The recomended posology of Rebif is 44 mcg given three time per week by subcutaneous injection.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

When first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing adverse events, it is recommended that 8.8 mcg (0.1 ml of the 44 mcg strenght) be administered during the initial 2 weeks of the therapy, 22 mcg (0.25 ml of the 44 mcg strenght) be administered in weeks 3 and 4 and the total of the 44 mcg strength be administered from the fifth week onwards.

There is no experience with Rebif in children under 16 years of age with multiple sclerosis and therefore Rebif should not be used in this population.

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.

Contraindications

Interferon beta-1a is contraindicated in patients with a known hypersensitivity to natural or recombinant interferon beta, human serum albumin, or any other component of the formulation.

Interferon beta-1a is containdicated in pregnant patients (also see pregnancy and lactation), patients with severe depressive disorders and/or suicidal ideation and in epileptic patients with a history of seizures not adequately controlled by treatment.

Special warnings and special precautions for use

Patients should be informed of the most common adverse events associated with interferon beta administartion, including symptoms of the flu-like syndrome (see undesirable effects). These sypmtoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.

Interferons should be used with caution in patients with depression. Depression and suicidal ideation are know to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with interferon beta-1a should be advised to immediately report any syptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with interferon beat-1a and treated appropriately.

Cessation of therapy with interferon beta- 1a should be considered.

Caution should be exercised when administering Interferon beta- 1a to patients with pre-existing seizure disorders. For patients without a pre-existing disorder who develop seizures during therapy with Interferon beta- 1a, an aetiological basis should eb established and appropriate anti-convulsant therapy instituted prior to resuming Interferon beat- 1a treatment.

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 therapy may prove stressful to patients with cardiac conditions.

Injection site necrosis (ISN) has been reporte din patients using Rebif (see Undesirable Effects). 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 occured.

If a 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 occured. Patients with single lesions may continue provided that the necrosis is not too extensive.

Patients should be advised about the abortifacient potential of interferon beta (see Pregnancy and lactation and Preclinical safety data).

Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests, normally required for monitoring patients with multiple sclerosis, complete and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests are recommended during Interferon beta- 1a therapy.

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 suggests that after 24 to 48 months of treatment with Rebif, approximately 24% of the patients on the dosage of 22 mcg and 13 to 14 % on the dosage of 44 mcg develop persistent serum antibodies to interferon beta- 1a. The presence of antibodies have been shown to attenuate the pharmacodynamic response to inferon beta- 1a (Beat-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 reduce efficacy on clinical and MRI variables. If a pateint responds poorly to the 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 definations of antibody positivity limits the ability to compare antigenicity among different products.

Interaction with other medicinal products and other forms of interaction

No formal drug interaction studies have been conducted with Rebif (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 taht have a narrow therapeutic cytochrome P450 system for clearence, e.g. antiepileptics and some classes of antidepressants.

The interaction of Rebif with corticosteroids or ACTH has been studies systematically. Clinical studies indicate that multiple scerosis patients can receive rebif and corticoseroids or ACTH during relapses.

Pregnancy and lactation

Rebif should not administered in case of pregnancy and lactation.

There are no studies of interferon beta- 1a in pregnant women. At high doses, in monkeys, abortifacient effects were observed with other interferons (see Preclinical safety data).

Fertile women receiving Rebif should take appropriate contraceptive measures. Patients planning for pregnancy and those becoming pregnant should be informed of the potential hazards of interferons to the foetus and Rebif should be discontinued.

It is not known wether Rebif is excreted in human milk. Bacause of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue Rebif therapy.

Effects on ability to drive and use machines

Less commonly reported central nervous system-related adverse events associated with the use of interferon beta might influence the patient's ability to drive or use machines (see undesirable effects).

Undesirable effects

The highest incidence of undesirable effects with the interferon therapy is related to flu syndrome. The most commonly reported symptoms of the flu syndrome are muscle ache, fever, arthralgia, chills, asthenia, headache, and nausea. Symptoms of the flu syndome tend to be usually mild and most prominent at the initiation of therapy and decrease in frequency with continued treatment.

Injection site reactions are commonly encountered and are usually mild and reversible. Injection site necrosis has uncommonly been reported. In all cases, the necrosis resolved spontaneously.

Other less common adverse events reported in association with interfeon beta include diarrhoea, anorexia, vomiting, insomnia, diziness, anxiety, rash, vasodilation and palpitation.

The administration of type 1 interferons has rarely been associated with serious CNS undesirable effects such as depression, suicide and depersonalisation as well as seizures and arrythmias.

Hypersensitivity reactions may occur.

Laboratory abnormalities suh as luekopenia, lymphopenia, thrombocytopenia and elevated AST, ALT, g-GT and alkaline phosphatase may occur. These are usually mild, asymptomatic and reversible.

In case of severe or persistent undesirable effects, the dose of Rebif may be temporarily lowered or interrupted, at the discretion of the physician.

Overdose

No case of overdose has been reported.However, in case of overdosage, patients should be hospitalised for observation and appropriate supportive treatment should be given.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic gruop: cytokines, ATC code: L03 AB.

Interferons (IFNs) are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiprolifeative properties.

Rebif (Interferon beta- 1a) is composed of the native amino acid sequence of natural 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 is multiple sclerosis is still under investigation.

The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple sclerosis at dose ranging from 11 to 44 mcg (3-12 million IU), administered subcutaneously three times per week. At licensed posology, Rebif has been demonstrated to decrease the incedence (approximately 30% over 2 years) and severity of clinical relapses. 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 mcg) and 27 % (Rebif 44 mcg). Over 4 years, the reduction in the mean exacerbation rate was 22 % in patients treated with Rebif 44 mcg gorup compared with a group of patients treated with placebo for 2 years and then either Rebif 22 or Rebif 44 mcg for 2 years.

Pharmacokinetic properties

In healthy volunteers after intravenous administration, interferon beta- 1a exhibits a sharp multi-exponential decline, with aserum levels proportional to the dose. The initial half-lfe is in the order of minutes and the terminal half-life is several hours, with the possibility presence of a deep compartment. When administered by the subcutaneous or intramuscular routes, serum levels of interferonbeta remain low, but are still measurable upto 12 to 24 hours post-dose. Subcutaneous and intramuscular administrations of Rebif produe 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, occuring 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 witht he administration of Rebif. After a single dose, intracellular and serum activity of 2 - 5 A 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 to 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.

Preclinical safety data

Rebif was tested in toxicology studies of up to 6 months in duration in monkeys and 3 months in rats and caused no overt signs of toxicity except for transient pyrexia.

Rebif has been shown to be neither mutagenic nor clastogenic. 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 imformation is available on the effects of the interferon beat- 1a on male fertility.

Incompabilities

Not applicable.

Special precautions for storage

Store at 2 - 8 C in the original package. Do not freeze. To prevent accidental freezing, avoid placing near the freezer compartment. Should refrigeration be temporarily unavailable, Rebif can be stored below 25 C for upto 30 day, then put back in the refrigerator and used before the expiry date. Keep medicines out of reach of children.

Presentations

Rebif (Interferon beta- 1a) is available as a package of 1, 3 or 12 individual doses of solution for injection (0.5 ml) filled in a 1 ml glass syringe with a stainless steel needle.

Instructions for use, handling and disposal

The solution for injection in a pre-filled syringe is ready for use.

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