BETAFERON

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PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) – 1986

The medicine is dispensed with a doctor’s prescription only

Betaferon

Powder and solvent for preparing a solution for

subcutaneous injection

Active ingredient and its quantity:

Interferon beta-1b 0.3 mg/vial

After reconstitution, 1 ml contains 250 micrograms (8.0 million international units) interferon beta-1b.

Inactive ingredients and allergens – see in section 2 “Important information regarding some of the

ingredients of the medicine” and section 6 “Further Information”.

Read this leaflet carefully in its entirety before using the medicine. This leaflet contains concise

information about the medicine. If you have further questions, refer to the doctor or pharmacist.

This medicine has been prescribed to treat your ailment. Do not pass it on to others. It may harm them

even if it seems to you that their medical condition is similar.

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ESSENTIAL INFORMATION ABOUT THE MEDICINE

This chapter presents a summary of the most essential information from the leaflet about treatment

with Betaferon.

∙ Before injection, prepare the Betaferon solution by using the vial that contains Betaferon powder

and the pre-filled syringe that contains a solvent. This will be prepared by your doctor or nurse, or

yourself after you have received appropriate training.

∙ Detailed instructions regarding preparation of the Betaferon solution and self-injection under the

skin are provided in the Annex “Self-injection procedure”.

∙ Routinely change the site of injection. See in section 2 “Special warnings regarding use of the medicine”

and follow the instructions in the Annex, in part

“Rotating injection sites”.

1)

WHAT IS THE MEDICINE INTENDED FOR?

∙ For treatment of ambulatory patients suffering from multiple sclerosis of the Relapsing-Remitting

MS type and of the Relapsing-Progressive MS type, to reduce the frequency of clinical relapses.

∙ For treatment of multiple sclerosis of the Secondary-Progressive MS type.

∙ For treatment of patients who experienced a single clinical event suggestive of multiple sclerosis,

with an active inflammatory process, if it is severe enough to justify intravenous administration

of corticosteroids, if other possible diagnoses have been ruled out, including the presence of MRI

abnormalities characteristic of multiple sclerosis, and if they are determined to be at high risk of

developing clinically definite multiple sclerosis.

Therapeutic group: The medicine belongs to a group called cytokines, interferons.

2)

BEFORE USING THE MEDICINE

Do not use the medicine if:

∙ You are sensitive (allergic) to natural or recombinant interferon beta, to human albumin or to

any of the other ingredients contained in the medicine (see section 6 “Further Information”).

∙ You are pregnant. Do not commence treatment with the medicine during pregnancy (see “Pregnancy

and breastfeeding” in this section).

∙ You are currently suffering from severe depression and/or suicidal thoughts (see “Special

warnings regarding use of the medicine” in this section and section 4 “Side Effects”).

∙ You have a severe liver disease (see “Special warnings regarding use of the medicine” and “Drug

interactions” in this section, and section 4 “Side Effects”).

Tell the doctor if any of the above-mentioned conditions apply to you.

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Special warnings regarding use of the medicine

Before using Betaferon, tell the doctor if:

∙ You are suffering from monoclonal gammopathy. This is a disorder of the immune system

where an abnormal protein is found in the blood. Use of Betaferon may cause problems with the

small blood vessels (capillaries), such as systemic capillary leak syndrome. This condition may lead

to shock and can even be fatal.

∙ You are suffering, or have suffered in the past, from depression or if you previously had suicidal

thoughts. Your doctor will closely monitor you during the course of treatment with the medicine.

If your depression and/or suicidal thoughts are severe, you will not be prescribed Betaferon (see “Do

not use the medicine if” in section 2).

∙ If you have suffered in the past from epileptic seizures or if you are taking medicines to treat

epilepsy, your doctor will closely monitor you during the course of treatment with the medicine (see

also “Drug interactions” in section 2 and section 4 “Side Effects”).

∙ You have severe kidney problems. Your doctor may monitor your kidney function during the course

of treatment with the medicine.

During the course of treatment with the medicine, your doctor needs to know if any of the

following conditions apply to you:

∙ If you experience symptoms such as itching all over the body, swelling of the face and/or the

tongue or sudden shortness of breath. These symptoms may be indicative of a serious allergic

reaction (hypersensitivity), which may be life-threatening.

∙ If you feel noticeably more sad or hopeless than before the treatment with Betaferon, or if you

develop suicidal thoughts. If you become depressed during the course of treatment with Betaferon,

you may need special treatment and your doctor will closely monitor you and will even consider

stopping the treatment. If you suffer from severe depression and/or suicidal thoughts, you will not

be treated with Betaferon (see “Do not use the medicine if” in section 2).

∙ If you notice unusual bruising, excessive bleeding after injury or if you suffer from many

infections. These symptoms may be indicative of a fall in your blood cell count or platelets

(blood

cells which help the blood clot). You may need closer monitoring by your doctor.

∙ If you experience reduced appetite, fatigue, nausea, repeated vomiting, especially if you

experience widespread itching, yellowing of the skin or whites of the eyes or easy bruising.

These symptoms may be indicative of a liver function problem. Changes in readings relating to liver

function were observed in patients treated with Betaferon during clinical studies with the medicine.

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As for other beta interferon preparations, severe liver damage, including cases of liver failure,

have rarely been reported in patients taking Betaferon. The most serious cases were reported in

patients taking additional medications or who were suffering from diseases that can affect the liver

(e.g., alcohol abuse, severe infections).

∙ If you experience symptoms like irregular heartbeat, swelling, such as of the ankles or legs,

or shortness of breath. These symptoms may be indicative of a disease of the heart muscle

cardiomyopathy

), which has been rarely reported in patients who took Betaferon.

∙ If you experience abdominal pain which radiates to the back, and/or you feel sick or have a

fever. These signs may suggest an inflammation of the pancreas (pancreatitis), which has been

reported in patients taking Betaferon. This condition is often associated with an increase of certain

blood fats (triglycerides).

Discontinue treatment with Betaferon and tell your doctor immediately if you are suffering from

one or more of the above-mentioned conditions.

Additional information to consider when being treated with Betaferon:

∙ Flu-like symptoms, which sometimes occur at the start of treatment, may prove difficult for

you if you suffer from a heart disease. Use of Betaferon must be with caution and your doctor will

monitor you to prevent deterioration of your heart function, especially at the beginning of treatment.

Betaferon itself does not directly affect heart function.

∙ Betaferon contains human albumin and therefore carries a potential risk for transmission of

viral diseases. A risk of transmission of Creutzfeldt-Jakob disease (CJD) cannot be ruled out.

∙ During the course of treatment with Betaferon, your body may produce substances called

neutralizing antibodies, that may react with Betaferon (neutralizing activity). It is not yet clear

whether the activity of these antibodies reduces the effectiveness of the treatment. Neutralizing

antibodies are not produced in all patients who take Betaferon. To date, it is impossible to predict

which patients will produce these antibodies and which will not.

∙ During the course of treatment with Betaferon, kidney problems, which can be manifested by

decreased kidney function, including scarring, may develop.

The doctor may perform tests to

monitor your kidney function.

∙ Blood clots may form in the small blood vessels during the course of treatment with Betaferon.

These blood clots may affect your kidney function.

This condition can develop several weeks up to

several years after starting treatment.

The doctor may check your blood pressure, ask you to perform

blood tests (including platelet count), and will monitor your kidney function.

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Injection site reactions

During the course of treatment with Betaferon, you may experience injection site reactions.

Symptoms include redness, swelling, discoloration of the skin, inflammation, pain, and hypersensitivity.

Cracks in the skin and tissue destruction (necrosis) around the injection site have been reported less

frequently. Injection site reactions usually become less frequent over time.

Breakdown of the injection site skin and tissue can result in formation of scars. If the scars are severe,

medical care by a doctor may be necessary to remove foreign matter and “dead” tissue (debridement)

and, in less common cases, skin grafting may be necessary and healing may take up to 6 months.

To reduce the risk of skin reactions at the injection site, you must:

∙ Use aseptic technique when injecting the medicine.

∙ Make a rotation among the various injection sites (see Annex “Self-injection procedure”).

Injection site reactions may occur less frequently if you use an auto-injector device. The doctor can

provide you with more details about this.

If you experience breakdown of the skin, which may be associated with swelling of the skin or

fluid leaking from the injection site:

∙ Stop the injections with Betaferon and contact your doctor.

∙ If you have only one sore injection site (lesion) and the tissue damage (necrosis) is not very

extensive, you may continue using Betaferon.

∙ If you have more than one sore injection site (multiple lesions), you must stop using Betaferon

until the skin has healed.

Your doctor will regularly check the way you inject yourself, particularly if you experience injection

site reactions.

Children and adolescents

No formal clinical trials have been performed to assess use of Betaferon in adolescents and children.

Nevertheless, there is information regarding use of Betaferon in children and adolescents between

the ages of 12-16 years. This information suggests that the safety of use of the medicine at these

ages is identical to use of the medicine in adults at a dosage of 8.0 million international units by

subcutaneous injection, when used once every two days (one day yes, one day no, and so on). There

are no data regarding use of Betaferon in children under the age of 12. Therefore, do not use Betaferon

in this population.

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Tests and follow-up

When using the medicine, you must undergo the following medical tests:

∙ You will need to have blood tests performed to measure the number of blood cells, blood chemistry

tests and liver enzyme level tests. These tests will be performed before commencing treatment with

Betaferon, routinely upon commencement of treatment and periodically during the course of

treatment, even if you do not experience any symptoms. Have these tests performed in addition to

routine tests your doctor performs for multiple sclerosis.

∙ You will have to perform thyroid function tests, routinely or whenever the doctor decides that it

is necessary.

Drug interactions

If you are taking, or have recently taken or are planning to take, other medicines, including

non-prescription medicines and nutritional supplements, tell the doctor or pharmacist.

No formal studies have been carried out to assess drug interactions between Betaferon and other

medicines.

Using Betaferon concomitantly with other medicines that may affect the immune system response

is not recommended, except for use of anti-inflammatory medicines called corticosteroids or the

adrenocorticotropic hormone (ACTH).

Use Betaferon with caution together with:

∙ Medicines which require the activity of a certain liver enzyme system (known as the cytochrome

P450 system) for their removal from the body, for example, medicines for treatment of epilepsy,

such as phenytoin.

∙ Medicines which affect the production of blood cells.

Use of Betaferon and food

Betaferon is injected under the skin, so consumption of any food or drink should not have any effect

on the activity of Betaferon.

Pregnancy and breastfeeding

Pregnancy

If you are of child-bearing age, use an appropriate method of contraception during the course of

treatment with Betaferon.

∙ If you are pregnant or there is a chance you are pregnant, tell the doctor. Do not start Betaferon

treatment if you are pregnant (see “Do not use the medicine if” in section 2). The existing data suggest

that there may be an increased risk of spontaneous abortion.

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∙ If you wish to become pregnant, first consult your doctor about this.

∙ If you become pregnant during the course of treatment with Betaferon, stop treatment with the

medicine and contact your doctor immediately. You and your doctor will decide if your Betaferon

treatment should be continued or not.

Consult with the doctor before taking any medicine.

Breastfeeding

It is not known whether interferon beta-1b (the active ingredient in Betaferon) passes into breast milk.

However, it is theoretically possible that a breastfed baby could experience serious side effects due to

Betaferon.

∙ Discuss with your doctor first in order to decide whether to stop breastfeeding or to stop using

Betaferon.

Consult with the doctor before taking any medicine.

Driving and use of machinery

Side effects in the central nervous system may result from use of Betaferon (see section 4 “Side Effects”). If

you are particularly sensitive, these effects may affect your ability to drive and to operate machines.

Important information regarding some of the ingredients of the medicine

The inactive ingredients of the medicine include:

A small amount of mannitol, a naturally occurring sugar, human albumin, a type of protein and

sodium.

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per 1 ml and is therefore essentially

‘sodium-free’.

If you have a known hypersensitivity (allergy) to one or more of the ingredients of the medicine, or if

you develop such a sensitivity, stop using Betaferon.

3)

HOW SHOULD YOU USE THE MEDICINE?

Treatment with Betaferon will be initiated under the supervision of a doctor who is experienced in the

treatment of multiple sclerosis.

Always use the preparation according to the doctor’s instructions. Check with the doctor or pharmacist

if you are uncertain regarding the dosage and treatment regimen of the preparation.

∙ The dosage and treatment regimen will be determined by the doctor only. The usual dosage is

generally 1.0 ml of the prepared Betaferon solution, once in two days (one day yes, one day no, and

so on) (see Annex “

Self-injection procedure”

), injected subcutaneously. This amount is equivalent to

250 micrograms (8.0 million international units) of interferon beta-1b.

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Generally, the first treatment will begin with administration of an initial low dosage of 0.25 ml

(62.5 micrograms). The dosage will be gradually increased up to the full dosage of 1.0 ml

(250 micrograms).

The dosage should be increased every fourth injection, in 4 stages (0.25 ml, 0.5 ml, 0.75 ml, 1.0 ml).

Your doctor will decide, together with you, whether to change the time interval between increases in

the dosage depending on side effects you may experience at the start of treatment.

Preparing the solution for injection:

∙ Before the injection, the Betaferon solution should be prepared for injection by using the vial

containing Betaferon powder and a pre-filled syringe containing 1.2 ml solvent. This will either be

prepared by your doctor or the nurse, or by yourself after you have received proper training.

∙ Detailed instructions for self-injection of Betaferon under the skin are provided in the Annex

“Self-injection procedure”. These instructions include directions for preparing the Betaferon solution

for injection.

Change the injection site regularly. See “Special warnings regarding use of the medicine” in section 2

and follow the instructions in Part

“Rotating injection sites” of the Annex.

Do not exceed the recommended dose.

Duration of treatment

At present, it is not known how long treatment with Betaferon should last. The duration of treatment

will be determined by your doctor together with you.

If you accidentally take too high a dosage, namely, too much or too often, talk to your doctor.

Administration of Betaferon many times for the treatment of multiple sclerosis has not led to

life-threatening situations.

If you forget to inject the medicine at the required time, inject as soon as you remember and inject

the next dose 48 hours later.

Do not inject a double dose to compensate for a single forgotten dose.

Adhere to the treatment regimen as recommended by the doctor.

If you stop taking the medicine

Talk to your doctor if you wish to stop or have stopped treatment with Betaferon.

Stopping treatment with Betaferon is not known to lead to severe withdrawal symptoms.

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∙ Do not take medicines in the dark! Check the label and the dose each time you take medicine.

Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult the doctor or pharmacist.

4)

SIDE EFFECTS

As with any medicine, use of Betaferon may cause side effects in some users. Do not be alarmed when

reading the list of side effects. You may not suffer from any of them.

Discontinue use and refer to a doctor immediately if:

∙ You experience signs such as itching all over the body, swelling of the face and/or tongue or

sudden shortness of breath.

∙ You feel noticeably more sad or hopeless than before treatment with Betaferon, or if you develop

suicidal thoughts.

∙ You notice unusual bruising, excessive bleeding after injury or if you suffer from many

infections.

∙ You experience reduced appetite, fatigue, nausea, repeated vomiting, especially if you notice

widespread itching, yellowing of the skin or whites of the eyes or easy bruising.

∙ You experience symptoms like irregular heartbeat, swelling of the ankles or legs, or shortness

of breath.

∙ You experience abdominal pain that radiates to the back, and/or feel sick or have a fever.

Refer to a doctor immediately if:

∙ You experience one of more of the following symptoms: foamy urine, fatigue, swelling, especially of

the ankles and eyelids, and weight gain, since they may be signs of a kidney function problem.

Side effects are common at the beginning of treatment, but usually decrease with continued use of

the medicine.

The most common side effects are:

∙ Flu-like symptoms such as fever, chills, joint pain, malaise, sweating, headache, or muscle pain.

These symptoms will be reduced by taking medicines containing paracetamol or non-steroidal

anti-inflammatory drugs such as medicines containing ibuprofen.

∙ Injection site reactions. Symptoms can include redness, swelling, discoloration of the skin,

inflammation, pain, hypersensitivity, tissue damage (necrosis). For more information and for

recommended actions for when you experience these reactions, see “Special warnings regarding use

of the medicine” in section 2. These reactions may be reduced when using an auto-injector device.

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Please talk to the doctor, pharmacist or nurse for further information.

To reduce side effects at the start of treatment, your doctor should start the treatment with a low dosage

of Betaferon and increase the dosage gradually (see section 3 “How Should You Use the Medicine?”).

The following side effects are based on reports from clinical trials with Betaferon (List 1) and

from side effects reported post-marketing (List 2).

List 1: Very common side effects which have been observed in clinical trials with Betaferon (in at

least 10% of cases) and at a higher percentage than those observed when using placebo. The list also

includes side effects which were observed in fewer than 10%, but which were significantly associated

with the treatment with Betaferon.

infection, abscess (pustular lesion)

reduced white blood cell count, swollen lymph glands

decrease of blood sugar level (hypoglycemia)

depression, anxiety

headache, dizziness, sleeplessness, migraine, tingling feeling and numbness

eye inflammation (conjunctivitis), abnormal vision

ear pain

rapid and irregular heart rate, or pulsation of the heart

redness and/or facial flushing due to widening of blood vessels, increased blood pressure

runny nose, cough, hoarseness due to infection of the upper respiratory tract, sinusitis, worsening

of cough, shortness of breath

diarrhea, constipation, nausea, vomiting, abdominal pain

rise in the blood levels of liver enzymes (will show up in blood tests)

skin disorders, rash

muscle stiffness, painful muscles, muscular weakness, back pain, pain in extremities such as fingers

and toes

difficulty passing water (urine retention), protein in the urine (will show up in urine tests), increased

frequency of urination, urinary incontinence, urinary urgency

menstrual pains, menstrual disorders, heavy uterine bleeding especially between menstrual periods,

impotence

injection site reaction (including redness, swelling, discoloration, inflammation, pain, allergic

reaction), skin and tissue destruction (necrosis) at the injection site (see “Special warnings regarding

use of the medicine” in section 2)

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flu-like symptoms, fever, pain, chest pain, accumulation of fluid in the arm, leg or face (peripheral

edema), weakness, chills, sweating, malaise

In addition, the following side effects have been identified from the information that has accumulated

after commencement of marketing.

List 2: Side effects of the marketed product (the frequency, if known, is based on the clinical studies).

Very common side effects - effects occurring in more than one in 10 users:

painful joints

Common side effects - effects occurring in up to in 10 users:

possible reduction in red blood cell counts (anemia)

impaired function of the thyroid gland (too little hormone is produced by the gland)

weight increase or decrease

confusion

fast, irregular heartbeat (tachycardia)

the red-yellow pigment (bilirubin), which is produced by the liver, may rise (this will show up in blood

tests)

swelled areas of skin or mucous membranes, usually with itching (hives/urticaria)

itching

loss of scalp hair (alopecia)

menstrual disorders (menorrhagia)

Uncommon side effects - effects occurring in up to one in 100 users:

possible reduction in blood platelet counts (cells which help the blood to clot) (thrombocytopenia)

the levels of certain types of blood fats (triglycerides) may increase (will show up in blood tests), see

“Special warnings regarding use of the medicine” in section 2

suicide attempts

mood swings

convulsions (epileptic seizures)

the blood levels of specific enzymes produced by the liver (gamma GT) may rise (this will show up

in blood tests)

hepatitis

skin discoloration

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Rare side effects - effects occurring in up to one in 1,000 users:

serious allergic reaction (anaphylaxis)

impaired function of the thyroid gland (too much hormone is produced, hyperthyroidism)

pancreatitis, see “Special warnings regarding use of the medicine” in section 2

blood clots in the small blood vessels may affect kidney function (thrombotic thrombocytopenic

purpura [TTP] or hemolytic uremic syndrome).

Symptoms such as increased bruising, bleeding, fever,

extreme fatigue, headache, dizziness or light headedness may occur.

The doctor may see changes in

your blood test results and in your kidney function.

Additional side effects only reported after commencement of marketing of the medicine:

kidney problems, including scarring, that may lead to decreased kidney function, occurs

infrequently

severe loss of appetite leading to weight loss (anorexia), rare

disease of the heart muscle, rare

sudden shortness of breath, rare

impaired function of the liver (hepatic damage, hepatic failure, including hepatitis), rare

problems with function of the small blood vessels may develop when using medicines like Betaferon

(systemic capillary leak syndrome), frequency unknown

rash, redness of the skin in the face, joint pain, fever, weakness and other reactions caused by the

medicine (drug-induced lupus erythematosus), frequency unknown

severe narrowing of the blood vessels in the lungs resulting in high blood pressure in the blood

vessels that carry blood from the heart to the lungs (pulmonary arterial hypertension), frequency

unknown. Pulmonary arterial hypertension has been seen at various time points during treatment,

including several years after starting treatment with Betaferon.

If a side effect occurs, if one of the side effects worsens, or if you are suffering from a side effect

not mentioned in the leaflet, consult the doctor.

Reporting side effects

Side effects can be reported to the Ministry of Health via the online side effects report form available

at the homepage of the Ministry of Health

www.health.gov.il) or via the following link:

https://sideeffects.health.gov.il

5)

HOW SHOULD THE MEDICINE BE STORED?

∙ Avoid poisoning! This medicine and any other medicine must be kept in a safe place out of the reach

and sight of children and/or infants in order to avoid poisoning. Do not induce vomiting unless

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explicitly instructed to do so by the doctor.

∙ Do not use the medicine after the expiry date (exp. date) that appears on the package. The expiry

date refers to the last day of that month.

∙ Store at a temperature below 25°C. Do not freeze.

∙ After preparing the solution for injection, use immediately. However, if you are not able to do so, it

can be used up to 3 hours after preparing it, if kept between 2-8°C (in the refrigerator).

∙ Do not use Betaferon if the solution contains particles or if its color has changed.

∙ Do not discard medicines in the household waste bin or wastewater. Consult a pharmacist as to how

to dispose of medicines you do not use. This will help protect the environment.

6)

FURTHER INFORMATION

∙ In addition to the active ingredient, the medicine also contains:

In the powder: mannitol, human albumin

In the solvent: sodium chloride solution 0.54%, water for injection.

∙ What the medicine looks like and the contents of the package

Betaferon powder is provided in a 3 ml vial. The white-cream powder is sterile.

The solvent is provided in a pre-filled syringe at a volume of 2.25 ml.

The volume of the solvent

is 1.2 ml.

Betaferon is available in pack sizes of:

A multipack that contains 15 single packs, each containing 1 vial with powder, 1 pre-filled syringe

(at a volume of 2.25 ml) with solvent, 1 vial adapter with needle, 2 alcohol wipes.

A titration multipack for the first 12 injections, which contains 4 three-packs, each containing 3

vials with powder, 3 pre-filled syringes (at a volume of 2.25 ml each) with solvent, 3 vial adapters

with needle, 6 alcohol wipes.

Not all pack sizes may be marketed.

∙ Registration holder and address: Bayer Israel Ltd., 36 Hacharash St., Hod Hasharon 45240.

∙ Manufacturer and address: Bayer AG, Berlin, Germany.

∙ This leaflet was checked and approved by the Ministry of Health in March 2016 and was updated in

accordance with the Ministry of Health guidelines in April 2019.

∙ Registration number of the medicine in the National Drug Registry of the Ministry of Health:

069 34 28359 00.

BETA POWD PL SH 280719

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Annex: SELF-INJECTION PROCEDURE

Your doctor has prescribed Betaferon to treat your ailment - multiple sclerosis.

To best adapt to the medicine, it is usually recommended to start with a low dose of Betaferon and

gradually increase it to the full dose (see section 3 “How Should You Use the Medicine?” in the patient

leaflet).

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

will refer you to a Betaferon guiding nurse who will guide you and help you to learn the process and

technique of self-injection. Do not attempt to self-inject until you are sure that you understand how

to prepare the solution for injection and give the injection to yourself.

PART

: STEP-BY-STEP INSTRUCTIONS

The instructions include the following main steps:

A. General information

B. Getting ready to inject

C. Reconstituting the solution, step-by-step

D. Drawing up the injection

E. Making the injection

F.

Quick review of the process

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A. GENERAL INFORMATION

Get a good start!

You will find that within a few weeks the treatment becomes a natural part of your routine. As you get

started, the following advice may be helpful for you:

Set up a permanent storage area in a convenient location out of the sight and reach of children so

your Betaferon package and other supplies are always easy to find.

For details on storage conditions see section 5 “How Should the Medicine Be Stored?” in the patient

leaflet.

Try to inject at the same time of day on each day in which you have to take Betaferon. This makes

it easier to remember and easier to plan a block of time when you will not be interrupted.

Prepare each dose only when you are ready for an injection. After the mixing process, you should

give the injection immediately (if Betaferon is not used immediately, see section 5 “How Should the

Medicine Be Stored?” in the patient leaflet).

Important tips to keep in mind

Be consistent - use Betaferon as described in section 3 “How Should You Use the Medicine?” in the

patient leaflet. Always double-check your dosage.

Keep your syringes and disposal units for syringes and needles out of the sight and reach of children;

lock these supplies away if possible.

Never re-use syringes or needles.

Always use aseptic technique as described below.

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.

Very important: Do not inject into any areas where you can feel lumps, firm knots, bumps, pain or an

area that is discolored, indented, scabbed, or where there is an open sore. Inform the doctor or Betaferon

guiding nurse about these or any other unusual conditions, if there are any.

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You should rotate and change the injection site at every injection. If some areas are too difficult for you

to reach, you can have a family member or friend help you inject in these areas. Follow the injection

rotation schedule described in the last part of these instructions (see Part

“Rotating injection sites”);

this way, 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” in Part

of this Annex to learn how to choose an injection site. In

addition, an explanation of how to keep track of your injection sites and dates is provided; see “Example

of a medication record”, in Part

of this Annex.

Checking the content of the pack

Each single package of Betaferon contains:

1 Betaferon vial (with powder for solution for injection).

1 pre-filled syringe, containing a solvent for the dilution of Betaferon (sodium chloride solution

5.4 mg/ml [0.54% w/v]).

1 vial adapter with a needle.

2 alcohol wipes to clean the skin and vial.

In addition, you will need a disposal unit for used syringes and needles (may be obtained from the

guiding nurse).

Use an appropriate disinfectant to disinfect the skin.

C. RECONSTITUTING THE SOLUTION, STEP-BY-STEP

Wash your hands thoroughly with soap and water before

beginning this process.

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Open a Betaferon vial and put it on the table. It is best to use

your thumb rather than your nail as it could break.

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.

Open the pack containing the vial adapter, but leave the vial

adapter inside.

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

Make sure not to touch the vial adapter in order to keep it

sterile.

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Before attaching the adapter, remove the alcohol wipe from the

top of the vial and place the vial on a flat surface.

Hold the vial adapter pack on the outside and place it on top of

the vial. Push it down firmly until you feel the adapter snap into

place.

Remove the adapter pack, while holding the edges of the pack.

Now you are ready to attach the solvent-containing syringe to

the vial adapter.

Pick up the syringe. Be sure that the orange tip cap is firmly

attached to the syringe. Remove the orange tip cap by twisting

it off. Throw away the tip cap.

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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).

You have now completed 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

solvent into the vial. Once you release the plunger, it may return

backwards to its original position.

11 -

With the syringe assembly still attached, swirl the vial around

gently to completely dissolve the Betaferon powder.

Do not shake the vial.

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12 -

Examine the solution carefully. It should be clear without any

particles. If the solution is cloudy or contains particles, discard

it and start again with a new single package. If foam is present,

which can happen when the vial is shaken or mixed too much,

let the vial sit undisturbed until the foam settles.

D. DRAWING UP THE INJECTION

13 -

If the plunger has moved back to its original position, push

it in again and hold it in place. To prepare the syringe, turn

the assembly over so that the vial is on top, and the cap side

pointing down. This will allow the solution to flow down into

the syringe.

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 your finger on the

syringe and pushing the plunger to the 1 ml mark, or to the

volume prescribed for you by the doctor.

If too much solution enters the vial along with the air bubbles,

get back into the horizontal position (see picture 13) and pull

the plunger back a little to withdraw the solution back into the

syringe.

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16 -

Next, hold the blue part of the 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 part of the plastic adapter when removing.

Keep the syringe in a horizontal position and the vial below

the syringe.

Removing the vial and adapter from the syringe ensures that

the solution will flow out from the needle when injected.

17 - Dispose of the vial and any unused portion of the solution in the designated disposal unit.

18 - You are now ready to inject.

If, for some reason, you are not able to inject 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 have passed, discard it and prepare

a new injection. When you use the solution, it is advised to warm it up a little with your hands before

injecting, to avoid pain.

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E. MAKING THE INJECTION

Choose an area for the injection (see at the beginning of this

Annex and in the diagrams at the end of this Annex), and make

a note of it in your records.

Use an alcohol wipe to clean the skin at the injection site. Let

the skin air-dry.

Throw the wipe away. Use an appropriate disinfectant to disinfect

the skin.

Remove the cap from the needle by pulling it. Do not twist it.

Gently pinch the skin upwards around the disinfected area (to

raise it a bit).

Hold the syringe like a pencil, and insert the needle straight into

the skin at a 90-degree angle with a quick, steady motion. Note:

Betaferon can also be injected with an auto-injector device.

Inject the medicine by pressing steadily and slowly (push the

plunger all the way in until the syringe is empty).

Discard the syringe in the designated disposal unit.

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F.

QUICK REVIEW OF THE PROCESS

Take out the contents of one single package

Attach vial adapter to the vial

Connect the syringe to the vial adapter

Push syringe plunger to transfer all the solvent into the vial

Turn the syringe assembly over and withdraw the prescribed amount of the solution

Remove vial from syringe - you are now ready to inject.

NOTE: The injection should be administered immediately after preparing the solution for injection (if

the injection is delayed, refrigerate the solution and inject it within 3 hours). Do not freeze.

PART

: ROTATING INJECTION SITES

It is essential 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 Annex. It is a good idea to

know where you plan to inject before you prepare the 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 most suitable areas of the body have been used. Keep a

record of where and when you gave yourself an injection. One way to do that is to note the injection

site on the enclosed medication record.

By following this schedule, you will come back to your first area (i.e., the right side of the abdomen)

after 8 injections (16 days). This is called a Rotation Cycle. On the example schedule, each area is split

again into 6 injection sites (which adds up to 48 injection sites all together), right and left parts: 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 guiding nurse

about choosing another injection site.

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Rotation Schedule

To help you rotate the injection sites appropriately we recommend that you keep a record of the date

and location of your injections. You can use the following rotation schedule:

Be sure to complete the full rotation cycle of 8 injection areas before going on to the next rotation

cycle.

There will be 8 injections in each cycle (16 days), starting from 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.

Rotation Cycle 5:

Lower left section of each area.

Rotation Cycle 6:

Middle right section of each area.

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ROTATION SCHEDULE:

AREA 1

AREA 7

AREA 8

AREA 6

AREA 4

AREA 3

AREA 2

AREA 5

Right Arm

(upper back portion)

Left Arm

(upper back portion)

Right Abdomen

(leave about 5

cm on right side

of navel)

Left Abdomen

(leave about 5

cm on left side of

navel)

Right Thigh

Left Thigh

Left Buttock

Right Buttock

10-15 cm

from shoulder

10-15 cm

from elbow

5 cm

10-15 cm

from groin

10-15 cm

above the

knee

Central leg line

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PART

: BETAFERON MEDICATION RECORD

Instructions for keeping track of your injection sites and dates

Select an injection site for your first injection.

Clean the injection site with an alcohol wipe and let it air-dry.

After your injection, fill in the injection site and date in the appropriate place in your medication

record (see the example: “Keeping track of your injection sites and dates”).

EXAMPLE OF A MEDICATION RECORD:

Keeping track of your injection sites and dates

Right Arm

Right Abdomen

Left Buttock

Right Thigh

Right Buttock

Left Thigh

Left Abdomen

Left Arm

15 cm

from shoulder

10-15 cm

from elbow

5 cm

10-15 cm

from groin

10-15

cm above

the knee

Central leg line

The content of this leaflet was approved by the Ministry of Health in March 2016 and

updated according to the guidelines of the Ministry of Health in April 2019.

1.

NAME OF THE MEDICINAL PRODUCT

BETAFERON

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Recombinant interferon beta-1b* 250 microgram (8.0 million IU) per ml when reconstituted.

Betaferon contains 300 microgram (9.6 million IU) of recombinant interferon beta-1b per vial.

For the full list of excipients, see section 6.1.

produced by genetic engineering from strain of Escherichia coli.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Sterile

white to off-white powder.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Betaferon is indicated for

Use in ambulatory patients with relapsing-remitting multiple sclerosis (RRMS) and

relapsing progressive M.S. to reduce the frequency of clinical exacerbations.

Treatment of secondary progressive (SP) form of multiple sclerosis.

Treatment of patients who have experienced a single demyelinating event with an

active inflammatory process, if it is severe enough to warrant treatment with

intravenous corticosteroids, if alternative diagnoses have been excluded, including

the presence of MRI abnormalities characteristic of M.S. and if they are determined to

be at high risk of developing clinically definite multiple sclerosis.

4.2

Posology and method of administration

The treatment with Betaferon should be initiated under the supervision of a physician

experienced in the treatment of the disease.

Posology

Adults

The recommended dose of Betaferon is 250 microgram (8.0 million IU), contained in 1 ml of

the reconstituted solution (see section 6.6), to be injected subcutaneously every other day.

Paediatric population

No formal clinical trials or pharmacokinetic studies have been conducted in children or

adolescents. However, limited published data suggest that the safety profile in adolescents

from 12 to 16 years of age receiving Betaferon 8.0 million IU subcutaneously every other day

is similar to that seen in adults. 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.

Generally, dose titration is recommended at the start of treatment.

Patients should be started at 62.5 microgram (0.25 ml) subcutaneously every other day, and

increased slowly to a dose of 250 microgram (1.0 ml) every other day (see Table A). The

titration period may be adjusted, if any significant adverse reaction occurs. In order to obtain

adequate efficacy, a dose of 250 microgram (1.0 ml) every other day should be reached.

Table A: Schedule for dose titration*

treatment day

dose

volume

1, 3, 5

62.5 microgram

0.25

7, 9, 11

microgram

0.5 ml

13, 15, 17

187.5

microgram

0.75

19, 21, 23 et seq.

microgram

* The titration period may be adjusted, if any significant adverse reaction occurs.

The optimal dose has not been fully clarified.

At the present time, it is not known how long the patient should be treated for. There are

follow-up data under controlled clinical conditions for patients with relapsing-remitting MS for

up to 5 years and for patients with secondary progressive MS for up to 3 years. For relapsing-

remitting MS, efficacy has been demonstrated for therapy for the first two years. The available

data for the additional three years are consistent with sustained treatment efficacy of

Betaferon over the whole time period.

In patients with a single clinical event suggestive of multiple sclerosis, the progression to

clinically definite multiple sclerosis was significantly delayed over a period of five years.

Treatment is not recommended in patients with relapsing-remitting multiple sclerosis who

have experienced less than 2 relapses in the previous 2 years or in patients with secondary-

progressive multiple sclerosis who have had no active disease in the previous 2 years.

If the patient fails to respond, for example a steady progression in EDSS for 6 months occurs

or treatment with at least 3 courses of ACTH or corticosteroids during a one year period is

required despite Betaferon therapy, treatment with Betaferon should be stopped.

Method of administration

For subcutaneous injection.

For instructions on reconstitution of the medicinal product before administration, see section

6.6.

4.3

Contraindications

Initiation of treatment in pregnancy (see section 4.6).

Patients with a history of hypersensitivity to natural or recombinant interferon beta,

human albumin or to any of the excipients listed in section 6.1.

Patients with current severe depression and/or suicidal ideation (see sections 4.4 and

4.8).

Patients with decompensated liver disease (see sections 4.4, 4.5 and 4.8).

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.

Gastrointestinal disorders

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

hypertriglyceridaemia.

Nervous system disorders

Betaferon should be administered with caution to patients with previous or current depressive

disorders, in particular to those with antecedents of suicidal ideation (see section 4.3).

Depression and suicidal ideation are known to occur with increased frequency in the multiple

sclerosis population and in association with interferon use. Patients treated with Betaferon

should be advised to report any symptoms of depression and/or suicidal ideation to their

prescribing physician immediately. Patients exhibiting depression should be monitored closely

during therapy with Betaferon and treated appropriately. Cessation of therapy with Betaferon

should be considered (see also sections 4.3 and 4.8).

Betaferon should be administered with caution to patients with a history of seizures and to

those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately

controlled with anti-epileptics (see sections 4.5 and 4.8).

This product contains human albumin and hence carries a potential risk for transmission of

viral diseases. A risk for transmission of Creutzfeld-Jacob disease (CJD) cannot be excluded.

Laboratory test

Thyroid function tests are recommended regularly in patients with a history of thyroid

dysfunction or as clinically indicated.

In addition to those laboratory tests normally required for monitoring patients with multiple

sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood

chemistries, including liver function tests (e.g. AST (SGOT), ALT (SGPT) and

-GT), are

recommended prior to initiation and at regular intervals following introduction of Betaferon

therapy, and then periodically thereafter in the absence of clinical symptoms.

Patients with anaemia, thrombocytopenia, leukopenia (alone or in any combination) may

require more intensive monitoring of complete blood cell counts, with differential and platelet

counts.

Patients who develop neutropenia should be monitored closely for the development of

fever or infection. There have been reports of thrombocytopenia, with profound decreases in

platelet count.

Hepatobiliary disorders

Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred

very commonly in patients treated with Betaferon during clinical trials. As for other beta

interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely

in patients treated with Betaferon. 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 comorbid 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. Withdrawal of

Betaferon should be considered if the levels significantly increase or if they are associated

with clinical symptoms such as 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

Renal and urinary disorders

Caution should be used and close monitoring considered when administering Interferon beta

to patients with severe renal failure.

Nephrotic Syndrome

Cases of nephrotic syndrome with different underlying nephropathies including collapsing

focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD),

membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN)

have been reported during treatment with interferon beta products. Events were reported at

various time points during treatment and may occur after several years of treatment with

interferon beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and

impaired renal function is recommended, especially in patients at higher risk of renal disease.

Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with

Betaferon should be considered.

Cardiac disorders

Betaferon should also be used with caution in patients who suffer from pre-existing cardiac

disorders. Patients with pre-existing significant cardiac disease, such as congestive heart

failure, coronary artery disease or arrhythmia, should be monitored for worsening of their

cardiac condition, particularly during initiation of treatment with Betaferon.

While Betaferon does not have any known direct-acting cardiac toxicity, symptoms of the flu-

like syndrome associated with beta interferons may prove stressful to patients with pre-

existing significant cardiac disease. During the post-marketing period very rare reports have

been received of worsening of cardiac status in patients with pre-existing significant cardiac

disease temporarily 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.

Thrombotic microangiopathy (TMA)

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura

(TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with

interferon beta products. Events were reported at various time points during treatment and

may occur several weeks to several years after starting treatment with interferon beta. Early

clinical features include thrombocytopenia, new onset hypertension, fever, central nervous

system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings

suggestive of TMA include decreased platelet counts, increased serum lactate

dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a

blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet

levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed,

prompt treatment is required (considering plasma exchange) and immediate discontinuation

of Betaferon is recommended.

General disorders and administration site conditions

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.

Injection site necrosis has been reported in patients using Betaferon (see section 4.8). 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 his/her

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.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in

controlled clinical trials were collected every 3 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% and 55% converted to a stable antibody negative status (based

on two consecutive negative titres) during the subsequent observational period of the

respective study.

The development of neutralising activity in these studies is associated with a reduction in

clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect

might be larger in patients with higher titre levels 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 5 year period. Within this period, the

development of neutralising activity was associated with a significant increase in newly active

lesions and T2 lesion volume on magnetic resonance imaging. However, this did not seem to

be 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).

New adverse events have not been associated with the development of neutralising activity.

It has been demonstrated in vitro that Betaferon cross-reacts with natural interferon beta.

However, this has not been investigated in vivo and its clinical significance is uncertain.

There are sparse and inconclusive data on patients who have developed neutralising activity

and have completed Betaferon therapy.

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.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say

essentially ‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

The effect of alternate-day administration of 250 microgram (8.0 million IU) of Betaferon on

drug metabolism in multiple sclerosis patients is unknown. Corticosteroid or ACTH treatment

of relapses for periods of up to 28 days has been well tolerated in patients receiving

Betaferon.

Due to the lack of clinical experience in multiple sclerosis patients, the use of Betaferon

together with immunomodulators other than corticosteroids or ACTH is not recommended.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent

enzymes in humans and animals. Caution should be exercised when Betaferon is

administered in combination with medicinal products that have a narrow therapeutic index and

are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. anti-

epileptics.

Additional caution should be exercised with any co-medication which has an effect

on the haematopoetic system.

No interaction studies with anti-epileptics have been carried out.

4.6

Pregnancy and breast-feeding

Pregnancy

There is limited information on the use of Betaferon in pregnancy. Available data indicate that

there may be an increased risk of spontaneous abortion. Initiation of treatment is

contraindicated during pregnancy (see section 4.3).

Women of child-bearing potential

Women of child-bearing potential should take appropriate contraceptive measures. If the

patient becomes pregnant or plans to become pregnant while using Betaferon, she should be

informed of the potential hazards and discontinuation of therapy should be considered (see

section 5.3). In patients with a high relapse rate before initiation of treatment, the risk of a

severe relapse following discontinuation of Betaferon in the event of pregnancy should be

weighed against a possible increased risk of spontaneous abortion.

Breast-feeding

It is not known whether interferon beta-1b is excreted in human milk. Because of the potential

for serious adverse reactions in nursing infants a decision should be made on whether to

discontinue breast-feeding or discontinue Betaferon therapy.

4.7

Effects on ability to drive and use machines

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

Central nervous system-related adverse events associated with the use of Betaferon might

influence the ability to drive and use machines in susceptible patients.

4.8

Undesirable effects

Summary of the safety profile

At the beginning of treatment adverse reactions are common but in general they subside with

further treatment. The most frequently observed adverse reactions are a flu-like symptom

complex (fever, chills, arthralgia, malaise, sweating, headache, or myalgia), which is mainly

due to the pharmacological effects of the medicinal product, and injection site reactions.

Injection site reactions occurred frequently after administration of Betaferon. Redness,

swelling, discolouration, inflammation, pain, hypersensitivity, necrosis and non-specific

reactions were significantly associated with 250 microgram (8.0 million IU) Betaferon

treatment.

Generally, dose titration is recommended at the start of treatment in order to increase

tolerability to Betaferon (see section 4.2). Flu-like symptoms may also be reduced by

administration of non-steroidal anti-inflammatory drugs. The incidence of injection site

reactions may be reduced by the use of an autoinjector.

Tabulated list of adverse reactions

The following adverse event listing is based on reports from clinical trials (Table 1, adverse

events and laboratory abnormalities) and from the post-marketing surveillance (Table 2,

frequencies – where known- based on pooled clinical trials (very common ≥1/10, common

≥1/100 to <1/10, uncommon ≥ 1/1,000 to < 1/100, rare ≥1/10,000 to <1/1,000, very rare <

1/10,000)) of Betaferon use. Experience with Betaferon in patients with MS is limited,

consequently those adverse events which occur very rarely may not yet have been observed.

Table 1: Adverse events and laboratory abnormalities with incidence rates ≥ 10% and the

respective percentages under placebo; significantly associated side effects < 10% based on

reports from clinical trials

System Organ Class

Adverse Event

and

Laboratory

Abnormalities

Single Event

suggestive of

Multiple

Sclerosis

(BENEFIT)

Secondary

Progressive

Multiple

Sclerosis

(European

Study)

Secondary

Progressive

Multiple

Sclerosis

(North

American

Study)

Relapsing-

Remitting

Multiple

Sclerosis

Betaferon

250

microgram

(Placebo)

n=292 (n=176)

Betaferon

250

microgram

(Placebo)

n=360 (n=358)

Betaferon

250 microgram

(Placebo)

n=317 (n=308)

Betaferon

250

microgram

(Placebo)

n=124 (n=123)

Infections and infestations

Infection

6% (3%)

13% (11%)

11% (10%)

14% (13%)

Abscess

0% (1%)

4% (2%)

4% (5%)

1% (6%)

Blood and lymphatic system disorders

Lymphocyte count

decreased (<1,500/mm³)

79% (45%)

53% (28%)

88% (68%)

82% (67%)

Absolute neutrophil count

decreased (<1,500/mm³)

* °

11% (2%)

18% (5%)

4% (10%)

18% (5%)

White blood cell count

decreased (<3,000/mm³)

* °

11% (2%)

13% (4%)

13% (4%)

16% (4%)

Lymphadenopathy

1% (1%)

3% (1%)

11% (5%)

14% (11%)

Metabolism and nutrition disorders

Blood glucose decreased

(<55 mg/dl)

3% (5%)

27% (27%)

5% (3%)

15% (13%)

Psychiatric disorders

Depression

10% (11%)

24% (31%)

44% (41%)

25% (24%)

Anxiety

3% (5%)

6% (5%)

10% (11%)

15% (13%)

Nervous system disorders

Headache

27% (17%)

47% (41%)

55% (46%)

84% (77%)

Dizziness

3% (4%)

14% (14%)

28% (26%)

35% (28%)

Insomnia

8% (4%)

12% (8%)

26% (25%)

31% (33%)

Migraine

2% (2%)

4% (3%)

5% (4%)

12% (7%)

Paraesthesia

16% (17%)

35% (39%)

40% (43%)

19% (21%)

Eye disorders

Conjunctivitis

1% (1%)

2% (3%)

6% (6%)

12% (10%)

Abnormal vision

3% (1%)

11% (15%)

11% (11%)

7% (4%)

Ear and labyrinth disorders

Ear pain

0% (1%)

<1% (1%)

6% (8%)

16% (15%)

Cardiac disorders

Palpitation *

1% (1%)

2% (3%)

5% (2%)

8% (2%)

Vascular disorders

Vasodilatation

0% (0%)

6% (4%)

13% (8%)

18% (17%)

Hypertension °

2% (0%)

4% (2%)

9% (8%)

7% (2%)

System Organ Class

Adverse Event

and

Laboratory

Abnormalities

Single Event

suggestive of

Multiple

Sclerosis

(BENEFIT)

Secondary

Progressive

Multiple

Sclerosis

(European

Study)

Secondary

Progressive

Multiple

Sclerosis

(North

American

Study)

Relapsing-

Remitting

Multiple

Sclerosis

Betaferon

250

microgram

(Placebo)

n=292 (n=176)

Betaferon

250

microgram

(Placebo)

n=360 (n=358)

Betaferon

250 microgram

(Placebo)

n=317 (n=308)

Betaferon

250

microgram

(Placebo)

n=124 (n=123)

Respiratory, thoracic and mediastinal disorders

Upper respiratory

infection

18% (19%)

3% (2%)

Sinusitis

4% (6%)

6% (6%)

16% (18%)

36% (26%)

Cough increased

2% (2%)

5% (10%)

11% (15%)

31% (23%)

Dyspnoea *

0% (0%)

3% (2%)

8% (6%)

8% (2%)

Gastrointestinal disorders

Diarrhoea

4% (2%)

7% (10%)

21% (19%)

35% (29%)

Constipation

1% (1%)

12% (12%)

22% (24%)

24% (18%)

Nausea

3% (4%)

13% (13%)

32% (30%)

48% (49%)

Vomiting

5% (1%)

4% (6%)

10% (12%)

21% (19%)

Abdominal pain °

5% (3%)

11% (6%)

18% (16%)

32% (24%)

Hepatobiliary disorders

Alanine aminotransferase

increased (SGPT> 5

times baseline)

* °

18% (5%)

14% (5%)

4% (2%)

19% (6%)

Aspartate

aminotransferase

increased (SGOT > 5

times baseline)

* °

6% (1%)

4% (1%)

2% (1%)

4% (0%)

Skin and subcutaneous tissue disorders

Skin disorder

1% (0%)

4% (4%)

19% (17%)

6% (8%)

Rash

11% (3%)

20% (12%)

26% (20%)

27% (32%)

Musculoskeletal and connective tissue disorders

Hypertonia°

2% (1%)

41% (31%)

57% (57%)

26% (24%)

Myalgia * °

8% (8%)

23% (9%)

19% (29%)

44% (28%)

Myasthenia

2% (2%)

39% (40%)

57% (60%)

13% (10%)

Back pain

10% (7%)

26% (24%)

31% (32%)

36% (37%)

Pain in extremity

6% (3%)

14% (12%)

0% (0%)

Renal and urinary disorders

Urinary retention

1% (1%)

4% (6%)

15% (13%)

Urinary protein positive (>

25% (26%)

14% (11%)

5% (5%)

5% (3%)

Urinary frequency

1% (1%)

6% (5%)

12% (11%)

3% (5%)

Urinary incontinence

1% (1%)

8% (15%)

20% (19%)

2% (1%)

Urinary urgency

1% (1%)

8% (7%)

21% (17%)

4% (2%)

Reproductive system and breast disorders

Dysmenorrhoea

2% (0%)

<1% (<1%)

6% (5%)

18% (11%)

Menstrual disorder *

1% (2%)

9% (13%)

10% (8%)

17% (8%)

Metrorrhagia

2% (0%)

12% (6%)

10% (10%)

15% (8%)

Impotence

1% (0%)

7% (4%)

10% (11%)

2% (1%)

General disorders and administration site conditions

Injection site reaction

(various kinds)

* °

52% (11%)

78% (20%)

89% (37%)

85% (37%)

Injection site necrosis * °

1% (0%)

5% (0%)

6% (0%)

5% (0%)

Flu-like symptoms

&

44% (18%)

61% (40%)

43% (33%)

52% (48%)

Fever

* °

13% (5%)

40% (13%)

29% (24%)

59% (41%)

Pain

4% (4%)

31% (25%)

59% (59%)

52% (48%)

Chest pain °

1% (0%)

5% (4%)

15% (8%)

15% (15%)

System Organ Class

Adverse Event

and

Laboratory

Abnormalities

Single Event

suggestive of

Multiple

Sclerosis

(BENEFIT)

Secondary

Progressive

Multiple

Sclerosis

(European

Study)

Secondary

Progressive

Multiple

Sclerosis

(North

American

Study)

Relapsing-

Remitting

Multiple

Sclerosis

Betaferon

250

microgram

(Placebo)

n=292 (n=176)

Betaferon

250

microgram

(Placebo)

n=360 (n=358)

Betaferon

250 microgram

(Placebo)

n=317 (n=308)

Betaferon

250

microgram

(Placebo)

n=124 (n=123)

Peripheral oedema

0% (0%)

7% (7%)

21% (18%)

7% (8%)

Asthenia *

22% (17%)

63% (58%)

64% (58%)

49% (35%)

Chills

* °

5% (1%)

23% (7%)

22% (12%)

46% (19%)

Sweating *

2% (1%)

6% (6%)

10% (10%)

23% (11%)

Malaise *

0% (1%)

8% (5%)

6% (2%)

15% (3%)

Laboratory abnormality

Significantly associated with Betaferon treatment for patients with first event suggestive of MS, p <

0.05

* Significantly associated with Betaferon treatment for RRMS, p < 0.05

° Significantly associated with Betaferon treatment for SPMS, p < 0.05

§ Injection site reaction (various kinds) comprises all adverse events occurring at the injection site,

i.e. the following terms: injection site haemorrhage, injection site hypersensitivity, injection site

inflammation, injection site mass, injection site necrosis, injection site pain, injection site reaction,

injection site oedema, and injection site atrophy

& “Flu-like symptom complex” denotes flu syndrome and/or a combination of at least two AEs from

fever, chills, myalgia, malaise, sweating.

During the BENEFIT follow-up study, no change in the known risk profile of Betaferon was

observed.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms

and related conditions.

Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance

(frequencies - where known - calculated based on pooled clinical trial data N= 1093)

System Organ

Class

Very

common

1/10)

1

Common

1/100 to

< 1/10)

1

Uncommon

1/1,000 to

< 1/100)

1

Rare

1/10,000 to

< 1/1,000)

1

Frequency

not known

Blood and

lymphatic

system

disorders

Anaemia

Thrombocytopenia

Thrombotic

microangiopathy

including

thrombotic

thrombocytopenic

purpura/

haemolytic

uraemic

syndrome

3

Immune system

disorders

Anaphylactic

reactions

Capillary leak

syndrome in

pre-existing

monoclonal

gammopathy

2

Endocrine

disorders

Hypothyroidism

Hyperthyroidism,

Thyroid disorders

Metabolism and

nutrition

disorders

Weight

increased,

Weight

decreased

Blood triglycerides

increased

Anorexia

2

Psychiatric

disorders

Confusional

state

Suicide attempt

(see also section

4.4),

Emotional lability

Nervous system

disorders

Convulsion

Cardiac

disorders

Tachycardia

Cardiomyopathy

2

Respiratory,

thoracic and

mediastinal

disorders

Bronchospasm

2

Pulmonary

arterial

hypertension

4

Gastrointestinal

disorders

Pancreatitis

Hepatobiliary

disorders

Blood bilirubin

increased

Gamma-glutamyl-

transferase

increased,

Hepatitis

Hepatic injury

(including

hepatitis),

Hepatic failure

2

Skin and

subcutaneous

tissue disorders

Urticaria,

Pruritus,

Alopecia

Skin discolouration

Musculoskeletal,

and connective

tissue disorders

Arthralgia

Drug-induced

lupus

erythematosus

Renal and

urinary

disorders

Nephrotic

syndrome,

glomerulosclerosis

(see section 4.4 )

Reproductive

system and

breast disorders

Menorrhagia

System Organ

Class

Very

common

1/10)

1

Common

1/100 to

< 1/10)

1

Uncommon

1/1,000 to

< 1/100)

1

Rare

1/10,000 to

< 1/1,000)

1

Frequency

not known

1

frequencies based on pooled clinical trials (very common ≥1/10, common ≥1/100 to <1/10,

uncommon ≥ 1/1,000 to < 1/100, rare ≥1/10,000 to <1/1,000, very rare < 1/10,000).

2

ADRs derived only during post-marketing

3

Class label for interferon beta products (see section 4.4).

4

Class label for interferon products, see below Pulmonary arterial hypertension.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms

and related conditions.

Pulmonary arterial hypertension

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta

products. Events were reported at various time points including up to several years after

starting treatment with interferon beta.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffec

tMedic@moh.gov.il

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 5,500 microgram

(176 million

IU) intravenously three times a week.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cytokines, Interferons.

ATC Code: L03 AB 08

Mechanism of action

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 species-restricted and therefore, the most pertinent

pharmacological information on interferon beta-1b is derived from studies of human cells in

culture or in human in vivo studies.

Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities.

The mechanisms by which interferon beta 1b exerts its actions in multiple sclerosis are not

clearly understood. However, it is known that the biologic response-modifying properties of

interferon beta-1b are mediated through its interactions 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-

gamma receptor. Interferon beta-1b also enhances the

suppressor activity of peripheral blood mononuclear cells.

No separate investigations were performed regarding the influence of Betaferon on the

cardiovascular system, respiratory system and the function of endocrine organs.

Clinical efficacy and safety

RR-MS

One controlled clinical trial with Betaferon in patients with relapsing-remitting multiple

sclerosis and able to walk unaided (baseline EDSS 0 to 5.5) was performed. Patients

receiving Betaferon showed a reduction in frequency (30%) and severity of clinical relapses,

as well as the number of hospitalisations due to disease. Furthermore, there was a

prolongation of the relapse-free interval. There is no evidence of an effect of Betaferon on the

duration of relapses or on symptoms in between relapses, and no significant effect was seen

on the progression of the disease in relapsing-remitting multiple sclerosis.

SP-MS

Two controlled clinical trials with Betaferon involving a total of 1,657 patients with secondary

progressive multiple sclerosis (baseline EDSS 3 to 6.5, i.e. patients were able to walk) were

performed. Patients with mild disease and those unable to walk were not studied. The two

studies showed inconsistent results for the primary endpoint time to confirmed progression,

representing delay of disability progression:

One of the two studies demonstrated a statistically significant delay in the time to disability

progression (Hazard Ratio = 0.69, 95% confidence interval (0.55, 0.86), p=0.0010,

corresponding to a 31% risk reduction due to Betaferon) and in the time to becoming

wheelchair bound (Hazard Ratio = 0.61, 95% confidence interval (0.44, 0.85), p=0.0036,

corresponding to a 39% risk reduction due to Betaferon) in patients who received Betaferon.

This effect continued over the observation period of up to 33 months. The treatment effect

occurred in patients at all levels of disability investigated and independent of relapse activity.

In the second trial of Betaferon in secondary progressive multiple sclerosis, no delay in the

time to disability progression was observed. There is evidence that the patients included in

this study had overall less active disease than in the other study in secondary progressive

multiple sclerosis.

In retrospective meta-analyses including the data of both studies, an overall treatment effect

was found which was statistically significant (p=0.0076; 8.0 million IU Betaferon versus all

placebo patients).

Retrospective analyses in subgroups showed that a treatment effect on disability progression

is most likely in patients with active disease before treatment commences (Hazard Ratio 0.72,

95% confidence interval (0.59, 0.88), p=0.0011, corresponding to a 28 % risk reduction due to

Betaferon in patients with relapses or pronounced EDSS progression, 8.0 million IU Betaferon

versus all placebo patients). From these retrospective subgroup analyses there was evidence

to suggest that relapses as well as pronounced EDSS progression (EDSS >1 point or >0.5

point for EDSS ≥6 in the previous two years) can help to identify patients with active disease.

In both trials secondary progressive multiple sclerosis patients receiving Betaferon showed a

reduction in frequency (30%) of clinical relapses. There is no evidence of Betaferon having an

effect on the duration of relapses.

Single clinical event suggestive of MS

One controlled clinical trial with Betaferon was performed in patients with a single clinical

event and MRI features suggestive of multiple sclerosis (at least two clinically silent lesions on

the T2-weighted MRI). Patients with monofocal or multifocal onset of the disease were

included (i.e. patients with clinical evidence for a single or at least two lesions, respectively, of

the central nervous system). Any disease other than multiple sclerosis that could better

explain signs and symptoms of the patient had to be excluded. This study consisted of two

phases, a placebo-controlled phase followed by a pre-planned 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 pre-planned follow-up phase with Betaferon to evaluate the effects of immediate versus

delayed start of Betaferon-treatment, comparing patients initially randomized to Betaferon

("immediate treatment group") or to placebo ("delayed treatment group"). Patients and

investigators remained blinded to the initial treatment allocation.

Table 3: Primary efficacy results of the BENEFIT and the BENEFIT Follow-up study

Year 2 results

Placebo-controlled

phase

Year 3 results

Open-label follow-up

Year 5 results

Open-label follow-up

Betaferon

250 mcg

n=292

Placebo

n=176

Imme-

diate

Betaferon

250 mcg

n=292

Delayed

Betaferon

250 mcg

n=176

Imme-

diate

Betaferon

250 mcg

n=292

Delayed

Betaferon

250 mcg

n=176

Number of patients

completed the trial

phase

271 (93%)

166 (94%)

249 (85%)

143 (81%)

(80%)

(70%)

Primary efficacy variables

Time to CDMS

Kaplan-Meier

estimates

Risk reduction

Hazard ratio with

95% confidence

interval

log-rank test

47% versus placebo

HR = 0.53 [0.39, 0.73]

p < 0.0001

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 the 25th

percentiles)

41% versus delayed

Betaferon

HR = 0.59 [0.42, 0.83]

p = 0.0011

37% versus delayed

Betaferon

HR = 0.63 [0.48, 0.83]

p = 0.0027

Time to McDonald MS

Kaplan-Meier

estimates

No primary endpoint

No primary endpoint

Risk reduction

Hazard ratio with

95% confidence

interval

log-rank test

43% versus placebo

HR = 0.57 [0.46, 0.71]

p < 0.00001

Time to confirmed EDSS progression

Kaplan-Meier

estimates

No primary endpoint

Risk reduction

Hazard ratio with

95% confidence

interval

log-rank test

40% versus delayed

Betaferon

HR = 0.60 [0.39, 0.92]

p = 0.022

24% versus delayed

Betaferon

HR = 0.76 [0.52, 1.11]

p=0.177

In the placebo-controlled phase, Betaferon delayed the progression from the first clinical

event to CDMS in a statistically significant and clinically meaningful manner. The robustness

of the treatment effect was also shown by the delay of progression to multiple sclerosis

according to McDonald criteria (Table 3).

Subgroup analyses according to baseline factors demonstrated evidence of efficacy on

progression to CDMS in all subgroups evaluated. The risk for progression to CDMS within

2 years was higher in monofocal patients with at least 9 T2-lesions or Gd-enhancement on

brain MRI at baseline. In multifocal patients, the risk for CDMS was independent from MRI

findings at baseline, indicating a high risk for CDMS because of the dissemination of the

disease based on clinical findings. For the time being there is no well established definition of

a high risk patient, although a more conservative approach is to accept at least nine T2

hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing

lesion on a follow-up scan taken at least 1 month after the initial scan. In any case, treatment

should only be considered for patients classified as high risk.

Therapy with Betaferon was well accepted as indicated by a high rate of trial completion (93%

in the Betaferon group). To increase tolerability of Betaferon, a dose titration was applied and

non-steroidal anti-inflammatory drugs were administered at start of therapy. Moreover, an

autoinjector was used by the majority of patients throughout the study.

In the open-label follow-up phase, the treatment effect on CDMS was still evident after 3 and

5 years (Table 3), even though the majority of patients from the placebo-group were treated

with Betaferon at least from the second year onwards. EDSS progression (confirmed increase

in EDSS of at least one point compared to baseline) was lower in the immediate treatment

group (Table 3, significant effect after 3 years, no significant effect after 5 years). The majority

of patients in both treatment groups had no disability progression over the 5-year period.

Robust evidence for benefit on this outcome parameter could not be demonstrated for

'immediate' treatment. No benefit, attributable to immediate Betaferon treatment, in quality of

life (as measured by FAMS - Functional Assessment of MS: Treatment Outcomes Index) was

seen.

RR-MS, SP-MS and single clinical event suggestive of MS

Betaferon was effective in all multiple sclerosis studies to reduce disease activity (acute

inflammation in the central nervous system and permanent tissue alterations) as measured by

magnetic resonance imaging (MRI). The relation of multiple sclerosis disease activity as

measured by MRI and clinical outcome is currently not fully understood.

5.2 Pharmacokinetic properties

Betaferon serum levels were followed in patients and volunteers by means of a not

completely specific bioassay.

Maximum serum levels of about 40 IU/ml were found 1-8

hours after subcutaneous injection of 500 microgram (16.0 million IU) interferon beta-

1b. From various studies mean clearance rates and half-lives of disposition phases

from serum were estimated to be at most 30 ml·min

·kg

and 5 hours, respectively.

Betaferon injections given every other day do not lead to serum level increases, and the

pharmacokinetics do not seem to change during therapy.

The absolute bioavailability of subcutaneously administered interferon beta-1b was approxi-

mately 50%.

5.3 Preclinical safety data

No acute toxicity studies have been carried out. As rodents do not react to human interferon

beta, repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia

was observed, as well as a significant rise in lymphocytes and a significant decrease in

thrombocytes and segmented neutrophils.

No long-term studies have been conducted. Reproduction studies with rhesus monkeys

revealed maternal toxicity and an increased rate of abortion, resulting in prenatal mortality. No

malformations have been observed in the surviving animals. No investigations on fertility have

been conducted. No influence on the monkey oestrous cycle has been observed. Experience

with other interferons suggests a potential for impairment of male and female fertility.

In one single genotoxicity study (Ames test), no mutagenic effect has been observed.

Carcinogenicity studies have not been performed. An in vitro cell transformation test gave no

indication of tumorigenic potential.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients:

Vial (with powder for solution for injection):

Human albumin

Mannitol

Solvent (sodium chloride solution 5.4 mg/ml (0.54% w/v)):

Sodium chloride

Water for injection

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except for the

supplied solvent mentioned in section 6.6.

6.3 Shelf life

The expiry date of the product is indicated on the packaging materials.

After reconstitution, immediate use is recommended. However, the in-use stability has been

demonstrated for 3 hours at 2-8°C.

6.4 Special precautions for storage

Store below 25°C.

Do not freeze.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

Vial (with powder for solution for injection):

3 ml clear vial (type I glass) with a butyl rubber stopper (type I) and aluminium overseal and

Solvent (with sodium chloride solution 5.4 mg/ml (0.54% w/v)):

2.25 ml pre-filled syringe (type I glass) with 1.2 ml solvent.

Pack sizes:

Pack with 12 or 15 single packs, each containing 1 vial with powder, 1 pre-filled syringe with

solvent, 1 vial adapter with needle, 2 alcohol wipes.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling of the product

Reconstitution

To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter with

attached needle on the vial. Connect the pre-filled syringe with solvent to the vial adapter and

inject the 1.2 ml of the solvent (sodium chloride solution, 5.4 mg/ml (0.54% w/v)) into the

Betaferon vial. Dissolve the powder completely without shaking.

After reconstitution, draw 1.0 ml from the vial into the syringe for the administration of

250 micrograms Betaferon.

For the dose titration at the start of treatment draw the respective volume as given in section

4.2.

Remove the vial with the vial adapter from the pre-filled syringe before injection.

Betaferon may also be administered with a suitable autoinjector.

Inspection prior to use

Inspect the reconstituted product visually before use. The reconstituted product is colourless

to light yellow and slightly opalescent to opalescent.

Discard the product before use if it contains particulate matter or is discoloured.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with

local requirements.

Manufactured by:

Bayer AG, Müllerstrasse 178, Berlin, Germany

Registration Holder:

Bayer Israel Ltd, 36 Hacharash St., Hod Hasharon 45240