Editorial correction

Note:

Text in black = unchanged text

Text in blue = added text

Section 4:

Reporting of side effects

[....]

You can also report side effects directly (see details below).

[....]

Betaferon - Var 130_type II_BEC17289+17137_CCDS15+IE tel. no

2. What you need to know before you use Betaferon

[…]

Other things to consider when using Betaferon

[…]

• Paleness, yellow skin or dark-colored urine, possibly accompanied by unusual dizziness, tiredness or shortness of breath may occur during your treatment. These may be symptoms of a breakdown of red blood cells. This might happen several weeks to several years after starting Betaferon. Your doctor may perform blood tests. Inform your doctor about other medicines that you are taking at the same time as Betaferon.

[…]

4. Possible side effects

[…]

Side effects derived only during post-marketing:

[…]

-        breakdown of red blood cells (haemolytic anaemia), frequency unknown

[…]

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects, you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

6. Contents of the pack and other information

Marketing Authorisation Holder and Manufacturer

<Local representative information was revised to only include information on Ireland and Malta.>

Ireland

Bayer Limited

Tel: +353 1 216 3300299 93 13

This leaflet was last revised in 10/2020.

Betaferon - Var 130_type II_BEC17289+17137_CCDS15+IE tel. no

4.4 Special warnings and precautions for use

Thrombotic microangiopathy (TMA) and Haemolytic anaemia (HA)

[…]

Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta.

[…]

Additionally, cases of HA not associated with TMA, including immune HA, have been reported with interferon beta products. Life-threatening and fatal cases have been reported. Cases of TMA and/or HA have been reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta.

If TMA and/or HA is diagnosed and a relationship to Betaferon is suspected, prompt treatment is required (in case of TMA considering plasma exchange) and immediate discontinuation of Betaferon is recommended.

[…]

4.8 Undesirable effects

Summary of the safety profile

[…]

The most serious adverse reactions reported include thrombotic microangiopathy (TMA) and haemolytic anaemia (HA).

[…]

Tabulated list of adverse reactions

[…]

Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data N= 1093)

Reporting of suspected adverse reactions

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. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

10. DATE OF REVISION OF THE TEXT

October 2020

PRAC recommendation (BEC13878): information for guidance while planning pregnancy and therapy during pregnancy

Section 2 - addition of the following: * produced by genetic engineering from strain of Escherichia coli.

Section 4.4 - Excipient warning:

Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free’.

Minor Editorial changes have been made to section 5.1 & 5.2

In section 4.8:

The table 2: Adverse drug reactions has had the following additions:

⁴ Class label for interferon products, see below Pulmonary arterial hypertension.

The following paragraph has also been added to the same section:

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.

4.4     Special warnings and precautions for use

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.

4.8     Undesirable effects

Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data N= 1093)

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. Healthcare professionals are asked to report any suspected adverse reactions via IMB HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax; +353 1 6762517. Website: www.imb.iewww.hpra.ie; Ee-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Clinical efficacy and safety

…

SP-MS

…

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.

6.       PHARMACEUTICAL PARTICULARS

6.1     List of excipients:

Vial (with powder for solution forand injection):

Human albumin

Mannitol

10.     DATE OF REVISION OF TEXT

Augustpril 2014

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

4.2     Posology and method of administration

Posology

Paediatric population(Children and adolescents)

age. and t Therefore Betaferon should not be used in this population.

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 Pregnancy and lactation).

-               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 Special warnings and special precautions for use and 4.8Undesirable effects).

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

4.4     Special warnings and precautions for use

Nervous system disorders

Betaferon and treated appropriately. Cessation of therapy with Betaferon should be considered (see also sections 4.3 and section 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 section  4.8).

Hepatobiliary disorders

As for other beta interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients treated withtaking Betaferon.

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.

4.6     Pregnancy and breast-feeding lactation

Women of child-bearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while usingtaking 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 treatmentstarted, 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 Lactation

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

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

Description of selected adverse reactions

Cases of nephrotic syndrome and glomerulosclerosis have been reported during interferon beta treatment (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions via IMB Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax; +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

5.1     Pharmacodynamic properties

Mechanism of action

Clinical efficacy and safetytrials

6.2     Incompatibilities

This medicinal product must not be mixed with other medicinal products except for the supplied solvent mentioned in section 6.6.

6.4     Special precautions for storage

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

6.6     Special precautions for disposal and other handling

Dosage and administration

Disposal

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

10.     DATE OF REVISION OF TEXT

May 2012 April 2014

(Inserted text; deleted text)

4.8          Undesirable effects

…………………………….

b)            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) reporting rates based on spontaneous adverse drug reaction reports classified as very common ≥1/10, common ≥1/100 to <1/10, uncommon ≥ 1/1,000 to < 1/100, rare ≥1/10,000 to <1/1,000, 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 (aAdverse 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).

 


The following updates have also been made to section 4.8:

BEFORE:

Table 2 (reporting rates (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) based on spontaneous adverse drug reaction reports).

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

AFTER:

Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data N= 1093)

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

5.1     Pharmacodynamic properties

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

10.     DATE OF REVISION OF TEXT

July 2012May 2012

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

Changed to: "December 2010"

Section 4.2 Posology and method of administration

In the third final paragraph of the section the text was changed from “….efficacy has been demonstrated over a period of two years.” to “….efficacy has been demonstrated over a period of three years.”

Section 4.4 Special warnings and precautions for use

In the section entitled “Immunogenicity” the text was changed from “In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at the respective visits in between 16.5 and 25.2% of Betaferon treated patients. Neutralising activity was found at least once in 30% (75) of the Betaferon treated patients; of these, 23% (17) returned to negative status before reaching the end of the study. Within the study period of two years, the development of neutralising activity was not associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS)).” to “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% (88) of the patients treated immediately with Betaferon; of these, 47% (41) returned to negative status over a 3 year period. Within this period, the development of neutralizing activity was not associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), and time to confirmed EDSS progression).”

Section 4.8 Undesirable effects

§         The headings in Table 1 were changed from;

To;

§         There was also a change to the key for Table 1. The following text was inserted; “# During the third year of the BENEFIT study, no change of the known risk profile of Betaferon was observed.”

Section 5.1 Pharmacodynamic properties

§         In the section entitled “Single clinical event suggestive of MS:” The following text was inserted between the first and second paragraph tying the two paragraphs together; “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, patient 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. In the placebo-controlled phase, Betaferon delayed….”

§         The following text was inserted at the end of the new first paragraph; “This treatment effect was still evident after the additional year of follow-up at which stage the risk reduction was 41% (Hazard Ratio = 0.59, 95% confidence interval (0.42, 0.83), p = 0.0011).Within the study period of three years, CDMS occurred in 51% of the delayed treatment group compared to 37% of the immediate treatment group (Kaplan-Meier estimates). The persistence of the treatment effect was observed although the majority of patients from the placebo-group was treated with Betaferon in the third year of the study.”

§         A new third paragraph was inserted; “After 3 years, a pre-planned interim analysis showed EDSS progression (confirmed increase in EDSS of greater than or equal 1.0 compared to baseline) occurred in 24% of the patients in the delayed treatment group compared to 16% in the immediate treatment group [Hazard ratio=0.6, 95% confidence interval (0.39, 0.92), p=0.022]. There is no evidence for benefit in terms of confirmed disability progression in the majority of patients receiving 'immediate' treatment. Follow-up of patients is continuing in order to provide additional data. No benefit, attributable to Betaferon, in quality of life (as measured by FAMS - Functional Assessment of MS: Treatment Outcomes Index) was seen.”

§         The title “RR-MS, SP-MS and single clinical event suggestive of MS:” was inserted above the final paragraph of this section.

Section 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

The section entitled “Reconstitution” was changed from “To reconstitute lyophilised interferon beta-1b for injection, use the pre-filled syringe with solvent provided and a needle to inject 1.2 ml of the solvent (sodium chloride solution, 5.4mg/ml (0.54% w/v)) into the Betaferon vial. Dissolve the powder completely without shaking.

After reconstitution, draw 1.0ml from the vial into the syringe for the administration of 250 micrograms Betaferon.” To “To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter with attached needle to 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, 5.4mg/ml (0.54% w/v)) into the Betaferon vial. Dissolve the powder completely without shaking.

After reconstitution, draw 1.0ml from the vial into the syringe for the administration of 250 micrograms Betaferon.

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

Section 10. Date of revision of the text

The date was changed from “March 2007” to “December 2007”

 The following text has been inserted;

 The following text has been deleted:

Children and adolescents(<18 years)

Betaferon is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

 Section 5. PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Heading, Clinical trials; Sub-heading, Single clinical event suggestive of MS:

The text has been changed from;

‘…in a highly statistically significant and clinically meaningful manner,…’

to;

‘…in a statistically significant and clinically meaningful manner,…

 Section 7. MARKETING AUTHORISATION HOLDER

The text has been changed from ‚Schering Aktiengesellschaft’ to ‚Bayer Schering Pharma AG’

 Section 10. DATE OF REVISION OF TEXT

The text has been changed from ’September 2006’ to ‘March 2007’

Main changes to the SPC include:

SECTION 6.5 NATURE AND CONTENTS OF CONTAINER

Updated description of Betaferon vials and pre-filled solvent syringes.

SECTION 6.6 SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

Precautions for handling now categorized under the following headings:

• Reconstitution
• Inspection Prior to Use
• Disposal

Main changes to the SPC include:

SECTION 4.1 THERAPEUTIC INDICATIONS

New indication: Treatment of patients with 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, and if they are determined to be at high risk of developing clinically definite multiple sclerosis.

SECTION 4.2 POSOLOGY AND METHOD OF ADMINISTRATION

Details of recommended slow upward titration of dose upon initiation of treatment.

Updated exposure and efficacy data.

SECTION 4.3 CONTRAINDICATIONS

Deletion of a contraindication: ‘patients with epilepsy not adequately controlled by treatment’.

Change from contraindication in patients with 'history of severe depressive disorders and/or suicidal ideation' to patients with 'current severe depression and/or suicidal ideation'. 

SECTION 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Section reformatted: precautions and warnings presented categorised under body system.

Changes to the following sections:         Nervous system disorders

                                                            Laboratory Test

                                                            Cardiac disorders

                                                            General disorders and administration site conditions

                                                            Immunogenicity

SECTION 4.6 PREGNANCY AND LACTATION

Additional information regarding the use of Betaferon in pregnancy and in women of child-bearing age.

SECTION 4.8 UNDESIRABLE EFFECTS

Table 1: Addition of details of adverse events observed in the ‘BENEFIT’ study (study examining use of Betaferon in single event suggestive of MS).

Table 2: Updated data regarding adverse events reported from the market.

SECTION 5.1 PHARMACODYNAMIC PROPERTIES

Updated ATC code.

Addition of clinical trial data obtained from the ‘BENEFIT’ study (study examining use of Betaferon in single event suggestive of MS).