ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rebif 22 micrograms solution for injection in pre-filled syringe
2.
Each pre-filled syringe (0.5 ml) contains 22 micrograms (6 MIU*) of interferon beta-1a**.
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house
IFN beta-1a standard which is calibrated against the current international NIH standard
(GB-23-902-531).
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology.
Excipient: 2.5 mg benzyl alcohol
For a full list of excipients, see section 6.1.
3.
Solution for injection in pre-filled syringe.
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/l.
4.
Rebif is indicated for the treatment of relapsing multiple sclerosis.
In clinical trials, this was characterised by two or more acute exacerbations in the previous two years
(see section 5.1).
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without
ongoing relapse activity (see section 5.1).
Treatment should be initiated under supervision of a physician experienced in the treatment of the
disease.
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a
package that corresponds to the patient needs for the first month of therapy.
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection,
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.
When first starting treatment with Rebif, the dose should be gradually escalated in order to allow
tachyphylaxis to develop thus reducing adverse reactions. The Rebif initiation package corresponds to
the patient needs for the first month of treatment.
Method of administration
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised
to decrease flu-like symptoms associated with Rebif administration.
2
At the present time, it is not known for how long patients should be treated. Safety and efficacy with
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and
a decision for longer term treatment should then be made on an individual basis by the treating
physician.
Paediatric use
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 Rebif 22 micrograms subcutaneously three times per week is similar to that seen in
adults. There is very limited information on the use of Rebif in children under 12 years of age and
therefore Rebif should not be used in this population.
Initiation of treatment in pregnancy (see section 4.6).
Hypersensitivity to natural or recombinant interferon-β, or to any excipients.
Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).
Patients should be informed of the most frequent adverse reactions associated with interferon beta
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued
treatment.
Rebif 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 Rebif 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 Rebif and treated appropriately. Cessation
of therapy with Rebif should be considered (see sections 4.3 and 4.8).
Rebif 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 sections 4.5 and 4.8).
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a.
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to
patients with cardiac conditions.
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). 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 procedure for the self-administration by the patient should be reviewed periodically especially if
injection site reactions have occurred.
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 their physician before
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too
extensive.
3
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms,
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated
with caution in patients with a history of significant liver disease, clinical evidence of active liver
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be
stopped if icterus or other clinical symptoms of liver dysfunction appear (see section 4.8).
Rebif, like other interferons beta, has a potential for causing severe liver injury (see section 4.8)
including acute hepatic failure. The mechanism for the rare symptomatic hepatic dysfunction is not
known. No specific risk factors have been identified.
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme
monitoring and complete and differential blood cell counts and platelet counts are recommended at
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically
thereafter in the absence of clinical symptoms.
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities.
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be
performed if clinical findings of thyroid dysfunction appear (see section 4.8).
Caution should be used, and close monitoring considered when administering interferon beta-1a to
patients with severe renal and hepatic failure and to patients with severe myelosuppression.
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic
response to interferon beta-1a (Beta-2 microglobulin and neopterin). Although the clinical significance
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the
benefit/risk ratio of continued Rebif therapy.
The use of various assays to detect serum antibodies and differing definitions of antibody positivity
limits the ability to compare antigenicity among different products.
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis
and should not be used in such patients.
This medicinal product contains 2.5 mg benzyl alcohol per dose. Must not be given to premature
babies or neonates. May cause toxic reactions and anaphylactoid reactions in infants and children up to
3 years old.
No interaction studies have been performed with interferon beta-1a in humans.
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes
in humans and animals. Caution should be exercised when administering Rebif 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. antiepileptics and some classes of antidepressants.
4
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and
corticosteroids or ACTH during relapses.
There is limited information on the use of Rebif in pregnancy. Available data indicates that there may
be an increased risk of spontaneous abortion. Therefore initiation of treatment is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should take appropriate contraceptive measures. If the patient
becomes pregnant or plans to become pregnant while taking Rebif 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 has started, the risk of a severe relapse following
discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk
of spontaneous abortion.
It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse
reactions in breast-fed infants, a decision should be made whether to discontinue breast-feeding or
Rebif therapy.
Central nervous system-related adverse events associated with the use of interferon beta
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8).
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to
experience the typical interferon flu-like syndrome within the first six months after starting treatment.
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and
decreases in white blood cells (WBC) are also common.
The majority of adverse reactions observed with IFN beta-1a are usually mild and reversible, and
respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of Rebif
may be temporarily lowered or interrupted, at the discretion of the physician.
The adverse reactions reported below are classified according to frequency of occurrence as follows:
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
Not known
Cannot be estimated
from the available data
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
5
The data presented is obtained from pooled clinical studies in multiple sclerosis (placebo=824
patients; Rebif 22 micrograms three times per week (TIW)=398 patients; Rebif 44 micrograms
TIW=727 patients) and shows the frequency of adverse reactions observed at six months (excess over
placebo). Adverse reactions are listed below by frequency of occurrence and by MedDRA System
Organ Class.
System Organ Class
Very common
Common
Uncommon
Not known*
Infections and
infestations
Injection site
abscess
Injection site
infections, including
cellulitis
Blood and lymphatic
system disorders
Neutropenia,
lymphopenia,
leucopenia,
thrombocytopenia,
anaemia
Thrombotic
thrombocytopenic
purpura/Haemolytic
uremic syndrome
Immune system
disorders
Anaphylactic
reactions
Endocrine Disorders
Thyroid
dysfunction most
often presenting
as
hypothyroidism
or
hyperthyroidism
Psychiatric disorders
Depression,
insomnia
Suicide attempt
Nervous system
disorders
Headache
Seizures, transient
neurological
symptoms (i.e.
hypoesthesia,
muscle spasm,
paraesthesia,
difficulty in
walking,
musculoskeletal
stiffness) that may
mimic multiple
sclerosis
exacerbations
Eye disorders
Retinal vascular
disorders (e.g.
retinopathy, cotton
wool spots and
obstruction of
retinal artery or
vein)
Vascular disorders
Thromboembolic
events
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea
Gastrointestinal
disorders
Diarrhoea,
vomiting,
nausea
Hepatobiliary
disorders
Hepatic failure,
hepatitis with or
without icterus
6
System Organ Class
Very common
Common
Uncommon
Not known*
Skin and subcutaneous
tissue disorders
Pruritus, rash,
erythematous
rash,
maculo-papular
rash
Angioedema,
urticaria, erythema
multiforme,
erythema
multiforme-like skin
reactions,
Stevens-Johnson
syndrome, alopecia
Musculoskeletal and
connective tissue
disorders
Myalgia,
arthralgia
General disorders and
administration site
conditions
Injection site
inflammation,
injection site
reaction,
influenza-like
symptoms
Injection site
pain, fatigue,
rigors, fever
Injection site
necrosis,
injection site
mass
Investigations
Asymptomatic
transaminase
increase
Severe
elevations of
transaminase
*Adverse reactions identified during post marketing surveillance (frequency not known)
Interferon beta has a potential for causing severe liver injury. The mechanism for the rare symptomatic
hepatic dysfunction is not known. The majority of the cases of severe liver injury occurred within the
first six months of treatment. No specific risk factors have been identified. Treatment with Rebif
should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see section 4.4).
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias,
vasodilation and palpitation, menorrhagia and metrorrhagia.
An increased formation of auto-antibodies may occur during treatment with interferon beta.
In case of overdose, patients should be hospitalised for observation and appropriate supportive
treatment should be given.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07.
Interferons (IFNs) are a group of endogenous glycoproteins endowed with immunomodulatory,
antiviral and antiproliferative properties.
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human interferon
beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the
natural protein.
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.
7
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of
patients with disability progression, as defined by at least one point increase in EDSS confirmed
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years.
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence
of clinical progression in the preceding two years and who had not experienced relapses in the
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and
those without relapses in the 2-year period prior to study entry), there was no effect on disability in
patients without relapses, but in patients with relapses, the proportion with progression in disability at
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be
interpreted cautiously.
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should
not be used in such patients.
5.2 Pharmacokinetic properties
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp
multi-exponential decline, with serum levels proportional to the dose. The initial half-life is in the
order of minutes and the terminal half-life is several hours, with the possible presence of a deep
compartment. When administered by the subcutaneous or intramuscular routes, serum levels of
interferon beta remain low, but are still measurable up to 12 to 24 hours post-dose. Subcutaneous and
intramuscular administrations of Rebif produce equivalent exposure to interferon beta. Following a
single 60 microgram dose, the maximum peak concentration, as measured by immunoassay, is around
6 to 10 IU/ml, occurring on average around 3 hours after the dose. After subcutaneous administration
at the same dose repeated every 48 hours for 4 doses, a moderate accumulation occurs (about 2.5 x for
AUC).
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the
administration of Rebif. After a single dose, intracellular and serum activity of 2-5A synthetase and
serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological
responses remain elevated, with no signs of tolerance development.
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated-dose toxicity, and genotoxicity.
Rebif has not been investigated for carcinogenicity.
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances.
Based on observations with other alpha and beta interferons, an increased risk of abortions cannot be
excluded. No information is available on the effects of the interferon beta-1a on male fertility.
8
6.
6.1 List of excipients
Mannitol
Poloxamer 188
L-methionine
Benzyl alcohol
Sodium acetate
Acetic acid for pH adjustment
Sodium hydroxide for pH adjustment
Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original
package in order to protect from light.
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and
used before the expiry date.
6.5 Nature and contents of container
One ml type 1 glass syringe, with a stainless steel needle, containing 0.5 ml solution.
Rebif 22 micrograms is available as a package of 1, 3 or 12 syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a
suitable auto-injector.
For single use only. Only clear to opalescent solution without particles and without visible signs of
deterioration should be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
9
8.
EU/1/98/063/001
EU/1/98/063/002
EU/1/98/063/003
9.
Date of first authorisation: 4th May 1998
Date of first renewal: 4th May 2003
Date of latest renewal: 4th May 2008
10
1.
Rebif 44 micrograms solution for injection in pre-filled syringe
2.
Each pre-filled syringe (0.5 ml) contains 44 micrograms (12 MIU*) of interferon beta-1a**.
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in house
IFN beta-1a standard which is calibrated against the current international NIH standard
(GB-23-902-531).
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology.
Excipient: 2.5 mg benzyl alcohol
For a full list of excipients, see section 6.1.
3.
Solution for injection in pre-filled syringe.
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/l.
4.
Rebif is indicated for the treatment of relapsing multiple sclerosis.
In clinical trials, this was characterised by two or more acute exacerbations in the previous two years
(see section 5.1).
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without
ongoing relapsing activity (see section 5.1).
Treatment should be initiated under supervision of a physician experienced in the treatment of the
disease.
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a
package that corresponds to the patient needs for the first month of therapy.
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection,
is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.
When first starting treatment with Rebif, the dose should be gradually escalated in order to allow
tachyphylaxis to develop thus reducing adverse reactions. The Rebif initiation package corresponds to
the patient needs for the first month of treatment.
Method of administration
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised
to decrease flu-like symptoms associated with Rebif administration.
11
At the present time, it is not known for how long patients should be treated. Safety and efficacy with
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and
a decision for longer term treatment should then be made on an individual basis by the treating
physician.
Paediatric use
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 Rebif 22 micrograms subcutaneously three times per week is similar to that seen in
adults. There is very limited information on the use of Rebif in children under 12 years of age and
therefore Rebif should not be used in this population.
Initiation of treatment in pregnancy (see section 4.6).
Hypersensitivity to natural or recombinant interferon-β, or to any excipients.
Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).
Patients should be informed of the most frequent adverse reactions associated with interferon beta
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued
treatment.
Rebif 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 Rebif 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 Rebif and treated appropriately. Cessation
of therapy with Rebif should be considered (see sections 4.3 and 4.8).
Rebif 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 sections 4.5 and 4.8).
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a.
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to
patients with cardiac conditions.
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). 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 procedure for the self-administration by the patient should be reviewed periodically especially if
injection site reactions have occurred.
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 their physician before
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too
extensive.
12
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms,
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated
with caution in patients with a history of significant liver disease, clinical evidence of active liver
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be
stopped if icterus or other clinical symptoms of liver dysfunction appear (see section 4.8).
Rebif, like other interferons beta, has a potential for causing severe liver injury (see section 4.8)
including acute hepatic failure. The mechanism for the rare symptomatic hepatic dysfunction is not
known. No specific risk factors have been identified.
Laboratory abnormalities are associated with the use of interferons. The overall incidence of these is
slightly higher with Rebif 44 than Rebif 22 micrograms. Therefore, in addition to those laboratory
tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and
complete and differential blood cell counts and platelet counts are recommended at regular intervals
(1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the
absence of clinical symptoms. These should be more frequent when initiating Rebif 44 micrograms.
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities.
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be
performed if clinical findings of thyroid dysfunction appear (see section 4.8).
Caution should be used, and close monitoring considered when administering interferon beta-1a to
patients with severe renal and hepatic failure and to patients with severe myelosuppression.
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with
Rebif 44 micrograms, approximately 13 to 14% of patients develop persistent serum antibodies to
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic
response to interferon beta-1a (Beta-2 microglobulin and neopterin). Although the clinical significance
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the
benefit/risk ratio of continued Rebif therapy.
The use of various assays to detect serum antibodies and differing definitions of antibody positivity
limits the ability to compare antigenicity among different products.
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis
and should not be used in such patients.
This medicinal product contains 2.5 mg benzyl alcohol per dose. Must not be given to premature
babies or neonates. May cause toxic reactions and anaphylactoid reactions in infants and children up to
3 years old.
No interaction studies have been performed with interferon beta-1a in humans.
13
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes
in humans and animals. Caution should be exercised when administering Rebif 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. antiepileptics and some classes of antidepressants.
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and
corticosteroids or ACTH during relapses.
There is limited information on the use of Rebif in pregnancy. Available data indicates that there may
be an increased risk of spontaneous abortion. Therefore initiation of treatment is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should take appropriate contraceptive measures. If the patient
becomes pregnant or plans to become pregnant while taking Rebif 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 has started, the risk of a severe relapse following
discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk
of spontaneous abortion.
It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse
reactions in breast-fed infants, a decision should be made whether to discontinue breast-feeding or
Rebif therapy.
Central nervous system-related adverse events associated with the use of interferon beta
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8).
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to
experience the typical interferon flu-like syndrome within the first six months after starting treatment.
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and
decreases in white blood cells (WBC) are also common.
The majority of adverse reactions observed with IFN beta-1a are usually mild and reversible, and
respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of Rebif
may be temporarily lowered or interrupted, at the discretion of the physician.
The adverse reactions reported below are classified according to frequency of occurrence as follows:
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
Not known
Cannot be estimated
from the available data
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
14
The data presented is obtained from pooled clinical studies in multiple sclerosis (placebo=824
patients; Rebif 22 micrograms three times per week (TIW)=398 patients; Rebif 44 micrograms
TIW=727 patients) and shows the frequency of adverse reactions observed at six months (excess over
placebo). Adverse reactions are listed below by frequency of occurrence and by MedDRA System
Organ Class.
System Organ Class
Very common
Common
Uncommon
Not known*
Infections and
infestations
Injection site
abscess
Injection site
infections, including
cellulitis
Blood and lymphatic
system disorders
Neutropenia,
lymphopenia,
leucopenia,
thrombocytopenia,
anaemia
Thrombotic
thrombocytopenic
purpura/Haemolytic
uremic syndrome
Immune system
disorders
Anaphylactic
reactions
Endocrine Disorders
Thyroid
dysfunction most
often presenting
as
hypothyroidism
or
hyperthyroidism
Psychiatric disorders
Depression,
insomnia
Suicide attempt
Nervous system
disorders
Headache
Seizures, transient
neurological
symptoms (i.e.
hypoesthesia,
muscle spasm,
paraesthesia,
difficulty in
walking,
musculoskeletal
stiffness) that may
mimic multiple
sclerosis
exacerbations
Eye disorders
Retinal vascular
disorders (e.g.
retinopathy, cotton
wool spots and
obstruction of
retinal artery or
vein)
Vascular disorders
Thromboembolic
events
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea
Gastrointestinal
disorders
Diarrhoea,
vomiting,
nausea
15
System Organ Class
Very common
Common
Uncommon
Not known*
Hepatobiliary
disorders
Hepatic failure,
hepatitis with or
without icterus
Skin and subcutaneous
tissue disorders
Pruritus, rash,
erythematous
rash,
maculo-papular
rash
Angioedema,
urticaria, erythema
multiforme,
erythema
multiforme-like skin
reactions,
Stevens-Johnson
syndrome, alopecia
Musculoskeletal and
connective tissue
disorders
Myalgia,
arthralgia
General disorders and
administration site
conditions
Injection site
inflammation,
injection site
reaction,
influenza-like
symptoms
Injection site
pain, fatigue,
rigors, fever
Injection site
necrosis,
injection site
mass
Investigations
Asymptomatic
transaminase
increase
Severe
elevations of
transaminase
*Adverse reactions identified during post marketing surveillance (frequency not known)
Interferon beta has a potential for causing severe liver injury. The mechanism for the rare symptomatic
hepatic dysfunction is not known. The majority of the cases of severe liver injury occurred within the
first six months of treatment. No specific risk factors have been identified. Treatment with Rebif
should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see section 4.4).
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias,
vasodilation and palpitation, menorrhagia and metrorrhagia.
An increased formation of auto-antibodies may occur during treatment with interferon beta.
In case of overdose, patients should be hospitalised for observation and appropriate supportive
treatment should be given.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07.
Interferons (IFNs) are a group of endogenous glycoproteins endowed with immunomodulatory,
antiviral and antiproliferative properties.
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human interferon
beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the
natural protein.
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.
16
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously
three times per week. At licensed posology, Rebif 44 micrograms has been demonstrated to decrease
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of
patients with disability progression, as defined by at least one point increase in EDSS confirmed
three months later, was reduced from 39% (placebo) to 27% (Rebif 44 micrograms). Over 4 years, the
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years.
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence
of clinical progression in the preceding two years and who had not experienced relapses in the
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and
those without relapses in the 2-year period prior to study entry), there was no effect on disability in
patients without relapses, but in patients with relapses, the proportion with progression in disability at
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be
interpreted cautiously.
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should
not be used in such patients.
5.2 Pharmacokinetic properties
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp multi-
exponential decline, with serum levels proportional to the dose. The initial half-life is in the order of
minutes and the terminal half-life is several hours, with the possible presence of a deep compartment.
When administered by the subcutaneous or intramuscular routes, serum levels of interferon beta
remain low, but are still measurable up to 12 to 24 hours post-dose. Subcutaneous and intramuscular
administrations of Rebif produce equivalent exposure to interferon beta. Following a single
60 microgram dose, the maximum peak concentration, as measured by immunoassay, is around 6 to
10 IU/ml, occurring on average around 3 hours after the dose. After subcutaneous administration at the
same dose repeated every 48 hours for 4 doses, a moderate accumulation occurs (about 2.5 x for
AUC).
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the
administration of Rebif. After a single dose, intracellular and serum activity of 2-5A synthetase and
serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological
responses remain elevated, with no signs of tolerance development.
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated-dose toxicity, and genotoxicity.
Rebif has not been investigated for carcinogenicity.
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances.
Based on observations with other alpha and beta interferons, an increased risk of abortions cannot be
excluded. No information is available on the effects of the interferon beta-1a on male fertility.
17
6.
6.1 List of excipients
Mannitol
Poloxamer 188
L-methionine
Benzyl alcohol
Sodium acetate
Acetic acid for pH adjustment
Sodium hydroxide for pH adjustment
Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original
package in order to protect from light.
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and
used before the expiry date.
6.5 Nature and contents of container
One ml type 1 glass syringe, with a stainless steel needle, containing 0.5 ml solution.
Rebif 44 micrograms is available as a package of 1, 3 or 12 syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a
suitable auto-injector.
For single use only. Only clear to opalescent solution without particles and without visible signs of
deterioration should be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
18
8.
EU/1/98/063/004
EU/1/98/063/005
EU/1/98/063/006
9.
Date of first authorisation: 4th May 1998
Date of first renewal: 4th May 2003
Date of latest renewal: 4th May 2008
19
1.
Rebif 8.8 micrograms solution for injection in pre-filled syringe
Rebif 22 micrograms solution for injection in pre-filled syringe
2.
Each pre-filled syringe (0.2 ml) contains 8.8 micrograms (2.4 MIU*) of interferon beta-1a**.
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house
IFN beta-1a standard which is calibrated against the current international NIH standard
(GB-23-902-531).
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology.
Excipient: 1.0 mg benzyl alcohol
For a full list of excipients, see section 6.1.
Each pre-filled syringe (0.5 ml) contains 22 micrograms (6 MIU*) of interferon beta-1a**.
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house
IFN beta-1a standard which is calibrated against the current international NIH standard
(GB-23-902-531).
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology.
Excipient: 2.5 mg benzyl alcohol
For a full list of excipients, see section 6.1.
3.
Solution for injection in pre-filled syringe.
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/l.
4.
Rebif is indicated for the treatment of relapsing multiple sclerosis.
In clinical trials, this was characterised by two or more acute exacerbations in the previous two years
(see section 5.1).
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without
ongoing relapse activity (see section 5.1).
Treatment should be initiated under supervision of a physician experienced in the treatment of the
disease.
20
The Rebif initiation package corresponds to the patient needs for the first month of treatment. When
first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing adverse
reactions, it is recommended that 8.8 micrograms be administered by subcutaneous injection
three times per week during the initial 2 weeks of therapy. Thereafter, 22 micrograms be administered
by subcutaneous injection three times per week in weeks 3 and 4, and the total of the 44 micrograms
strength be administered from the fifth week onwards.
Method of administration
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised
to decrease flu-like symptoms associated with Rebif administration.
At the present time, it is not known for how long patients should be treated. Safety and efficacy with
Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should
be evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and
a decision for longer term treatment should then be made on an individual basis by the treating
physician.
Paediatric use
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 Rebif 22 micrograms subcutaneously three times per week is similar to that seen in
adults. There is very limited information on the use of Rebif in children under 12 years of age and
therefore Rebif should not be used in this population.
Initiation of treatment in pregnancy (see section 4.6).
Hypersensitivity to natural or recombinant interferon-β, or to any excipients.
Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).
Patients should be informed of the most frequent adverse reactions associated with interferon beta
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued
treatment.
Rebif 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 Rebif 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 Rebif and treated appropriately. Cessation
of therapy with Rebif should be considered (see sections 4.3 and 4.8).
Rebif 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 sections 4.5 and 4.8).
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a.
Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to
patients with cardiac conditions.
21
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). 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 procedure for the self-administration by the patient should be reviewed periodically especially if
injection site reactions have occurred.
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 their physician before
continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until
healing has occurred. Patients with single lesions may continue provided that the necrosis is not too
extensive.
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms,
serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy
and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times
the ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated
with caution in patients with a history of significant liver disease, clinical evidence of active liver
disease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should be
stopped if icterus or other clinical symptoms of liver dysfunction appear (see section 4.8).
Rebif, like other interferons beta, has a potential for causing severe liver injury (see section 4.8)
including acute hepatic failure. The mechanism for the rare symptomatic hepatic dysfunction is not
known. No specific risk factors have been identified.
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme
monitoring and complete and differential blood cell counts and platelet counts are recommended at
regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically
thereafter in the absence of clinical symptoms.
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities.
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following
initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be
performed if clinical findings of thyroid dysfunction appear (see section 4.8).
Caution should be used, and close monitoring considered when administering interferon beta-1a to
patients with severe renal and hepatic failure and to patients with severe myelosuppression.
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with
Rebif 22 micrograms, approximately 24% of patients develop persistent serum antibodies to
interferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic
response to interferon beta-1a (Beta-2 microglobulin and neopterin). Although the clinical significance
of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies
is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to
therapy with Rebif, and has neutralising antibodies, the treating physician should reassess the
benefit/risk ratio of continued Rebif therapy.
The use of various assays to detect serum antibodies and differing definitions of antibody positivity
limits the ability to compare antigenicity among different products.
22
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple
sclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosis
and should not be used in such patients.
This medicinal product contains 1.0 mg benzyl alcohol per dose of 0.2 ml and 2.5 mg benzyl alcohol
per dose of 0.5 ml. Must not be given to premature babies or neonates. May cause toxic reactions and
anaphylactoid reactions in infants and children up to 3 years old.
No interaction studies have been performed with interferon beta-1a in humans.
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes
in humans and animals. Caution should be exercised when administering Rebif 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. antiepileptics and some classes of antidepressants.
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been
studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and
corticosteroids or ACTH during relapses.
There is limited information on the use of Rebif in pregnancy. Available data indicates that there may
be an increased risk of spontaneous abortion. Therefore initiation of treatment is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should take appropriate contraceptive measures. If the patient
becomes pregnant or plans to become pregnant while taking Rebif 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 has started, the risk of a severe relapse following
discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk
of spontaneous abortion.
It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse
reactions in breast-fed infants, a decision should be made whether to discontinue breast-feeding or
Rebif therapy.
Central nervous system-related adverse events associated with the use of interferon beta
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8).
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like
syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in
frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to
experience the typical interferon flu-like syndrome within the first six months after starting treatment.
Approximately 30% of patients will also experience reactions at the injection site, predominantly mild
inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and
decreases in white blood cells (WBC) are also common.
The majority of adverse reactions observed with IFN beta-1a are usually mild and reversible, and
respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of Rebif
may be temporarily lowered or interrupted, at the discretion of the physician.
23
The adverse reactions reported below are classified according to frequency of occurrence as follows:
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
Not known
Cannot be estimated
from the available data
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The data presented is obtained from pooled clinical studies in multiple sclerosis (placebo=824
patients; Rebif 22 micrograms three times per week (TIW)=398 patients; Rebif 44 micrograms
TIW=727 patients) and shows the frequency of adverse reactions observed at six months (excess over
placebo). Adverse reactions are listed below by frequency of occurrence and by MedDRA System
Organ Class.
System Organ Class
Very common
Common
Uncommon
Not known*
Infections and
infestations
Injection site
abscess
Injection site
infections, including
cellulitis
Blood and lymphatic
system disorders
Neutropenia,
lymphopenia,
leucopenia,
thrombocytopenia,
anaemia
Thrombotic
thrombocytopenic
purpura/Haemolytic
uremic syndrome
Immune system
disorders
Anaphylactic
reactions
Endocrine Disorders
Thyroid
dysfunction most
often presenting
as
hypothyroidism
or
hyperthyroidism
Psychiatric disorders
Depression,
insomnia
Suicide attempt
Nervous system
disorders
Headache
Seizures, transient
neurological
symptoms (i.e.
hypoesthesia,
muscle spasm,
paraesthesia,
difficulty in
walking,
musculoskeletal
stiffness) that may
mimic multiple
sclerosis
exacerbations
24
System Organ Class
Very common
Common
Uncommon
Not known*
Eye disorders
Retinal vascular
disorders (e.g.
retinopathy, cotton
wool spots and
obstruction of
retinal artery or
vein)
Vascular disorders
Thromboembolic
events
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea
Gastrointestinal
disorders
Diarrhoea,
vomiting,
nausea
Hepatobiliary
disorders
Hepatic failure,
hepatitis with or
without icterus
Skin and subcutaneous
tissue disorders
Pruritus, rash,
erythematous
rash,
maculo-papular
rash
Angioedema,
urticaria, erythema
multiforme,
erythema
multiforme-like skin
reactions,
Stevens-Johnson
syndrome, alopecia
Musculoskeletal and
connective tissue
disorders
Myalgia,
arthralgia
General disorders and
administration site
conditions
Injection site
inflammation,
injection site
reaction,
influenza-like
symptoms
Injection site
pain, fatigue,
rigors, fever
Injection site
necrosis,
injection site
mass
Investigations
Asymptomatic
transaminase
increase
Severe
elevations of
transaminase
*Adverse reactions identified during post marketing surveillance (frequency not known)
Interferon beta has a potential for causing severe liver injury. The mechanism for the rare symptomatic
hepatic dysfunction is not known. The majority of the cases of severe liver injury occurred within the
first six months of treatment. No specific risk factors have been identified. Treatment with Rebif
should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see section 4.4).
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias,
vasodilation and palpitation, menorrhagia and metrorrhagia.
An increased formation of auto-antibodies may occur during treatment with interferon beta.
In case of overdose, patients should be hospitalised for observation and appropriate supportive
treatment should be given.
25
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07.
Interferons (IFNs) are a group of endogenous glycoproteins endowed with immunomodulatory,
antiviral and antiproliferative properties.
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore
glycosylated like the natural protein.
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple
sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously
three times per week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease
the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at
least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of
patients with disability progression, as defined by at least one point increase in EDSS confirmed
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and
29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated
with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years.
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence
of clinical progression in the preceding two years and who had not experienced relapses in the
preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was
reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and
those without relapses in the 2-year period prior to study entry), there was no effect on disability in
patients without relapses, but in patients with relapses, the proportion with progression in disability at
the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be
interpreted cautiously.
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should
not be used in such patients.
5.2 Pharmacokinetic properties
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp multi-
exponential decline, with serum levels proportional to the dose. The initial half-life is in the order of
minutes and the terminal half-life is several hours, with the possible presence of a deep compartment.
When administered by the subcutaneous or intramuscular routes, serum levels of interferon beta
remain low, but are still measurable up to 12 to 24 hours post-dose. Subcutaneous and intramuscular
administrations of Rebif produce equivalent exposure to interferon beta. Following a single
60 microgram dose, the maximum peak concentration, as measured by immunoassay, is around 6 to
10 IU/ml, occurring on average around 3 hours after the dose. After subcutaneous administration at the
same dose repeated every 48 hours for 4 doses, a moderate accumulation occurs (about 2.5 x for
AUC).
26
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the
administration of Rebif. After a single dose, intracellular and serum activity of 2-5A synthetase and
serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to
decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable
responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological
responses remain elevated, with no signs of tolerance development.
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated-dose toxicity, and genotoxicity.
Rebif has not been investigated for carcinogenicity.
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances.
Based on observations with other alpha and beta interferons, an increased risk of abortions cannot be
excluded. No information is available on the effects of the interferon beta-1a on male fertility.
6.
6.1 List of excipients
Mannitol
Poloxamer 188
L-methionine
Benzyl alcohol
Sodium acetate
Acetic acid for pH adjustment
Sodium hydroxide for pH adjustment
Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original
package in order to protect from light.
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not
above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and
used before the expiry date.
6.5 Nature and contents of container
For patients initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available
in an initiation pack composed of 6 individual doses of a 1 ml type 1 glass syringe with a stainless steel
needle containing 0.2 ml of Rebif 8.8 micrograms solution for injection and 6 individual doses of a 1 ml
type 1 glass syringe with a stainless steel needle containing 0.5 ml of Rebif 22 micrograms solution for
injection.
27
This package corresponds to the patient needs for the first month of therapy.
6.6 Special precautions for disposal and other handling
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a
suitable auto-injector.
For single use only. Only clear to opalescent solution without particles and without visible signs of
deterioration should be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
8.
EU/1/98/063/007
9.
Date of first authorisation: 4th May 1998
Date of first renewal: 4th May 2003
Date of latest renewal: 4th May 2008
28
1.
FURTHER INFORMATION
What Rebif contains
The active substance is interferon beta-1a.
Each 8.8 micrograms pre-filled pen contains 8.8 micrograms of interferon beta-1a (2.4 million
IU).
Each 22 micrograms pre-filled pen contains 22 micrograms of interferon beta-1a (6 million IU).
The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate,
acetic acid, sodium hydroxide and water for injections.
What Rebif looks like and contents of the pack
Rebif 8.8 micrograms is a solution for injection in a pre-filled pen for self-administration. The
pre-filled pen is ready for use and contains 0.2 ml of solution.
Rebif 22 micrograms is a solution for injection in a pre-filled pen for self-administration. The
pre-filled pen is ready for use and contains 0.5 ml of solution.
Rebif solution is clear to opalescent.
Rebif 8.8 micrograms and Rebif 22 micrograms are supplied in an initiation pack that is intended for
use during the initial 4 weeks of treatment, during which a gradual increase in Rebif dose is
recommended.
One-month treatment pack contains six Rebif 8.8 micrograms pre-filled pens and
six Rebif 22 micrograms pre-filled pens.
Marketing Authorisation Holder
Merck Serono Europe Limited
56, Marsh Wall
London E14 9TP
United Kingdom
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
MERCK NV/SA
Brusselsesteenweg 288
B-3090 Overijse
Tél/Tel: +32-2-686 07 11
Luxembourg/Luxemburg
MERCK NV/SA
Brusselsesteenweg 288
B-3090 Overijse, Belgique/Belgien
Tél/Tel: +32-2-686 07 11
200
България
Мерк България" ЕАД
Бул. Проф. Цветан Лазаров“ 83
София 1582
България
Teл: +359 28075 111
Magyarország
Merck Kft.
Bocskai út 134-146.
H-1113 Budapest
Tel: +36-1-463-8100
Česká republika
Merck spol. s r.o.
Na Hřebenech II. 1718/10
CZ-140 00 Praha 4
Tel. +420 272084211
Malta
Cherubino Ltd
Delf Building
Sliema Road
MT-GZR 06 Gzira Malta
Tel: +356-21-343270/1/2/3/4
Danmark
Merck AB
Strandvejen 102 B, 4th
DK-2900 Hellerup
Tlf: +45 35253550
Nederland
Merck BV
Tupolevlaan 41-61
NL-1119 NW Schiphol-Rijk
Tel: +31-20-6582800
Deutschland
Merck Serono GmbH
Alsfelder Straße 17
D-64289 Darmstadt
Tel: +49-6151-6285-0
Norge
Merck Serono Norge
Luhrtoppen 2
N-1470 Lørenskog
Tlf: +47 67 90 35 90
Eesti
Merck Serono OÜ
Tornimäe 7 - 132
EE-10145, Tallinn
Tel: +372 682 5882
Österreich
Merck GesmbH.
Zimbagasse 5
A-1147 Wien
Tel: +43 1 57600-0
Ελλάδα
Merck A.E.
Κηφισίας 41-45, Κτίριο Β
GR-151 23 Μαρούσι
Αθήνα
T: +30-210-61 65 100
Polska
Merck Sp. z o.o.
Al. Jerozolimskie 178
PL-02-486 Warszawa
Tel.: +48 22 53 59 700
España
Merck S.L.
María de Molina, 40
E-28006 Madrid
Línea de Información: 900 200 400
Tel: +34-91-745 44 00
Portugal
Merck, s.a.
Rua Alfredo da Silva, 3-C
P-1300-040 Lisboa
Tel: +351-21-361 35 00
France
Merck Serono s.a.s.
37, rue Saint-Romain
F-69379 Lyon cedex 08
Tél.: +33-4-72 78 25 25
Numéro vert : 0 800 888 024
România
MERCK d.o.o.,
Dunajska cesta 119
SI-1000 Lubliana, Slovenia
Tel: +386 1 560 3 800
201
Ireland
Merck Serono Ltd
Bedfont Cross, Stanwell Road
Feltham, Middlesex TW14 8NX
United Kingdom
Tel: +44-20 8818 7200
Slovenija
MERCK d.o.o.
Dunajska cesta 119
SI-1000 Ljubljana
Tel: +386 1 560 3 800
Ísland
Icepharma hf
Lynghálsi 13
IS-110 Reykjavík
Tel: + 354 540 8000
Slovenská
republika
Merck spol. s r.o.
Tuhovská 3
SK-831 06 Bratislava
Tel: + 421 2 49 267 111
Italia
Merck Serono S.p.A.
Via Casilina 125
I-00176 Roma
Tel: +39-06-70 38 41
Suomi/Finland
Merck Oy
Pihatörmä 1 C
FIN-02240 Espoo
Puh/Tel: +358-9-8678 700
Κύπρος
Χρ. Γ. Παπαλοϊζου Λτδ
Λεωφόρος Κιλκίς 35,
CY-2234 Λατσιά, Λευκωσία
Τηλ.: +357 22490305
Sverige
Merck AB
S-195 87 Stockholm
Tel: +46-8-562 445 00
Latvija
Merck Serono SIA
Duntes iela 23A
LV-1005, Rīga
Tel: +371 67152500
United Kingdom
Merck Serono Ltd
Bedfont Cross, Stanwell Road
Feltham, Middlesex TW14 8NX- UK
Tel: +44-20 8818 7200
Lietuva
Merck Serono UAB
Savanoriu pr. 192,
LT-44151 Kaunas
Tel: +370 37320603
This leaflet was last approved in
INSTRUCTIONS FOR HANDLING OF REBIF IN PRE-FILLED PEN (RebiDose)
This section contains information on how to properly use RebiDose. The first injection(s) must be
performed under the supervision of an appropriately qualified healthcare professional. After receiving
adequate training, you, a family member, friend or carer can use RebiDose to administer the medicine
at home. If you have questions about how to inject, please ask your doctor, nurse or pharmacist for
assistance.
How do you, or the person injecting you, use RebiDose
Your doctor has prescribed Rebif in the RebiDose for injection into the tissue just under the skin.
Only use each RebiDose for one injection.
Read all the following instructions carefully before using RebiDose.
202
Equipment
To give yourself an injection you will need:
A new RebiDose and
Alcohol wipes or similar.
Below is a diagram that shows what RebiDose looks like.
Before the injection
After the injection
A. Cap
E. Main body
B. Transparent control area
F. Button
C. Plunger
G. Safety guard
What to do before you give yourself a subcutaneous injection with RebiDose
Wash your hands thoroughly with soap and water.
Remove RebiDose from the blister pack by peeling back the plastic covering.
Check the appearance of Rebif through the transparent control area. It must be clear to
opalescent, without particles and without any visible signs of deterioration. If there are particles
or other visible signs of deteriorations, do not use it and contact your doctor, nurse or
pharmacist for assistance.
Check the expiry date on the RebiDose label (as indicated as “EXP”). You can also check the
expiry date on the RebiDose outer box. Do not use RebiDose if the expiry date has passed.
Where to inject with RebiDose
Choose an injection site. Your doctor will advise you on the
possible injection sites (good sites include the upper thighs
and the lower abdomen.)
It is recommended that you keep track of and rotate your
injection sites, so that one area is not injected too frequently
in order to minimise the risk of injection site necrosis.
NOTE: do not use any areas in which you feel lumps, firm
knots, or pain; talk to your doctor or healthcare professional
about anything you find.
203
D. Label
H. Needle
How to inject with RebiDose
Do not
remove the cap until you are ready to administer the injection.
Before the injection use an alcohol wipe to clean the skin at the injection site. Let the skin dry.
If a bit of alcohol is left on the skin, you may get a stinging sensation.
Hold RebiDose by the main body and use your other hand to
remove the cap.
Hold RebiDose at a right angle (90 degrees) to the injection
site. Push the pen down until you feel resistance. This action
unlocks the button.
Keep enough pressure on the skin and press the button with
your thumb. You will hear a click which indicates the start of
the injection and the plunger will start moving. Keep
RebiDose pressed against the skin for at least 10 seconds in
order to deliver the full medicinal product.
It is not necessary to keep the button pressed down with your
thumb after the injection has begun.
Remove RebiDose from the injection site.
The safety guard automatically surrounds the needle and locks
into place to protect you from the needle.
Look through the transparent control area to make sure that
the plunger has moved to the bottom as indicated in the figure.
Visually check that there is no liquid left. If there is liquid left,
not all of the medicinal product has been injected and you
should consult your doctor or nurse for assistance.
Gently massage the injection site with a dry cotton ball or gauze.
204
In case of any difficulties while using RebiDose, please contact your doctor or nurse for assistance.
How to dispose of used RebiDose
RebiDose is for single use only and should
never
be reused.
Never
put the needle cap back on the used RebiDose.
Once you have finished your injection, immediately discard RebiDose in an appropriate
disposal unit.
To avoid any injury,
never insert your fingers in the opening of the safety guard
covering
the needle.
205
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/rebif.html
Copyright © 1995-2021 ITA all rights reserved.