Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

Traceability
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Immune system disorders

The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome.

Gastrointestinal disorders

In rare cases, pancreatitis was observed with Betaferon use, often associated with hypertriglyceridemia.

Nervous system disorders

Betaferon 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 with increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Betaferon should be advised to report any symptoms of depression and/or suicidal ideation to their prescribing physician immediately. Patients exhibiting depression should be monitored closely during therapy with Betaferon and treated appropriately. Cessation of therapy with Betaferon should be considered (see also sections 4.3 and 4.8).

Betaferon should be administered with caution to patients with a history of seizures and 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).

This product contains human albumin and hence carries a potential risk for transmission of viral diseases. A risk for transmission of Creutzfeld-Jacob disease (CJD) cannot be excluded.

Laboratory test

Thyroid function tests are recommended regularly in patients with a history of thyroid dysfunction or as clinically indicated.

In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests (e.g. AST (SGOT), ALT (SGPT) and Gamma-GT), are recommended prior to initiation and at regular intervals following introduction of Betaferon therapy, and then periodically thereafter in the absence of clinical symptoms.

Patients with anaemia, thrombocytopenia, leukopenia (alone or in any combination) may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Patients who develop neutropenia should be monitored closely for the development of fever or infection. There have been reports of thrombocytopenia, with profound decreases in platelet count.

Hepatobiliary disorders
Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with Betaferon during clinical trials. As for other beta interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients treated with Betaferon. The most serious events often occurred in patients exposed to other drugs or substances known to be associated with hepatotoxicity or in the presence of comorbid medical conditions (e.g. metastasising malignant disease, severe infection and sepsis, alcohol abuse).

Patients should be monitored for signs of hepatic injury. The occurrence of elevations in serum transaminases should lead to close monitoring and investigation. Withdrawal of Betaferon should be considered if the levels significantly increase or if they are associated with clinical symptoms such as jaundice. In the absence of clinical evidence for liver damage and after normalisation of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.

Renal and urinary disorders
Caution should be used and close monitoring considered when administering interferon beta to patients with severe renal failure.

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 Betaferon should be considered.


Cardiac disorders
Betaferon should also be used with caution in patients who suffer from pre-existing cardiac disorders. Patients with pre-existing significant cardiac disease, such as congestive heart failure, coronary artery disease or arrhythmia, should be monitored for worsening of their cardiac condition, particularly during initiation of treatment with Betaferon.
While Betaferon does not have any known direct-acting cardiac toxicity, symptoms of the flu- like syndrome associated with beta interferons may prove stressful to patients with pre- existing significant cardiac disease. During the post-marketing period very rare reports have been received of worsening of cardiac status in patients with pre-existing significant cardiac disease temporarily associated with the initiation of Betaferon therapy.

Rare cases of cardiomyopathy have been reported. If this occurs and a relationship to Betaferon is suspected, treatment should be discontinued.

Thrombotic microangiopathy (TMA) and Haemolytic anaemia (HA)
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. 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. Additionally, cases of HA not associated with TMA, including immune HA, have been reported with interferon beta products. Life-threatening and fatal cases have been reported. Cases of TMA and/or HA have been reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta.
If TMA and/or HA is diagnosed and a relationship to Betaferon is suspected, prompt treatment is required (in case of TMA considering plasma exchange) and immediate discontinuation of Betaferon is recommended.


Hypersensitivity reactions
Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon should be discontinued and appropriate medical intervention instituted.

Injection site reactions
Injection site reactions, including injection site infection and injection site necrosis have been reported in patients using Betaferon (see section 4.8). Injection site necrosis can be extensive and may involve muscle fascia as well as fat and therefore can result in scar formation. Occasionally debridement and, less often, skin grafting are required, and healing may take up to 6 months.
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 his/her physician before continuing injections with Betaferon.

If the patient has multiple lesions Betaferon should be discontinued until healing has occurred. Patients with single lesions may continue on Betaferon provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Betaferon.

To minimise the risk of injection site infection and injection site necrosis, patients should be advised to:
- use an aseptic injection technique
- rotate the injection sites with each dose

The incidence of injection site reactions may be reduced by the use of an autoinjector. In the pivotal study of patients with a single clinical event suggestive of multiple sclerosis an autoinjector was used in the majority of patients. Injection site reactions as well as injection site necroses were observed less frequently in this study than in the other pivotal studies.

The procedure for the self-administration by the patient should be reviewed periodically, especially if injection site reactions have occurred.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlled clinical trials were collected every 3 months for monitoring of development of antibodies to Betaferon.

In the different controlled clinical trials in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, between 23% and 41% of the patients developed serum interferon beta-1b neutralising activity confirmed by at least two consecutive positive titres; of these patients, between 43% and 55% converted to a stable antibody negative status (based on two consecutive negative titres) during the subsequent observational period of the respective study.

The development of neutralising activity in these studies is associated with a reduction in clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect might be larger in patients with higher titre levels of neutralising activity.

In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at least once in 32% (89) of the patients treated immediately with Betaferon; of these, 60% (53) returned to negative status based on the last available assessment within the 5 year period. Within this period, the development of neutralising activity was associated with a significant increase in newly active lesions and T2 lesion volume on magnetic resonance imaging. However, this did not seem to be associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), time to confirmed EDSS progression and relapse rate).

New adverse events have not been associated with the development of neutralising activity.

It has been demonstrated in vitro that Betaferon cross-reacts with natural interferon beta.
However, this has not been investigated in vivo and its clinical significance is uncertain.
There are sparse and inconclusive data on patients who have developed neutralising activity and have completed Betaferon therapy.

The decision to continue or discontinue treatment should be based on all aspects of the patient’s disease status rather than on neutralising activity status alone.

Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free’.


Effects on Driving

4.7       Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed.

Central nervous system-related adverse events associated with the use of Betaferon might influence the ability to drive and use machines in susceptible patients.