Rebif 8.8 micrograms/0.1 ml solution for injection in cartridge

Rebif 22 micrograms/0.25 ml solution for injection in cartridge

Rebif 22 micrograms/0.5 ml solution for injection in cartridge

Rebif 44 micrograms/0.5ml solution for injection in cartridge

Rebif 8.8 mcg/0.1ml and Rebif 22 mcg/0.25ml:

Each pre-filled cartridge contains 132 micrograms (36 MIU*) of interferon beta-1a** in 1.5 ml solution, corresponding to 88 micrograms/ml.

Rebif 22mcg/0.5ml:

Each pre-filled cartridge contains 66 micrograms (18 MIU*) of interferon beta-1a** in 1.5 ml solution, corresponding to 44 micrograms/ml.

Rebif 44mcg/0.5ml:

Each pre-filled cartridge contains 132 micrograms (36 MIU*) of interferon beta-1a** in 1.5 ml solution, corresponding to 88 micrograms/ml.

* 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: 7.5 mg benzyl alcohol

For a full list of excipients, see section 6.1.

Solution for injection in cartridge.

Clear to opalescent solution, with pH 3.7 to 4.1 and osmolarity 250 to 450 mOsm/l.

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.

Posology

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 the view of the treating specialist.

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.

Paediatric population

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.

Method of administration

Rebif solution for injection in cartridge is intended for multidose use with either the RebiSmart electronic injection device or the RebiSlide manual pen-injector device following adequate training of the patient and/or carer. The physician should discuss with the patient which device is the most appropriate. Patients with poor vision should not use RebiSlide unless someone with good eyesight can provide support.

For administration, the instructions provided in the package leaflet and the instruction manual (Instructions for Use) provided with RebiSmart and RebiSlide should be followed.

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 eva luated 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.

• 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.

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 22 micrograms, approximately 24% of patients develop persistent serum antibodies to interferon beta-1a and 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.

Rebif 8.8 mcg/0.1ml and Rebif 22 mcg/0.25ml:

This medicinal product contains 0.5 mg benzyl alcohol per dose of 0.1 ml and 1.25 mg benzyl alcohol per dose of 0.25 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.

Rebif 22mcg/0.5ml:

Rebif 44 mcg/0.5ml:

This medicinal product contains 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.

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 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.

Pregnancy

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).

Breastfeeding

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 either to discontinue nursing or to discontinue 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:

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.

*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.

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 eva luated 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 and Rebif 44 micrograms have 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) and 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.

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.

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.

Mannitol

Poloxamer 188

L-methionine

Benzyl alcohol

Sodium acetate

Acetic acid for pH adjustment

Sodium hydroxide for pH adjustment

Water for injections

Not applicable.

18 months.

After first injection use within 28 days.

Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store the cartridge in the original package in order to protect from light.

The device (RebiSmart or RebiSlide) containing a pre-filled cartridge of Rebif must be stored in the device storage box in a refrigerator (2°C – 8°C).

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.

Cartridges (type 1 glass) with a plunger stopper (rubber) and crimp cap (aluminium and halobutyl rubber) containing 1.5 ml solution for injection.

Rebif 8.8 mcg/0.1ml and Rebif 22 mcg/0.25ml:

Pack size of 2 cartridges.

This package corresponds to the patient needs for the first month of therapy.

Rebif 22mcg/0.5ml:

Rebif 44mcg/0.5ml:

Pack size of 4 or 12 cartridges.

Not all pack sizes may be marketed.

The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart electronic injection device or the RebiSlide manual pen-injector device. For storage of the device with the cartridge, see section 6.4. Not all injection devices may be available.

For multidose use. Only clear to opalescent solution without particles should be used and without visible signs of deterioration.

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

Merck Serono Europe Limited

56, Marsh Wall

London E14 9TP

United Kingdom

Rebif 22mcg/0.5ml:

EU/1/98/063/008

EU/1/98/063/0018

Rebif 44mcg/0.5ml:

EU/1/98/063/009

EU/1/98/063/0019

Rebif 8.8 mcg/0.1ml and Rebif 22 mcg/0.25ml:

EU/1/98/063/010

Date of first authorisation: 4th May 1998

Date of latest renewal: 4th May 2008

08/2011

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