium chloride solution (as diluent).

The inactive ingredients of Betaferon include small amounts of mannitol (a naturally occurring sugar) and human albumin (a protein). If you know that you are hypersensitive to any of the ingredients or if you become so, you must not use Betaferon.

Further information

You can obtain more information from your doctor, pharmacist or the MS Society in your State.

https://www.nps.org.au/australian-prescriber/articles/ms-australia

NSW free call: 1800 042 138

TAS free call: 1800 676 721

Patient support kits that include a step-by-step instruction DVD and video are available.

Supplier

Made in Germany for:

Bayer Australia Limited
ABN 22 000 138 714
875 Pacific Highway
Pymble, NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest
North Shore, Auckland 0627

Freephone 0800 229 376

Australian Registration number

Betaferon - AUST R 83309

Date of preparation

September 2019

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered Trademark of the Bayer Group, Germany

© Bayer Australia Ltd

All rights reserved

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Betaferon

Active ingredient

Interferon beta-1b

Schedule

S4

 

1 Name of Medicine

Betaferon is interferon beta-1b (rbe), 8 million IU (0.25 mg).

2 Qualitative and Quantitative Composition

1 mL of the reconstituted solution for injection contains 8 million IU (0.25 mg) of interferon beta-1b. 1 mL of solution for injection contains 5.4 mg sodium chloride.
Interferon beta-1b is a purified, sterile lyophilised protein that has 165 amino acids and an approximate molecular weight of 18,500 daltons. It is produced by recombinant DNA techniques from a strain of Escherichia coli that bears a genetically engineered plasmid containing a modified human interferon beta gene.
Interferon beta-1b differs structurally from natural human interferon beta by the presence of serine instead of cysteine in position 17, lack of methionine in position 1 and absence of carbohydrate moieties.
Betaferon contains mannitol. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Betaferon is presented as a sterile lyophilised white to off-white cake or powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Betaferon is indicated for:
The treatment of patients with a single clinical event suggestive of multiple sclerosis and at least two clinically silent magnetic resonance imaging (MRI) lesions characteristic of multiple sclerosis, if alternative diagnoses have been excluded.
The treatment of ambulatory patients with relapsing remitting multiple sclerosis (MS) characterised by at least two attacks of neurologic dysfunction over a two year period followed by complete or incomplete recovery.
The reduction of frequency and severity of clinical relapses, and for the slowing of progression of disease in patients with secondary progressive multiple sclerosis.

4.2 Dose and Method of Administration

General.

Treatment with interferon beta-1b should be initiated under the supervision of a physician experienced in the treatment of multiple sclerosis. There are follow-up data under controlled clinical trial conditions for patients with relapsing remitting MS for up to five years and for patients with secondary progressive MS for up to 3 years.
To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter with attached needle on to the vial. Connect the pre-filled syringe with solvent to the vial adapter and inject the 1.2 mL of the diluent (sodium chloride, 0.54% w/v solution) it contains, into the Betaferon vial. Dissolve the powder completely without shaking.
Inspect the reconstituted product visually before use. The reconstituted product is colourless to light yellow and slightly opalescent to opalescent. Discard the product if it contains particulate matter or is discoloured. The reconstituted solution contains 8 million IU (0.25 mg) of interferon beta-1b per mL.
After reconstitution, draw 1.0 mL from the vial into the syringe for administration of 0.25 mg Betaferon. Remove the vial with the vial adapter from the prefilled syringe by twisting the vial and then pulling it down, away from the syringe before injection. For dose titration at the start of treatment, draw the respective volume as given in Table 1. Proceed to inject appropriate volume of injection. Discard any unused reconstituted solution.
To reduce microbiological hazard, the reconstituted solution should be used as soon as practicable after reconstitution. If storage is necessary, hold at 2°C to 8°C for not more than 3 hours.
In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Relapsing remitting multiple sclerosis.

For relapsing remitting multiple sclerosis, the recommended dose of Betaferon (interferon beta-1b) is 8 million IU (0.25 mg) contained in 1 mL of reconstituted solution, injected subcutaneously every other day.
Treatment should start as soon as the definite diagnosis of relapsing remitting multiple sclerosis has been made and the patient has had at least two exacerbations in the previous two years. In case there are fewer than two relapses during the last two years the decision should be made on an individual basis; the treating physician should inform the patient on the possible risk and benefit of a treatment with interferon beta-1b and decide with him/her whether he/she would be willing to accept possible side effects and inconveniences that might be related to the treatment with interferon beta-1b.
For relapsing remitting MS, the available data for up to five years suggest sustained treatment efficacy of Betaferon over the whole time period.

Secondary progressive multiple sclerosis.

For secondary progressive multiple sclerosis, the recommended dose of Betaferon (interferon beta-1b) is 8 million IU (0.25 mg) contained in 1 mL of reconstituted solution, injected subcutaneously every other day.
Treatment should start as soon as the definite diagnosis of secondary progressive multiple sclerosis has been made. For secondary progressive MS, efficacy for a period of two years with limited data for a period of up to three years of treatment has been demonstrated under controlled clinical trial conditions.
According to the results of the clinical studies the treatment should last at least two years. The follow-up studies in relapsing remitting patients indicate a persistence of the treatment effect until the end of four to five years. Since the statement on the efficacy after four to five years is based on a small number of patients, a decision for long-term treatment should be made on an individual basis by the treating physician.

Single clinical event suggestive of multiple sclerosis.

For a single clinical event suggestive of multiple sclerosis, dose titration is recommended at the start of treatment.
Patients should be started at 2 million IU (0.0625 mg) contained in 0.25 mL of solution subcutaneously every other day, and increased slowly to a dose of 8 million IU (0.25 mg) contained in 1.0 mL of solution every other day. The titration period may be adjusted according to individual tolerability.
In the BENEFIT study in patients with a single clinical event, dosage was increased as shown in Table 1.
At the present time it is not known how long the patient should be treated for. In patients with a single clinical event suggestive of multiple sclerosis, data suggest efficacy over a period of five years.

4.3 Contraindications

Betaferon is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Immune system disorders.

The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome.
Serious hypersensitivity reactions (rare but severe acute reactions, such as bronchospasm, anaphylaxis, urticaria) may occur. If reactions are severe, interferon beta-1b should be discontinued and appropriate medical intervention instituted. Other moderate to severe adverse experiences may require modifications of the interferon beta-1b dosage regimen or even discontinuation of the agent.

Gastrointestinal disorders.

In rare cases, pancreatitis was observed with Betaferon use, often associated with hypertriglyceridaemia.

Depression and suicide.

Patients to be treated with interferon beta-1b should be informed that depression and suicidal ideation may be a side effect of the treatment and should report these symptoms immediately to the prescribing physician. In rare cases these symptoms may result in a suicide attempt. Patients exhibiting depression and suicidal ideation should be monitored closely and cessation of therapy should be considered.
In the study with patients with a single demyelinating event suggestive of MS and in the study with patients with secondary progressive multiple sclerosis, there were no significant differences between Betaferon treated patients and placebo treated patients for depression and suicidal ideation. However, because it cannot be excluded that Betaferon treatment may be associated with depression and suicides in individual patients, Betaferon should be administered with caution to patients with previous or current depressive disorders or suicidal ideation. Cessation of Betaferon therapy should be considered if such events develop during therapy.

Nervous system disorders.

Seizures.

Betaferon should be administered with caution to patients with a history of seizures. Betaferon should be withdrawn from patients who develop seizures while on medication until the cause of the seizure is investigated. If it is determined that Betaferon is not the cause of the seizure, treatment can be reinitiated.
This product contains human albumin, a derivative of human blood. Based on effective product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jacob disease (CJD) is also considered extremely remote.

Haemolymphatic system.

As therapy with interferons can lead to abnormal laboratory findings, it is proposed that, apart from the laboratory tests usually required for monitoring MS patients, regular checks of complete blood cell counts, with differential white blood cell counts, and platelet counts be carried out following the introduction of Betaferon therapy, and then periodically thereafter in the absence of clinical symptoms.
Patients who develop neutropaenia should be monitored closely for the development of fever or infection.
Patients with anaemia, thrombocytopaenia, leukopaenia (alone or in combination) may require more extensive monitoring of complete blood counts, with differential and platelet counts.

Endocrine function.

Thyroid function tests are recommended regularly in patients with a history of thyroid dysfunction or as clinically indicated.

Cardiac disorders.

Betaferon should be used with caution in patients with pre-existing significant cardiac disease such as congestive heart failure, coronary artery disease or arrhythmias. These patients should be monitored for worsening of their cardiac condition. This applies particularly during initiation of treatment with Betaferon, where flu-like symptoms, commonly associated with beta interferons, exert cardiac stress through fever, chills and tachycardia. This may aggravate cardiac symptoms in patients with pre-existing significant cardiac disease. Such patients should be closely observed for worsening of their cardiac disease during therapy with Betaferon.
During the postmarketing period very rare reports have been received of worsening of cardiac status in patients with pre-existing significant cardiac disease, temporally associated with the initiation of Betaferon therapy. Rare cases of cardiomyopathy have been reported; if this occurs and a relationship to Betaferon is suspected, treatment should be discontinued.

Skin and appendages.

Injection site necrosis (ISN) has been reported in patients using Betaferon (see Section 4.8 Adverse Effects (Undesirable Effects)). It can be extensive and may involve muscle fascia as well as fat and, therefore, can result in scar formation. Occasionally debridement and, less often, skin grafting are required and healing may take up to 6 months.
If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with their physician before continuing injections with Betaferon.
If the patient has multiple lesions Betaferon should be discontinued until healing has occurred. Patients with single lesions may continue on Betaferon provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Betaferon.
To minimise the risk of injection site necrosis patients should be advised to: use an aseptic injection technique; rotate the injection sites with each dose.
The incidence of injection site reactions may be reduced by the use of an autoinjector. In the pivotal study of patients with a single clinical event suggestive of multiple sclerosis an autoinjector was used in the majority of patients. Injection site reactions as well as injection site necroses were observed less frequently in this study than in the other pivotal studies.
The procedure for the self administration by the patient should be reviewed periodically especially if injection site reactions have occurred.

Use in hepatic impairment.

Hepato-biliary disorders.

Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with Betaferon during clinical trials. Rare cases of severe hepatic injury, including cases of hepatic failure have been reported.
The most serious events often occurred in patients exposed to other drugs or substances known to be associated with hepatotoxicity or in the presence of co-morbid medical conditions (e.g. metastasising malignant disease, severe infection and sepsis, alcohol abuse). Patients should be monitored for signs of hepatic injury.
The occurrence of elevations in serum transaminases should lead to close monitoring and investigation, including liver function tests (e.g. AST (SGOT), ALT (SGPT) and γ-GT), which are recommended at regular intervals following the introduction of Betaferon therapy, and then periodically thereafter in the absence of clinical symptoms.
Withdrawal of Betaferon should be considered if the levels significantly increase or if they are associated with clinical symptoms suggesting the development of hepatitis, e.g. jaundice. In the absence of clinical evidence for liver damage and after normalisation of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.

Use in renal impairment.

In patients with renal impairment, renal function should be monitored carefully when such patients receive Betaferon therapy.

Thrombotic microangiopathy and haemolytic anaemia.

Cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, as well as cases of haemolytic anaemia not associated with TMA, have been reported with interferon beta therapy, including life-threatening and fatal cases (see Section 4.8 Adverse Effects (Undesirable Effects)). Cases have been reported several weeks to years after starting interferon beta products.
Monitoring of early symptoms in all patients is recommended, e.g. new onset hypertension, impaired renal function and thrombocytopenia. Prompt treatment is required and discontinuation of 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 therapies (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 interferon should be considered.

Use in the elderly.

No data available.

Paediatric use.

Efficacy and safety of Betaferon has not been investigated in children and adolescents less than 18 years of age.

Effects on laboratory tests.

At the recommended dose, leukopaenia (lymphopaenia, neutropaenia), thrombocytopaenia, anaemia or elevated SGPT, SGOT, γ-GT may be seen.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been carried out with Betaferon, the effect of Betaferon on drug metabolism in MS patients is unknown.
Corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been well tolerated in patients receiving Betaferon. However, in the clinical trials, patients receiving Betaferon had a significantly reduced steroid usage compared with placebo patients.
Due to the lack of clinical experience in MS patient's use of Betaferon together with immunomodulators other than corticosteroids or ACTH is not recommended.
Interferons have been reported to cause a down regulation of hepatic cytochrome P450 dependent enzymes in humans and animals. Caution should be exercised when Betaferon is administered in combination with drugs that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance. Caution should be exercised with any comedication which has an effect on the haematopoietic system.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in rhesus monkeys at doses up to 10.7 million IU/kg/day SC showed no effects on menstrual cycle or hormone profiles, however, there have been no animal studies investigating effects on fertility. It is not known whether Betaferon can affect human reproductive capacity.
(Category D)
Betaferon was not teratogenic in rhesus monkeys at doses up to 13.3 million IU/kg/day SC, but demonstrated an abortifacient activity when administered at doses ranging from 0.89 to 24 million IU/kg/day. It is not known whether interferon beta-1b can cause foetal harm when administered to a pregnant woman or can affect human reproductive capacity. Data from pregnancy registries and post-marketing experience on the use of Betaferon in pregnant women (exposures mostly during the first trimester) suggest that frequencies of miscarriage and congenital abnormalities were comparable with the estimated background risk in the general population. Miscarriages have been reported in subjects with MS in controlled clinical trials with incidence rates not exceeding those in the general population. Therefore, women of child-bearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking interferon beta-1b, she should be informed of the potential hazards and discontinuation of therapy should be considered; the benefits and possible risks of continuing Betaferon therapy are recommended to be weighed. The individual disease severity and the potential detrimental effects that could occur if medication is stopped should be discussed with the patient.
It is not known whether interferon beta 1b is excreted in the human milk. A potential risk to the breastfed child cannot be excluded. A decision should be made whether nursing or the drug should be discontinued, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Experience with interferon beta-1b in patients with MS is limited, consequently adverse events with low incidence may not yet have been observed. Table 2 lists the adverse experiences reported at an incidence of ≥ 2% by 124 relapsing remitting MS patients receiving 8 million IU of Betaferon in multicentre clinical trials conducted in the United States and Canada. The adverse events reported in the secondary progressive study (360 patients) were consistent with the known side effect profile; the most frequently reported adverse events reported in this study are shown in Table 3.
Injection site reactions occurred frequently after administration of Betaferon. Redness, swelling, discolouration, inflammation, pain, hypersensitivity, necrosis, and non-specific reactions were significantly associated with 8 million IU Betaferon treatment. Lymphadenopathy has also been reported. The incidence rate of injection site reactions usually decreased over time.
Flu-like symptom complex (fever, chills, arthralgia, headache or myalgia, malaise, or sweating) has been seen frequently. The incidence rate of the symptoms decreased over time. Generally, dose titration is recommended at the start of treatment (see Section 4.2 Dose and Method of Administration). Flu-like symptoms may also be reduced by administration of nonsteroidal anti-inflammatory drugs.
The most serious adverse reaction reported are thrombotic microangiopathy (TMA) and haemolytic anaemia (HA).
Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon should be discontinued and appropriate medical intervention instituted.

Serum neutralising antibodies.

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlled clinical trials were collected every 3 months (in the study of patients with a single clinical event suggestive of MS every 6 months) for monitoring of development of antibodies to Betaferon. In the different controlled clinical trials in relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis, between 23% and 41% of the patients developed serum interferon beta-1b neutralising activity confirmed by at least two consecutive positive titres; of these patients, between 43% to 55% converted to a stable antibody negative status (based on two consecutive negative titres) during the subsequent observational period of the respective study.
No consistent attenuating effects on clinical outcomes have been demonstrated related to the presence of neutralising antibodies, across studies, endpoints, different statistical approaches and varying definitions of neutralising antibody positive status. Adverse events have not been associated with the development of neutralising activity.
In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at least once in 32% (89) of the patients treated immediately with Betaferon; of these, 60% (53) returned to negative status based on the last available assessment within the five year period. Within the study period of five years, the development of neutralising activity was not associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), time to confirmed EDSS progression and relapse rate.
The decision to continue or discontinue treatment should be based on all aspects of the patient's disease status rather than on neutralising activity status alone.
See Table 4.

Post marketing information.

Anecdotal evidence from post marketing experience suggests that systemic flu-like symptoms can be substantially suppressed by the concomitant administration of paracetamol or ibuprofen.
The following adverse reactions have been reported at the approximate frequencies (not necessarily implicating a causal relationship) indicated below:
Very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000 and < 1/1,000; very rare: < 1/10,000. See Table 5.
Capillary leak syndrome in pre-existing monoclonal gammopathy, hepatic failure and drug-induced lupus erythematosus has been reported in postmarketing surveillance. The frequency cannot be estimated from the available data and is therefore unknown.

Reporting suspected adverse 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. In Australia, healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. In New Zealand, healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Interferon beta-1b has been given without serious adverse events compromising vital functions to adult cancer patients at individual doses as high as 5.5 mg (176 million IU) i.v. three times a week. There have been no reported cases of accidental overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
For advice on the management of overdose please contact the National Poisons Centre (New Zealand) on 0800 POISON (0800 764766).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: Cytokines, interferons.
ATC code: L03AB08.
Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons have molecular weights ranging from 15,000 to 21,000 daltons. Three major classes of interferons have been identified: alpha, beta and gamma. Interferon alpha, interferon beta and interferon gamma have overlapping yet distinct biologic activities. The activities of interferon beta-1b are generally species restricted and, therefore, the most pertinent pharmacologic information on interferon beta-1b is derived from studies of human cells in culture or in human in vivo studies.
Betaferon has been shown to possess both antiviral and immunoregulatory activities. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis (MS) are not clearly understood. However, it is known that the biological response modifying properties of interferon beta-1b are mediated through its interaction with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces the expression of a number of gene products that are believed to be the mediators of the biological actions of interferon beta-1b.
A number of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b. Interferon beta-1b both decreases the binding affinity and enhances the internalisation and degradation of the interferon-γ receptor. Interferon beta-1b also enhances the suppressor activity of peripheral blood mononuclear cells.

Clinical trials.

Relapsing remitting multiple sclerosis.

Betaferon was shown to reduce the frequency and severity of clinical relapses, to reduce the number of MS related hospitalisations and steroid usage and to prolong the exacerbation free time in patients with both relapsing remitting multiple sclerosis (EDSS 0-5.5) and secondary progressive multiple sclerosis (EDSS 3.0-6.5).
Furthermore, Betaferon has a significant beneficial effect on disease burden and activity as measured by magnetic resonance imaging (MRI); an increase in MRI disease burden has been demonstrated to correlate with an increase in disability as measured by expanded disability status scale (EDSS).

Secondary progressive multiple sclerosis.

Patients with secondary progressive disease receiving Betaferon showed a delay of up to 12 months in time to progression of disability including time to severely disabling stages, i.e. patients becoming wheelchair bound. This delay in disability occurred in patients with or without relapses and at all levels of disability investigated (EDSS 3-6.5).

Single clinical event suggestive of multiple sclerosis.

One multi-centred, randomised, placebo controlled, double blind, clinical efficacy and safety study (BENEFIT) was performed in patients with a single clinical demyelinating event suggestive of MS and at least two clinically silent magnetic resonance imaging (MRI) lesions characteristic of MS. The study enrolled patients within 60 days after the onset of a single clinical event suggestive of MS, based on the appearance of a new neurological abnormality which had to be present for at least 24 hours. The T2 weighted brain MRI scan had to show at least two clinically silent lesions with a size of at least 3 mm, at least one of which had to be ovoid or periventricular or infratentorial. Patients were aged 18 to 45 years with an EDSS of < 5.0. Patients with monofocal or multifocal onset of the disease were included (i.e. patients with clinical evidence of a single or at least two lesions, respectively, of the central nervous system). Patients with any disease other than multiple sclerosis that could better explain the signs and symptoms had to be excluded.
This study consisted of two phases, a placebo controlled phase followed by a preplanned follow-up phase. The placebo controlled phase lasted for 2 years or until the patient developed clinically definite multiple sclerosis (CDMS), whichever came first. After the placebo controlled phase, patients entered a preplanned follow-up phase with Betaferon to evaluate the effects of immediate versus delayed start of Betaferon treatment, comparing patients initially randomised to Betaferon ("immediate treatment group") or to placebo ("delayed treatment group"). Patients and investigators remained blinded to the initial treatment allocation.
The two primary efficacy variables were time to onset of clinically definite MS (CDMS) and time to onset of MS according to McDonald diagnostic criteria. Clinically definite MS was reached if the patient experienced a relapse of the disease, or a sustained progression of ≥ 1.5 points on the EDSS scale as compared to the lowest EDSS obtained during the screening on day 1, reaching a total EDSS score of ≥ 2.5. Multiple sclerosis according to the McDonald criteria was reached if, in addition to the single clinical demyelinating event, both dissemination in space and dissemination in time had been established.
Patients selected for the study were randomized to treatment with either 0.25 mg (8 million IU) Betaferon (n = 292) or placebo (n = 176) self administered subcutaneously every second day for a treatment duration of up to 2 years.
In the placebo controlled phase, Betaferon delayed the progression from the first clinical event to CDMS in a statistically significant and clinically meaningful manner compared with placebo, corresponding to a risk reduction of 47% (hazard ratio = 0.53; 95% confidence interval [0.39, 0.73], p < 0.0001). A post hoc analysis adjusting for standard baseline covariates revealed a risk reduction by 50%. Within two years, CDMS occurred in 45% of the placebo group compared to 28% of the Betaferon group (Kaplan-Meier estimates). Betaferon prolonged the time to CDMS by 363 days, from 255 days in the placebo group to 618 days in the Betaferon group (based on 25th percentiles).
Betaferon also statistically significantly delayed the progression to MS according to the McDonald criteria compared with placebo, corresponding to a risk reduction of 43% (hazard ratio = 0.57; 95% confidence interval [0.46, 0.71], p < 0.00001). In the first six months, a diagnosis of MS according to the McDonald criteria was made in 51% of placebo and 28% of Betaferon patients, and after two years, the respective incidences were 85% and 69% (Kaplan-Meier estimates).
After the placebo controlled phase, patients entered a preplanned follow-up phase with Betaferon to evaluate the effects of immediate versus delayed start of Betaferon treatment, comparing patients initially randomised to Betaferon ("immediate treatment group") or to placebo ("delayed treatment group"). Patients and investigators remained blinded to the initial treatment allocation. The two analyses at three and five years include integrated data of the placebo controlled and the follow-up phase for the first three years and the entire five year observation period, respectively.
Immediate Betaferon treatment delayed the progression from the first clinical event to CDMS in a statistically significant and clinically meaningful manner. At three years, the risk for CDMS was 51% in the delayed treatment group compared to 37% in the immediate treatment group (log rank p = 0.0011). At the end of the five year observation period, the risk for CDMS was 57% in the delayed treatment group and 46% in the immediate treatment group (log rank p = 0.0027) (Kaplan-Meier estimates, see Figure 1). The majority of patients from the original placebo group were treated with Betaferon from the end of the second year.
At three years the risk (Kaplan-Meier estimates, see Figure 2) for disability progression (as measured by EDSS progression) was 24% in the delayed treatment group and 16% in the immediate treatment group (log rank p = 0.0218). Over five years the risk (Kaplan-Meier estimates) for disability progression was not statistically significantly different (log rank p = 0.177) between delayed (29%) and immediate (25%) treatment groups.
Two MRI derived parameters, the cumulative number of newly active lesions and the change in T2 lesion volume, were analysed as secondary efficacy variables. The cumulative number of newly active lesions up to end of study was statistically significantly lower in the Betaferon group when nonannualised (median number of newly active lesions was 4.0 for Betaferon and 7.0 for placebo) values were considered (p = 0.00602). The T2 lesion volume reduction up to the last scan was not statistically significantly different between the groups.
In a questionnaire assessing health related quality of life as reported by the patient (Functional Assessment of MS), scores remained high and stable throughout the five years, significant differences between the two treatment groups could not be demonstrated.

5.2 Pharmacokinetic Properties

Because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 8 million IU (0.25 mg) or less of interferon beta-1b, pharmacokinetic information in patients with MS receiving the recommended dose of interferon beta-1b is not available.

Absorption.

Following single and multiple daily subcutaneous administration of 16 million IU (0.5 mg) interferon beta-1b to healthy volunteers, interferon beta-1b concentrations in serum were generally below 100 IU/mL. Peak serum interferon beta-1b concentrations occurred between 1 to 8 hours, with a mean peak interferon concentration in serum of 40 IU/mL. Bioavailability, based on a total dose of 16 million IU (0.5 mg) interferon beta-1b given as two subcutaneous injections at different sites, was approximately 50%.
After intravenous administration of interferon beta-1b in a dosage range of 0.2 million IU (0.0006 mg) to 64 million IU (2.0 mg), similar pharmacokinetic profiles were obtained from healthy volunteers and from patients with diseases other than MS. In patients receiving single intravenous doses of up to 64 million IU (2.0 mg), increases in serum concentrations were dose proportional. Mean serum clearance values of up to 28.9 mL/min.kg-1 were observed.

Excretion.

Mean terminal elimination half-life and steady-state volume of distribution were estimated to be at most 4.3 hours and 2.88 L/kg. Three times a week intravenous dosing for 2 weeks resulted in no accumulation of interferon beta-1b in the serum of patients. Pharmacokinetic parameters after single and multiple intravenous doses of interferon beta-1b were comparable.
Following every other day subcutaneous administration of 0.25 mg (8 million IU) of interferon beta-1b in healthy volunteers, biologic response marker levels (neopterin, β2-microglobulin and the immunosuppressive cytokine, IL-10) increased significantly above baseline levels within 6 to 12 hours after the first Betaferon dose. Biologic response marker levels peaked between 40 and 124 hours, and remained above baseline throughout the seven day (168 hour) study period. The relationship between serum interferon beta-1b levels or the levels of induced biologic response markers to the mechanism by which Betaferon exerts its effects in MS is unknown.

5.3 Preclinical Safety Data

Although acute toxicity studies have not been carried out, an experimental primate study using daily intravenous and subcutaneous administration did not reveal any untoward acute effects of treatment. This study showed a potential for interferon beta-1b treatment to elicit transient pyrogenic and haematological effects, including neutropaenia and thrombocytopaenia. Pronounced thrombocytopaenia or anaemia was seen in some pregnant experimental primates after daily treatment with high doses of interferon beta-1b (8 million IU/kg and above). The long-term toxicity of interferon beta-1b has not been investigated in any experimental species.
Based on experiments using other interferons, a potential risk of impaired male and female fertility cannot be ruled out.
Specific testing for contact sensitivity was not carried out, but delayed type hypersensitivity reactions specific for interferon beta-1b were not seen in experimental primates after daily intravenous or subcutaneous administration. However, serum anti-interferon beta-1b antibodies were measurable in these animals.

Genotoxicity.

Interferon beta-1b was inactive in a bacterial gene mutation assay, and in a short-term assay for mammalian cell transformation in vitro. No mutagenic effect has been observed in a genotoxicity study (Ames test).

Carcinogenicity.

Long-term in vivo studies for tumourigenic potential have not been carried out.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients (powder for solution for injection).

Human albumin and mannitol.

Excipients (solvent for solution for injection).

Sodium chloride and water for injection.

6.2 Incompatibilities

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

6.3 Shelf Life

The product as packaged for sale: 24 months.
After reconstitution according to directions: up to 3 hours.

6.4 Special Precautions for Storage

The product as packaged for sale: below 25°C.
After reconstitution according to directions: 2 to 8°C.

6.5 Nature and Contents of Container

3 mL clear glass vial with a 13 mm butyl rubber stopper and aluminium overseal containing powder for solution for injection.
Each Betaferon vial is provided with a separate 2.25 mL pre-filled syringe of diluent, containing 1.2 mL of sterile sodium chloride solution (0.54% w/v). Each vial contains 0.3 mg (9.6 million IU) of interferon beta-1b at a calculated overfill of 20% allowing extraction of the nominal content of 8 million IU (0.25 mg) in 1 mL after reconstitution with 1.2 mL of diluent.
Multipack comprising 15 single use packs, each containing 1 Betaferon vial with powder, 1 pre-filled syringe with diluent, 1 vial adapter with needle, and 2 alcohol wipes.

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.

Due to the complex nature of Betaferon, its structure has not been included.

CAS number.

CAS registry no: 145155-23-3.

7 Medicine Schedule (Poisons Standard)

S4, Prescription Only Medicine.

Summary Table of Changes