Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to imporve the traceabilty of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General recommendations

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.

Thrombotic microangiopathy (TMA)

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed,
further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate discontinuation of Rebif is recommended.

Depression and suicidal ideation

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).


Seizure disorders

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 antiepileptics (see sections 4.5 and 4.8).

Cardiac disease

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

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.

Hepatic dysfunction

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.

Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six months of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No specific risk factors have been identified.


Renal and urinary disorders

Nephrotic syndrome

Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Rebif should be considered.

Laboratory abnormalities

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 count, 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.

Thyroid disorders

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).

Severe renal or hepatic failure and severe myelosuppression

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.

Neutralising antibodies

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, 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.

Other forms of multiple sclerosis

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 these patients.

Excipients

Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.

Benzyl alcohol

This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions.

Monitor patients less than 3 years of age for respiratory symptoms.

Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol, which might accumulate over time and cause metabolic acidosis. Use with caution in patients with hepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which might accumulate over time and cause metabolic acidosis.

Effects on Driving

4.7    Effects on ability to drive and use machines

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).