| 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
|
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
"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.
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). Within the study period of two years, CDMS occurred in 45% of the placebo group compared to 28% of the Betaferon group (Kaplan-Meier estimates). 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).
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
Section 10
|
