Drug Description

Presentation

Indications

Adult Dosage

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

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

Rebif solution for injection in cartridge is intended for multidose use and should only be used with the RebiSmart autoinjector device following adequate training of the patient and/or carer.

For administration, the instructions provided in the package leaflet and in the instruction manual provided with the RebiSmart autoinjector device should be followed.

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flulike 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 4year 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 subcutaneous 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.

Contra Indications

• Initiation of treatment in pregnancy.

• Hypersensitivity to natural or recombinant interferonβ, or to any excipients.

• Current severe depression and/or suicidal ideation

Special Precautions

Patients should be informed of the most frequent adverse reactions associated with interferon beta administration, including symptoms of the flulike syndrome. 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. 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.

Rebif should be administered with caution to patients with a history of seizures, to those receiving treatment with antiepileptics, particularly if their epilepsy is not adequately controlled with antiepileptics.

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 beta1a. Symptoms of the flu-like syndrome associated with interferon beta1a therapy may prove stressful to patients with cardiac conditions.

Injection site necrosis (ISN) has been reported in patients using Rebif. 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 13% 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 reescalated 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.

Rebif, like other interferons beta, has a potential for causing severe liver injury 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 612 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.

Caution should be used, and close monitoring considered when administering interferon beta1a to patients with severe renal and hepatic failure and to patients with severe myelosuppression.

Serum neutralising antibodies against interferon beta1a 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 beta1a. The presence of antibodies has been shown to attenuate the pharmacodynamic response to interferon beta1a (Beta2 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 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.

Interactions

No interaction studies have been performed with interferon beta1a in humans.

Interferons have been reported to reduce the activity of hepatic cytochrome P450dependent 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.

Adverse Reactions

The highest incidence of adverse reactions associated with Rebif therapy is related to flulike 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 beta1a 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.

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
Endocrine Disorders
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)
Gastrointestinal disorders		Diarrhoea, vomiting, nausea
Skin and subcutaneous tissue disorders		Pruritus, rash, erythematous rash, maculopapular rash		Angioedema, urticaria, erythema multiforme, erythema multiformelike skin reactions, StevensJohnson syndrome, hair loss
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
Respiratory, thoracic and mediastinal disorders				Dyspnoea
Immune system disorders				Anaphylactic reactions
Vascular disorders				Thromboembolic events
Hepatobiliary disorders				Hepatitis with or without icterus

*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.

The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, vasodilation and palpitation, menorrhagia and metrorrhagia.

An increased formation of autoantibodies may occur during treatment with interferon beta.

Manufacturer

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