special instructions
The drug should be prescribed with caution to patients with depression.
Such patients require careful medical monitoring and conditions to ensure that they receive the necessary care during treatment with Rebif. In some cases, it may be necessary to discontinue treatment with interferon beta. Patients should be warned that they should immediately report any symptoms of depression and/or suicidal ideation to their healthcare provider.
Caution should also be exercised when prescribing interferon beta-1a to patients who have previously had seizures or to patients receiving anticonvulsants, especially if they are not effective enough. If seizures occur during treatment with Rebif in patients who have not previously suffered from such disorders, it is necessary to discontinue Rebif, determine the etiology of the seizures, and prescribe anticonvulsant therapy before resuming treatment with Rebif.
During the first stages of treatment with interferon beta-1a, strict monitoring of patients suffering from cardiovascular diseases such as angina pectoris, congestive heart failure and arrhythmias is necessary. This observation should be aimed at timely detection of possible deterioration of the condition. In heart disease, flu-like symptoms associated with interferon beta-1a therapy may complicate the patient's condition.
There are isolated reports of the development of necrosis at the injection site. To minimize the risk of developing necrosis, strict adherence to the rules of asepsis when performing injections and constant change of injection sites is necessary. If skin damage is noted with swelling and fluid discharge at the injection site, the patient should consult a doctor before continuing to administer the drug. In case of multiple skin lesions, the drug should be discontinued until they heal. In case of a single lesion, it is possible to continue therapy with Rebif, provided that the lesion is moderate.
In clinical trials, an increase in the activity of hepatic transaminases, especially ALT, was observed. In the absence of clinical symptoms, it is necessary to monitor the level of ALT in plasma before starting therapy with Rebif and repeat it after 1, 3 and 6 months, as well as periodically during further treatment. It is necessary to reduce the dose of the drug if the ALT level exceeds 5 times the ULN, and gradually increase the dose after it normalizes. Caution must be exercised when prescribing interferon beta-1a to patients with a history of severe liver failure, signs of liver disease, signs of alcohol abuse, and an ALT level 2.5 times the ULN. Therapy should be discontinued if jaundice or other symptoms of liver dysfunction occur.
Rebif, like other beta interferons, has the potential to cause serious liver damage, including acute liver failure. The mechanism of these conditions is unknown, and specific risk factors have not been identified.
In addition to laboratory tests, which are always carried out in patients with multiple sclerosis, it is recommended that in the 1st, 3rd and 6th months after the start of therapy with Rebif, as well as periodically, in the absence of clinical symptoms, during further treatment, a general clinical blood test with determination of the leukocyte formula of the blood, platelet content, as well as conduct a biochemical blood test, including liver function tests.
Patients receiving Rebif sometimes develop or worsen thyroid dysfunction. It is recommended to test the function of the thyroid gland immediately before starting treatment and, if disorders are detected, every 6-12 months from the moment it begins. If thyroid function is normal before treatment, then periodic studies of its function are not required, but they are necessary when clinical signs of thyroid dysfunction appear.
Patients receiving beta interferons may develop neutralizing antibodies. Their clinical significance has not been established. If there is an insufficient therapeutic response to therapy with Rebif, and this is due to the persistent presence of neutralizing antibodies, then the physician should evaluate the advisability of continuing interferon therapy.
Caution should be exercised when prescribing the drug to patients with severe renal failure and myelosuppression.
Use in pediatrics
The safety profile in adolescents 12 to 16 years of age receiving Rebif 22 mcg subcutaneously three times weekly is similar to that in adult patients.
International Neurological Journal 2(18) 2008
Multiple sclerosis (MS) belongs to the group of chronic progressive demyelinating diseases of the central nervous system, characterized by the formation of multiple scattered inflammatory foci of demyelination (plaques) in the white matter of the brain and spinal cord, predominantly affecting people of young working age, quickly leading to persistent disability up to the complete loss of self-care function . In recent years, MS has been proposed to be classified as an autoimmune degenerative disease based on the results of numerous studies that have proven the constant activity of the pathological process, the main indicators of which are the emergence of new foci of demyelination and the progression of brain atrophy, persistent disorders in the immune system during clinical remissions.
Currently, the most generally accepted is the multifactorial etiology of the disease, which consists of an unfavorable combination of environmental factors (climatogeographical, toxic, dietary, infectious, etc.) and genetic predisposition, including the characteristics of the immune response and a certain type of metabolism - a predisposition to accelerated catabolism of proteins with insufficiency of function myelin-producing oligodendrocytes, resulting in chronic inflammation, autoimmune reactions and demyelination.
The main hypothesis of the immunopathogenesis of MS is the assumption of active penetration of T-lymphocytes activated to myelin antigens through the damaged blood-brain barrier (BBB). An indicator of impaired BBB permeability is the appearance of diseased brain antigens in the blood serum and cerebrospinal fluid. The main autoantigens are: myelin basic protein, myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein, proteolipid protein and others. As a result of the interaction of antigens and antibodies, T1 lymphocytes begin to produce pro-inflammatory cytokines: IL-1, IL-2, TNF-α, interferon-γ, lymphotoxin, which play a major role in the chronicization of the inflammatory and autoimmune process in the central nervous system. TNF-α is the main pathogenic factor in the development of MS, enhancing the expression of adhesion molecules and antigen presentation on the vascular endothelium, increasing the permeability of the BBB, activating micro- and astroglial cells, promoting the death of oligodendrocytes and neurons, activating nitric oxide synthase, which is a potential mediator of primary demyelination, associated with microglial activation. At the same time, T2 lymphocytes secrete anti-inflammatory cytokines - IL-4, IL-10, IL-13, which have an antagonistic effect on T1 lymphocytes, stimulating the differentiation of T lymphocytes towards the T2 profile.
It is believed that disease activity is caused by an imbalance between pro-inflammatory and anti-inflammatory cytokines. This is precisely what modern immunomodulatory therapy is based on, the goal of which is to prevent exacerbations, increase the duration of remissions and, therefore, slow down the accumulation of neurological deficits. Today, the leading position among drugs for the pathogenetic therapy of multiple sclerosis is occupied by interferon drugs - β-INF-1b (betaferon and betaseron) and β-INF-1a (Rebif and Avonex) and glatiramer acetate (Copaxone). Betaferon - β-INF-1b - a genetically engineered form obtained by recombination of human DNA from the E. coli strain, Rebif and Avonex - β-INF-1a, synthesized from hamster ovary cells. β-INF-1a is closer in structure to natural β-INF, which results in greater activity and better tolerability than β-INF-1b. The mechanism of action of β-INF-1a and β-INF-1b is the same and consists of suppressing the proliferation of T cells, reducing the level of pro-inflammatory cytokines (TNF-α, INF-γ, IL-1, IL-2), increasing the level of anti-inflammatory cytokines ( IL-4, IL-10, etc.). In addition, betaferons inhibit the replication of viruses, prevent demyelination, the development of gliosis, and slow down brain atrophy, thereby preventing the increase in persistent neurological deficits and the degree of disability. Copaxone is the only antigen-specific drug consisting of four amino acids: alanine, glutamine, lysine and tyrosine. Its action is based on competitive interaction with antigen-presentation molecules and displacement of the main antigen, the common myelin protein, from the trimolecular complex.
The use of preventive therapy is limited by the degree of disability as measured by the Kurtzke Disability Scale (EDSS). Thus, Betaferon is indicated for patients with a severity level on the EDSS scale of up to 6.5 points, Rebif - up to 6 points, Avonex - up to 5 points, Copaxone - up to 5.5 points. Contraindications to immunomodulatory therapy are pregnancy or planning pregnancy, lactation, episyndrome, severe depression, suicidal tendencies, severe allergic reactions, especially to protein drugs, malignant neoplasms, liver dysfunction, etc.
On the basis of the angioneurological department of the Institute of Internal Medicine of the Academy of Medical Sciences of Ukraine named after. VC. Gusak for 5 years, we observed 9 patients with MS - 5 women and 4 men aged from 20 to 40 years, who received immunomodulatory therapy with the drug Rebif at a dose of 44 mcg 3 times a week. The basis for prescribing immunomodulatory therapy for these patients was the establishment of a reliable diagnosis of multiple sclerosis, according to the criteria of McDonald et al. (2005), relapsing nature of the disease, severity on the EDSS scale up to 5 points, absence of contraindications, age of patients from 18 to 50 years. Clinically isolated syndrome (as the onset of MS) was registered in 5 out of 9 patients: optic neuropathy - 2 people, polyneuropathy - 2 people, acute transversive myelopathy - 1 person. The time interval between the onset and the full clinical picture of MS ranged from 6 months to 5 years. All patients underwent a thorough somatic examination, general clinical, biochemical parameters of blood and cerebrospinal fluid were examined, and a study was performed using visual and auditory evoked potentials. From 2003 to 2005 3 patients took the drug. All of them had a positive effect in the form of a decrease in the frequency of exacerbations and stabilization of the condition. 1 patient with a severity of condition of 3.5–4.0 points took Rebif for 1.5 years. During pregnancy and in the first 2 months of lactation, the drug was discontinued, and subsequently treatment was continued. The uniqueness of this case is that no exacerbations were recorded either during pregnancy or during the postpartum period. 2 women took the drug from 2003 to 2005, but subsequently stopped taking it due to lack of financial resources. However, even after discontinuation of the drug, no exacerbations were recorded for 2 years. From 2006 to 2007 the drug was taken by 3 women and 2 men aged 22 to 29 years. The severity level on the EDSS scale was 3.0–4.5 points. In these patients, dysfunctions of the pyramidal system, cerebellum, pain and vibration sensitivity (reduced to 6–10 s), and brainstem functions predominated. The clinic was dominated by: ataxia, hemiparesis, impaired vibration and pain sensitivity. According to generally accepted recommendations, it is recommended to start taking the drug using a dose titration method, but our patients started taking Rebif with a dose of 22 mcg subcutaneously 3 times a week. for a week without any complications, then the dose was increased to 44 mcg subcutaneously 3 times a week. Neurological status was assessed monthly. MRI of the brain was performed once every 6 months. In general, the drug was well tolerated. However, in 3 people, during the first 3 weeks of taking the drug, moderate hyperemia was observed at the injection sites; no flu-like syndrome was recorded. All patients did not experience any exacerbations while taking Rebif. The positive effect was confirmed by the results of a repeated MRI study of the brain with intravenous Omniscan contrast. There was no increase in the number and size of lesions; there was a decrease in the size of old lesions and no accumulation of contrast, which indicated the absence of process activity in all patients. Against the background of immunomodulatory therapy, an improvement was noted in the form of a decrease in the degree of ataxia, severity of paresis, sensory disorders, and an improvement in vibration sensitivity to 10–12 s was recorded. This group of patients was provided with the drug free of charge by the company. Then, a year later, all 5 people continued taking the drug according to the state program.
Thus, our observation showed the effectiveness and safety of Rebif in the treatment of multiple sclerosis, as evidenced by a decrease in the frequency, severity and duration of exacerbations, and good tolerability of the drug. These results confirm the feasibility of using immunomodulatory therapy for the treatment of predominantly relapsing-remitting forms of multiple sclerosis.
