Tizabry - instructions for use, dose, side effects, contraindications

Active substanceNatalizumabNatalizumab

Similar drugsTo uncover

concentrate d / infusion

Dosage form: & nbspconcentrate for solution for infusion

Composition:1 ml of concentrate contains:
Active substance: Natalizumab 20.0 mg / ml
Auxiliary components: Sodium dihydrogen phosphate monohydrate 1.13 mg / mL, disodium hydrogen phosphate heptahydrate 0.48 mg / mL sodium chloride 8.20 mg / ml, polysorbate 80 (E433) 0.20 mg / ml, Water for injections 983,00 mg / ml .

Description:

Colorless transparent or slightly opalescent solution.

Pharmacotherapeutic group:antibodies monoclonal.

ATX: & nbsp

L.04.A.A.23 Natalizumab

Pharmacodynamics:

Tisabree's preparation contains natalizumab - Selective inhibitor of adhesion molecules. Tisabry binds to the ἄ4 subunit of human integrin, in a large amount of all the leukocytes expressed on the surface, with the exception of neutrophils. Natalizumab specifically binds to the ἄ4β1-integrin, blocking the interaction with the corresponding receptor, the adhesive molecule of the vascular cells (VCAM-1) and ligand of osteopontin, the domain of fibronectin formed as a result of alternative splicing, connective segment-1 (CS-1). Besides, natalizumab blocks the interaction of the ἄ4β7 integrin with the mucosal adhesion molecule, adresin-1 (MadCAM-1). The effect on these molecular interactions prevents the migration of mononuclear leukocytes through the endothelium into the foci of inflammation of the parenchymal organs. The further mechanism of the action of natalizumab may be due to the suppression of inflammatory reactions in the affected tissues by suppressing the interaction of the ἄ4-expressing leukocytes with their ligands in the extracellular substance and on the parenchyma cells. In this way natalizumab can suppress inflammatory activity in the affected tissues and further attraction of immune cells to the focus of inflammation.

Damage to brain tissue in multiple sclerosis (PC) occurs when the activated T-lymphocytes pass through the blood-brain barrier (BBB). Migration of leukocytes through the BBB involves the interaction between adhesion molecules on surface of activated leukocytes and endothelium of blood vessels. The interaction between 6401 and its targets is an important component of the pathogenesis of the formation of foci of inflammation in the brain, so the violation of these interactions reduces the activity of inflammation. Under normal conditions VCAM-1 is not expressed in the parenchyma of the brain.However, in the presence of pro-inflammatory cytokines, production VCAM-1 in endothelial cells and, probably, in glial cells located near the focus of inflammation, is regulated by the mechanism of positive feedback. Under conditions of inflammation of the central nervous system PC interaction ἄ4β1 from VCAM-1, CS- 1 and osteopontin mediates the strong adhesion and migration of leukocytes in the brain and can enhance the inflammatory cascade in the tissues of the central nervous system. Blockade of molecular interactions ἄ4β1with its targets reduces inflammatory activity in the parenchyma of the brain at PC and suppresses the further attraction of immune cells to the foci of inflammation, thereby reducing the formation or slowing the increase in the lesion volume at PC.

Pre-clinical safety study data

Numerous pre-clinical safety studies have not shown any specific risk factors for human and genotoxicity.

In most studies in vivo a change in the migration of lymphocytes was found, which is consistent with the pharmacological activity of natalizumab; there was an increase in the number of leukocytes and the mass of the spleen. These changes were reversible and did not have any visible toxicological consequences.

In studies on mice with the administration of natalizumab, there was no acceleration of the division of melanoma cells and lymphoblastic leukemia. When researching the Ames method or an analysis of chromosome aberrations, there was no mutagenic effect in the use of natalizumab in humans. When studying the proliferation of tumor cell lines containing ἄ4-integrin, in vitro, no signs of cytotoxicity. In a study on guinea pigs using doses exceeding those recommended for humans, the effect of natalizumab on the reproductive capacity of males was not revealed.

To evaluate the effect of natalizumab on reproductive function, 5 studies were conducted, 3 of them on guinea pigs and 2 on monkeys Cynomolgus. These studies did not show teratogenic effects or effects on the growth of offspring. In one study in guinea pigs, a slight decrease in the survival rate of the young was observed. In a monkey study in the group receiving 30 mg / kg of natalizumab, the incidence of spontaneous abortion doubled compared to the control group. This was the result of a high incidence of spontaneous abortions in the first group, which was not observed in the second group. In another study, no effect was found on the frequency of spontaneous abortions.Study on pregnant monkey females Cynomolgus showed the effect of natalizumab on the fetus, including complete anemia, a decrease in platelet count, an increase in the mass of the spleen, and a decrease in the weight of the liver and thymus. These changes were associated with an increase in extramedullary hematopoiesis in the spleen, atrophy of the thymus and a decrease in hematopoiesis in the liver. Decrease in platelet concentration was also noted in offspring of females who received natalizumab before delivery, however, they showed no signs of anemia. All changes were observed at doses exceeding recommended for humans and returned to normal after discontinuation of natalizumab. Some female monkeys Cynomolgus, who received natalizumab before giving birth, there is an insignificant concentration of natalizumab in milk, which indicates the possibility of natalizumab with breast milk in women.

Pharmacokinetics:

The mean maximum serum natalizumab concentration after repeated intravenous administration at a dose of 300 mg to patients PC was 110 ± 52 μg / ml. The mean steady-state concentration of natalizumab during the administration period ranged from 23 to 29 μg / ml.The predicted time to reach the equilibrium concentration was approximately 36 weeks.

The sample for pharmacokinetic analysis included more than 1100 patients PC, who received natalizumab in a dose of 3 to 6 mg / kg. Of these, 581 received a fixed dose of 300 mg as monotherapy. Average ± SD (standard deviation) the clearance time for the steady state was 13.1 ± 5.0 ml / h with an average ± SD the elimination half-life is 16 ± 4 days. In the analysis, the effect of selective variables, including body weight, age, sex, liver and kidney function, and the presence of antibodies to natalizumab on pharmacokinetics were investigated. It was shown that the distribution of the drug is affected only by body weight and antibodies to natalizumab. It was found that the body weight affects the clearance of natalizumab, and this effect is less proportional; for example, 43% of the change in body weight leads to a change in the clearance by 31-34%. Changes in clearance are not clinically important. Circulating antibodies to natalizumab increase its clearance by about three times, which corresponds to the observed decrease in the concentration of natalizumab in patients with circulating antibodies.The pharmacokinetics of natalizumab in children with PC or in patients with hepatic or renal failure was not studied.

Studies of pharmacodynamics and the efficacy of plasmapheresis to reduce the concentration of natalizumab in the blood were performed with the participation of 12 patients with PC. The results of excretion of the drug after three procedures of plasmapheresis (with more than 5-8 day intervals) were approximately 70-80%. This compares with 40% of those identified in the previous study after drug withdrawal over the same period of time. The effect of plasmapheresis on the restoration of lymphocyte migration and, ultimately, on clinical use is unknown.

Indications:

Tisabry is indicated for monotherapy of the remitting form of multiple sclerosis in the following groups of patients:

- Patients with active disease, despite treatment with interferon beta. This group of patients can be defined as a group of patients who can not be treated with a complete and adequate course (for at least one year) of interferon beta. They should have at least one recurrence during the previous year of therapy and at least 9 T2-hypertensive foci on magnetic resonance imaging of the brain (MRI) or at least one focus seen with contrast agents for MRI,containing gadolinium. Patients under "no response" to treatment should be understood in patients with unchanged or increased relapse rate compared with the previous year, or ongoing severe relapses, even with treatment duration of at least one year.

- Patients with rapidly progressive severe remitting multiple sclerosis (i.e. suffered two or more relapses within one year, and having one or more lesions on brain MRI, accumulating contrast agents for MRI containing gadolinium or a significant increase in lesion T2 mode compared with the results of previous MRI).

Contraindications:

- hypersensitivity to natalizumab or any of the excipients;

- progressive multifocal leukoencephalopathy (PML);

- increased risk of opportunistic infections by microorganisms, including immunodeficient state (for example, patients receiving immunosuppressive or treated, such as mitoxantrone or cyclophosphamide, see also the section "Special instructions");

- simultaneous use of interferon beta or glatiramer acetate;

- Malignant neoplasms, except for basal cell skin cancer;

- children and adolescents.

Carefully:not described

Pregnancy and lactation:

Data on the introduction of natalizumab to pregnant women is not enough. Studies in animals have shown reproductive toxicity. The possible risk to people is unknown. Do not assign natalizumab during pregnancy without extreme necessity. If the patient becomes pregnant while taking Tisabree, therapy should be discontinued.

Tisabree is excreted in breast milk. Patients receiving Tisabree should stop breastfeeding.

Dosing and Administration:

Tizabry therapy should be prescribed and under constant monitoring by physicians specializing in the diagnosis and treatment of neurological diseases in institutions with the ability to carry out MRI.

Patients receiving Tisabry should be given a special patient card and inform about the risks of the drug. After 2 years of treatment, patients should be re-informed of the risks of using Tisabree, especially the increased risk of PML. Early signs and symptoms of PML should also be reported to caregivers.

The medical institutions should have everything necessary for the development of hypersensitivity reactions and equipment for MRI.

After dilution, the solution is administered in the form of an infusion for about an hour; during infusion and within an hour after it, patients should remain under observation in connection with the possibility of hypersensitivity reactions.

The bolus injection of Tisabry is not allowed.

In the absence of violations related to treatment, for example, neutropenia, patients receiving interferon beta or glatiramer acetate, can be directly translated into natalizumab. If abnormalities are present, natalizumab can be started only after the indicators return to normal.

Some patients could previously receive immunosuppressants (for example, mitoxantrone, cyclophosphamide, azathioprine). These drugs can cause a prolonged immunosuppressive state, which persists even after their withdrawal. Therefore, before Tizabree's appointment, you need to make sure there is no immunodeficiency in the patient.

In the absence of signs of improvement, after 6 months, the feasibility of continuing therapy should be carefully evaluated.

Data on the safety and efficacy of natalizumab for 2 years were obtained from controlled, double-blind studies. The decision to prolong therapy longer than this time should be taken only after an assessment of the relationship between possible risk and benefit.

Adults

Tisabree 300 mg is given intravenously in the form of infusion once every 4 weeks.

Elderly people

The use of Tisabree in patients over 65 years of age is not recommended because of the lack of safety data for this category of patients.

Children and teens

Tizabri is contraindicated in children and adolescents.

Patients with impaired renal and hepatic function

Studies to evaluate the effects of the drug with impaired liver and kidney function were not conducted.

The elimination mechanism and the results of the study of pharmacokinetics suggest that the drug can be administered to patients with impaired renal and hepatic function without changing the dose.

Repeated administration

The efficacy and safety of the drug with repeated administration was not determined.

Rules for the preparation, introduction, storage and disposal of the drug

1. Before dilution and administration, examine the preparation for the presence of solid impurities.Do not use a preparation containing solid particles or which does not correspond to the description "colorless, transparent or slightly opalescent solution".

2. Prepare the solution for internal administration under aseptic conditions. Remove the top cover from the vial. Puncture the stopper in the center with a syringe needle and take 15 ml of concentrate to prepare a solution for intravenous administration.

3. Add 15 ml of concentrate to 100 ml of 0.9% sodium chloride solution. Carefully turn the bottle several times to mix the contents. Do not shake.

4. Do not mix Tisabree with other solvents and preparations.

5. Before administration, inspect the diluted solution for solids or discoloration. A solution with foreign impurities or discoloration is not suitable for use.

6. The diluted drug should be used as soon as possible and not later than 8 hours after breeding. If the solution was stored at a temperature of 2-8 ° C (it was not frozen!), Allow it to warm up to room temperature before infusion.

7. The diluted solution is administered as an infusion for about an hour at a rate of about 2 ml / min.

8. After completion of the drug, rinse the system with 0.9 % solution of sodium chloride.

9. Each bottle is for single use only.

10. Any unused product or waste should be disposed of in accordance with local regulations.

Side effects:

During a placebo-controlled study in 1617 patients PC, who received natalizumab for 2 years (placebo 1135), adverse events that led to early termination of participation were observed in 5.8% of patients who received natalizumab (and 4.8% of those receiving placebo). For 2 years of study, adverse events were noted in 43.5% of patients who received natalizumab, and 39.6% (undesirable events regarded as treatment-related by the treating physician) who received the placebo. The incidence of adverse events in the natalizumab group was 0.5% higher than in the placebo group, as shown below. Reactions were indicated by preferred terms taken from the medical vocabulary for regulatory activities (MedDRA), in accordance with the system-organ classes. Their frequency was as follows:

Frequent (> 1/100, <1/10), rare (> 1/1000, <1/100).

In each group, undesirable phenomena are divided by frequency.

Infections and invasions

Frequent Urinary tract infections; Nasopharyngitis

Immune system disorders Frequent Hives

Rare Hypersensitivity

Disturbances from the nervous system Frequent Headache; Dizziness

Gastrointestinal disorders Frequent Vomiting; thenwnote

Bone mumps and connective tissue lesions Frequent Joint pain

General disorders and reactions at the site of administration Frequent Chills; Fever; Fatigability

Reactions to infusion

According to a 2-year controlled clinical trial on patients PC, Influenza-related phenomena were considered to be side effects that occurred during infusion or within 1 hour after its completion. They were observed in 23.1% of patients PC, who received natalizumab (and in 18.7% who received placebo). The phenomena more often observed in the natalizumab group included dizziness, nausea, urticaria, and chills (see the section on "Hypersensitivity Reactions" below).
Hypersensitivity reactions
According to a two-year controlled clinical trial on patients PC, frequency cases hypersensitivity has reached 4%. Anaphylactic / anaphylactoid reactions are noted in less than 1% of patients receiving Tisabree.Hypersensitivity reactions usually occur during infusion or within an hour after it.
Immunogenicity
During a biennial controlled clinical trial, antibodies to natalizumab were detected in 10% of patients PC. Circulating antibodies to natalizumab (a double positive result) were found in approximately 6% of patients. A single positive result was noted in 4% of patients. Circulating antibodies reduce Tisabree's effectiveness and increase the frequency of hypersensitivity reactions. Other reactions to infusion due to circulating antibodies included chills, nausea, vomiting, and "hot flashes" of blood.
If there is a suspicion of circulating antibodies after about 6 months of therapy, either due to a decrease in efficacy or a response to infusion, another analysis should be made 6 weeks after the first positive result. Given the possible reduction in efficacy or increased frequency of hypersensitivity reactions in patients with circulating antibodies, treatment should be discontinued.
Infections, including PML and infections with opportunistic microorganisms
According to a two-year controlled clinical trial on patients PC the incidence of infections was approximately 1.5 per patient-year, both in the natalizumab group and in the placebo group. The nature of the infections in both groups was approximately similar. A case of diarrhea due to Cryptosporidium. During other clinical trials, other opportunistic infections were noted, including deaths. During clinical trials in the group receiving natalizumab, there was a slightly higher incidence of herpesvirus infection (herpes zoster virus and herpes simplex virus) than in the placebo group. During early post-marketing surveillance, one fatal case of herpesviral encephalitis was registered.
The majority of patients who developed infections did not stop natalizumab therapy and, with appropriate treatment, recovery came.
During clinical trials, cases of PML have also been recorded. They usually led to serious disability or death. During the basic clinical trials, two cases were recorded, including one fatal, in patients PC with concomitant infection, treated with interferon beta for more than 2 years. In another trial, PML developed in a patient with Crohn's disease, who was treated with immunosuppressants for a long time and suffered from lymphopenia, this patient died. The development of PML was observed in the postmarketing study in patients who received Tizabry as a monotherapy.
Reactions with hand liver
During the postmarketing period, spontaneous reports of cases of severe liver damage, increased activity of "liver enzymes" and hyperbilirubinemia were obtained.
Malignant neoplasms
For more than 2 years of therapy, there was no difference in the incidence of malignant neoplasms in the natalizumab and placebo groups. However, in order to completely eliminate the effect of natalizumab on the incidence of malignant neoplasms, longer studies are needed.
Impact on laboratory performance
Treatment with Tizabry is accompanied by an increase in the number of lymphocytes, monocytes, eosinophils, basophils and nuclear forms of red blood cells in the circulating blood. No increase in the neutrophil concentration was observed.The increase in the number of lymphocytes, monocytes, eosinophils and basophils reaches 35-140% compared to the initial value, but the total number of cells remains within normal limits. During Tizabry therapy, a small decrease in hemoglobin concentration (mean decrease of 0.6 g / dl), hematocrit (mean decrease of 2%), and erythrocytes (mean decrease of 0.1 x 10⁶ / l). Usually, within 16 weeks after the last dose of Tisabree, all hematologic indices returned to baseline and these changes were not accompanied by clinical symptoms.

Overdose:No cases of overdose have been reported.

Interaction:Interaction with medicines and other types of interaction: The safety and efficacy of Tisabree in combination with other immunosuppressants or antitumor drugs have not been adequately established. The concomitant administration of these drugs may increase the risk of infection, including opportunistic microorganisms, and is therefore contraindicated. In patients who received immunosuppressant therapy earlier, the risk of developing PML was increased. Prescribe the drug to patients who have previously received immunosuppressants, with caution; it is necessary to wait for the restoration of the function of the immune system. Before appointing Tisabree, the attending physician should evaluate each individual case to identify possible signs of immunodeficiency. Based on the results of Phase III clinical trials in patients PC, The concomitant treatment of relapse with a short-term course of glucocorticosteroids was not accompanied by an increase in cases of infections. Thus, short-term therapy with glucocorticosteroids can be carried out in parallel with Tizabry therapy.
Incompatibility
Do not mix Tisabree with other medications, except for 0,9 % solution of sodium chloride.
Immunization
In randomized open trials conducted with 60 of patients with multiple sclerosis, there were no significant deviations in the immune response of patients to the antigen administered. The comparison was performed in groups of patients treated with Tisabree during 6 months and a control group not treated with Tisabree.

Special instructions:

Progressive multi-focal leukoencephalopathy (PML)

The use of Tisabri may increase the risk of developing PML.Infection caused by opportunistic JC DNA poliomavirus, can lead to death or severe disability.

Due to the risk of developing PML, the doctor and the patient should individually consider the benefit-risk relationship in the treatment with Tisabree.

Patients, as well as carers, should be instructed about the early signs and symptoms of PML.

Each of the independent risk factors described below is associated with a high risk of developing PML:

- The presence of antibodies to JC virus

- Long-term treatment, especially more than 2 years. Due to the limited experience of using Tisabree, for more than 4 years, the risk of developing PML in such patients is currently impossible to assess.

- Use of immunosuppressors before Tisabree treatment.

Depending on the presence of antibodies JC the virus is determined by the riceto the development of PML in patients receiving treatment with Tisabree. In patients with antibodies to JC the virus has an increased risk of developing PML. In the absence of antibodies to JC the risk of PML is much lower. Patients have a significant risk of developing PML if all three risk factors are present: the presence of antibodies to JC virus, the duration of therapy with the drug for more than 2 years, and the use of immunosuppressors before treatment.

The risk and benefit of continued Tisabree treatment should be carefully reviewed in patients who have all of the listed risk factors.

In this regard, an antibody test should be performed at the beginning of Tisabree treatment or in patients already receiving Tisabree, with an unknown status of antibodies to JC virus.

To determine the risk of PML in different subgroups of patients, it is necessary to consult the medical information and treatment recommendations.

Determination of antibodies to JC the virus should not be used to diagnose PML. Determination of antibodies to JC the virus should not be performed at that time, or at least within 2 weeks after the plasmapheresis, because After this procedure, the antibodies are removed from the blood serum.

After 2 years from the start of treatment, the patient should be re-informed of the risk of developing PML on the background of taking Tisabree.

Start Tisabry therapy should only be available the results magneto-resonance imaging (MRI), conducted no earlier than 3 months before the start of therapy. This MRI is the base. Each subsequent study (MRI) should be conducted at least once a year.Regular monitoring of the patient on everything treatment for timely detection emergence of new neurologic symptoms, characteristic of PML or worsening of existing ones.

When new neurologic symptoms appear, it is necessary to suspend therapy before the exclusion of PML.

The attending physician should continue to monitor the patient to identify possible symptoms of neurological dysfunction and, if available, determine whether they are typical for PC and are not the reason for suspicion of PML. In the latter and other doubtful cases, further diagnosis is needed, including MRI (its results should be compared with the results of basic MRI before treatment with natalizumab), the study of cerebrospinal fluid (CSF) for the presence of DNA poliomavirus (JCvirus) and repeated neurologic examination.

If PML is not confirmed, therapy with natalizumab can be resumed.

The treating physician should be especially careful about the symptoms of PML, which may go unnoticed by the patient himself (for example, symptoms of cognitive or mental disorders).It should be advised the patient to warn close relatives or carers that he is being treated; perhaps they will be able to notice the symptoms left undetected by the patient.

With the development of PML, Tisabree therapy should be completely discontinued.

In patients with PML on the background of immunosuppression after restoration of immunity improvement in clinical outcomes is noted.

PML and Inflammatory Immune Deficiency Syndrome (IRIS) Virtually all patients treated with Tisabree, with the development of PML and the subsequent abolition of Tizabry, were noted by IRIS. To accelerate the reduction in concentration natalizumab When PML is detected, plasmapheresis is used. IRIS is the result of restoration of immunity in patients with PML, which can result to serious neurologic complications, and also to death.

Careful monitoring of the IRIS syndrome should be carried out, which usually develops within a few days or weeks after plasmapheresis in patients with PML who received Tisabree, as well as appropriate anti-inflammatory treatment during recovery from PML.

Other infections by conditionally pathogenic microorganisms

Other infections of opportunistic pathogens have been described with Tisabree, mainly in Crohn's disease, immunodeficiency states and concomitant diseases, but such infections can develop in the absence of concomitant diseases. Infections opportunistic microorganisms are also described in patients PC, who received monotherapy Tisabree.

When prescribing the drug, it is necessary to remember the possibility of infection with opportunistic pathogens, which should be included in the list of differential diagnoses. If the infection is suspected to be opportunistic microorganisms should suspend Tizabree therapy until infection is excluded from the results of the relevant studies.

When the infection is opportunistic microorganisms should completely stop Tisabree therapy. Teaching guides The doctor should discuss the benefits and risks of Tisabree therapy with the patient and provide him with a special card containing important safety information. Patients should be instructed that, in the event of infection, they should notify the attending physician about Tisabree's use.

Doctors should explain to the patient the importance of continuous treatment, especially in the first months of treatment.

Hypersensitivity

Tisabry can cause hypersensitivity reactions, including serious general reactions. These reactions usually develop during infusion or within an hour after it. The risk of developing hypersensitivity is greatest at the onset of infusion, and also with the reintroduction of Tisabree after a long break (three months or more) following the first short-term course (one or two infusions). However, the risk of developing hypersensitivity reactions should be considered with any infusion.

Patients should remain under the institution should there be everything necessary to treat hypersensitivity reactions. At the first sign of a hypersensitivity reaction, Tisabree's administration should be discontinued and treatment should begin immediately.

Patients who developed hypersensitivity-yusti reactions should immediately stop Tisabree therapy.

Concomitant or previous treatment with immunosuppressants

The safety and efficacy of Tisabree in combination with other immunosuppressors or antitumor drugs have not been adequately established.The concomitant administration of these drugs may increase the risk of infection, including opportunistic microorganisms, and, therefore, is contraindicated.

In patients receiving immunosuppressors, the risk of developing PML has been increased. Prescribe the drug to patients who have previously received immunosuppressors, should be carefully; it is necessary to wait for the restoration of the immune system. Before appointing Tisabree, the attending physician should evaluate each individual case to identify possible signs of immunodeficiency.

Based on the results of Phase III clinical trials in patients PC, The concomitant treatment of relapse with a short-term course of glucocorticosteroids was not accompanied by an increase in cases of infections. Thus, short-term therapy with glucocorticosteroids can be carried out in parallel with Tizabry therapy.

Immunogenicity

Deterioration of symptoms of the disease or unwanted reactions to the infusion may indicate the development of antibodies to natalizumab. If such phenomena occur, it is necessary to make an analysis for antibodies to natalizumab twice with an interval of 6 weeks; if the result remains positive after 6 weeks, therapy should be discontinued,Because the constant presence of antibodies reduces the effectiveness of Tizabry and increases the likelihood of hypersensitivity reactions.

Since with a long break in treatment after a short-term course, Tizabree rises risk hypersensitivity reactions with repeated administration, a test for antibodies should be performed, and if the result of the confirmatory study remains positive after 6 weeks, therapy should not be resumed.

Reactions from the liver

During the postmarketing period, spontaneous serious adverse events from the liver were recorded. Liver involvement is possible at any time during the course of treatment, even after the administration of the first dose. In some cases, the reaction occurred again when Tisabree therapy was resumed. In some patients with liver diseases, a history of hepatic impairment during Tisabree therapy was noted. It is necessary to carefully monitor patients to identify possible violations of liver function, and to warn them about the need to consult a doctor if symptoms of liver damage, such as jaundice and vomiting, appear.With a significant liver damage, Tisabree therapy should be discontinued.

Abolition of Tisabree therapy

If the attending physician decides to discontinue natalizumab therapy, he should remember that the drug is stored in circulating blood and continues to have pharmacodynamic action (eg, leading to lymphocytosis) approximately 12 weeks after the last dose. With the appointment of other drugs during this period, they can interact with natalizumab. According to the results of clinical studies, simultaneous use of such drugs as interferon beta and glatiramer acetate, poses a threat to patient safety. Data on the safety of simultaneous administration of Tizabry and immunosuppressants to patients PC no. The use of these drugs soon after the cessation of therapy with natalizumab may lead to an additional immunosuppressive effect. This should be carefully considered in each case; after glucocorticosteroids for the treatment of relapses PC do not increase the risk of infection.

After dilution of the drug in 100 ml of 0.9 % solution of sodium chloride, the preparation ready for administration contains 17.7 mmol (or 406 mg) of sodium per dose.

Patients who adhere to a diet that controls the sodium content should take this information into account.

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of the drug on the ability to drive vehicles and engage in other activities that require increased concentration and speed of psychomotor reactions have not been carried out. Based on the mechanism of action of natalizumab, the probability of its effect on these abilities is negligible.

Form release / dosage:

Concentrate for cooking solution for infusions of 20 mg / ml.

Packaging:

For 15 ml of the drug in a bottle of glass (type I) ukuporenny bromobutyl cork and aluminum cap for running in, on the closed lid, providing control of the first autopsy.

1 bottle with instructions for application is placed in cardboard pack with inner dividers and perforation applied from the outside Front side, providing control of the first autopsy.

The cardboard pack is sealed with a protective sticker, also being the control of the first autopsy.

Storage conditions:

Concentrate and ready-to-use solution:

At a temperature of 2-8 ° C in the dark place.Do not freeze. Keep out of the reach of children.

Shelf life:

Concentrate: 4 years.

Ready-to-use solution: 8 ocloc'k.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008582/10

Date of registration:23.08.2010 / 23.09.2014

Expiration Date:Unlimited

The owner of the registration certificate:Biogen Aidek LimitedBiogen Aidek Limited United Kingdom

Manufacturer: & nbsp

Vetter Pharma-Fertigung, GmbH & Co. KG. KG Germany

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp23.09.2014

Illustrated instructions

Instructions

Tisabry (Tizabri)