Betaferon 250 micrograms/ml, powder and solvent for solution for injection

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Betaferon 250 micrograms/ml, powder and solvent for injectable solution

interferon beta-1b

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only, and you should not give it to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any adverse reactions, consult your doctor, pharmacist, or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

1. What Betaferon is and what it is used for
2. What you need to know before using Betaferon
3. How to use Betaferon
4. Possible side effects
5. How to store Betaferon
6. Contents of the pack and other information

Annex – procedure for self-injection

1. What Betaferon is and what it is used for

What Betaferon is

Betaferon is a type of medicine known as an interferon, used in the treatment of multiple sclerosis. Interferons are proteins produced by the body that help it fight attacks from the immune system, such as viral infections.

How Betaferon works

Multiple sclerosis (MS) is a chronic disorder affecting the central nervous system (CNS), particularly the functioning of the brain and spinal cord. In MS, inflammation destroys the protective covering (called myelin) that surrounds the nerves in the CNS, impairing proper nerve function. This is known as demyelination.

The exact cause of MS is unknown. It is thought that an abnormal immune response plays a key role in the process that damages the CNS.

Damage to the CNS can occur during an MS attack (relapse). It may cause temporary disability, such as difficulty walking. Symptoms may disappear completely or partially.

Interferon beta-1b has been shown to modify the immune response and help reduce disease activity.

How Betaferon helps fight your disease

Clinically isolated syndrome suggestive of a high risk of developing multiple sclerosis: Betaferon has been shown to delay progression to definite multiple sclerosis.

Relapsing-remitting multiple sclerosis: People with relapsing-remitting MS experience occasional attacks or relapses during which symptoms worsen significantly. Betaferon has been shown to reduce the number of attacks and make them less severe, reduce the number of hospitalizations due to the disease, and prolong the time free from relapses.

Secondary progressive multiple sclerosis: In some cases, people with relapsing-remitting MS notice that their symptoms increase and progress to another form of MS called secondary progressive MS. With this form, people become increasingly disabled, whether or not relapses occur. Betaferon may reduce the number and severity of attacks and delay the progression of disability.

What Betaferon is used for

Betaferon is for use in patients

?Who have experienced first-time symptoms indicating a high risk of developing multiple sclerosis. Your doctor will rule out other possible causes of these symptoms before starting your treatment.

?With relapsing-remitting multiple sclerosis, with at least two relapses having occurred within the previous two years.

?With secondary progressive multiple sclerosis, with active disease demonstrated by the occurrence of relapses.

2. What you need to know before using Betaferon

Do not use Betaferon

• If you are allergic (hypersensitive) to natural or recombinant interferon beta, human albumin, or any of the other components of this medicine (listed in section 6).
• If you currently have severe depression and/or suicidal thoughts (see also “Warnings and precautions” and section 4. “Possible side effects”).

– If you have severe liver disease (see “Warnings and precautions”, “Use of Betaferon with other medicines”, and section 4. “Possible side effects”).

? Inform your doctor if any of the above situations apply to you.

Warnings and precautions

Talk to your doctor before starting to use Betaferon:

• If you havemonoclonal gammopathy . This is an immune system disorder in which an abnormal protein is present in the blood. Problems may occur in the smallest blood vessels (capillaries ) when using medicines such as Betaferon (systemic capillary leak syndrome) . This may lead to shock (collapse) and can even be fatal.

• If you have had or currently have depression, or previously experienced suicidal thoughts. Your doctor will monitor you closely during treatment. If your depression and/or suicidal thoughts are severe, Betaferon will not be prescribed (see also “Do not use Betaferon”).

• If you have ever had seizures , or if you are taking medicines to treat epilepsy*(antiepileptics)* , your doctor will monitor your treatment carefully (see also “Use of Betaferon with other medicines” and section 4. “Possible side effects”).

• If you have severe kidney problems , your doctor may monitor your kidney function during treatment.

Your doctor should also be informed about the following conditions while you are using Betaferon:

• If you experience symptoms such as itching all over your body, swelling of the face and/or tongue, or sudden difficulty breathing. These may be signs of a serious allergic reaction (hypersensitivity) , which could become life-threatening.

• If you feel significantly sadder or more hopeless than before starting treatment with Betaferon, or if you have suicidal thoughts. If you become depressed while being treated with Betaferon, you may require special treatment, and your doctor will monitor you closely and may consider stopping your treatment. If you have severe depression and/or suicidal thoughts, you should not be treated with Betaferon (see also “Do not use Betaferon”).

• If you notice that you bruise easily, bleed excessively when injured, or get frequent infections. These may be signs of a reduced blood cell count or a low platelet count (cells that help blood to clot). You may need closer monitoring by your doctor.

• If you have loss of appetite, fatigue, dizziness(nausea) , repeated vomiting, especially if you also notice widespread itching, yellowing of the skin or the whites of the eyes, or easy bruising.** These symptoms may indicate liver problems. Changes in liver function test results have been observed in some clinical studies in patients treated with Betaferon. As with other beta interferons, severe liver damage, including cases of liver failure, has been reported in patients treated with Betaferon. The most severe cases occurred in patients who were taking other medications or had conditions that may affect the liver (e.g., alcohol abuse, serious infection).

• If you experience symptoms such as irregular heartbeat, swelling in the ankles or legs, or difficulty breathing. These may indicate a heart muscle disorder (cardiomyopathy) , which has been reported rarely in patients using Betaferon.

• If you experience abdominal pain radiating to your back, and/or dizziness or fever. This may indicate inflammation of the pancreas (pancreatitis) , which has been reported with the use of Betaferon. This is often associated with elevated levels of certain fats in the blood (triglycerides) .

? Stop using Betaferon and contact your doctor immediately if any of these occur.

Other things to consider when using Betaferon

• A blood test will be required to measure your blood cell counts, blood biochemistry, and liver enzymes. This will be done before you start using Betaferon, regularly after starting treatment, and periodically while continuing treatment, even if you have no specific symptoms. These blood tests will be in addition to the tests routinely performed to monitor your MS.

• If you have heart disease, flu-like symptoms, which commonly occur at the start of treatment, may place an additional strain on you. Betaferon should be used with caution, and your doctor will monitor for possible worsening of your heart condition, especially at the beginning of treatment. Betaferon itself does not directly affect the heart.

• Your thyroid gland function will be checked regularly or whenever your doctor considers it necessary for other reasons.

• Betaferon contains human albumin and therefore carries a potential risk of transmitting viral diseases . A risk of transmitting Creutzfeldt-Jakob disease (CJD) cannot be excluded.

• During treatment with Betaferon, your body may produce substances calledneutralizing antibodies, which may react with Betaferon (neutralizing activity) . It is not clear whether these neutralizing antibodies reduce the effectiveness of treatment. Neutralizing antibodies do not develop in all patients. Currently, it is not possible to predict which patients will develop them.

• During treatment with Betaferon, kidney problems may occur that may affect your kidney function, including scarring (glomerulosclerosis ). Your doctor may perform tests to monitor your kidney function.

• During treatment, blood clots may form in small blood vessels. These clots could affect your kidneys. This may occur several weeks or years after starting Betaferon treatment. Your doctor may want to monitor your blood pressure, blood (platelet count), and kidney function.

• During treatment, you may develop paleness, yellow skin, or dark-colored urine, possibly accompanied by unusual dizziness, tiredness, or difficulty breathing. These may be symptoms of red blood cell breakdown. This may occur several weeks or years after starting Betaferon treatment. Your doctor may perform blood tests. Inform your doctor about any other medicines you are taking at the same time as Betaferon.

Injection site reactions

During treatment with Betaferon, you are likely to experience injection site reactions. Symptoms include redness, swelling, skin discoloration, inflammation, pain, and tenderness. Less frequently, infections around the injection site, skin lesions, and tissue damage (necrosis) may occur. Injection site reactions usually become less frequent over time.

Skin lesions and tissue damage may result in scarring. If severe, a doctor may need to perform removal of foreign material and dead tissue (debridement) and, less frequently, a skin graft, with healing potentially taking up to six months.

To reduce the risk of injection site reactions such as infection or necrosis, you should:

• Use a sterile (aseptic) injection technique.
• Rotate injection sites with each injection (see Annex “Procedure for self-injection”, Part II, in the second part of this leaflet).

Injection site reactions may occur less frequently if you use an auto-injection device and rotate injection sites. Your doctor or nurse can provide further information on this.

If you experience a break in the skin, which may be associated with swelling or fluid leakage at the injection site:

• Stop Betaferon injections and contact your doctor.

? If you have a single ulcerated injection site*(lesion)and tissue destruction(necrosis)*is not extensive, you may continue using Betaferon.

? If you have more than one ulcerated injection site*(multiple lesions),* you must stop using Betaferon until your skin has healed.

Your doctor will regularly check your self-injection technique, especially if you have experienced injection site reactions.

Children and adolescents

Formal clinical trials have not been conducted in children or adolescents.

However, some data are available in children and adolescents aged 12 to 16 years. These data suggest that the safety profile in this age group is similar to that in adults when administering 8.0 million IU of Betaferon subcutaneously on alternate days. There is no information on the use of Betaferon in children under 12 years of age. Therefore, Betaferon should not be used in this population.

Other medicines and Betaferon

Tell your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines, including those obtained without a prescription.

No formal interaction studies have been conducted to determine whether Betaferon affects other medicines or is affected by them.

The use of Betaferon with other medicines that modify the immune system response is not recommended, except for anti-inflammatory medicines called corticosteroids or adrenocorticotropic hormone (ACTH) .

Betaferon should be used with caution with:

• Medicines that require a specific liver enzyme system for elimination from the body (known as the cytochrome P450 system ), for example, medicines used to treat epilepsy (such as phenytoin).
• Medicines that affect blood cell production.

Use of Betaferon with food and drink

Betaferon is injected under the skin, so it is not expected that any food or drink you consume will affect Betaferon.

Pregnancy and breastfeeding

If you are pregnant, breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

No harmful effects on the newborn/infant during breastfeeding are expected. Betaferon may be used during breastfeeding.

Driving and using machines

Betaferon may cause adverse effects on the central nervous system (see section 4. “Possible side effects”). If you are particularly sensitive, this may affect your ability to drive or operate machinery.

Betaferon contains mannitol, human albumin, and sodium

Inactive components of Betaferon include:

• small amounts of mannitol, a natural sugar, and human albumin, a protein.
• Sodium – this medicine contains less than 1 mmol of sodium (23 mg) per ml; hence, it is essentially “sodium-free”.

If you are allergic (hypersensitive) to any of the components or become hypersensitive, you must not use Betaferon.

3. How to use Betaferon

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

Follow exactly the administration instructions for this medicine provided by your doctor. If in doubt, consult your doctor, pharmacist, or nurse again.

Recommended dose:

On alternate days (once every two days), 1.0 ml of the prepared solution is injected under the skin (subcutaneously) (see the Annex “Procedure for self-injection” in the second part of this leaflet). This corresponds to 250 micrograms (8.0 million IU) of interferon beta-1b.

When starting treatment with Betaferon, better tolerance may be achieved by initiating treatment with a lower dose and gradually increasing it, i.e. starting with only 0.25 ml of the medication, then increasing after three injections first to 0.5 ml, then to 0.75 ml, and finally to the full dose (1 ml) of Betaferon.

Your doctor may decide together with you to adjust the time interval between dose increases, depending on any adverse effects you may experience at the beginning of treatment. To facilitate dose escalation during the first 12 injections, you may be provided with a special dose-escalation pack containing four packs in different colors, including syringes with special markings and an “introductory leaflet for the dose-escalation pack” with detailed instructions.

Preparation of the injection

Prior to injection, the Betaferon injectable solution is prepared from a vial of Betaferon powder and 1.2 ml of diluent from one of the pre-filled diluent syringes. This will be done by your doctor or nurse, or by yourself once you have been carefully trained in the technique. For more information on how to prepare the Betaferon injectable solution, see the Annex “Procedure for self-injection”, Part I.

Detailed instructions for subcutaneous self-injection of Betaferon are included in Part IE of the Annex “Procedure for self-injection”.

The injection site must be rotated regularly. See section 2. “Warnings and precautions” and follow the instructions provided in Part II “Rotation of injection sites” and Part III (Administration schedule for Betaferon) of the Annex “Procedure for self-injection”.

Duration of treatment

Currently, it is not known for how long a patient should be treated. The duration of treatment should be decided by your doctor together with you.

If you use more Betaferon than you should

Administration of Betaferon doses significantly higher than those recommended for multiple sclerosis has not resulted in life-threatening situations.

? Inform your doctor if you have injected too much Betaferon or injected it too frequently.

If you forget to use Betaferon

If you have forgotten to administer an injection at the scheduled time, do it as soon as possible and then continue with the next injection 48 hours later.

Do not inject a double dose to make up for missed doses.

If you stop using Betaferon

Talk to your doctor if you stop or intend to stop treatment. It is unknown whether discontinuation of Betaferon causes acute withdrawal symptoms.

? If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Betaferon may cause serious adverse effects. If you consider any of the adverse effects you experience to be severe, or if you notice any adverse effects not listed in this leaflet, inform your doctor, pharmacist, or nurse immediately.

• Tell your doctor immediately and stop using Betaferon if:

• You experience symptoms such as itching all over the body, swelling of the face and/or tongue, or sudden difficulty breathing.

• You feel markedly more sad or hopeless than before starting treatment with Betaferon, or if you have thoughts of suicide.

• You notice that you bruise easily, bleed excessively from wounds, or suffer frequent infections.

• You have loss of appetite, fatigue, nausea, repeated vomiting, especially if accompanied by widespread itching, yellowing of the skin or the whites of the eyes, or easy bruising.

• You develop symptoms such as irregular heartbeat, swelling in the ankles or legs, or difficulty breathing.

• You experience abdominal pain radiating to the back, and/or dizziness or fever.

? Tell your doctor immediately if:

• You have one or more of the following symptoms: foamy urine, fatigue, swelling (especially in the ankles and eyelids), and weight gain, as these may be signs of a possible kidney problem.

Adverse effects are common when starting treatment, but usually decrease with continued use.

The most common adverse effects are:

? A flu-like syndrome, including fever, chills, joint pain, malaise, sweating, headache, or muscle pain. These symptoms can be reduced by taking paracetamol or non-steroidal anti-inflammatory drugs such as ibuprofen.

? Injection site reactions. Symptoms may include redness, swelling, discoloration, inflammation, infection, pain, hypersensitivity, or tissue damage (necrosis). See "Warnings and precautions" in section 2 for more information and what to do if you experience an injection site reaction. These reactions can be minimized by using an auto-injector device and rotating injection sites. Speak with your doctor, pharmacist, or nurse for further advice.

To reduce adverse effects at the start of treatment, your doctor should begin with a low dose of Betaferon and increase it gradually (see section 3, "How to use Betaferon").

The list of adverse effects below is based on reports from clinical trials with Betaferon and from adverse effects reported for the marketed medicine.

? Very common (may affect more than 1 in 10 patients):

• decrease in the number of white blood cells
• headache
• sleep disorders (insomnia)
• abdominal pain
• a specific liver enzyme (alanine aminotransferase or ALT) may increase (this will be detected in blood tests)
• skin rash
• skin disorder
• muscle pain (myalgia)
• muscle stiffness (hypertonia)
• joint pain (arthralgia)
• urinary urgency
• injection site reaction (including redness, swelling, discoloration, inflammation, pain, infection, allergic reactions (hypersensitivity))
• flu-like symptoms, pain, fever, chills, fluid accumulation in the arm or leg (peripheral edema), lack of or loss of strength (asthenia)

? Common (may affect up to 1 in 10 patients):

• swelling of the lymph nodes (lymphadenopathy)

• decrease in the number of red blood cells in the blood (anemia)

• thyroid gland not functioning properly (producing too little hormone) (hypothyroidism)

• weight gain or weight loss

• confusion

• abnormally rapid heartbeat (tachycardia)

• increase in blood pressure (hypertension)

• a specific liver enzyme (aspartate aminotransferase or AST) may increase (this will be detected in blood tests)

• difficulty breathing (dyspnea)

• increase in a red-yellow pigment (bilirubin) produced by the liver (this will be detected in blood tests)

• skin or mucous membrane lesions that are swollen and often itchy (urticaria)

• itching (pruritus)

• hair loss (alopecia)

• menstrual disorders (menorrhagia)

• heavy uterine bleeding (metrorrhagia), especially between menstrual periods

• impotence

• skin lesions and tissue damage (necrosis) at the injection site (see section 2, "Warnings and precautions")

• chest pain

• malaise

? Uncommon (may affect up to 1 in 100 patients):

• decrease in the number of platelets (which help blood to clot) (thrombocytopenia)
• increase in a fraction of blood fats (triglycerides) (this will be detected in blood tests); see section 2, "Warnings and precautions"
• suicide attempt
• emotional instability
• seizures
• increase in a specific liver enzyme (gamma GT) produced by the liver (this will be detected in blood tests)
• inflammation of the liver (hepatitis)
• skin discoloration
• kidney problems, including scarring (glomerulosclerosis), which may reduce kidney function

? Rare (may affect up to 1 in 1,000 patients):

• blood clots in small blood vessels that may affect your kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, dizziness, or lightheadedness. Your doctor may detect abnormalities in your blood and kidney function.

• severe allergic reactions (anaphylactic)

• thyroid gland not functioning properly (thyroid disorders), producing too much hormone (hyperthyroidism)

• significant loss of appetite leading to weight loss (anorexia)

• heart muscle disease (cardiomyopathy)

• sudden difficulty breathing (bronchospasm)

• inflammation of the pancreas (pancreatitis); see section 2, "Warnings and precautions"

• liver not functioning properly (liver injury including hepatitis, liver failure)

• Frequency not known (frequency cannot be estimated from available data):

• breakdown of red blood cells (hemolytic anemia)

• problems with small blood vessels may occur when using medicines like Betaferon (systemic capillary leak syndrome)

• depression, anxiety

• dizziness

• faster and irregular heartbeat or palpitations (palpitations)

• redness and/or facial erythema due to dilation of blood vessels (vasodilation)

• significant narrowing of blood vessels in the lungs, causing increased pressure in the blood vessels carrying blood from the heart to the lungs (pulmonary arterial hypertension). Pulmonary arterial hypertension has been reported at various times during treatment, even several years after starting Betaferon.

• nausea

• vomiting

• diarrhea

• skin rash, facial redness, joint pain, fever, weakness, and other symptoms caused by the medicine (drug-induced lupus erythematosus)

• menstrual disorder

• sweating

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Betaferon

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the container. The expiry date refers to the last day of the month indicated.

Do not store above 25 °C. Do not freeze.

The solution should be used immediately after preparation. However, if this is not possible, it will remain suitable for use for up to 3 hours if stored between 2 and 8 °C (in a refrigerator).

Do not use Betaferon if you notice particles or any discoloration.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Betaferon

The active substance is interferon beta-1b, 250 micrograms per milliliter of reconstituted solution.

The other components are

• In the powder: mannitol and human albumin.
• In the solvent: (sodium chloride solution with 5.4 mg/mL (0.54% w/v)): sodium chloride, water for injections.

Betaferon powder is supplied in a 3-millilitre vial containing 300 micrograms (9.6 million IU) of interferon beta-1b per vial. After reconstitution, each millilitre contains 250 micrograms (8.0 million IU) of interferon beta-1b.

The solvent for Betaferon is supplied in a 2.25-millilitre pre-filled syringe and contains 1.2 millilitres of a sodium chloride solution with 5.4 mg/mL (0.54% w/v).

Appearance of the product and contents of the pack

Betaferon is a sterile white or almost white powder for solution for injection.

Betaferon is supplied in:

• Multi-pack containing 5 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• Multi-pack containing 12 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• Multi-pack containing 14 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• Multi-pack containing 15 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• 2-month packs containing 2 x 14 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• 3-month packs containing 3 x 15 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• 3-month packs containing 3 x 14 individual packs, each containing 1 vial of powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, and 2 alcohol wipes, or
• Dose-escalation pack for the first 12 injections containing 4 triple packs, each containing 3 vials of powder, 3 pre-filled syringes with solvent, 3 vial adapters with needles, and 6 alcohol wipes.

Only certain pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Bayer AG

51368 Leverkusen

Germany

Manufacturer

Bayer AG

Müllerstraße 178

13353 Berlin

Germany

Further information on this medicinal product is available upon request to the local representative of the Marketing Authorisation Holder:

Belgium / Belgique / Belgien Bayer SA/NV Tél/Tel: +32-(0)2-535 63 11	Lithuania UAB Bayer Tel. +370 5 23 36 868
Bulgaria Bayer Bulgaria EOOD Tel. +359 02 4247280	Luxembourg / Luxemburg Bayer SA/NV Tél/Tel: +32-(0)2-535 63 11
Czech Republic Bayer s.r.o. Tel: +420 266 101 111	Hungary Bayer Hungária Kft. Tel.: +36-14 87-41 00
Denmark Bayer A/S Tlf: +45-45 23 50 00	Malta Alfred Gera and Sons Ltd. Tel: +356-21 44 62 05
Germany Bayer Vital GmbH Tel: +49-(0)214-30 513 48	Netherlands Bayer B.V. Tel: +31-(0)23 799 1000
Estonia Bayer OÜ Tel: +372 655 85 65	Norway Bayer AS Tlf. +47 23 13 05 00
Greece Bayer Hellas S.A. Tel: +30 210 618 75 00	Austria Bayer Austria Ges. m. b. H. Tel: +43-(0)1-711 46-0
Spain Bayer Hispania S.L. Tel: +34-93-495 65 00	Poland Bayer Sp. z o.o. Tel.: +48-22-572 35 00
France Bayer HealthCare Tél (Free phone): +33-(0)800 87 54 54	Portugal Bayer Portugal, Lda. Tel: +351-21-416 42 00
Croatia Bayer d.o.o. Tel: +385-(0)1-6599 900	Romania SC Bayer SRL Tel: +40 21 529 59 00
Ireland Bayer Limited Tel: +353 1 216 3300	Slovenia Bayer d. o. o. Tel.: +386-(0)1-58 14 400
Iceland Icepharma hf. Tel: +354 540 80 00	Slovakia Bayer, spol. s r.o. Tel: +421 2 59 21 31 11
Italy Bayer S.p.A. Tel: +39-02-397 81	Finland Bayer Oy Puh/Tel: +358-20 785 21
Cyprus NOVAGEM Limited Tel: +357 22 48 38 58	Sweden Bayer AB Tel: +46-(0)8-580 223 00
Latvia SIA Bayer Tel: +371 67 84 55 63	United Kingdom (Northern Ireland) Bayer AG Tel: +44 (0) 118 206 3000

Date of the most recent review of this leaflet:

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu.

Annex: SELF-INJECTION PROCEDURE

Your doctor has prescribed Betaferon for your treatment of MS. You will tolerate Betaferon better if you start with a low dose and gradually increase it to the full standard dose (see section 3 of this leaflet, “How to use Betaferon”). To make dose escalation easier during the first 12 injections, you may be provided with a special dose-escalation pack, which contains four triple packs in different colours, including syringes with special markings and an “Introductory leaflet for the dose-escalation pack” with detailed instructions. The syringes in this dose-escalation pack are marked according to the corresponding doses (0.25; 0.5; 0.75 or 1.0 ml).

The following instructions and illustrations are intended to explain how to prepare the Betaferon injection and how to self-administer it. Please read the instructions carefully and follow them step by step. Your doctor or nurse will instruct and train you in the procedure and technique of self-administration. Do not attempt self-injection until you are certain that you fully understand how to prepare the injection solution and how to administer it.

PART I: STEP-BY-STEP INSTRUCTIONS

The instructions include the following main steps:

1. General tips
2. Preparing to inject
3. Reconstituting the solution step by step
4. Preparing the injection
5. Administering the injection
6. Quick review of the process

A) General tips

? Get off to a good start!

You will find that within a few weeks the treatment will become part of your routine. To get started, the following may help:

• Always keep a suitable area prepared at home, out of sight and reach of children, where you can easily find Betaferon and the other supplies.

See storage conditions in section 5 of the leaflet: “Storage of Betaferon” in the first part of this leaflet.

• Try to inject yourself at the same time every day, as this will make it easier to remember and to set aside a time when you will not be interrupted.

• Prepare each dose only when you are ready to inject, as the injection must be given immediately after reconstituting Betaferon (if you do not use Betaferon immediately, refer to section 5 in the first part of this leaflet: “Storage of Betaferon”).

? Important tips to keep in mind

• Be consistent. Use Betaferon exactly as described in section 3 of the first part of this leaflet: “How to use Betaferon”. Always double-check the dose you have prepared.
• Keep the container used for disposing of syringes and the syringes themselves out of sight and reach of children. Lock away the materials if possible.
• Never reuse syringes or needles.
• Always use a sterile (aseptic) technique, as described below.
• Always dispose of used syringes only in the appropriate container.

B) Preparing to inject

? How to choose the injection site

Before preparing the Betaferon injection, decide where you will inject. Betaferon must be injected into the fatty layer between the skin and muscle (i.e., into the subcutaneous tissue, 8 to 12 mm below the skin). The best injection sites are areas where the skin is soft and pliable, and away from joints, nerves, or bones, such as the abdomen, upper arm, thigh, or buttocks.

Important: Do not inject into areas where you notice lumps, bruises, firm nodules, pain, or areas where the skin is discoloured, indented, scabbed, or has an open wound. Speak with your doctor or nurse about these or any other unusual conditions you may notice.

You must rotate the injection site each time you inject. If a particular area is difficult to reach, a family member or friend may need to help you administer the injection. Follow the sequence shown in the diagram at the end of this Annex (see Part II “Rotation of injection sites”), returning to your first injection site after 8 injections (16 days). By then, each injection site will have fully recovered before receiving the next injection.

Refer to the rotation diagram at the end of this Annex to help you select the injection site. A sample “Administration schedule” is also included (see Annex Part III). This will help you keep track of the sites and dates of your injections.

? Checking the pack contents

Each individual Betaferon pack contains:

• 1 Betaferon vial (containing powder for injectable solution)
• 1 pre-filled syringe with solvent for Betaferon (sodium chloride solution with 5.4 mg/ml (0.54% w/v))
• 1 vial adapter with attached needle
• 2 alcohol wipes

In addition, you will need a sharps container for the disposal of used syringes and needles.

Use an appropriate skin disinfectant to clean the injection site.

If you have a Betaferon dose-escalation pack, you will receive 4 colour-coded and numbered triple packs, each containing:

• 3 Betaferon vials (containing powder for injectable solution)
• 3 pre-filled syringes with solvent for Betaferon powder (sodium chloride solution 5.4 mg/ml (0.54% w/v))
• 3 vial adapters with attached needles
• 6 alcohol wipes

In addition, you will need a sharps container for used syringes and needles.

Use an appropriate skin disinfectant to clean the injection site.

Begin with the yellow triple pack 1, containing 3 syringes marked at 0.25 ml, for treatment days 1, 3 and 5.

Next, use the red triple pack 2, containing 3 syringes marked at 0.5 ml, for treatment days 7, 9 and 11.

Then proceed with the green triple pack 3, containing 3 syringes marked at 0.75 ml, for treatment days 13, 15 and 17.

Use the blue triple pack 4, containing 3 syringes marked at 0.25, 0.5, 0.75 and 1.0 ml, for treatment days 19, 21 and 23.

C) Reconstituting the solution, step by step

	1 - Wash your hands thoroughly with water and soap before starting this process.
	2 - Open the Betaferon vial and place it on the table. It is better to use your thumb rather than your nails, as nails could break.
	3 - Clean the top of the vial with an alcohol wipe, moving it in one direction only. Leave it placed on top of the vial.
	4 – Open the blister containing the vial adapter, but do not remove it yet. Do not remove the vial adapter from the blister at this point. Do not touch the adapter. This ensures it remains sterile.
	5 – Before attaching the adapter, remove and discard the alcohol wipe and place the vial on a flat surface. 6 - Hold the blister by its outer surface and place it over the vial. Push down firmly until you feel it snap securely into place on the vial.
	7 - Remove the blister from the vial adapter by holding its edges. The adapter is now ready for connecting the pre-filled syringe with solvent to the vial adapter.
	Hold the syringe. Make sure the orange cap is securely attached to the solvent syringe! Remove the cap by twisting it off. Discard the cap.
	9 - Connect the syringe into the side opening of the vial adapter by inserting the syringe tip and pressing it carefully while simultaneously turning clockwise (see arrow). This will properly secure the syringe.
	10 - Hold the connected syringe at the bottom of the vial. Slowly push the plunger all the way down to transfer the entire solvent into the vial. Release the plunger, which should return to its original position. This also applies to the dose-scaling container.
	11 – Without detaching the connected syringe, gently rotate the vial in circular motions to dissolve all the dry Betaferon powder. Do not shake the vial.
	12 - Carefully examine the solution, which should be colorless (clear) and free of particles. If the solution is discolored or contains particles, discard it and start again using a new container. If foam appears—which may occur if the vial is shaken or swirled too vigorously—allow it to stand until the foam disappears.

D) Preparation of the injection

	13 - If the plunger has returned to its original position, push it again and hold it in that position. To prepare the injection, rotate the system so that the vial is above the syringe, with the stopper facing downward. This allows the solution to flow into the syringe. Keep the syringe in a horizontal position. Slowly pull back the plunger to withdraw all the solution from the vial into the syringe. Using the dose-scaling container, withdraw the solution only up to the mark on the syringe: 0.25 ml for the first three injections (on treatment days 1, 3, and 5), or 0.5 ml for injections on treatment days 7, 9, and 11, or 0.75 ml for injections on treatment days 13, 15, and 17. Discard the vial with any remaining solution. Starting on day 19, you will be injecting the full dose of 1.0 ml.
	14 – After withdrawing the solution, rotate the connected syringe so that the needle points upward. This allows air bubbles to move to the top of the solution.
15 - Remove air bubbles by gently tapping the syringe and pushing the plunger until it reaches the 1 ml mark, or the volume prescribed by your doctor. If you are injecting less than 1 ml using the dose-scaling container, there may be no air bubbles; however, when administering the full dose, some air bubbles may appear. Remove them by gently tapping the syringe with your finger and pushing the plunger to the corresponding mark on the syringe. If too much solution re-enters the vial along with the air bubbles, return to the horizontal position (see Figure 13) and slightly pull back the plunger to draw the solution again from the vial into the syringe.
	16 - Next, hold the blue vial adapter attached to the vial and disconnect it from the syringe by turning it downward to remove it from the syringe. When doing this, hold only the blue plastic adapter. Keep the syringe in a horizontal position with the vial below the syringe.
	Separate the vial and adapter from the syringe so that the solution can flow properly when injected.
17 – Discard the vial and any unused portion of the solution into the waste container.
18 - You are now ready for the injection. If, for any reason, you cannot inject Betaferon immediately, you may store the reconstituted solution in the syringe in the refrigerator for up to 3 hours before use. Never freeze it, and never wait more than 3 hours to inject it. If more than three hours have passed, discard the reconstituted Betaferon solution and prepare a new injection. When using the solution, warm the syringe in your hands before injection to help prevent pain.

E) Performing the injection

	1 - Choose an injection site (see tips at the beginning and diagrams at the end of this Annex) and record it in your "Administration Schedule".
	2 - Use an alcohol wipe to clean the skin at the injection site. Allow the skin to air dry. Dispose of the wipe. Use an appropriate disinfectant to disinfect the skin.
	3 - Remove the needle cap by pulling it straight off without twisting.
	4 - Gently pinch the skin around the previously disinfected injection site (to lift it slightly).
5 - Hold the syringe like a pencil or dart; insert the needle quickly and firmly at a 90° angle, keeping it straight. Note: Betaferon may also be administered using an autoinjector.
6 - Inject the medication by slowly and steadily pushing the plunger (press the plunger fully until the syringe is empty).
	7 - Dispose of the syringe and needle by placing them in the sharps container.

F) Quick review of the process

• Withdraw the required content for one injection.
• Attach the vial adapter to the vial.
• Connect the syringe to the vial adapter.
• Push the syringe plunger to transfer all solvent into the vial.
• Turn the system (vial above the syringe) and withdraw the prescribed amount of solution.
• Remove the vial from the syringe; the injection is now ready to be administered.

NOTE: The injection must be administered immediately after mixing (if administration is delayed, refrigerate the solution and inject within the next three hours). Do not freeze.

PART II: INJECTION SITE ROTATION

You should select a new injection site each time to allow the previous area time to heal and help prevent infection. Guidance on which areas to choose is provided in the first part of this Annex. It is advisable to decide on the injection site before preparing the syringe. The diagram shown later will help you rotate sites appropriately. For example, administer your first injection on the right side of the abdomen, choose the left side for the second injection, then move to the right thigh for the third injection, and continue through the diagram until all possible appropriate body areas have been used. Keep a record of where and when your last injection was given. One way to do this is to note this information in the accompanying "Administration Calendar."

Following this scheme, you will return to the initial site (i.e., the right side of the abdomen) after 8 injections (16 days). This is known as the "Rotation Cycle." In our example calendar, each of the 8 body areas has been further divided into 6 injection sites (totaling 48 possible injection sites across left and right sides: upper, middle, and lower sections of each body area). When returning to an injection area after completing a rotation cycle, choose the spot farthest away within that area. If any ulceration occurs, consult your doctor or nurse before selecting alternative injection sites.

Rotation Calendar:

To help you rotate injection sites appropriately, we recommend keeping a record of the date and injection site. You may use the following rotation schedule.

Work through each successive rotation cycle. Each cycle will consist of eight injections (16 days), administered sequentially from the first area to the eighth area. Following this sequence ensures each area has sufficient time to recover before the next injection.

First rotation cycle: Upper left section of each area
Second rotation cycle: Lower right section of each area
Third rotation cycle: Center left section of each area
Fourth rotation cycle: Upper right section of each area
Fifth rotation cycle: Lower left section of each area
Sixth rotation cycle: Center right section of each area

ROTATION SCHEDULE:

PART III: BETAFERON ADMINISTRATION SCHEDULE

Instructions for tracking injection sites and dates

• Select an injection site for your first injection.
• Clean the injection site with an alcohol wipe and allow it to air dry.
• After the injection, fill in the injection site and date on the "Administration Schedule" (see example in the following figure with instructions for tracking injection sites and dates).

EXAMPLE SCHEDULE FOR ADMINISTRATION:

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Annex: INTRODUCTORY PACKAGE LEAFLET FOR THE DOSE TITRATION PACK

Your doctor has prescribed Betaferon for your MS. You will tolerate Betaferon better if you start with a low dose and gradually increase it to the full standard dose (see the first part of the leaflet, section 3, “How to use Betaferon”). The syringes in this dose titration pack are marked according to the corresponding doses (0.25; 0.5; 0.75 or 1.0 ml).

? Check the contents of the pack

In the Betaferon dose titration pack you will find 4 triple packs of different colours and numbered, each containing:

• 3 vials of Betaferon (powder for injectable solution)
• 3 pre-filled syringes with solvent for Betaferon powder (sodium chloride solution 5.4 mg/ml (0.54% w/v))
• 3 vial adapters with integrated needle
• 6 alcohol wipes

Each triple pack contains the syringes you will need to prepare each dose. The syringes have special markings for that dose. Please follow the instructions for use below carefully. For each dose adjustment step, use the full amount of solvent to reconstitute the Betaferon powder, and then withdraw the required dose using the syringe.

Start by using the yellow triple pack, clearly marked with a “1” in the top right corner of the box.

This first triple pack should be used on treatment days 1, 3 and 5.

It contains syringes specially marked with 0.25 ml markings. This will help you to inject only the required dose.

After finishing the yellow pack, begin using the red triple pack, clearly marked with a “2” in the top right corner of the box.

This second triple pack should be used on treatment days 7, 9 and 11.

It contains syringes specially marked with 0.50 ml markings. This will help you to inject only the required dose.

After finishing the red pack, begin using the green triple pack, clearly marked with a “3” in the top right corner of the box.

This third triple pack should be used on treatment days 13, 15 and 17.

It contains syringes specially marked with 0.75 ml markings. This will help you to inject only the required dose.

Finally, after finishing the green pack, begin using the blue triple pack, clearly marked with a “4” in the top right corner of the box. This final triple pack should be used on treatment days 19, 21 and 23.

It contains syringes with markings at 0.25, 0.5, 0.75 and 1.0 ml. With the “4” triple pack, you can inject the full dose of 1.0 ml.

For instructions on how to prepare and use Betaferon powder, please refer to section 3, “How to use Betaferon” in the first part of the leaflet and the Annex “Procedure for self-injection” in the second part of the leaflet.

In addition, you will need a container for used syringes and needles.