Instructions for use BETAFERON
Patients should be informed that side effects of the drug may include depression and suicidal thoughts, which should immediately consult a doctor if they occur. In rare cases, these conditions can lead to suicide attempts. If depression or suicidal thoughts are present, therapy should be discontinued immediately.
In patients with a history of depressive reactions or seizures, as well as in patients receiving antiepileptic drugs, the drug should be used with caution.
The drug should be used with caution in patients with heart disease, in particular in patients with heart failure of functional class III-IV according to the NYHA classification, in patients with cardiomyopathies.
Before prescribing Betaferon and during its use, a detailed blood test should be regularly performed, including determination of the leukocyte formula, as well as determining the activity of AST, ALT and GGT. In case of increased serum transaminase activity, the patient should be carefully monitored and examined. The drug should be discontinued if there is a significant increase in the activity of liver enzymes or the appearance of symptoms of hepatitis. In the absence of clinical signs of liver damage, after normalization of liver enzyme levels, an attempt can be made to resume therapy under close monitoring of liver function.
There is no information on the use of the drug in patients with impaired renal or liver function.
In clinical studies, 41% of patients with relapsing-remitting multiple sclerosis had serum antibodies neutralizing interferon beta-1b (two consecutive titers >20). In a study of patients with secondary progressive multiple sclerosis, the appearance of neutralizing antibodies was detected in 28% of cases. The effect of antibody formation on the clinical efficacy of the drug is currently being studied. The available results are contradictory and do not allow us to draw a clear conclusion. There were no signs of a negative effect of neutralizing antibodies on the course of the disease in secondary progressive multiple sclerosis.
In vitro, neutralizing antibodies against recombinant interferon beta-1b have been shown to also interact with naturally occurring interferon beta, although to a lesser extent. This effect has not been studied in vivo and its clinical significance is unknown.
Information about patients who completed drug therapy despite the appearance of neutralizing antibodies is scarce and inconclusive.
Cases of necrosis at the injection site of the drug in a number of patients have been described. If multiple foci of necrosis appear, treatment with the drug should be stopped until they are completely healed, which can last up to 6 months. In the presence of one lesion and the absence of extensive necrosis, treatment with the drug can be continued.
To reduce the risk of necrosis at the injection site, patients should be advised to observe aseptic rules when performing injections; constantly change injection sites. The doctor should periodically monitor the correctness of self-injections, especially if local reactions occur.
Caution must be exercised when treating patients with impaired bone marrow hematopoiesis (including anemia or thrombocytopenia).
The use of cytokines in patients with monoclonal gammopathy was sometimes accompanied by a systemic increase in capillary permeability with the development of shock and death.
Impact on the ability to drive vehicles and operate machinery
This effect has not been studied. Side effects observed from the central nervous system during the use of the drug in predisposed patients may affect the ability to drive a car or operate machinery.
Betaferon®
Immune disorders
The use of cytokines in patients with monoclonal gammopathy is sometimes accompanied by a systemic increase in capillary permeability with the development of shock and death.
Gastrointestinal disorders
In rare cases, during the use of the drug Betaferon, the development of pancreatitis was observed, in most cases associated with the presence of hypertriglyceridemia.
Nervous system diseases
Caution should be exercised when prescribing Betaferon to patients with current or history of depressive disorders, especially patients with a history of suicidal thoughts. Depression and suicidal ideation are more common in patients with multiple sclerosis than in the general population and are associated with interferon use.
Patients should be informed that if depression or suicidal ideation occurs, they should report it to their healthcare provider immediately. Patients exhibiting depression should be closely monitored and therapy with Betaferon should be adjusted accordingly. The need to continue treatment with Betaferon should be reconsidered. Betaferon should be used with caution in patients with a history of seizures and in patients taking anticonvulsants, especially if epilepsy cannot be controlled with these drugs (see sections “Side effects”, “Interaction with other drugs and other forms of interaction” ).
This medicine contains human albumin and for this reason there is a very low risk of transmitting viral diseases. The risk of transmission of Creutzfeldt-Jakob disease cannot be excluded.
Changes in laboratory parameters
Patients with thyroid dysfunction are advised to have their thyroid function checked regularly and otherwise as clinically indicated.
In addition to standard laboratory tests prescribed for the management of patients with multiple sclerosis, before starting therapy with Betaferon, as well as regularly during treatment, it is recommended to conduct a detailed blood test, including determining the leukocyte count, platelet count and biochemical blood test, as well as checking liver function ( for example, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (g-GT) activity).
When managing patients with anemia, thrombocytopenia, leukopenia (individually or in combination), more careful monitoring of a complete blood count may be required, including determination of the number of red blood cells, white blood cells, platelets and leukocyte formula. Neutropenic patients should be closely monitored for fever or infection. There are reports of cases of thrombocytopenia with a marked decrease in platelet count.
Liver and biliary tract dysfunctions
Clinical studies have shown that therapy with Betaferon can often lead to an asymptomatic increase in the activity of liver transaminases, which in most cases is mild and transient.
There are rare reports of cases of severe liver damage, including liver failure, with the use of beta interferons. The most severe cases have been observed in patients exposed to hepatotoxic drugs or substances, as well as certain concomitant diseases (eg, metastatic malignancies, severe infections and sepsis, alcohol abuse).
When treating with Betaferon, it is necessary to monitor liver function (including assessment of the clinical picture). Increased transaminase activity in the blood serum requires careful monitoring and examination. If there is a significant increase in transaminase activity in the blood plasma or signs of liver damage (for example, jaundice) appear, the drug should be discontinued. In the absence of clinical signs of liver damage or after normalization of the activity of liver enzymes, it is possible to resume therapy with Betaferon with monitoring of liver function.
Renal and urinary tract dysfunction
Betaferon should be used with caution in patients with severe renal failure under close supervision.
Nephrotic syndrome
There have been case reports of the occurrence of nephrotic syndrome with various nephropathies, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN), when treated with drugs containing interferon beta. The onset of the disease was noted both at various periods during treatment and several years after the start of interferon beta therapy. It is recommended to regularly monitor for early symptoms such as edema, proteinuria and renal dysfunction, especially in patients at high risk of developing kidney disease. Treatment of nephrotic syndrome should be initiated early, and the need for continued treatment with Betaferon should be reconsidered.
Diseases of the cardiovascular system
Betaferon should be used with caution in patients with heart disease. Patients with severe heart disease, in particular with clinically significant chronic heart failure with clear symptoms of fluid stagnation, coronary heart disease or arrhythmia, should be under the supervision of a physician for timely detection of possible deterioration of the condition, especially at the beginning of treatment.
Although there is no evidence of a direct cardiotoxic effect of Betaferon, flu-like symptoms that typically occur with the administration of beta interferons may be a precipitating factor in patients with severe heart disease.
During post-marketing use, deterioration in cardiac status in patients with severe heart disease associated with initiation of Betaferon has been very rarely reported. There have been rare reports of cases of cardiomyopathy. If it is suspected that the development of cardiomyopathy is associated with the use of the drug, then treatment with Betaferon should be discontinued.
Thrombotic microangiopathy (TMAP)
There are reports of cases of thrombotic microangiopathy, which manifested itself in the form of thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), including death, when treated with drugs containing interferon beta. The onset of the disease was noted both during various periods of treatment and several weeks and even years after the start of interferon beta therapy. Early clinical signs include thrombocytopenia, new episode of hypertension, fever, central nervous system symptoms (eg, confusion, paresis), and renal dysfunction. Laboratory indicators, such as a decrease in platelet count, an increase in lactate dehydrogenase (LDH) in plasma, suggest the occurrence of thrombotic microangiopathy (TMAP) due to activation of hemolysis and the detection of schizocytes (fragments of red blood cells) in the blood smear. If clinical signs of TMAP occur, continued testing of platelet levels, plasma lactate dehydrogenase (LDH), blood smears, and renal function should be performed. When thrombotic microangiopathy (TMAP) is diagnosed, early treatment (including plasmapheresis) is necessary. It is recommended to discontinue therapy with Betaferon.
General disorders and injection site disorders
Serious allergic reactions (rare but acute and severe, such as bronchospasm, anaphylaxis and urticaria) may occur. If a severe reaction occurs, Betaferon should be discontinued and appropriate treatment should be prescribed.
Cases of necrosis at the injection site have been observed in patients receiving Betaferon (see section "Side Effects"). Necrosis can be extensive and extend into muscle fascia as well as fatty tissue and, as a result, lead to scar formation. In some cases, removal of dead areas or, less commonly, skin grafting is necessary. The healing process can take up to 6 months.
If there are signs of damage to the integrity of the skin (for example, leakage of fluid from the injection site), the patient should consult a doctor before continuing with Betaferon injections.
If multiple foci of necrosis appear, treatment with Betaferon should be stopped until the damaged areas are completely healed. In the presence of one focus, if the necrosis is not too extensive, the use of the drug Betaferon can be continued, since in some patients the healing of the dead area at the injection site occurred during the use of the drug Betaferon.
In order to reduce the risk of reaction and necrosis at the injection site, patients should be advised to:
- administer injections strictly following the rules of asepsis;
- change the injection site each time.
The use of an auto-injector helps reduce the incidence of reactions at the injection site. In the pivotal study, in which the autoinjector was used in the majority of patients with clinically isolated syndrome suggestive of multiple sclerosis, injection site necrosis was less common than in other pivotal studies. You should periodically monitor the correctness of self-injections, especially if local reactions occur.
Immunogenicity
As with the treatment of any other protein drugs, there is a possibility of immunogenicity when using the drug Betaferon. In a number of controlled clinical studies, blood serum was analyzed every 3 months to detect antibodies to the drug Betaferon.
It has been shown that neutralizing antibodies to interferon beta-lb developed in 23% to 41% of patients with relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, which was confirmed by at least two subsequent positive laboratory test results. Of these patients, 43% to 55% were consistently negative for interferon beta-lb antibodies on subsequent laboratory testing, as confirmed by at least two subsequent negative laboratory tests.
In these studies, the emergence of neutralizing activity was associated with a decrease in clinical efficacy only in terms of relapse rate. The results of some analyzes suggest a greater severity of this effect in patients with higher titers of neutralizing antibodies.
In a study of patients with a clinically isolated syndrome suggestive of multiple sclerosis, neutralizing activity, measured every 6 months, was detected at least once in 32% (89) of Betaferon-treated patients. Based on laboratory tests performed at the end of the 5-year period, 60% (53) of these patients were consistently negative for interferon beta-lb antibodies. In this study, the development of neutralizing activity was associated with a significant increase in the number of newly detected lesions and an increase in the volume of lesions on T2-weighted magnetic resonance images. It is unlikely that the development of neutralizing activity is associated with a decrease in clinical efficacy relative to the time to the onset of clinically definite multiple sclerosis or progression on the EDSS scale.
The development of neutralizing activity is not associated with the appearance of any new adverse reactions.
In in vitro studies, Betaferon has demonstrated cross-reactivity with native interferon beta. However, due to the lack of in vivo studies, the clinical significance of this fact has not been confirmed.
There are limited inconclusive data from patients who developed neutralizing activity and completed treatment with Betaferon.
The decision to continue or discontinue therapy should be based on all aspects of disease status, not just neutralizing activity status.
