Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a colorless, clear or slightly opalescent solution.
natalizumab 20 mg
[PRING] sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate heptahydrate, sodium chloride, polysorbate 80, water d / u.
15 ml - bottles of glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
Tizabry contains natalizumab, a selective inhibitor of adhesion molecules. Tisabry binds to the? 4 subunit of human integrin, in a large amount of all the white blood cells expressed on the surface, with the exception of neutrophils. Natalizumab specifically binds to the? 4 1-integrin, blocking the interaction with the corresponding receptor, the adhesive vascular cell molecule (VCAM-1) and the osteopontin ligand, the fibronectin domain resulting from the alternative splicing, by connecting segment-1 (CS-1) . In addition, natalizumab blocks the interaction of the? -7-integrin with the mucosal adhesion molecule, adressin-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? 4-expressing leukocytes with their ligands in the extracellular and parenchymal cells. Thus, natalizumab can suppress inflammatory activity in the affected tissues and further attract immune cells to the focus of inflammation.
Damage to brain tissue in multiple sclerosis (PC) occurs when activated T-lymphocytes pass through the blood-brain barrier (GEB). Migration of leukocytes through the BBB involves the interaction between adhesion molecules on the surface of activated leukocytes and the endothelium of blood vessels. The interaction between? 4? 1 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 proinflammatory cytokines, the production of VCAM-1 in endothelial cells and possibly in glial cells located near the inflammation focus is regulated by the positive feedback mechanism. Under the conditions of CNS inflammation, the interaction of? 4-1 with VCAM-1, CS-1 and osteopontin mediates the solid adhesion and migration of leukocytes in the brain and can enhance the inflammatory cascade in the CNS tissues. The blockade of molecular interactions? 4? 1 with its targets reduces inflammatory activity in the parenchyma of the brain at PC and suppresses the further attraction of immune cells to inflammation sites, thereby reducing the formation or slowing the increase in lesion volume in the PC.
Pre-clinical safety study data
Numerous pre-clinical safety studies have not shown any specific risk factors for human and genotoxicity.
In most in vivo studies, a change in the migration of lymphocytes was found, 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. In the study of proliferation of tumor cell lines containing? 4-integrin, in vitro, no signs of cytotoxicity were found.
In the study on guinea pigs with the use of doses exceeding those recommended for humans, the effect of natalizumab on 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 increased by half 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. The study on pregnant female monkeys Cynomolgus showed the effect of natalizumab on the fetus, including complete anemia, a decrease in platelet count, an increase in the weight 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. Reduction of platelet concentration was also observed 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 Cynomolgus monkeys who received natalizumab before the birth noted a small concentration of natalizumab in the milk, indicating the possibility of natalizumab with breast milk in women.
The mean maximum serum concentration of natalizumab after repeated intravenous administration at a dose of 300 mg in patients with PC was 110 В± 52 Ојg / ml. The mean steady-state concentration of natalizumab during the administration period ranged from 23 to 29 Ојg / ml. The predicted time to reach the equilibrium concentration was approximately 36 weeks.
The sample for pharmacokinetic analysis included more than 1100 PC patients who received natalizumab at a dose of 3 to 6 mg / kg. Of these, 581 received a fixed dose of 300 mg as monotherapy. The mean В± SD (standard deviation) clearance time for the steady state was 13.1 В± 5.0 ml / h with an mean В± SD half-life of 16 В± 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 insufficiency has not been studied.
Studies of the pharmacodynamics and 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.
For monotherapy of the remitting form of multiple sclerosis, the following groups of patients:
- patients with active course of the 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 must have at least one relapse 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 visible with contrast agents for MRI containing gadolinium. Unexplained patients for ongoing therapy should be understood as patients with a constant or increased frequency of exacerbations compared to the previous year, or current severe exacerbations even with treatment lasting less than a year;
- for patients with rapidly progressive severe remitting multiple sclerosis (ie, who underwent 2 or more exacerbations during the year and who had 1 or more foci on the MRI of the brain, accumulated contrast agents for MRI containing gadolinium, or a significant increase in the lesion volume in the mode T2 in comparison with the results of the previous MRI).
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 infusions for about an hour; during infusions 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 disorders related to treatment, for example, neutropenia, patients receiving interferon beta or glatiramer acetate, can directly be converted to 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.
Tisabree 300 mg is administered intravenously as an infusion once every 4 weeks.
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.
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. Inspect the preparation for presence of solid impurities before dilution and administration. Do not use a preparation containing solid particles or that does not correspond to the description "colorless, clear 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 introduction, 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 В° C (was not frozen!), Allow it to warm up to room temperature before infusion.
7. The diluted solution is administered as an infusion for about 1 hour at a rate of about 2 ml / min.
8. After completion of the drug, flush the system with 0.9% sodium chloride solution.
9. Each vial is for single use only.
10. Any unused product or waste should be disposed of in accordance with local regulations.
During a placebo-controlled study in 1617 PC patients 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). In 2 years of the 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 the following: 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.
Disorders from the immune system: frequent - hives; rare - hypersensitivity.
Violations from the nervous system: frequent - headache, dizziness.
Gastrointestinal disorders: frequent - vomiting, nausea.
Musculoskeletal disorders and connective tissue lesions: frequent - joint pain.
General disorders and reactions at the injection site: frequent - chills, fever, fatigue.
Infusion reactions: Based on data from a 2-year controlled clinical trial on PC patients, infusion-related phenomena were considered to be side effects occurring during infusion or within 1 hour after completion. They were observed in 23.1% of PC patients 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 biennial controlled clinical trial in patients with PC,
the incidence of gynsensitivity 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 PC patients. 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 biennial controlled clinical trial in patients with PC, the incidence of infections was approximately 1.5 per patient year in both the natalizumab group and the placebo group. The nature of the infections in both groups was approximately similar. A case of diarrhea due to Cryptosporidium has been reported. During other clinical trials, other opportunistic infections were noted, including deaths. During clinical trials in the group treated with natalizumab, it marked a little higher rate of herpes virus infection (herpes zoster virus and herpes simplex virus) than in the placebo group. During the early post-marketing surveillance is one fatal case of herpes virus encephalitis registered.
Most of the patients who developed an infection, did not stop natalizumab therapy and appropriate treatment recovery occurs.
During clinical studies have also reported cases of PML. They usually leads to severe disability or death. During clinical studies, two basic cases were registered, including one death, in patients co-infected PCs treated with beta interferon for over 2 years. In another test of PML occurred in patients with Crohn's disease, long-term immunosuppressive lechivshegosya and suffered lymphopenia, the patient died. Development of PML observed in post-marketing study in patients receiving Tizabri monotherapy.
The reaction of the liver: in the period of post-marketing surveillance were received spontaneous reports of serious liver disease, increased activity of "liver enzymes" and giperbilirubinemni.
Malignancies: for more than 2 years of treatment was not observed any difference in the incidence of malignant tumors in the natalizumab and placebo groups. However, to completely eliminate the effect of natalizumab on the incidence of malignant tumors, a need for more long-term studies.
Influence on laboratory parameters:Tizabri treatment is accompanied by increased number of lymphocytes, monocytes, eosinophils, basophils and nuclear forms of erythrocytes in the blood circulation. Increasing the concentration of neutrophils were observed. Increasing the number of lymphocytes, monocytes, eosinophils and basophils reaches 35-140% compared with the initial value, but the total number of cells remains within a normal range. During therapy Tizabri was a slight decrease in hemoglobin concentration (mean reduction of 0.6 g / dl), hematocrit (mean decrease of 2%) and erythrocytes (mean reduction of 0.1 Г— 10 6 / l). Usually within 16 weeks after the last dose Tizabri all hematologic parameters returned to the original value and the changes were not accompanied by clinical symptoms.
- natalizumab or hypersensitivity to any of the excipients;
- progressive multifocal leukoencephalopathy (PML);
- increased risk of infections with opportunistic pathogens, including immunodeficiency (e.g., patients receiving or receiving immunosuppressive drugs, such as mitoxantrone or cyclophosphamide, see also "special instructions" section).
- simultaneous use of beta interferon or glatiramer acetate;
- cancer, with the exception of basal cell skin cancer;
- children and adolescents.
PREGNANCY AND LACTATION
The introduction of natalizumab for pregnant women is not enough data. Animal studies have shown reproductive toxicity. The potential risk for humans is unknown.Natalizumab should not be administered during pregnancy unless absolutely necessary. If the patient becomes pregnant while taking Tizabri, therapy should be discontinued.
Tizabri excreted in breast milk. Patients receiving Tizabri should stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Studies evaluating drug effects with impaired renal function was conducted.
The mechanism of excretion and results of studies of pharmacokinetics suggest that the drug may be administered to patients with impaired renal function, without changing the dose.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Studies evaluating drug effects with impaired liver function was conducted.
The mechanism of excretion and results of studies of pharmacokinetics suggest that the drug may be administered to patients with impaired liver function no dose change.
APPLICATION FOR CHILDREN
Tizabri is contraindicated in children and adolescents.
APPLICATION IN ELDERLY PATIENTS
Application Tizabri in patients older than 65 years is not recommended due to lack of safety data for this patient population
Progressive multifocal leukoencephalopathy (PML)
Use of Tizabri may increase the risk of developing PML, and as a result, lead to death or severe disability.
The risk of PML increased as the duration of treatment, especially in the treatment of a preparation of more than 2 years. Currently, information about patients receiving Tizabri over 3 years, is limited, so to evaluate the risk of PML in this patient population is not currently possible.
The risk of PML increases in patients treated with immunosuppressants prior to application Tizabri drug. This risk is independent of the duration of treatment Tizabri.
Due to the increased risk of PML physician and patient should individually consider the ratio of benefits and risks in the treatment of drug Tizabri. Before starting work with the product Tizabri, the physician should be trained in the program, "Use of the drug Tizabri and monitoring of patients undergoing treatment."
After 2 years of treatment, patients should be re-informed about the risks of the use of Tizabri, especially to increase the risk of PML. It is also about the early signs and symptoms of PML should inform both patients and caregivers.
Tizabri begin therapy should only be in the presence of the MRI results, carried out not earlier than 3 months before the start of therapy. This is the basic MRI.
Necessary to organize regular monitoring of the patient throughout the treatment with the aim of early detection of new neurological symptoms typical of PML or worsening of existing ones.
When new neurological symptoms should suspend therapy to exclude PML.
The attending doctor should continue to monitor the patient to detect possible symptoms of neurological dysfunction and, if available, to determine whether they are for PC and whether a cause for suspicion of PML typical. In the latter, and other questionable cases need further diagnostics, including MRI scan (the results should be compared with the results of the basic MRI before treatment with natalizumab), a study of cerebrospinal fluid (CSF) for the presence of DNA polyomavirus (JC-virus) and repeat neurological evaluation. If PML is not confirmed, natalizumab therapy may be resumed.
PCP should be particularly attentive to the PML symptoms that may go unnoticed by the patient (e.g., cognitive symptoms or psychiatric disorders). The patient should be advised to notify relatives or caregivers that he is being treated; perhaps they will be able to notice the symptoms go unnoticed by the patient.
With the development of PML is necessary to completely discontinue therapy Tizabri.
In patients with PML in the background immunosuppression after immune reconstitution observed improvement in clinical outcomes.
PML inflammatory and immune reconstitution syndrome (IRIS)
Virtually all patients treated Tizabri, with the development of PML and subsequent cancellation Tizabri, was marked by IRIS. For accelerated reducing natalizumab at a concentration of PML detection using plasmapheresis.
IRIS is the result of immune reconstitution in patients with PML, which can lead to serious neurological complications and death.
It should be closely monitored IRIS syndrome that usually develops within a few days or weeks after the plasmapheresis in patients with PML receiving Tizabri and the corresponding anti-inflammatory treatment during recovery from PML.
Other infections with opportunistic pathogens
Described and other infections with opportunistic pathogens at application Tizabri, mainly Crohn's disease and related immunodeficiency diseases, however, such an infection may develop in the absence of concomitant diseases. Infections opportunistic pathogens are also described in PC patients receiving monotherapy Tizabri.
In appointing the drug must be aware of the possibility of opportunistic pathogens of infection, which should be included in the list of differential diagnoses. If you suspect an infection opportunistic pathogens should be suspended Tizabri therapy to the exclusion of infection by the results of relevant studies.
With the development of infection by opportunistic organisms should be completely discontinue therapy Tizabri.
The physician should discuss the benefits and risks of therapy Tizabri with the patient and provide him with a special card containing important safety information. Patients should be instructed that in case of infection, they should alert the physician about the use of Tizabri.
Doctors should explain to the patient the importance of continuous treatment, especially in the first months of treatment.
Tizabri may cause hypersensitivity reactions, including serious systemic reactions. These reactions usually occur during the infusion and for one hour thereafter. The risk of hypersensitivity of the largest in the beginning infusions, as well as the re-introduction Tizabri after a long break (three months or more) following the first short course (one or two infusions). However, the risk of hypersensitivity reactions should be considered in any infusions.
Patients should be monitored during infusion and for an hour afterwards. The hospital should be all you need for the treatment of hypersensitivity reactions.
At first signs of hypersensitivity reactions should be discontinued immediately and the introduction Tizabri start therapeutic measures.
Patients who have developed hypersensitivity reactions should immediately discontinue therapy Tizabri.
Concomitant or previous immunosuppressive treatment
safety and efficacy Tizabri in combination with other immunosuppressive or antineoplastic agents is not sufficient yet installed. Concomitant intake of these drugs can increase the risk of infections, including opportunistic infections, and therefore contraindicated.
Patients treated with immunosuppressants, increased risk of developing PML. Assign the drug to patients previously treated with caution immunosuppressants; you must wait for the recovery of immune system function. Before the appointment Tizabri physician must evaluate each individual case, to identify possible signs of immunodeficiency.
According to the results of phase 3 clinical trials in PC patients, concomitant treatment relapse short course of corticosteroids was not associated with increased incidence of infections. Thus, short-term therapy with glucocorticosteroids can be carried out in parallel with Tizabri therapy.
Worsening of symptoms or adverse reactions to the infusion may indicate the development of antibodies against natalizumab. When such phenomena occur is necessary to make an analysis on the antibody natalizumab twice with an interval of 6 weeks; if the result is still positive after 6 weeks, the therapy should be discontinued because the permanent presence of antibodies Tizabri reduces the efficiency and increases the likelihood of hypersensitivity reactions.
Since the long break in treatment after a short course Tizabri increased risk of hypersensitivity reactions upon repeated administration should conduct a study on the antibody, and if the result confirms the study after 6 weeks remains positive, therapy should not be reopened.
Reaction of the liver
During the period of post-marketing surveillance were reported spontaneous serious adverse events of the liver. Liver damage is possible at any time during the course of treatment, even after the first dose. In some cases, the reaction has arisen once again when resuming therapy Tizabri. Some patients with liver diseases in history have experienced a worsening of hepatic parameters during therapy Tizabri. It is necessary to carefully monitor patients to detect possible violations of the liver, and to warn them of the need to call your doctor if symptoms of liver damage, such as jaundice and vomiting. When significant liver damage Tizabri discontinue therapy.
Cancel Tizabri therapy
If the doctor decides to stop treatment with natalizumab, it should be remembered that the drug is retained in the circulating blood, and continues to provide pharmacodynamic action (for example, leading to lymphocytosis) approximately 12 weeks after the last dose. In the appointment of other drugs in this period, they can interact with natalizumab. According to the results of clinical trials, the simultaneous use of drugs such as interferon beta and glatiramer acetate is a threat to the safety of patients. safety data Tizabri simultaneous administration of immunosuppressants and patients do not have PC. The use of these drugs soon after the discontinuation of natalizumab may lead to an additional immunosuppressive effect. It should be carefully considered in each case;after natalizumab discontinuation of therapy requires a certain period of "wash-out". According to clinical studies, short courses of corticosteroids for the treatment of PC relapses do not increase the risk of infections.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effect of the drug on the ability to drive and engage in other activities that require high concentration and psychomotor speed reactions, have been conducted. Based on the mechanism of action of natalizumab, the probability of its impact on the data capacity is negligible.
No cases of overdose have been reported.
The safety and efficacy Tizabri in combination with other immunosuppressive or anticancer drugs long enough established. Concomitant intake of these drugs can increase the risk of infections, including opportunistic infections, and therefore contraindicated.
In patients previously treated with immunosuppressants, increased risk of developing PML. Assign the drug to patients previously treated with immunosuppressants with caution; you must wait for the recovery of immune system function. Before the appointment Tizabri physician must evaluate each individual case, to identify possible signs of immunodeficiency.
By results of the third phase of clinical trials in PC patients, concomitant treatment relapse short course of corticosteroids was not associated with increased incidence of infections. Thus, short-term therapy with glucocorticosteroids can be carried out in parallel with Tizabri therapy.
Do not mix Tizabri with other medications, except 0.9% sodium chloride solution.
In a randomized, open-label studies, conducted with the participation of 60 patients with multiple sclerosis, there were no significant variations in the patient's immune response to the antigen. Comparison was carried out in groups of patients treated with the drug Tizabri for 6 months and the control group not receiving drug treatment Tizabri.
TERMS OF RELEASE FROM PHARMACY
TERMS AND CONDITIONS OF STORAGE
Store the concentrate and ready-to-use solution at a temperature of 2-8 В° C, protected from light. Do not freeze. Keep out of the reach of children.
Shelf Life: Concentrate - 4