BETAFERON®

Interferon beta-1b 0.25 mg in 1 mL - Subcutaneous Injection

What is in this leaflet

This leaflet has been written to provide you with some background information on BETAFERON and how you should use this medicine. Your doctor and pharmacist have detailed information on BETAFERON, they are trained to help you to understand why you are taking this medicine.

Read this information carefully before you start taking BETAFERON. Keep this leaflet in a handy place; you may wish to refer to it again. Please contact your doctor, clinic or pharmacist if you have any questions about your treatment with BETAFERON or if you have any problems or difficulties before, during or after taking BETAFERON.

It is important to remember that BETAFERON is a PRESCRIPTION ONLY MEDICINE - you should only use BETAFERON as directed by your doctor.

What is BETAFERON used for and how does it work

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) (i.e. brain and spinal cord) and its exact cause 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.

Interferon beta-1b has been shown to change the immune system response.

Interferons are part of a group of substances called cytokines, which are naturally occurring proteins.

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.

BETAFERON is for use in patients who are able to walk and who have relapsing-remitting multiple sclerosis. 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 is also for use in patients with secondary progressive multiple sclerosis. This is the form of multiple sclerosis where patients progressively experience deterioration of signs and symptoms. In patients with this type of MS BETAFERON has been shown to slow down the progression of the disease for up to 12 months. This delay occurred in patients with or without relapses and with all levels of disability.

In people with both types of multiple sclerosis, BETAFERON has been shown to reduce how often attacks occur, to decrease the severity of the attacks, to increase the time between attacks and to lower the number of times people need to be hospitalised because of attacks.

Also, 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.

Before you use BETAFERON

You must not use BETAFERON if:

• you are allergic to interferon-beta or human albumin or any other ingredient of the preparation
• you are pregnant or if you are trying to become pregnant
• you have liver failure
• you suffer from epilepsy (fits or seizures) which is not controlled by other medicines

Tell your doctor if:

• you wish to become pregnant while using BETAFERON. While using BETAFERON women of child-bearing age should take appropriate contraceptive measures. If you do become pregnant you should stop your treatment and contact your doctor immediately.
• you wish to breastfeed
• you have had any fits or seizures
• you have been or are depressed or have had thoughts of suicide
• you have any heart problems
• you are taking other medicines used to control attacks of MS, as use with such medicines (other than prednisone/prednisolone/ACTH) is not recommended.
• you are taking any other medicines as care must be taken when BETAFERON is used with some other medicines. These medicines include some widely used medicines used to treat fever and pain, fits and seizures.
• you have any blood disorders
• you have a bone marrow disorder
• you have a pre-existing rare disturbance of the immune system where abnormal proteins are found in the blood (monoclonal gammopathy)
• you have had pancreatitis
• you have an increase of blood fats (triglycerides)
• you have kidney disease
• you have a break in the skin, which may be associated with swelling or drainage of fluid from the injection site

What else you should know

BETAFERON and Other Medicines

With the exception of corticoids or ACTH (anti-inflammatory medicines) BETAFERON was not studied with the co-administration of substances that modify the immune system response.

BETAFERON and Depression

Depression and suicidal thoughts have been reported by patients using BETAFERON. Even though in the clinical studies there were no significant differences between BETAFERON patients and those who did not receive BETAFERON in terms of depression and suicidal thoughts, an association cannot be ruled out in individual patients and you should contact your doctor promptly if you are depressed or have suicidal thoughts.

BETAFERON and Pregnancy

You should avoid becoming pregnant while using BETAFERON and therefore, should take appropriate contraceptive measures. If you wish to become pregnant, first discuss the matter with your doctor. If you do become pregnant while using BETAFERON, you should stop your treatment and contact your doctor immediately.

It is not known if BETAFERON can cause harm to the fetus or decrease your ability to have children in the future.

BETAFERON and Breast-feeding

It is not known whether interferon beta-1b in BETAFERON is transferred to breast milk. However, since serious adverse reactions are possible, you should discuss this with your doctor to make a decision whether breast-feeding or BETAFERON should be stopped.

BETAFERON and Ability to Drive and Use Machines

BETAFERON might influence the ability to drive and use machines in susceptible patients but this has not been investigated.

BETAFERON and Children/Adolescents

You should be aware that BETAFERON has not been investigated in children and adolescents under 18 years of age.

BETAFERON and the Immune System

During treatment with BETAFERON your body may produce neutralizing antibodies. It has been shown in different controlled clinical studies that in 23% to 41% of the patients such antibodies were produced. In 43% to 55% of the patients who develop such antibodies they disappeared during the further course of treatment with BETAFERON. In the study with a single clinical event neutralizing antibodies were produced in 16.5% to 25.2% of the patients. Neutralizing activity was found at least once in 30% of the BETAFERON treated patients and in 23% of these patients the antibodies disappeared before the end of the study.

At present, no consistent effects of such antibodies on treatment efficacy have been noted. Adverse events have not been associated with the development of neutralizing activity.

It is suggested that the decision to continue treatment with BETAFERON in patients who develop antibodies should be based on clinical disease activity and not antibody status.

BETAFERON and Other Conditions

BETAFERON contains a protein (albumin) extracted from blood and so carries a very remote risk of transmission of viral diseases. A theoretical risk for transmission of a disease affecting the nervous system (Creutzfeldt-Jakob disease) is also considered extremely remote.

If the levels of some of your liver enzymes called transaminases, which are measured in your blood, increase, your doctor will monitor and investigate you closely for any sign of injury to your liver during your treatment. If the levels of transaminases in your blood increase significantly, your doctor will consider stopping your treatment with BETAFERON.

Thyroid function tests are recommended in patients with a history of thyroid dysfunction. If you suffer from anemia, a low platelet level, or low white blood cells, this may require more intensive monitoring.

Injection site necrosis (skin breakdown and tissue destruction) has been reported in patients using BETAFERON. It can be extensive and may involve muscle fascia as well as fat and can therefore result in scar formation. Occasionally debridement and, less often, skin grafting are required and healing may take up to 6 months.

If you experience any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, you should consult your doctor before continuing injections with BETAFERON.

If you have multiple lesions BETAFERON should 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 whilst on BETAFERON.

To minimize the risk of injection site necrosis you should:

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

Injection site reactions may occur less frequently when using an auto-injector.

The procedure for self-administration should be reviewed periodically by your physician especially if injection site reactions have occurred.

How to use BETAFERON properly

The treatment with BETAFERON should be started under the supervision of a specialist doctor experienced in the treatment of your disease.

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

Before administration, the BETAFERON solution for injection has to be prepared from a vial of BETAFERON and 1.2 mL of liquid from a pre-filled syringe of diluent. 1.0 mL of the prepared BETAFERON solution for injection is then injected subcutaneously (under the skin) every other day. This is equal to 0.25 mg (8 million IU) Interferon beta-1b.

For those patients who for the first time have experienced symptoms which indicate a high risk for development of multiple sclerosis, treatment should be started at a low dose of 0.25 mL (0.0625 mg). The dose should be increased at every fourth injection in four steps (0.25 mL, 0.5 mL, 0.75 mL up to a final dose of 1.0 mL (0.25 mg) which is equal to 8 million IU. The timing of the dose increase may be modified depending on side effects you may experience at the start of treatment, your doctor will decide this together with you.

You will need to be carefully instructed and trained in the self-injection technique. The instructions below tell you how the BETAFERON solution for injection is prepared.

To reduce the risk of the injection solution becoming contaminated it should be used as soon as possible after it is prepared. If this is not possible and storage is necessary, keep the made-up BETAFERON in the refrigerator (not freezer) at 2°C to 8°C and use within 3 hours of preparation.

Self-injection Procedure

The following instructions are intended to explain how to prepare BETAFERON for administration and how to proceed in injecting BETAFERON yourself. Please read the instructions carefully and follow them step by step. It is important to wash your hands thoroughly with soap and water before beginning. Do not attempt self-administration until you are sure that you understand the requirements of preparing the injection solution and giving the injection to yourself. The instructions comprise the following main steps:

I. Preparing for self-injection

II. Injecting the required volume of diluent (1.2 mL) into the vial of BETAFERON

III. Drawing up the required volume of the solution for injection (1.0 mL) into the
syringe

IV. Choosing and preparing the injection site and injecting the BETAFERON
solution (1.0 mL) subcutaneously (under the skin)

I. Preparing for self-injection

Collect all your equipment before you begin the process

You will need:

• pre-filled syringe of diluent for BETAFERON (sodium chloride solution 0.54 %)
• vial of BETAFERON
• 23-gauge needle (blue)
• 1 mL insulin syringe (orange cap) with 29-gauge needle attached
• pouch containing Auto-injector device
• sharps waste container (for used needles)
• alcohol wipes

Wash your hands thoroughly with soap and water

Prepare the Auto-injector using the following instructions.

Preparing the Auto-injector

1. Unzip the pouch and take everything out. Inside you will find two depth adjusters, a yellow primer and two halves of the "Autoject 2" device.
2. The Auto-injector consists of an injector body and a narrower end called the syringe housing.
3. Take the smaller depth adjuster and screw this onto the narrow end of the Auto-injector syringe housing. You will notice some lines with letters of the alphabet. Screw in the depth adjuster until you reach the letter "q". It should appear that the letter "q" is cut in half.
4. You now need to prime the Auto-injector. Take the yellow primer and insert either end into the depth adjuster which you have just screwed into the narrow end of the syringe housing.
5. Take the injector body in one hand. Then turn the narrow end of the syringe housing with the yellow primer protruding around so that the yellow primer rests against the yellow spring cover in the injector body. Push it in firmly all the way so that the spring stays compressed at the end of the injector body. You will feel it click into place.
6. Separate the two halves of the Auto injector. Pull out the yellow primer and check the depth adjuster is still on the letter "q".
7. Set the two halves to one side. Your Auto-injector is now primed and ready for use.

II. Injecting the required volume of diluent (1.2 mL) into the vial of BETAFERON.

1. Remove the protective cap from the vial of BETAFERON by flipping this off with your thumb.
2. Use the alcohol wipe to clean the top of the BETAFERON vial - move in one direction and use one wipe. Flip over the alcohol wipe and leave on top of the vial until you are ready to use it.
3. Open the packet of the 23-gauge needle. Do not take it out of its wrapper. Place the needle down.
4. Resting your hands on a stable surface, take the pre-filled diluent syringe from its wrapper by peeling back the paper at the plunger end and remove the syringe from its plastic casing. Discard wrapping. Hold the barrel of the syringe and firmly pull/twist off the grey rubber cap from the tip of the syringe. Be careful not to touch the exposed end of the syringe. Do not push the plunger.
5. Holding the syringe like a pencil, take the blue 23-gauge needle out of its wrapper. Ensure you do not touch the blue end of the needle with your fingers and slide firmly onto the tip of the syringe. It does not screw on. Hold the syringe and needle vertically with the tip pointing upwards.
6. Holding the needle on with one hand, gently tap the syringe to release any air bubbles. Still holding the needle on, push the plunger up to the 1.2 mL mark to remove the air bubbles from the syringe. Do not be concerned if a little fluid comes out the end of the needle into the clear plastic needle guard. Remove the needle guard from the needle, being careful not to touch the needle.
7. Holding the BETAFERON vial on a stable surface (e.g. with your elbows resting firmly on a table), slowly insert the needle all the way through the stopper of the vial. Do not hold the plunger at this time. If required, a MAGNAGUIDE^® device is available from this step on to help support the vial and read the syringe markings until you have drawn up the required volume for injection. Please ask your instructor for a demonstration.
8. Push the plunger down slowly, directing the needle toward the side of the vial to allow the liquid to run down the inside wall (injecting diluent directly onto the powder will cause excess foaming). Make sure that the needle does not come into contact with the powder.
9. After the diluent in the syringe has been completely injected into the BETAFERON vial, remove the needle and empty syringe. Place the needle in the sharps waste container provided.
10. Hold the vial between your thumb, forefinger and middle finger. Gently roll or rotate your fingers to completely dissolve the white powder of BETAFERON. DO NOT SHAKE!
11. Look closely at the solution (it should be clear). NOTE: If the mixture contains particles or is discoloured, throw it away and start again.

III. Drawing up the required volume of the solution for injection (1.0 mL) into the syringe.

1. Take the 1 mL insulin syringe, remove the wrapper from the plunger end and take the orange needle guard off. (Keep the orange needle guard - in case you need to recap the syringe later). Pull the plunger back to the 1.0 mL (or 100 units) mark.
2. Insert the needle through the centre of the rubber bung into the BETAFERON vial containing the reconstituted solution and carefully push the plunger in all the way.
3. Turn the vial of BETAFERON solution upside down and keep the needle tip at the lowest point of the vial. The needle should protrude into the neck of the vial for 3-4 mm only. This is to ensure that the needle stays below the level of the fluid at all times.
4. Withdraw the plunger slowly back to withdraw 1 mL of liquid.
5. Tap, or flick, the syringe gently with your finger until any air bubbles rise to the top. Gently push the plunger to eject ONLY THE AIR through the needle. Ensure that 1 mL of liquid remains in the syringe.
6. Withdraw the needle and syringe. Discard the empty BETAFERON vial.
7. The preloaded syringe is now ready to place in the Auto-injector. Pick up the narrow end of the Auto-injector and carefully slide the full syringe (needle-end first) into the wide end of the syringe housing. The guides on the syringe barrel should come to rest on the inside of the Auto-injector with the plunger protruding. Take care not to touch the inside wall of the Auto-injector with the bare needle.
8. Take the injector body and screw the two halves of the Auto-injector together so the full syringe is now inside the device.

IV.Choosing and preparing the injection site and injecting the BETAFERON solution (1.0 mL) subcutaneously (under the skin).

Picking an Injection Site

BETAFERON (Interferon beta-1b) should be injected into subcutaneous (under the skin) tissue. The best places for injection are loose and soft (flabby) areas, away from joints and nerves. Try to avoid the panty or belt line at the waist and the seat portion of your buttocks as daily activity may irritate these areas. It's a good idea to know where your injection will be given before you prepare your syringe. If there are any sites that are difficult for you to reach, you can ask your support person (or someone who has been trained to give injections) to help you.

Rotating Injection Sites

Changing sites each time helps prevent injection site reactions; it gives the site time to "bounce back" from the last injection. Today's injection should not be given in the same area as the last one. Keep a record of where and when you last gave yourself an injection. One way to do that is to note this information on the medication record card enclosed with each box of BETAFERON. By following this schedule you will come back to your first area after 8 injections (16 days). You should still try not to use the same section of that area for your next injection. If the areas described become tender, talk to your doctor about choosing other injection sites.

1. Choose an injection site (see enclosed medication record card with an injection site diagram). Use a different site each time you inject:
   • Arms (upper back portion)
   • Abdomen (except around navel and waistline)
   • Buttocks
   • Thighs (front and sides except at groin and knee)

   NOTE: Do not use any areas in which you feel lumps, firm knots, depressions or pain. Do not use any area in which the skin is discoloured, scabbed or has broken open. Talk to your doctor or health care professional about anything you may find.

2. Pick up the prepared Auto-injector and check that the depth adjuster has remained on the letter "q".
3. Pinch the skin together around the site of the area to be injected (to lift it up a bit).
4. Hold the Auto-injector vertically with the narrow end against the skin and press down firmly so that the back half meets the front half. (Only 2 mm of the blue middle section should now be visible). This automatically releases the safety catch.
5. Press the button and count to five slowly (or time for 5 seconds). Ensure that the Auto-injector is held firmly against the skin in the compressed position for all of this time so as not to interrupt the flow of the medicine into the skin.
6. Set the Auto-injector down and gently massage the injection site with your fingers to disperse the fluid through the surrounding tissue. (You may use a dry cotton ball or gauze square if you wish.)
7. Dismantle the Auto-injector and replace in the blue pouch. Discard the used needle in the yellow sharps waste container provided.

Points to Remember

• If you forget to administer your injection at the correct time you should give it as soon as you remember. Your next injection should be given 48 hours later.

It is not necessary to store either the BETAFERON vials or the pre-filled diluent syringes in the refrigerator. In fact, it may be painful injecting a cold solution. These should be stored together with all your other equipment in a cool, safe place. However, it is important that the storage temperature does not exceed 25°C and a chilli-bin might be required for travelling in summer months.

• When making up your BETAFERON solution, ensure everything is kept clean and sterile at all times. If in any doubt, discard needles, syringes or solution and start again.
• Occasionally, your Auto-injector syringe housing (not the injector body) will need to be cleaned with boiling water.
• Choose the same time each treatment day to give your injection. Choose a time that is convenient for you.
• Make sure you take two paracetamol tablets prior to giving yourself the injection and another two at bedtime. You should do this for at least the first month to minimise flu-like symptoms such as fever and chills.
• You may ice the area before and after the injection, if you wish, to reduce pain and inflammation.
• If injecting into the leg, extend the leg out forward to reduce the chance of injecting into the muscle.

Overdose

Overdose is not generally serious. However, if you are concerned that you have given yourself too much BETAFERON or you have injected it too frequently (e.g. one injection every 24 hours instead of one injection every 48 hours) you should consult your doctor. BETAFERON has been given at many times the recommended dose for MS without serious consequence.

When Using BETAFERON

Tell your doctor immediately if:

• You experience depression or suicidal thoughts
• You experience symptoms like irregularity of your heart beat 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
• You think you may be pregnant. BETAFERON use must be stopped immediately
• You develop a disturbance of the immune system where abnormal proteins are found in the blood (monoclonal gammopathy)
• You suffer from severe hypersensitivity reactions such as difficulty in breathing, hives, shock

Tell your doctor if:

• You suffer from signs of frequent infections such as fever or sore throat
• You notice a yellowish change in the colour of your skin (jaundice)

Side Effects

Like all medicines, BETAFERON can have side effects although not every one gets them.

The most common side effects are:

• Flu-like symptoms (fever, chills, headache, muscular pain, painful joints, a general feeling of being unwell or sweating) have been seen frequently. The occurrence of these symptoms decreased over time.

Other relatively common side effects include:

• Injection site reactions including, redness, swelling, discolouration, inflammation, pain, allergy, skin cell-death where the injection was given, and nonspecific reactions occurred frequently but decreased over time.

Listed below are the side effects reported from post-marketing information and classified as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000) and very rare (< 1/10,000).

Blood and Lymphatic System Disorders

Uncommon

• Fall in the number of white and red cells in the blood
• Fall in the number of platelets in the blood

Rare

• Swollen lymph glands

Hormonal Disorders

Rare

• Thyroid gland does not work properly (too much/little hormone produced)

Psychiatric Disorders

Uncommon

• Depression

Rare

• Emotional instability or confusion
• Anxiety
• Suicide attempt

Nervous System Disorders

Rare

• Convulsions
• Dizziness

Heart and Blood Supply Disorders

Uncommon

• High blood pressure

Rare

• Disease of the heart muscle
• Faster heart beat
• Palpitations

Very rare

• Widening of the blood vessels

Metabolism and Nutrition Disorders

Uncommon

• The activity of the liver may be affected shown by rises in the blood levels of enzymes it produces
• Nausea
• Vomiting

Rare

• A specific liver enzyme (gamma T) and a reddish yellow pigment (bilirubin) may rise
• Hepatitis
• Diarrhea

Respiratory Disorders

Rare

• Bronchospasm
• Shortness of breath

Skin and Subcutaneous Tissue

Uncommon

• Loss of scalp hair
• Raised and itching patches of the skin or mucus membranes (urticaria)
• Puritus
• Rash

Rare

• Skin discolouration

Musculoskeletal Disorders

Uncommon

• Painful muscles
• Muscle spasms

Rare

• Bone pain

Reproductive System Disorders

Rare

• Menstrual disorders

Very rare

• Heavy Menstrual bleeding

General Disorders and Administration Site Conditions

Very common *

• Flu-like symptoms
• Chills
• Fever
• Injection site reaction
• Injection site inflammation
• Pain at the injection site

Common *

• Skin breakdown and tissue destruction (necrosis) at injection site

Rare

• Serious hypersensitivity reactions
• Malaise
• Chest pain

(*Frequencies based on clinical trials)

Other side effects may occur. If side effects are severe, or if you notice any other side effects, please tell your doctor.

Storage

BETAFERON must be kept below 25°C.

Store BETAFERON in a cool dry place before preparing the BETAFERON solution for injection. If, after preparation, you do not inject BETAFERON at once, you can store the reconstituted solution in a refrigerator (but not in a freezer or the freezing compartment) for up to 3 hours. Once you have given the injection, you should throw away any unused portion.

Please note the expiry date on the pack. Do not use after this date or if the contents do not look right.

Store all medicines properly and keep them out of the reach of children.

Further Information

The BETAFERON combi-pack contains:

15 vials of lyophilizate containing interferon beta-1b 0.25 mg (8.0 million IU), human albumin and mannitol.

15 pre-filled syringes of solvent containing sodium chloride and water for injection.

Should you wish to discuss any aspect of BETAFERON, you should contact your doctor or pharmacist.