Package Leaflet
Introduction
This package insert for Betaferon® has been approved for use in material that is distributed within the European Community (EU). The text may not correspond exactly to the insert in other countries.
What Betaferon is and what it is used for
Betaferon belongs to the pharmacotherapeutic group of interferons, which are naturally occurring proteins.
How Betaferon works
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) (i.e. brain and spinal cord) and its exact cause is unknown. An abnormal response by the body's immune system is thought to play an important part in the process which damages the CNS.
Interferon beta-1b has been shown to modify the immune system response and thus helps to reduce the disease activity.
What Betaferon is used for
Betaferon is indicated for use in patients who for the first time have experienced symptoms which indicate a high risk for development of multiple sclerosis. Your doctor will rule out any other reasons which could explain these symptoms before you are treated.
Betaferon is also indicated for use in ambulatory patients (patients who can walk) with relapsing-remitting multiple sclerosis characterised by at least two attacks of neurologic dysfunction over a two year period followed by complete or incomplete recovery. In this patient population Betaferon was shown to reduce the frequency and severity of clinical relapses, to reduce the number of multiple sclerosis rela¬ted hospitalisations and to prolong the relapse-free time.
Betaferon is further indicated for patients suffering from secondary progressive multiple sclerosis with active disease evidenced by relapses. In this patient population Betaferon is used to slow the progression of disability and to reduce the frequency of relapses.
Before you use Betaferon
If you suffer from the so-called ‘relapsing-remitting multiple sclerosis’ and have had fewer than two multiple sclerosis attacks in the previous two years you are not recommended to use Betaferon. If you suffer from the so called ‘secondary-progressive multiple sclerosis’ and have had no active disease in the previous two years you are not recommended to use Betaferon. In case of doubt ask your doctor.
Do not use Betaferon:
- if you are pregnant, since therapy with Betaferon must not be started (see ‘Pregnancy’).
- if you have been allergic (hypersensitive) to natural or recombinant interferon beta, human albumin or any of the other ingredients of Betaferon.
- if you currently suffer from severe depression and/or suicidal thoughts (see ‘Take special care’ and 4. Possible side effects).
- if you have a history of liver failure.
Take special care with Betaferon:
- If you might have a disorder of the immune system in which abnormal proteins are found in the blood (monoclonal gammopathy), you must check this with your doctor before you use Betaferon. Patients who have the rare condition known as monoclonal gammopathy may develop problems with their small blood vessels (capillaries) leading to shock (collapse) which can be fatal, when they use medicines like Betaferon. See also 4. Possible side effects.
- If you know that you have suffered from an increase of certain blood fats (triglycerides) or if you have suffered from pancreatitis, please inform your doctor. In rare cases, pancreatitis was observed with Betaferon use, often associated with an increase of triglycerides.
- If you feel noticeably more sad or more hopeless than before the therapy had started, or if you develop thoughts of killing yourself, contact your doctor immediately. If you have had depression and/or thoughts of killing yourself before therapy with Betaferon has been started, inform your doctor. Such side effects have been reported by patients. If you experience such symptoms, your doctor will closely monitor you during therapy and treat you for the depressions and/or suicidal thoughts. He/she may also consider to stop your therapy.
- 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.
- If you have experienced seizures in the past, inform your doctor. Tell him/her, if you are taking anti-epileptics for it, see also section ‘Using other medicines’ and 4. Possible side effects. Your doctor may then treat you with caution.
- Function tests of the thyroid gland are recommended regularly in patients with a history of thyroid dysfunction (inform your doctor if you have suffered from problems with your thyroid) or if deemed necessary by your doctor for other reasons.
- In addition to those laboratory tests normally required for monitoring your disease, your doctor will usually order blood tests (a complete blood cell count and measurement of liver enzymes in the blood) before you start Betaferon and regularly whilst you are on it.
- If you have noticed any unusual bruising, excessive bleeding after injury or if you seem to be catching a lot of infections, tell your doctor. Your doctor will consider if you need more blood tests to check your blood cell counts. If your white blood cell count decreases, your doctor should monitor you closely for the development of fever or infection. The number of platelets (which help the blood to clot) may also fall.
- Your liver function may be affected. Elevations of liver function values, in most cases mild and transient, occurred very commonly in patients treated with Betaferon during clinical studies. As for other beta interferons, severe liver injury, including cases of liver failure, has been reported rarely in patients taking Betaferon.
Symptoms of changes in your liver may include loss of appetite, nausea, repeated vomiting, diffuse itching, yellowing of the skin, or of the whites of the eyes and easy bruising. Inform your doctor if you get such symptoms and inform your doctor as well about any other drugs or substances you are taking. - If you have severe kidney problems, your doctor will consider, if your kidney function will be closely monitored during treatment.
- If you already suffer from a heart disorder, Betaferon must be administered with caution. You should inform your doctor. He/she will monitor you for worsening of your heart condition, particularly during the start of treatment with Betaferon.
At the start of Betaferon treatment the flu-like syndrome may prove stressful to you, if you already have a heart disorder. - If you experience symptoms like irregularity of your heart beat or fluid retention (swelling) in the lower part of your body (e.g. ankles, legs) or shortness of breath, contact your doctor immediately. During treatment with Betaferon a disease of the heart muscle (cardiomyopathy) has been reported in rare cases.
- It is not known if Betaferon has a negative effect on your fertility but based on the experience with other interferons, a decrease in male or female fertility cannot be ruled out.
- If a serious hypersensitivity reaction occurs (possible symptoms of which are for example: itching all over your body, swelling of your face, your tongue or a strong shortness of breath), contact a doctor immediately because such a reaction may become life threatening. Treatment with Betaferon must be discontinued.
- Injection site reactions including redness, swelling, discoloration, inflammation, pain, hypersensitivity, and non-specific reactions occur frequently. Skin breakdown and tissue destruction (necrosis) are reported less frequently. The occurrence of injection site reactions usually decreases over time.
- Injection site skin breakdown and tissue destruction (necrosis, see section “4. Possible side effects”) can be extensive and may involve muscle fascia as well as fat and can therefore result in scar formation. Occasionally debridement (the removal of foreign matter and dead tissue) and, less often, skin grafting are required and healing may take up to 6 months.
- If you experience any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, you should consult your doctor before continuing injections with Betaferon.
- If you have multiple lesions Betaferon must be discontinued until healing has taken place. Patients with single lesions may continue on Betaferon, injecting at different sites, and 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 you must:
- use an aseptic injection technique
- rotate the injection sites with each dose.
Injection site reactions may occur less frequently when using an autoinjector. - The procedure for self-administration must be reviewed periodically by your doctor, especially if injection site reactions have occurred.
- During the treatment with Betaferon your body may produce substances which are called neutralising antibodies. It is not possible to foresee whether or not you belong to this group of patients, in whom this happens. It is also not yet clear whether these neutralising antibodies reduce the effectiveness of the treatment.
Using other medicines:
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines without prescription.
With the exception of corticoids or ACTH (anti-inflammatory medicines), Betaferon should not be used with substances that modify the immune system response.
Caution must be exercised when Interferon beta-1b is administered in combination with other medicines which need a certain liver enzyme system (known as cytochrome P450 system) for their metabolism. These medicines include some widely used antipyretics (medicines against fever and pain) and anti-epileptics.
Caution should also be exercised with medicines having an effect on the production of blood cells.
Using Betaferon with food and drink:
Betaferon is injected under the skin. An influence by food or drinks is thus not to be expected.
Children and adolescents:
There have been no formal clinical trials undertaken in children or adolescents.
However, there is some data available in children and adolescents from 12 to 16 years. This data suggests that the safety profile from this age is the same as in adults for use of Betaferon 8 million IU under the skin (subcutaneously) every other day. Betaferon should not be used in children under 12 years of age as there is no information on this use.
Pregnancy:
If you are pregnant or you think you may be, inform your doctor. Betaferon therapy should not be started if you are pregnant.
You should take appropriate contraceptive measures while you are on Betaferon.
If you wish to become pregnant, discuss the matter with your doctor first. If you do become pregnant when using Betaferon, you should stop your treatment and contact your doctor immediately.
Your doctor will decide together with you, if your Betaferon treatment will be continued or not.
Ask your doctor or pharmacist for advice before taking any medicine.
Breast-feeding:
It is not known whether Interferon beta-1b is excreted in the breast milk. However, since serious side effects to Interferon beta-1b in breast-fed infants are theoretically possible, you must discuss the matter with your doctor and make a decision whether to stop breast-feeding or using Betaferon.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines:
No studies on the effects of Betaferon on the ability to drive and use machines have been performed. However, if you are susceptible, your ability to drive and use machines might be influenced due to central nervous system-related side effects, associated with the use of Betaferon.
Important information about some of the ingredients of Betaferon:
The inactive ingredients of Betaferon include small amounts of mannitol (a naturally occurring sugar) and human albumin (a protein). If you know that you are hypersensitive to any of the ingredients or if you become so, you must not use Betaferon.
How to use Betaferon
The treatment with Betaferon should be initiated under the supervision of a physician experienced in the treatment of the disease.
Always use Betaferon exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure.
The usual dose is:
Every other day, 1.0 ml of the prepared Betaferon solution (see Annex) must be injected under the skin (subcutaneously). This equals 250 microgram (8 million IU) Interferon beta-1b.
In general, treatment should be started at a low dose of 0.25 ml (62.5 micrograms). Your doses will then be increased slowly to a final dose of 1.0 ml (250 micrograms).
The dose should be increased at every fourth injection in four steps (0.25 ml, 0.5 ml, 0.75 ml, 1.0 ml). The time period for the dose increase may be modified depending on side effects you may experience at the start of treatment. Your doctor will decide this together with you.
If you have the impression that the effect of Betaferon is too strong or too weak, talk to your doctor or pharmacist.
Before administration, the Betaferon solution for injection has to be prepared from a vial of Betaferon and 1.2 ml of liquid from the pre-filled solvent syringe. This will either be done by your doctor or his/her assistant or by yourself after you have been carefully and sufficiently instructed and trained.
To assist you in subcutaneous self-administration of Betaferon (injection under the skin), detailed instructions for self-injection are provided with this leaflet (see “Annex: Self-injection”). These instructions also tell you how the Betaferon solution for injection is prepared.
The injection site must be changed regularly. See also “Take special care with Betaferon” and follow the instructions under “Rotating injection sites” under “Self-injection procedure” in the Annex of this leaflet.
Betaferon should be injected under the skin every other day.
At present it is not known how long treatment with Betaferon should last. 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, efficacy has been demonstrated over a period of two years.
The duration of treatment will be decided by your doctor together with you.
If you use more Betaferon than you should:
Administration of many times the dose of Betaferon recommended for the treatment of multiple sclerosis has not led to life-threatening situations.
Please consult the doctor who prescribed Betaferon for you in the case of accidental overdose. In addition, should you administer your injection too frequently by mistake (e.g. one injection every 24 h instead of one injection every 48 h) you should consult your doctor.
If you forget to use Betaferon:
If you forget to administer your injection at the correct time you must take it as soon as you remember. The following injection should be given 48 hours later.
Do not administer a double dose to make up for a forgotten individual dose.
If you stop using Betaferon:
Acute withdrawal symptoms are not to be expected if you have forgotten to inject Betaferon or if you have stopped using it. If you stop or wish to stop treatment, you should discuss this with your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Possible sied effects
Like all medicines, Betaferon can cause side effects, although not everybody gets them.
a) At the beginning of treatment side effects are common but in general they subside with further treatment. The most frequently observed adverse reactions are flu-like symptoms (fever, chills, painful joints, malaise, sweating, headache, or muscular pain) and injection site reactions.
Generally, a step-wise increase of the dose is recommended at the start of treatment in order to increase tolerability of Betaferon (see section 3. How to use Betaferon). Flu-like symptoms may also be reduced by administration of anti-inflammatory drugs. Injection site reactions may be reduced by the use of an autoinjector. Please consult your doctor for further information.
b) The following side effects listing is based on reports from clinical trials with Betaferon (table 1) and from side effects reports on the marketed product (table 2).
In general, frequencies of side effects obtained from clinical trials are higher than those from the marketed product. This can be explained by the fact that patients included into clinical trials are directly asked for such side effects, whereas the data of the marketed product mostly consist of spontaneous reports.
Experience with Betaferon in patients with multiple sclerosis is limited, consequently those adverse events which occur very rarely may not yet have been observed:
Table 1: (side effects which have occurred in clinical trials with Betaferon very commonly (at a percentage of ≥ 10%) and at a higher percentage than those observed with placebo. The table also includes side effects which occur in less than 10% of the cases but which are of statistical importance)
| Infections and infestations | |
| infection, abscess |
|
| Blood and the lymphatic system disorders | |
| decrease of white cells in the blood, swollen lymph glands |
|
| Metabolism and nutrition disorders | |
| increase of sugar in the blood | |
| Psychiatric disorders | |
| depression, anxiety |
|
| Nervous system disorders | |
| headache, dizziness, sleeplessness, migraine, numbness or tingling feeling (paresthesia) |
|
| Eye disorders | |
| conjunctivitis, abnormal vision |
|
| Ear and labyrinth disorders | |
| ear pain | |
| Cardiac disorders | |
| palpitation | |
| Vascular disorders | |
| dilatation of blood vessels, increased blood pressure |
|
| Respiratory, thoracic and mediastinal disorders | |
| infection of the upper respiratory tract, sinusitis, cough (increased), shortness of breath |
|
| Gastrointestinal disorders | |
| diarrhoea, constipation, nausea, vomiting, abdominal pain |
|
| Hepatobiliary disorders | |
| the activity of the liver may be affected shown by rises in the blood levels of enzymes it produces | |
| Skin and subcutaneous tissue disorders | |
| skin disorder, rash |
|
| Musculoskeletal and connective tissue disorders | |
| muscle stiffness, painful muscles, muscular debility, back pain, pain in extremity |
|
| Renal and urinary disorders | |
| urinary retention, occurrence of protein in the urine, urinary frequency, urinary incontinence, urinary urgency |
|
| Reproductive system and breast disorders | |
| painful monthly bleeding, menstrual disorder, profuse uterine bleeding especially between menstrual periods, impotence |
|
| General disorders and administration site conditions | |
| injection site reaction (including redness, swelling, discoloration, inflammation, pain, hypersensitivity, see “Take special care with Betaferon”), skin breakdown and tissue destruction (necrosis) at injection site (see “Take special care with Betaferon”), flu-like symptoms, fever, pain, chest pain, accumulation of fluid in arm, leg or face, lack/loss of strength, chills, sweating, malaise |
|
Table 2: side effects reports on the marketed product classified as:
very common: means 10 or more in every 100 people are likely to get these,
common: between 1 and 10 in every 100 people are likely to get these,
uncommon: between 1 and 10 in every 1,000 people are likely to get these,
rare: between 1 and 10 in every 10,000 people are likely to get these,
very rare: less than 1 in every 10,000 people are likely to get these effects.
| Blood and the lymphatic system disorders | |
| uncommon | the number of white cells and red cells in the blood may fall, the number of platelets (which help the blood to clot) may fall |
| rare | swollen lymph glands |
| Immune system disorders | |
| rare | serious hypersensitivity reactions (contact a doctor immediately, for symptoms and necessary action see “Take special care with Betaferon”) |
| Endocrine disorders | |
| rare | the thyroid gland does not work properly (too much or too little hormone is produced) |
| Metabolism and nutrition disorders | |
| rare | a fraction of blood fats (triglycerides) may increase (see “Take special care with Betaferon”), severe loss of appetite leading to weight loss (anorexia) |
| Psychiatric disorders | |
| uncommon | depression (see “Take special care with Betaferon”) |
| rare | confusion, anxiety, emotional lability, suicide attempt (see “Take special care with Betaferon”), |
| Nervous system disorders | |
| rare | convulsion |
| Cardiac disorders | |
| rare | disease of the heart muscle (cardiomyopathy, see “Take special care with Betaferon”), faster heart beat, palpitation |
| Vascular disorders | |
| uncommon | increase of blood pressure |
| Respiratory, thoracic and mediastinal disorders | |
| rare | bronchospasm, shortness of breath |
| Gastrointestinal disorders | |
| uncommon | nausea, vomiting |
| rare | pancreatitis (see “Take special care with Betaferon”) |
| Hepatobiliary disorders | |
| uncommon | the activity of the liver may be affected shown by rises in the blood levels of enzymes it produces |
| rare | a specific liver enzyme (gamma GT) and a reddish yellow pigment (bilirubin), which is produced by your liver, may rise, hepatitis |
| Skin and subcutaneous tissue disorders | |
| uncommon | raised edematous and usually itching patches of skin or mucous membranes (urticaria), rash, pruritus, loss of scalp hair |
| rare | skin discoloration |
| Musculoskeletal disorders | |
| uncommon | painful muscles, muscle stiffness |
| Reproductive system and breast disorders | |
| rare | menstrual disorders |
| General disorders and administration site conditions | |
| very common* | flu-like symptoms, chills, fever, injection site reaction (see “Take special care with Betaferon”), injection site inflammation, injection site pain |
| common* | skin breakdown and tissue destruction (necrosis) at injection site (see “Take special care with Betaferon”) |
| rare | chest pain, malaise, sweating |
| Investigations | |
| rare | loss of weight |
*frequencies based on clinical trials
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
How to store Betaferon
Do not store above 25°C. Do not freeze.
Do not use after the expiry date which is stated on the pack.
After reconstitution an immediate use is recommended. However, the in-use stability has been demonstrated for 3 hours at 2-8 °C.
Keep out of the reach and sight of children.
Do not use Betaferon if you notice it contains particulate matter or is discoloured.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
Further information
What Betaferon contains:
- The active substance is Interferon beta-1b, 250 microgram per millilitre when reconstituted.
- The other ingredients are
- in the powder: mannitol and human albumin
- in the solvent: (sodium chloride solution 5.4 mg/ml (0.54 % (w/v))): sodium chloride, water for injections.
The powder of Betaferon is provided in a 3-ml vial, containing 300 microgram (9.6 million IU) Interferon beta-1b per vial. After reconstitution each ml contains 250 microgram (8 million IU) Interferon beta-1b.
The solvent of Betaferon is provided in a 2.25-ml pre-filled syringe and contains 1.2 ml sodium chloride solution 5.4 mg/ml (0.54%).
What Betaferon looks like and contents of the pack:
Betaferon is a sterile white to off-white powder for solution for injection.
Betaferon is available in pack sizes of:
- multipacks comprising 5 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent, 1 vial adapter with needle, 2 alcohol wipes or
- multipacks comprising 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.
Marketing authorisation holder and manufacturer:
Bayer Schering Pharma AG, D-13342 Berlin, Germany
