ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Betaferon 250 microgram/ml, powder and solvent for solution for injection.
2.
Betaferon contains 300 microgram (9.6 million IU) of recombinant interferon beta-1b per vial.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
Sterile white to off-white powder.
4.
Betaferon is indicated for the 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 (see section 5.1).
•
patients with relapsing remitting multiple sclerosis and two or more relapses within the last two
years.
•
patients with secondary progressive multiple sclerosis with active disease, evidenced by
relapses.
The treatment with Betaferon should be initiated under the supervision of a physician experienced in
the treatment of the disease.
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.
Children and adolescents:
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.
Generally, dose titration is recommended at the start of treatment.
*
produced by genetic engineering from strain of
Escherichia coli
.
2
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, 21, 23 et seq. 250 microgram 1.0 ml
* 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.
−
−
Patients with a history of hypersensitivity to natural or recombinant interferon beta, human
albumin or to any excipients.
−
Patients with current severe depression and/or suicidal ideation (see section 4.4 Special
−
Patients with decompensated liver disease (see sections 4.4, 4.5, 4.8).
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.
3
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 section 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 section 4.5 and section 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 γ-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.
Hepato-biliary 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 taking 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
jaundices. 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.
4
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 postmarketing 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.
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.
5
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.
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.
•
Pregnancy
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
Women of child-bearing potential should take appropriate contraceptive measures. If the patient
becomes pregnant or plans to become pregnant while taking Betaferon, she should be informed of the
potential hazards and discontinuation of therapy should be considered (see section 5.3). In patients
6
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
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.
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.
a)
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,
discoloration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were
significantly associated with 250 microgram (8 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.
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,
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.
7
Table 1
(adverse events and laboratory abnormalities with incidence rates
≥
10% and the respective
percentages under placebo; significantly associated side effects < 10%).
System Organ Class
Single Event
suggestive of
Multiple
Sclerosis
(BENEFIT)
#
Secondary
Progressive
Multiple
Sclerosis
(European
Study)
Secondary
Progressive
Multiple
Sclerosis
(North
American
Study)
Relapsing
Remitting
Multiple
Sclerosis
Adverse Event
and
Laboratory Abnormalities
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 (<1500/mm³)
×
Λ
°
79% (45%)
53% (28%)
88% (68%)
82% (67%)
Absolute neutrophil count
decreased (<1500/mm³)
×
Λ
* °
11% (2%)
18% (5%)
4% (10%)
18% (5%)
White blood cell count
decreased (<3000/mm³)
×
Λ
* °
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
Λ
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%)
Paresthesia
16% (17%)
35% (39%)
40% (43%)
19% (21%)
Eye disorders
Conjunctivitis
1% (1%)
2% (3%)
6% (6%)
12% (10%)
Abnormal vision
Λ
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%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory
infection
18% (19%)
3% (2%)
Sinusitis
4% (6%)
6% (6%)
16% (18%)
36% (26%)
8
System Organ Class
Single Event
suggestive of
Multiple
Sclerosis
(BENEFIT)
#
Secondary
Progressive
Multiple
Sclerosis
(European
Study)
Secondary
Progressive
Multiple
Sclerosis
(North
American
Study)
Relapsing
Remitting
Multiple
Sclerosis
Adverse Event
and
Laboratory Abnormalities
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)
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
Λ
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)
× Λ
* °
18% (5%)
14% (5%)
4% (2%)
19% (6%)
Aspartate
aminotransferase
increased (SGOT > 5
times baseline)
× Λ
* °
6% (1%)
4% (1%)
2% (1%)
4% (0%)
Skin and subcutaneous tissue disorders
Skin disorder
1% (0%)
4% (4%)
19% (17%)
6% (8%)
Rash
Λ
°
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
(> 1+)
×
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)
Λ
* °
§
52% (11%)
78% (20%)
89% (37%)
85% (37%)
Injection site necrosis * °
1% (0%)
5% (0%)
6% (0%)
5% (0%)
Flu-like symptoms
& Λ
*°
44% (18%)
61% (40%)
43% (33%)
52% (48%)
Fever
Λ
* °
13% (5%)
40% (13%)
29% (24%)
59% (41%)
9
System Organ Class
Single Event
suggestive of
Multiple
Sclerosis
(BENEFIT)
#
Secondary
Progressive
Multiple
Sclerosis
(European
Study)
Secondary
Progressive
Multiple
Sclerosis
(North
American
Study)
Relapsing
Remitting
Multiple
Sclerosis
Adverse Event
and
Laboratory Abnormalities
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)
Pain
4% (4%)
31% (25%)
59% (59%)
52% (48%)
Chest pain °
1% (0%)
5% (4%)
15% (8%)
15% (15%)
Peripheral oedema
0% (0%)
7% (7%)
21% (18%)
7% (8%)
Asthenia *
22% (17%)
63% (58%)
64% (58%)
49% (35%)
Chills
Λ
* °
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
Λ
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 hemorrhage, 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
(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).
System Organ
Class
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
Blood and
lymphatic system
disorders
Anaemia,
Thrombocytopenia,
Leukopenia
Lymphadenopathy
Immune system
disorders
Anaphylactic
reactions
Endocrine
disorders
Hyperthyroidism,
Hypothyroidism,
Thyroid disorder
Metabolism and
nutrition disorders
Blood triglycerides
increased
Anorexia
10
System Organ
Class
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
Psychiatric
disorders
Depression (see
also section 4.4)
Confusion,
Anxiety,
Emotional lability,
Suicide attempt
(see also section
4.4)
Nervous system
disorders
Convulsion
Cardiac disorders
Cardiomyopathy,
Tachycardia,
Palpitation
Vascular
disorders
Hypertension
Respiratory,
thoracic and
mediastinal
disorders
Bronchospasm,
Dyspnoea
Gastrointestinal
disorders
Vomiting,
Nausea
Pancreatitis
Hepatobiliary
disorders
Alanine amino-
transferase
increased,
Aspartate amino-
transferase
increased
Blood bilirubin
increased,
Gamma-glutamyl-
transferase
increased,
Hepatitis
Skin and
subcutaneous
tissue disorders
Urticaria,
Rash,
Pruritus,
Alopecia
Skin discolouration
Musculoskeletal,
connective tissue
and bone
disorders
Myalgia,
Hypertonia
Reproductive
system and breast
disorders
Menstrual disorder
General disorders
and
administration site
conditions
Flu-like
symptoms*,
Chills*,
Fever*,
Injection site
reaction*,
Injection site
inflammation*,
Injection site pain
Injection site
necrosis*
Chest pain,
Malaise,
Sweating
Investigations
Weight decrease
* frequencies based on clinical trials
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.
11
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytokines, Interferons,
ATC Code: L03 AB 08
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 trials:
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 1657 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 =
12
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 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 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
Placebo
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
n=292
n=176
Number of patients
completed the trial
phase
271 (93%)
166 (94%)
249 (85%)
143 (81%)
235
(80%)
123
(70%)
Primary efficacy variables
Time to CDMS
13
Kaplan-Meier
estimates
28%
45%
37%
51%
46%
57%
Risk reduction
47% versus placebo
41% versus delayed
Betaferon
37% versus delayed
Betaferon
Hazard ratio with
95% confidence
interval
HR = 0.53 [0.39, 0.73]
HR = 0.59 [0.42, 0.83]
HR = 0.63 [0.48, 0.83]
p < 0.0001
p = 0.0011
p = 0.0027
log-rank test
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)
Time to McDonaldMS
Kaplan-Meier
estimates
69%
85%
No primary endpoint
No primary endpoint
Risk reduction
43% versus placebo
Hazard ratio with
95% confidence
interval
HR = 0.57 [0.46, 0.71]
p < 0.00001
log-rank test
Time to confirmed EDSS progression
Kaplan-Meier
estimates
No primary endpoint
16%
24%
25%
29%
Risk reduction
40% versus delayed
Betaferon
24% versus delayed
Betaferon
Hazard ratio with
95% confidence
interval
HR = 0.60 [0.39, 0.92]
HR = 0.76 [0.52, 1.11]
p = 0.022
p=0.177
log-rank test
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
14
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 was 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
-1
·kg
-1
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 approximately
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 suggest a potential for impairment of male and
female fertility.
15
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.
6.1 List of excipients:
Vial (with powder for solution and injection):
Human albumin
Mannitol
Solvent (sodium chloride solution 5.4 mg/ml (0.54% w/v)):
Sodium chloride,
Water for injections.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except for the supplied
solvent mentioned in 6.6.
6.3 Shelf life
2 years.
After reconstitution an 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
Do not store above 25°C.
Do not freeze.
For storage conditions of the reconstituted 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%)):
1.2 ml pre-filled syringe (type I glass) with 1.2 ml solvent.
Pack sizes
-
5 vials with powder and 5 pre-filled syringes with solvent, or
-
15 vials with powder and 15 pre-filled syringes with solvent.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
•
Reconstitution:
To reconstitute lyophilised interferon beta-1b for injection, use the pre-filled syringe with solvent
provided and a needle to 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.
16
After reconstitution, draw 1.0 ml from the vial into the syringe for the administration of 250
micrograms Betaferon.
•
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 product or waste material should be disposed of in accordance with local requirements.
7.
Bayer Schering Pharma AG
D-13342 Berlin
Germany
8.
EU/1/95/003/003
EU/1/95/003/004
9.
Date of first authorisation: 30 November 1995
Date of last renewal: 31 January 2006
17
1.
Betaferon 250 microgram/ml, powder and solvent for solution for injection.
2.
Betaferon contains 300 microgram (9.6 million IU) of recombinant interferon beta-1b per vial.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
Sterile white to off-white powder.
4.
Betaferon is indicated for the 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 (see section 5.1).
•
patients with relapsing remitting multiple sclerosis and two or more relapses within the last two
years.
•
patients with secondary progressive multiple sclerosis with active disease, evidenced by
relapses.
The treatment with Betaferon should be initiated under the supervision of a physician experienced in
the treatment of the disease.
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.
Children and adolescents:
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.
Generally, dose titration is recommended at the start of treatment.
*
produced by genetic engineering from strain of
Escherichia coli
.
18
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.
A titration pack composed of four triple packs is available for the titration period and the patient’s
initial treatment with Betaferon. This package meets the patient’s needs for the first 12 injections. The
triple packs are highlighted in different colours (see section 6.5).
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, 21, 23 et seq. 250 microgram 1.0 ml
* 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.
−
−
Patients with a history of hypersensitivity to natural or recombinant interferon beta, human
albumin or to any excipients.
−
Patients with current severe depression and/or suicidal ideation (see section 4.4 Special
−
Patients with decompensated liver disease (see sections 4.4, 4.5, 4.8).
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.
19
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 section 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 section 4.5 and section 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 γ-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.
Hepato-biliary 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 taking 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
jaundices. 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.
20
Renal and urinary disorders
Caution should be used and close monitoring considered when administering Interferon beta to
patients with severe renal failure.
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 postmarketing 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.
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.
21
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.
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.
•
Pregnancy
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).
22
•
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 taking 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 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
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.
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.
a)
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,
discoloration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were
significantly associated with 250 microgram (8 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.
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,
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.
23
Table 1
(adverse events and laboratory abnormalities with incidence rates
≥
10% and the respective
percentages under placebo; significantly associated side effects < 10%).
System Organ Class
Single Event
suggestive of
Multiple
Sclerosis
(BENEFIT)
#
Secondary
Progressive
Multiple
Sclerosis
(European
Study)
Secondary
Progressive
Multiple
Sclerosis
(North
American
Study)
Relapsing
Remitting
Multiple
Sclerosis
Adverse Event
and
Laboratory Abnormalities
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 (<1500/mm³)
×
Λ
°
79% (45%)
53% (28%)
88% (68%)
82% (67%)
Absolute neutrophil count
decreased (<1500/mm³)
×
Λ
* °
11% (2%)
18% (5%)
4% (10%)
18% (5%)
White blood cell count
decreased (<3000/mm³)
×
Λ
* °
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
Λ
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%)
Paresthesia
16% (17%)
35% (39%)
40% (43%)
19% (21%)
Eye disorders
Conjunctivitis
1% (1%)
2% (3%)
6% (6%)
12% (10%)
Abnormal vision
Λ
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%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory
infection
18% (19%)
3% (2%)
Sinusitis
4% (6%)
6% (6%)
16% (18%)
36% (26%)
24
System Organ Class
Single Event
suggestive of
Multiple
Sclerosis
(BENEFIT)
#
Secondary
Progressive
Multiple
Sclerosis
(European
Study)
Secondary
Progressive
Multiple
Sclerosis
(North
American
Study)
Relapsing
Remitting
Multiple
Sclerosis
Adverse Event
and
Laboratory Abnormalities
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)
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
Λ
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)
× Λ
* °
18% (5%)
14% (5%)
4% (2%)
19% (6%)
Aspartate
aminotransferase
increased (SGOT > 5
times baseline)
× Λ
* °
6% (1%)
4% (1%)
2% (1%)
4% (0%)
Skin and subcutaneous tissue disorders
Skin disorder
1% (0%)
4% (4%)
19% (17%)
6% (8%)
Rash
Λ
°
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
(> 1+)
×
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)
Λ
* °
§
52% (11%)
78% (20%)
89% (37%)
85% (37%)
Injection site necrosis * °
1% (0%)
5% (0%)
6% (0%)
5% (0%)
Flu-like symptoms
& Λ
*°
44% (18%)
61% (40%)
43% (33%)
52% (48%)
Fever
Λ
* °
13% (5%)
40% (13%)
29% (24%)
59% (41%)
25
System Organ Class
Single Event
suggestive of
Multiple
Sclerosis
(BENEFIT)
#
Secondary
Progressive
Multiple
Sclerosis
(European
Study)
Secondary
Progressive
Multiple
Sclerosis
(North
American
Study)
Relapsing
Remitting
Multiple
Sclerosis
Adverse Event
and
Laboratory Abnormalities
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)
Pain
4% (4%)
31% (25%)
59% (59%)
52% (48%)
Chest pain °
1% (0%)
5% (4%)
15% (8%)
15% (15%)
Peripheral oedema
0% (0%)
7% (7%)
21% (18%)
7% (8%)
Asthenia *
22% (17%)
63% (58%)
64% (58%)
49% (35%)
Chills
Λ
* °
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
Λ
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
(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).
System Organ
Class
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
Blood and
lymphatic system
disorders
Anaemia,
Thrombocytopenia,
Leukopenia
Lymphadenopathy
Immune system
disorders
Anaphylactic
reactions
Endocrine
disorders
Hyperthyroidism,
Hypothyroidism,
Thyroid disorder
Metabolism and
nutrition disorders
Blood triglycerides
increased
Anorexia
26
System Organ
Class
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
Psychiatric
disorders
Depression (see
also section 4.4)
Confusion,
Anxiety,
Emotional lability,
Suicide attempt
(see also section
4.4)
Nervous system
disorders
Convulsion
Cardiac disorders
Cardiomyopathy,
Tachycardia,
Palpitation
Vascular
disorders
Hypertension
Respiratory,
thoracic and
mediastinal
disorders
Bronchospasm,
Dyspnoea
Gastrointestinal
disorders
Vomiting,
Nausea
Pancreatitis
Hepatobiliary
disorders
Alanine amino-
transferase
increased,
Aspartate amino-
transferase
increased
Blood bilirubin
increased,
Gamma-glutamyl-
transferase
increased,
Hepatitis
Skin and
subcutaneous
tissue disorders
Urticaria,
Rash,
Pruritus,
Alopecia
Skin discolouration
Musculoskeletal,
connective tissue
and bone
disorders
Myalgia,
Hypertonia
Reproductive
system and breast
disorders
Menstrual disorder
General disorders
and
administration site
conditions
Flu-like
symptoms*,
Chills*,
Fever*,
Injection site
reaction*,
Injection site
inflammation*,
Injection site pain
Injection site
necrosis*
Chest pain,
Malaise,
Sweating
Investigations
Weight decrease
* frequencies based on clinical trials
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.
27
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytokines, Interferons,
ATC Code: L03 AB 08
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 trials:
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 1657 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 =
28
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 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 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
Placebo
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
n=292
n=176
Number of patients
completed the trial
phase
271 (93%)
166 (94%)
249 (85%)
143 (81%)
235
(80%)
123
(70%)
Primary efficacy variables
Time to CDMS
29
Kaplan-Meier
estimates
28%
45%
37%
51%
46%
57%
Risk reduction
47% versus placebo
41% versus delayed
Betaferon
37% versus delayed
Betaferon
Hazard ratio with
95% confidence
interval
HR = 0.53 [0.39, 0.73]
HR = 0.59 [0.42, 0.83]
HR = 0.63 [0.48, 0.83]
p < 0.0001
p = 0.0011
p = 0.0027
log-rank test
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)
Time to McDonaldMS
Kaplan-Meier
estimates
69%
85%
No primary endpoint
No primary endpoint
Risk reduction
43% versus placebo
Hazard ratio with
95% confidence
interval
HR = 0.57 [0.46, 0.71]
p < 0.00001
log-rank test
Time to confirmed EDSS progression
Kaplan-Meier
estimates
No primary endpoint
16%
24%
25%
29%
Risk reduction
40% versus delayed
Betaferon
24% versus delayed
Betaferon
Hazard ratio with
95% confidence
interval
HR = 0.60 [0.39, 0.92]
HR = 0.76 [0.52, 1.11]
p = 0.022
p=0.177
log-rank test
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
30
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 was 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
-1
·kg
-1
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 approximately
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 suggest a potential for impairment of male and
female fertility.
31
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.
6.1 List of excipients:
Vial (with powder for solution and injection):
Human albumin
Mannitol
Solvent (sodium chloride solution 5.4 mg/ml (0.54% w/v)):
Sodium chloride,
Water for injections.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except for the supplied
solvent mentioned in 6.6.
6.3 Shelf life
2 years.
After reconstitution an 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
Do not store above 25°C.
Do not freeze.
For storage conditions of the reconstituted 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%)):
2.25 ml pre-filled syringe (type I glass) with 1.2 ml solvent.
Pack sizes
−
Pack with 5 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,
1 vial adapter with needle, 2 alcohol wipes or
−
Pack with 15 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,
1 vial adapter with needle, 2 alcohol wipes or
−
Pack with 14 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,
1 vial adapter with needle, 2 alcohol wipes or
−
3-month pack with 3x14 single packs, each containing 1 vial with powder, 1 pre-filled syringe
with solvent, 1 vial adapter with needle, 2 alcohol wipes or
−
3-month pack with 3x15 single packs, each containing 1 vial with powder, 1 pre-filled syringe
with solvent, 1 vial adapter with needle, 2 alcohol wipes or
−
Titration pack for dose titration with 4 differently coloured and numbered triple packs:
- yellow, with the number “1”(treatment days 1, 3 and 5; 0.25-ml syringe marking),
32
- red, with number “2” (treatment days 7, 9 and 11; 0.5-ml syringe marking)
- green, with number “3” (treatment days 13, 15 and 17; 0.75-ml syringe marking)
- blue, with number “4” (treatment days 19, 21 and 23; 0.25, 0.5, 0.75 and 1-ml syringe
marking)
Each triple pack contains 3 vials with powder, 3 pre-filled syringes with solvent, 3 vial adapters
with pre-attached needle and 6 alcohol wipes for skin and vial cleaning.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
•
Reconstitution:
To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter with the 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 Dosage and administration.
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 product or waste material should be disposed of in accordance with local requirements.
7.
Bayer Schering Pharma AG
D-13342 Berlin
Germany
8.
EU/1/95/003/005
EU/1/95/003/006
EU/1/95/003/007
EU/1/95/003/008
EU/1/95/003/009
EU/1/95/003/010
9.
Date of first authorisation: 30 November 1995
Date of last renewal: 31 January 2006
33
10. DATE OF REVISION OF TEXT
34
ANNEX II
A.
MANUFACTURERS OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
35
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Boehringer Ingelheim RCV GmbH & Co KG,
Dr.-Boehringer-Gasse 5-11,
A-1121 Vienna,
Austria
Bayer Healthcare Pharmaceuticals Inc.
5650 Hollis Street,
Emeryville, CA 94608,
USA
Name and address of the manufacturer responsible for batch release
Bayer Schering Pharma AG
D-13342 Berlin
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
36
ANNEX III
LABELLING AND PACKAGE LEAFLET
37
A. LABELLING
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(15 VIALs / 15 PRE-FILLED SYRINGES)
1.
Betaferon 250 microgram/ml, Powder and solvent for solution for injection
Interferon beta-1b
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml contains250 microgram (8 million IU) Interferon beta-1b when reconstituted.
3.
LIST OF EXCIPIENTS
Excipients: Human albumin, mannitol
4.
15 vials with powder and 15 pre-filled syringes with solvent:
I. 1 vial with powder for solution for injection
contains 300 microgram (9.6 million IU). After
reconstitution 1 ml contains 250 microgram (8 million IU)Interferon beta-1b*
II. 1 pre-filled syringe with 1.2 ml solvent for reconstitution
contains: sodium chloride solution 5.4
mg/ml.
*Betaferon is formulated to contain a calculated overfill of 20 %.
5.
METHOD AND ROUTE OF ADMINISTRATION
For subcutaneous injection after reconstitution with 1.2 ml of solvent.
Single use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
39
8.
EXPIRY DATE
EXP
{MM/YYYY}
After reconstitution an immediate use is recommended. In-use stability demonstrated for 3 hours at 2-
8 °C.
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Schering Pharma AG
D-13342 Berlin
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/95/003/003
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Betaferon
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(CARTON OF MULTIPACK (15x 1 SINGLE PACKS) (INCLUDING BLUE BOX)
1.
doctor for further information.
To reduce side effects at the start of treatment, your doctor should start you on a low dose of Betaferon
and increase it gradually (see section 3. ‘How to use Betaferon’).
Betaferon may also cause serious side effects. 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.
►
Tell your doctor immediately and stop using Betaferon:
−
if you experience
symptoms such as
itching all over your body, swelling of your face and/or
your tongue or sudden shortness of breath.
−
if you feel
noticeably more sad or hopeless than before the treatment with Betaferon, or if
you develop thoughts of suicide.
−
if you notice
any unusual bruising, excessive bleeding after injury or if you seem to be
catching a lot of infections.
−
if you have
loss of appetite, fatigue, feeling sick
(nausea)
, repeated vomiting, especially if
you notice widespread itching, yellowing of the skin, or of the whites of the eyes or easy
bruising.
−
if you experience symptoms like
irregular heart beat, swelling such as of the ankles or legs,
or shortness of breath.
−
if you notice
pain in your belly which is radiating to your back, and/or you feel sick or have
a fever.
The following side effects listing is based on reports from clinical trials with Betaferon (table 1)
and from side effects reported on the marketed product (table 2).
Table 1:
Side effects which have occurred in clinical trials with Betaferon very commonly (at least 10
per 100 of the cases) and at a higher percentage than those observed with placebo. The table also
includes side effects which occur in less than 10 per 100 but which were significantly associated with
the treatment):
-
infection,
abscess
-
reduced number of white
blood cells
, swollen
lymph glands
-
depression, anxiety
-
headache, dizziness,
sleeplessness, migraine,
numbness or tingling
feeling
(paresthesia)
-
conjunctivitis, abnormal vision
-
ear
pain
107
-
decrease of
sugar in the blood
