Tysabri (Concentrate) Instructions for Use

Marketing Authorization Holder

Biogen Idec, Ltd. (United Kingdom)

Manufactured By

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

Packaging and Quality Control Release

PHARMSTANDART-UfaVITA, JSC (Russia)

Or

BIOGEN (DENMARK) MANUFACTURING, ApS (Denmark)

ATC Code

L04AG03 (Natalizumab)

Active Substance

Natalizumab (Rec.INN registered by WHO)

Dosage Form

Tysabri

Concentrate for solution for infusion 20 mg/1 ml: fl. 15 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a colorless, clear or slightly opalescent solution.

Excipients: sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate heptahydrate, sodium chloride, polysorbate 80, water for injections.

15 ml – glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Monoclonal antibodies

Pharmacological Action

The drug Tysabri contains Natalizumab, a selective inhibitor of adhesion molecules. Tysabri binds to the α4-subunit of human integrin, which is highly expressed on the surface of all leukocytes except neutrophils. Natalizumab specifically binds to α4β1-integrin, thereby blocking its interaction with the corresponding receptor, vascular cell adhesion molecule (VCAM-1), the osteopontin ligand, the fibronectin domain formed as a result of alternative splicing, and the connecting segment-1 (CS-1). Furthermore, Natalizumab blocks the interaction of α4β7-integrin with mucosal addressin cell adhesion molecule-1 (MadCAM-1). The effect on these molecular interactions prevents the migration of mononuclear leukocytes across the endothelium into inflammatory foci in parenchymal organs. The further mechanism of action of natalizumab may be due to the suppression of inflammatory reactions in affected tissues by suppressing the interaction of α4-expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells. Thus, Natalizumab may suppress inflammatory activity in affected tissues and further recruitment of immune cells to the site of inflammation.

Brain tissue damage in multiple sclerosis (MS) occurs when activated T-lymphocytes cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves the interaction between adhesion molecules on the surface of activated leukocytes and the vascular endothelium. The interaction between α4β1 and its targets is an important component of the pathogenesis of inflammatory lesion formation in the brain, so disrupting these interactions reduces inflammatory activity. Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. However, in the presence of pro-inflammatory cytokines, the production of VCAM-1 in endothelial cells and possibly in glial cells near the inflammatory focus is regulated by a positive feedback mechanism. Under conditions of CNS inflammation in MS, the interaction of α4β1 with VCAM-1, CS-1, and osteopontin mediates firm adhesion and migration of leukocytes into the brain and may enhance the inflammatory cascade in CNS tissues. Blocking the molecular interactions of α4β1 with its targets reduces inflammatory activity in the brain parenchyma in MS and suppresses further recruitment of immune cells to inflammatory foci, thereby reducing the formation or slowing the increase in lesion volume in MS.

Preclinical safety data

Repeatedly conducted preclinical safety studies did not show any special risk factors for humans or genotoxicity.

In most in vivo studies, a change in lymphocyte migration was found, which is consistent with the pharmacological activity of natalizumab; an increase in the number of leukocytes and spleen weight was noted. These changes were reversible and had no apparent toxicological consequences.

In studies in mice, administration of natalizumab did not accelerate the division of melanoma cells and lymphoblastic leukemia cells.

No mutagenic effect of natalizumab in humans was detected in Ames tests or chromosomal aberration analysis. In studies on the proliferation of tumor cell lines containing α4-integrin in vitro, no signs of cytotoxicity were detected.

In a study on guinea pigs using doses exceeding those recommended for humans, no effect of natalizumab on male fertility was detected.

To evaluate the effect of natalizumab on reproductive function, 5 studies were conducted, 3 of them on guinea pigs and 2 on Cynomolgus monkeys. These studies did not show teratogenic effects or effects on offspring growth. In one study on guinea pigs, a slight decrease in offspring survival was noted. In a study on monkeys, the group that received 30 mg/kg of natalizumab had twice the frequency of spontaneous abortions compared to the control group. This was the result of a high frequency of spontaneous abortions in the first group, which was not observed in the second group. Another study did not reveal an effect on the frequency of spontaneous abortions. A study on pregnant Cynomolgus monkeys showed an effect of natalizumab on the fetus, which included total anemia, decreased platelet concentration, increased spleen weight, and decreased liver and thymus weight. These changes were associated with increased extramedullary hematopoiesis in the spleen, thymus atrophy, and decreased hematopoiesis in the liver. A decrease in platelet concentration was also noted in the offspring of females who received Natalizumab before delivery, however, no signs of anemia were noted in them. All changes were observed at doses exceeding those recommended for humans and returned to normal after discontinuation of natalizumab.

In some Cynomolgus monkeys that received Natalizumab before delivery, a low concentration of natalizumab was noted in the milk, indicating the possibility of natalizumab excretion in breast milk in women.

Pharmacokinetics

The mean maximum serum concentration of natalizumab after repeated intravenous administration of a 300 mg dose to MS patients 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 steady-state concentration was approximately 36 weeks.

The sample for pharmacokinetic analysis included more than 1100 MS patients who received Natalizumab at doses from 3 to 6 mg/kg. Of these, 581 received a fixed dose of 300 mg as monotherapy. The mean ± SD (standard deviation) clearance at steady state was 13.1±5.0 ml/h with a mean ± SD half-life of 16±4 days. The analysis examined the influence of selected variables, including body weight, age, gender, liver and kidney function, and the presence of antibodies to natalizumab on pharmacokinetics. It was shown that only body weight and antibodies to natalizumab influence the distribution of the drug. Body weight was found to influence the clearance of natalizumab, and this influence is less than proportional; for example, a 43% change in body weight leads to a 31-34% change in clearance. Changes in clearance are not clinically significant. Circulating antibodies to natalizumab increase its clearance approximately threefold, which corresponds to the observed decrease in natalizumab concentration in patients with circulating antibodies.

The pharmacokinetics of natalizumab in children with MS or in patients with hepatic or renal impairment has not been studied.

Pharmacodynamic studies and studies on the effectiveness of plasmapheresis to reduce the concentration of natalizumab in the blood were conducted with the participation of 12 MS patients. The results of drug elimination after three plasmapheresis procedures (with an interval of more than 5-8 days) were approximately 70-80%. This is comparable to the 40% found in a previous study after drug withdrawal over a similar period. The effect of plasmapheresis on the restoration of lymphocyte migration and, ultimately, on clinical use is unknown.

Indications

For monotherapy of the relapsing 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 patients who are unresponsive to a full and adequate course (at least one year) of interferon beta. They must have had at least one relapse during the previous year of therapy and at least 9 T2-hyperintense lesions on brain magnetic resonance imaging (MRI) or at least one lesion visible with the use of gadolinium-containing contrast agents for MRI. Patients “without response” to ongoing therapy should be understood as patients with unchanged or increased frequency of exacerbations compared to the previous year, or with current severe exacerbations even with treatment lasting less than a year;
• Patients with rapidly progressing severe relapsing multiple sclerosis (i.e., who have experienced 2 or more exacerbations within a year and have 1 or more lesions on brain MRI that accumulate gadolinium-containing MRI contrast agents, or a significant increase in lesion volume in T2 mode compared to previous MRI results).

ICD codes

Dosage Regimen

Tysabri therapy should be prescribed and continuously monitored by physicians specializing in the diagnosis and treatment of neurological diseases, in institutions with MRI capabilities.

Patients receiving Tysabri must be given a special patient card and informed about the risks of this drug. After 2 years of treatment, patients should be re-informed about the risks of using Tysabri, especially the increased risk of PML. Caregivers should also be informed about the early signs and symptoms of PML.

Medical institutions must have everything necessary in case of hypersensitivity reactions and equipment for performing MRI.

After dilution, the solution is administered as an infusion over approximately one hour; during the infusion and for one hour after it, patients should remain under observation due to the possibility of hypersensitivity reactions.

Bolus administration of Tysabri is not allowed.

In the absence of treatment-related disorders, for example, neutropenia, patients who were receiving interferon beta or glatiramer acetate can be directly switched to Natalizumab. If disorders are present, natalizumab therapy can be started only after the parameters return to normal.

Some patients may have previously received immunosuppressants (e.g., mitoxantrone, cyclophosphamide, azathioprine). These drugs can cause a prolonged immunosuppressive state that persists even after their discontinuation. Therefore, before prescribing Tysabri, it is necessary to ensure that the patient does not have immunodeficiency.

If there are no signs of improvement after 6 months, the advisability of continuing therapy should be carefully assessed.

Data on the safety and efficacy of natalizumab use over 2 years were obtained from controlled, double-blind studies. The decision to extend therapy beyond this period should be made only after assessing the balance of potential risk and benefit.

Adults

Tysabri 300 mg is administered intravenously as an infusion once every 4 weeks.

Elderly

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

Children and adolescents

Tysabri is contraindicated in children and adolescents.

Patients with impaired renal and hepatic function

No studies have been conducted to evaluate the effects of the drug in impaired liver and kidney function.

The elimination mechanism and pharmacokinetic study results suggest that the drug can be prescribed to patients with impaired renal and hepatic function without dose adjustment.

Re-administration

The efficacy and safety of the drug upon re-administration have not been determined.

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

1. Before dilution and administration, inspect the drug for particulate matter. Do not use the drug if it contains particles or does not match the description “colorless, clear or slightly opalescent solution”.
2. Prepare the solution for intravenous administration under aseptic conditions. Remove the top cap from the vial. Pierce the stopper in the center with a syringe needle and withdraw 15 ml of concentrate for the preparation of a solution for intravenous infusion.
3. Add 15 ml of concentrate to 100 ml of 0.9% sodium chloride solution. Gently invert the vial several times to mix the contents. Do not shake.
4. Do not mix Tysabri with other solvents and drugs.
5. Before administration, inspect the diluted solution for particles or discoloration. A solution with foreign particles or discoloration is unsuitable for use.
6. The diluted drug should be used as soon as possible and no later than 8 hours after dilution. If the solution has been stored at a temperature of 2-8°C (35.6-46.4°F) (not frozen!), allow it to warm to room temperature before infusion.
7. The diluted solution is administered as an infusion over approximately 1 hour at a rate of about 2 ml/min.
8. After completion of drug administration, 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 requirements.

Adverse Reactions

During a placebo-controlled study in 1617 MS patients who received Natalizumab for 2 years (placebo 1135), adverse events leading to premature discontinuation were observed in 5.8% of patients receiving Natalizumab (and 4.8% receiving placebo). Over the 2-year study period, side effects were noted in 43.5% of patients receiving Natalizumab and in 39.6% (adverse events considered related to treatment by the treating physician) receiving placebo. The frequency of side effects in the natalizumab group was 0.5% higher than in the placebo group, as shown below. Reactions were designated by preferred terms taken from the Medical Dictionary for Regulatory Activities (MedDRA), according to system organ classes. Their frequency was as follows: common (>1/100, <1/10), uncommon (>1/1000, <1/100).

In each group, adverse events are divided by frequency

Infections and infestations common – urinary tract infections, nasopharyngitis.

Immune system disorders common – urticaria; uncommon – hypersensitivity.

Nervous system disorders common – headache, dizziness.

Gastrointestinal disorders common – vomiting, nausea.

Musculoskeletal and connective tissue disorders common – arthralgia.

General disorders and administration site conditions common – chills, pyrexia, fatigue.

Infusion reactions according to a 2-year controlled clinical study in MS patients, events associated with infusion were considered adverse events occurring during infusions or within 1 hour after its completion. They were observed in 23.1% of MS patients receiving Natalizumab (and in 18.7% receiving placebo). Events more frequently observed in the natalizumab group included dizziness, nausea, urticaria, and chills (see section “Hypersensitivity reactions” below).

Hypersensitivity reactions according to a two-year controlled clinical study in MS patients, the frequency of hypersensitivity cases reached 4%. Anaphylactic/anaphylactoid reactions were noted in less than 1% of patients receiving Tysabri. Hypersensitivity reactions usually occur during the infusion or within an hour after it.

Immunogenicity during a two-year controlled clinical study, antibodies to natalizumab were detected in 10% of MS patients. Circulating antibodies to natalizumab (double positive result) were detected in approximately 6% of patients. A single positive result was noted in another 4% of patients. Circulating antibodies reduce the effectiveness of Tysabri and increase the frequency of hypersensitivity reactions. Other infusion reactions due to circulating antibodies included chills, nausea, vomiting, and flushing. If circulating antibodies are suspected after approximately 6 months of therapy, either due to decreased efficacy or the occurrence of an infusion reaction, another test should be performed 6 weeks after the first positive result. Given the possible decrease in efficacy or increase in the frequency of hypersensitivity reactions in patients with circulating antibodies, treatment should be discontinued.

Infections, including PML and opportunistic infections: according to a two-year controlled clinical study in MS patients, the frequency of infections was approximately 1.5 per patient-year both in the natalizumab group and in the placebo group. The nature of infections in both groups was approximately similar. A case of diarrhea caused by Cryptosporidium was reported. During other clinical studies, other opportunistic infections were noted, including fatal cases. During clinical studies, the group receiving Natalizumab had a slightly higher frequency of herpesvirus infection (varicella-zoster virus and herpes simplex virus) than the group receiving placebo. During early post-marketing surveillance, one fatal case of herpesvirus encephalitis was registered.

Most patients who developed infections did not discontinue natalizumab therapy and recovered with appropriate treatment.

Cases of PML were also registered during clinical studies. They usually led to severe disability or death. During the baseline clinical studies, two cases were registered, including one fatal, in MS patients with a concomitant infection who were treated with interferon beta for more than 2 years. In another trial, PML developed in a patient with Crohn’s disease who had been treated with immunosuppressants for a long time and suffered from lymphopenia; this patient died. The development of PML was noted in post-marketing research in patients receiving Tysabri as monotherapy.

Hepatic reactions: during the post-marketing surveillance period, spontaneous reports of cases of serious liver damage, increased activity of “liver enzymes” and hyperbilirubinemia were received.

Malignant neoplasms: over more than 2 years of therapy, no differences in the frequency of malignant neoplasms were noted in the natalizumab and placebo groups. Nevertheless, longer studies are needed to completely rule out the influence of natalizumab on the incidence of malignant neoplasms.

Effect on laboratory parameters: treatment with Tysabri is accompanied by an increase in the number of lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cell forms in the circulating blood. No increase in neutrophil concentration was observed. The increase in the number of lymphocytes, monocytes, eosinophils, and basophils reaches 35-140% compared to the baseline value, but the total cell count remains within normal limits. During Tysabri therapy, a slight decrease in hemoglobin concentration (mean decrease 0.6 g/dL), hematocrit (mean decrease 2%), and red blood cells (mean decrease 0.1×10⁶/L) was noted. Usually, within 16 weeks after the last dose of Tysabri, all hematological parameters returned to baseline and these changes were not accompanied by clinical symptoms.

Contraindications

• Hypersensitivity to natalizumab or any of the excipients;
• Progressive multifocal leukoencephalopathy (PML);
• Increased risk of opportunistic infections, including immunodeficiency states (for example, patients receiving or having received immunosuppressants such as mitoxantrone or cyclophosphamide, see also the “Special Precautions” section);
• Concomitant use of interferon beta or glatiramer acetate;
• Malignant neoplasms, except for basal cell carcinoma of the skin;
• Children and adolescents.

Use in Pregnancy and Lactation

There is insufficient data on the administration of natalizumab to pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Natalizumab should not be prescribed during pregnancy unless absolutely necessary. If a patient becomes pregnant while taking Tysabri, therapy should be discontinued.

Tysabri is excreted in breast milk. Patients receiving Tysabri should discontinue breastfeeding.

Use in Hepatic Impairment

No studies have been conducted to evaluate the effects of the drug in impaired liver function.

The elimination mechanism and pharmacokinetic study results suggest that the drug can be prescribed to patients with impaired liver function without dose adjustment.

Use in Renal Impairment

No studies have been conducted to evaluate the effects of the drug in impaired renal function.

The elimination mechanism and pharmacokinetic study results suggest that the drug can be prescribed to patients with impaired renal function without dose adjustment.

Pediatric Use

Tysabri is contraindicated in children and adolescents.

Geriatric Use

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

Special Precautions

Progressive multifocal leukoencephalopathy (PML)

The use of Tysabri may increase the risk of developing PML and, as a result, lead to a fatal outcome or severe disability.

The risk of PML occurrence increased with the duration of treatment, especially with treatment for more than 2 years. Currently, data on patients receiving Tysabri for more than 3 years are limited, so it is currently impossible to assess the risk of PML in this group of patients.

The risk of PML occurrence is increased in patients who underwent treatment with immunosuppressants prior to the use of Tysabri. This risk is independent of the duration of treatment with Tysabri.

Due to the increased risk of developing PML, the physician and patient should individually consider the benefit-risk ratio when treating with Tysabri. Before starting work with Tysabri, the physician must undergo training under the “Tysabri Use and Patient Monitoring” program.

After 2 years of treatment, patients should be re-informed about the risks of using Tysabri, especially the increased risk of PML. Early signs and symptoms of PML should also be communicated to both patients and caregivers.

Tysabri therapy should be started only if MRI results are available, performed no earlier than 3 months before the start of therapy. This MRI serves as a baseline.

Regular monitoring of the patient should be organized throughout the entire treatment period for the timely detection of the appearance of new neurological symptoms characteristic of PML or worsening of existing ones.

If new neurological symptoms appear, therapy should be suspended until PML is ruled out.

The treating physician should continue to monitor the patient to identify possible symptoms of neurological dysfunction and, if present, determine whether they are typical for MS and whether they are grounds for suspicion of PML. In the latter and other doubtful cases, further diagnosis is necessary, including MRI (its results should be compared with the results of the baseline MRI before natalizumab treatment), examination of cerebrospinal fluid (CSF) for the presence of polyomavirus DNA (JC virus), and repeated neurological examination. If PML is not confirmed, natalizumab therapy can be resumed.

The treating physician should be especially attentive to PML symptoms that may go unnoticed by the patient themselves (for example, symptoms of cognitive or psychiatric disorders). The patient should be advised to inform close relatives or caregivers that they are undergoing treatment; they may be able to notice symptoms that the patient missed.

If PML develops, Tysabri therapy must be completely discontinued.

In patients with PML against the background of immunosuppression, improvement in clinical outcomes is noted after immune reconstitution.

PML and immune reconstitution inflammatory syndrome (IRIS)

IRIS was noted in almost all patients treated with Tysabri who developed PML and subsequently discontinued Tysabri. Plasmapheresis is used to accelerate the reduction of natalizumab concentration when PML is detected.

IRIS is a result of immune reconstitution in patients with PML, which can lead to serious neurological complications, as well as death.

Careful monitoring for IRIS, which usually develops within several days or weeks after plasmapheresis in patients with PML who were treated with Tysabri, should be carried out, as well as appropriate anti-inflammatory treatment during recovery from PML.

Other opportunistic infections

Other opportunistic infections have been described with the use of Tysabri, mainly in Crohn’s disease, immunodeficiency states, and comorbidities; however, such infections can also develop in the absence of comorbidities. Opportunistic infections have also been described in MS patients receiving Tysabri monotherapy.

When prescribing the drug, the possibility of developing opportunistic infections should be kept in mind, and they should be included in the list of differential diagnoses. If an opportunistic infection is suspected, Tysabri therapy should be suspended until the infection is ruled out based on appropriate investigations.

If an opportunistic infection develops, Tysabri therapy should be completely discontinued.

Educational guides

The physician should discuss the benefits and risks of Tysabri therapy with the patient and provide them with a special card containing important safety information. Patients should be instructed that if an infection develops, they should inform their treating physician about the use of Tysabri.

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

Hypersensitivity

Tysabri can cause hypersensitivity reactions, including serious systemic reactions. These reactions usually develop during the infusion or within an hour after it. The risk of developing hypersensitivity is highest at the beginning of infusions, as well as upon re-administration of Tysabri after a long break (three months or more) following the first short course (one or two infusions). However, the risk of developing hypersensitivity reactions should be considered with any infusion.

Patients should remain under observation during the infusion and for one hour after its completion. The medical facility must have everything necessary to treat hypersensitivity reactions.

At the first signs of a hypersensitivity reaction, the administration of Tysabri should be stopped and therapeutic measures should be started immediately.

Patients who have developed hypersensitivity reactions should immediately discontinue Tysabri therapy.

Concomitant or previous treatment with immunosuppressants

The safety and efficacy of Tysabri in combination with other immunosuppressants or antineoplastic drugs have not been sufficiently established. Concomitant use of these drugs may increase the risk of infection, including opportunistic infections, and is therefore contraindicated.

In patients who have received immunosuppressants, the risk of developing PML is increased. The drug should be prescribed with caution to patients who have previously received immunosuppressants; it is necessary to wait for the restoration of immune system function. Before prescribing Tysabri, the treating physician must evaluate each individual case to identify possible signs of immunodeficiency.

According to the results of phase 3 clinical trials in MS patients, concomitant treatment of relapse with a short course of glucocorticosteroids was not accompanied by an increase in the incidence of infections. Thus, short-term therapy with glucocorticosteroids can be carried out in parallel with Tysabri therapy.

Immunogenicity

Worsening of disease symptoms or infusion-related adverse reactions may indicate the production of antibodies to natalizumab. If such phenomena occur, it is necessary to test for antibodies to natalizumab twice with an interval of 6 weeks; if the result remains positive after 6 weeks, therapy should be discontinued, as the persistent presence of antibodies reduces the effectiveness of Tysabri and increases the likelihood of hypersensitivity reactions.

Since a long break in treatment after a short course of Tysabri increases the risk of hypersensitivity reactions upon re-administration, an antibody test should be performed, and if the result of the confirmatory test after 6 weeks remains positive, therapy should not be resumed.

Hepatic reactions

During the post-marketing surveillance period, spontaneous serious adverse events related to the liver were registered. Liver damage is possible at any time during the course of treatment, even after the first dose. In some cases, the reaction recurred upon resumption of Tysabri therapy. In some patients with a history of liver disease, worsening of liver parameters was noted during Tysabri therapy. Patients should be carefully monitored to identify possible liver function disorders, and they should be warned about the need to contact their treating physician if symptoms of liver damage appear, such as jaundice and vomiting. In case of significant liver damage, Tysabri therapy should be discontinued.

Discontinuation of Tysabri therapy

If the treating physician decides to discontinue natalizumab therapy, they should be aware that the drug persists in the circulating blood and continues to exert a pharmacodynamic effect (for example, leading to lymphocytosis) for approximately 12 weeks after the last dose is administered. When prescribing other medicinal products during this period, they may interact with natalizumab. According to clinical trial results, the concomitant use of drugs such as interferon beta and glatiramer acetate poses a safety risk to patients. There are no data on the safety of concomitant administration of Tysabri and immunosuppressants to MS patients. The use of these drugs soon after discontinuation of natalizumab therapy may lead to an additional immunosuppressive effect. This should be carefully considered in each case; a certain “washout” period is necessary after discontinuation of natalizumab therapy. According to clinical trial data, short courses of glucocorticosteroids for the treatment of MS relapses do not increase the risk of infections.

Effect on the ability to drive vehicles and machinery

No studies have been conducted on the effect of the drug on the ability to drive vehicles and engage in other activities requiring increased concentration and speed of psychomotor reactions. Based on the mechanism of action of natalizumab, the likelihood of its effect on these abilities is insignificant.

Overdose

No cases of overdose have been reported.

Drug Interactions

The safety and efficacy of Tysabri in combination with other immunosuppressants or antineoplastic drugs have not been sufficiently established. Concomitant use of these drugs may increase the risk of infection, including opportunistic infections, and is therefore contraindicated.

In patients who have previously received therapy with immunosuppressants, the risk of developing PML is increased. The drug should be prescribed with caution to patients who have previously received immunosuppressants; it is necessary to wait for the restoration of immune system function. Before prescribing Tysabri, the treating physician must evaluate each individual case to identify possible signs of immunodeficiency.

According to the results of phase 3 clinical trials in MS patients, concomitant treatment of relapse with a short course of glucocorticosteroids was not accompanied by an increase in the incidence of infections. Thus, short-term therapy with glucocorticosteroids can be carried out in parallel with Tysabri therapy.

Incompatibility

Tysabri should not be mixed with other medicinal products, except for 0.9% sodium chloride solution.

Immunization

In randomized open-label studies involving 60 patients with multiple sclerosis, no significant deviations in the patients’ immune response to the administered antigen were identified. The comparison was made between groups of patients treated with Tysabri for 6 months and a control group that did not receive Tysabri treatment.

Storage Conditions

Store the concentrate and the ready-to-use solution at a temperature of 2-8°C (35.6-46.4°F), protected from light. Do not freeze. Keep out of reach of children.

Shelf Life

Shelf life: concentrate – 4 years, ready-to-use solution – 8 hours. Do not use after the expiration date.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.