Reasons for adding or updating:

• Change to section 4.8 - Undesirable effects
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 25-Sep-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



SmPC - Section 4.8 ‘Undesirable effects’

Pulmonary arterial hypertension (with a footnote that this is a Class label for interferon products) and Drug-induced lupus erythematosus have been added to the ADR table under ‘Frequency not known’.

In addition the following statement has been added below the ADR table:

‘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.’

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.8 - Undesirable effects - how to report a side effect
• Change to section 6.1 - List of excipients

Date of revision of text on the SPC: 26-Aug-2014

Legal Category:POM

Black Triangle (CHM): NO

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The key changes are:

·        To include class labelling wording on Thrombotic Microangiopathy  

o   Section 4.4 – Thrombotic microangiopathy added

o   Section 4.8 – Table 2 updated

o   Section 6.1 – minor correction made

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.7 - Effects on ability to drive and use machines
• Change to section 9 - Date of first authorisation/renewal of the authorisation

Date of revision of text on the SPC: 01-Apr-2014

Legal Category:POM

Black Triangle (CHM): NO

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A summary of the changes are listed below:

 

·        SmPC:

o   SmPC updated to latest template

o   Section 4.2 – method of administration added

o   Section 4.4 – Nephrotic  syndrome added

o   Section 4.7 – Table 2.2 updated 

Reasons for adding or updating:

• Change to section 4.8 - Undesirable Effects
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 6. 5 - Nature and Contents of Container
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 25-May-2012

Legal Category:POM

Black Triangle (CHM): NO

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·         Update of section 4.8 of the SmPC in order to add the following adverse reactions identified during post-marketing surveillance: weight increased, menorrhagia, arthralgia, dizziness, vasodilatation, diarrhoea and the following terms which are described in section 4.4: capillary leak syndrome, hepatic injury and hepatic failure. Table 2 in section 4.8 used to state “spontaneous adverse drug reports” , now states “Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data N= 1093)” and was amended such that reaction frequencies are based on pooled clinical trial data.

Sections 5.1 & 6.5 -Minor editorial modifications were made.
Section 10: Revision date is now 25 May 2012

Reasons for adding or updating:

• Change to section 7 - Marketing Authorisation Holder
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Jul-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

The Marketing Authorisation Holder details have been updated from Bayer Schering Pharma AG to Bayer Pharma AG
Revsion date is now 1 July 2011.

Reasons for adding or updating:

• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Jan-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Revision date has been amended from December 2010 to Janaury 2011 to ensure EU consistency

Reasons for adding or updating:

• Change to section 6. 5 - Nature and Contents of Container
• Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Dec-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



SmPC Section 6.5 has been updated to include 2 new pack sizes: pack with 12 single packs, 2 month pack with 2 x 14 packs. These pack sizes have been added to the (European) licence for marketing specifically in Germany.

SmPC Section 8 has been updated with 2 new Marketing Authorisation numbers for these new pack sizes.

SmPC Section 10 date of revision has been updated. to December 2010

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.8 - Undesirable Effects
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Jan-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.2 ( Posology and method of administration) - The text in this section has been updated to include data from 5 years rather than 3.
Section 4.4 (Special warnings and precautions for use) - Under the immunogenicity section the figures have been amended following change of assessment from 3 to 5 years
Section 4.8 (Undesirable effects) - Mention of the BENEFIT follow-up study has been incorporated into the table.
Section 5.1 (Pharmacodynamic properties) - For ease of use, a new table has been inserted (table 3) to include the 5 year results. Explanatory text has also been incorporated into the section.
Section 10 ( Date of revision) - this is now January 2010.

Reasons for adding or updating:

• Change to section 6. 5 - Nature and Contents of Container
• Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
• Change to section 10 date of revision of the text
• Correction of spelling/typing errors

Date of revision of text on the SPC: 01-Feb-2009

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 6.5: New Pack sizes of 14 and 3 X 14 (planned for German market only, but licence is centralised)
Section 8: Additional Licence Numbers have been added for new pack sizes.
Section 10: Revision Date is now February 2009.

Correction of minor typographical amendments. 

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 6. 5 - Nature and Contents of Container
• Change to section 6. 6 - Instructions for use, handling and disposal
• Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Oct-2008

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.2 ( Posology and Method of Administration) addition of  a titration pack consisting of 4 triple packs has been included.
Section 6.5 ( Nature and contents)   information of titration pack has been inserted.
Section 6.6 ( Special precautions) - information on auto injector has been added.
Section 8 ( Marketing Authorisation numbers) - licence EU/1/95/003/008 has been removed.
Section 10 ( Date of revision) - this is now 10/2008.

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.8 - Undesirable Effects
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Dec-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 7 - Marketing Authorisation Holder
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Mar-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.2: Deletion of the recommendation that Betaferon is not for use in children under 18 years: Addition of new text regarding the use of Betaferon in adolescents aged 12 to 16 years. New text: “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 and therefore Betaferon should not be used in this population.”

 

Section 5.1: Deletion: of “ highly” from the sentence “Betaferon delayed the progression from the first clinical event to clinically definite multiple sclerosis (CDMS) in a “highly”statistically significant and clinically meaningful manner, corresponding to a risk reduction of 47% (Hazard Ratio = 0.53, 95% confidence interval (0.39, 0.73), p<0.0001).

 

Section 7: Change of name of MA holder from Schering AG to Bayer Schering Pharma AG

 

Section 10: Date of revision changed to 29 March 2007

Reasons for adding or updating:

• Change to section 6. 5 - Nature and Contents of Container
• Change to section 6. 6 - Instructions for use, handling and disposal
• Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 01-Sep-2006

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 6.5 – addition of details and pack sizes for 2.25 ml pre-filled syringe

 

Section 6.6 – addition of reconstitution details for 2.25 ml pre-filled syringe

 

Section 8 – addition of MA numbers for 2.25 ml pre-filled syringe

 

Section 10 – date of revision of text changed to 1 September 2006

Reasons for adding or updating:

• Change to section 10 (date of (partial) revision of the text
• Change to section 4.2 - Posology and Method of Administration
• Change to section 4.1 - Therapeutic Indications
• Change to section 4.3 - Contra-indications
• Change to section 4.4 - Special Warnings and Precautions for Use
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.8 - Undesirable Effects
• Change to section 5.1 - Pharmacodynamic Properties
• Change to section 9 - Date of Renewal of Authorisation

Date of revision of text on the SPC: 01-Jun-2006

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

 Betaferon SPC changes

Section 4.1

o       Addition of new indication "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 (see section 5.1)"

o       All other indications have been re-formatted into bullet points

Section 4.2

o        Addition of advice regarding dose titration at the start of treatment

 

"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	ml
7, 9, 11	125	microgram	0.5	ml
13, 15, 17	187.5	microgram	0.75	ml
> 19	250	microgram	1.0	ml

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

o       Revised information regarding the extent of follow up and efficacy data

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

Section 4.3

The text has been amended:

•  From  "pregnancy" to "Initiation of treatment in pregnancy (see section 4.6 Pregnancy and lactation)."
• From  "Hypersensitivity to the active substance or to any of the excipients or to natural or recombinant interferon beta" to "    Patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin or to any excipients"
•  From "Patients with a history of severe depressive disorders and/or suicidal ideation to Patients with current severe depression and/or suicidal ideation (see section 4.4 Special warnings and special precautions for use and 4.8 Undesirable effects)."
•   "Patients with epilepsy not adequately controlled by treatment" has been deleted from section 4.3 and moved to section 4.4 under Nervous system disorders with amended wording. 

Section 4.4 

•      Order of text has been changed and text placed under new sub-headings as appropriate e.g. Immune System Disorders
•        Nervous system disorders: Addition of new text  "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 in increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Betaferon should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with Betaferon and treated appropriately. Cessation of therapy with Betaferon should be considered (see also section  4.3 and section 4.8). "
•       Nervous system disorders: Addition of text from section 4.3 and re-worded "Betaferon should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics (see section 4.5 and section 4.8)."
•       General disorders: Addition of new text "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."
•        Immunogenicity: Addition of new text  "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, 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."
•       Immunogenicity: Addition of new text  "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))."
•        Immunogenicity: Addition of new text  "The decision to continue or discontinue treatment should be based on clinical disease activity rather than on neutralising activity status."

Section 4.6

•    Pregnancy: text has been revised to : "There is limited information on the use of Betaferon in pregnancy. Available data indicates 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: text has been changed from  " ... ­and it should be recommended to discontinue therapy" to  "discontinuation of therapy should be considered"
•    Women of child bearing potential: addition of new text " In patients with a high relapse rate before treatment started, 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."
• Lactation: text has been changed from  " ­ whether nursing or Betaferon should be disciontinued" to  " whether to discontinue breast-feeding or Betaferon".

Section 4.8

•         Addition of new text  "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."
•         Table 1 : new column added giving adverse events seen in new study - Single event suggestive of multiple sclerosis (BENEFIT) study
•       Table 1 : order of side effects listed changed
•      Table 1: additional data given for all studies for Psychiatric disorders - depression and anxiety
•        Table 1 : heading changed from Respiratory disorders to Respiratory, thoracic and mediastinal disorders. addition of new adverse event data for  "Upper respiratory tract infection"
•         Table 1: heading changed from musculoskeletal disorders to musculoskeletal and connective tissue disorders
•         Table 2: new layout of table with new System Organ Class headings. Various adverse drug reactions have been moved into the new sections e.g. anaphylactic  reactions moved from. General disorders to Immune system disorders
•         Table 2: New term  "weight decrease"  added in under new heading  "investigations"

Section 5.1

•        New information added : details of a clinical trial in patients with a single clinical event and MRI features suggestive of multiple sclerosis.

                            "Single clinical event suggestive of MS:

The robustness of the treatment effect was also shown by the delay of progression to multiple sclerosis according to the McDonald criteria. In two years, the risk in the placebo group was 85 % and 69 % in the Betaferon group (Hazard Ratio = 0.57, 95% confidence interval (0.46, 0.71), p<0.00001).

Subgroup analyses according to baseline factors demonstrated evidence of efficacy in all subgroups evaluated. Significant effects were also obtained in patients with less disseminated and less active disease at the time of the first event, the risk in two years for progression to CDMS in patients with monofocal onset was 47 % for placebo and 24 % for Betaferon, without gadolinium (Gd-) enhancement 41 % and 20 %, with less than 9 T2 lesions 39 % and 18 %. Further subgroup analyses indicated a high risk for progression to CDMS within 2 years in monofocal patients with at least 9 T2-lesions (55% risk for placebo, 26 % for Betaferon) or Gd-enhancement (63% versus 33 %). 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. However, the long-term impact of early treatment with Betaferon is unknown even in these high risk subgroups as this study was mainly designed to assess the time to CDMS rather than the long term evolution of the disease. Furthermore, 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 in the study of patients with a single clinical event as indicated by a high rate of trial completion (92.8% in the Betaferon group). To increase tolerability of Betaferon in the study of patients with a first clinical event, 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."

Section 9

•         Date of last renewal changed

Section 10

•          Date of last revision changed 

 

 

 

 

 

Reasons for adding or updating:

• Change to section 3 - pharmaceutical form
• Change to section 4.4 - Special Warnings and Precautions for Use
• Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.8 - Undesirable Effects
• Change to section 4.9 - Overdose
• Change to section 6.2 - Incompatibilities
• Change to section 6. 3 - Shelf Life
• Change to section 6. 4 - Special Precautions for Storage
• Change to section 6. 5 - Nature and Contents of Container
• Change to section 6. 6 - Instruction for Use/Handling
• Change to section 9 - Date of Renewal of Authorisation
• Change from datasheet to SPC

Reasons for adding or updating:

• Change to section 6. 4 - Special Precautions for Storage
• Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

• Change to section 6. 3 - Shelf Life
• Change to section 6. 4 - Special Precautions for Storage

Reasons for adding or updating:

• Correction of spelling/typing errors

Reasons for adding or updating:

• Change to section 2 - qualitative and quantitative composition
• Change to section 4.1 - Therapeutic Indications
• Change to section 4.2 - Posology and Method of Administration
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.8 - Undesirable Effects
• Change to section 6.1 - List of Excipients
• Change to section 6. 3 - Shelf Life
• Change to section 6. 5 - Nature and Contents of Container

Reasons for adding or updating:

• Transferred from eMC version 1

Reasons for adding or updating:

• No reasons supplied

Reasons for adding or updating:

• No reasons supplied