Tysabri - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Natalizumab

TYSABRI 300 mg concentrate for solution for infusion

Why is Tysabri used? What is it for?

TYSABRI is used to treat Multiple Sclerosis (MS). MS causes inflammation in the brain that damages nerve cells. TYSABRI prevents the cells responsible for the inflammation from entering the brain and, as a result, reduces the nerve damage caused by MS.

TYSABRI contains the active substance natalizumab, an active substance called a monoclonal antibody. This antibody binds to certain proteins present in the body in order to eliminate their harmful effects.

What are the symptoms of multiple sclerosis?

MS symptoms vary from patient to patient and you may have some or none at all.

Symptoms may include: problems with walking, a feeling of numbness in the face, arms or legs, problems with vision, fatigue, loss of balance or lightheadedness, bladder and bowel problems, difficulty with thinking and concentration, depression, acute or chronic pain, sexual problems, stiffness and muscle spasms. In the event of an exacerbation of symptoms, it is referred to as a relapse (also called exacerbation or attack). When a relapse occurs, you may notice that your symptoms progress suddenly, within a few 29 hours, or slowly, over the course of a few days. As a rule, then the symptoms will gradually improve (in this case we speak of remission).

In clinical trials, TYSABRI reduced the progression of the disabling effects of MS by about half and also reduced the number of MS attacks by about two-thirds. While being treated with TYSABRI, you may not notice any effects on your MS, but TYSABRI can help prevent your disease from getting worse.

Contraindications When Tysabri should not be used

Before starting treatment with TYSABRI, it is important that you discuss with your doctor the possible benefits you may have from treatment and the associated risks.

Do not use TYSABRI

  • If you are allergic to natalizumab or any of the other ingredients of this medicine
  • If your doctor has told you that you have progressive multifocal leukoencephalopathy (PML). PML is a rare brain infection.
  • If your doctor has told you that you have a serious problem with your immune system (for example due to a disease such as HIV, or because of some medicine you are taking or have taken in the past, for example mitoxantrone or cyclophosphamide ).
  • If you are taking interferon beta or glatiramer acetate. These medicines treat MS and cannot be used with TYSABRI (see Taking other medicines, below).
  • If you have active cancer (unless it is a type of skin cancer called basal cell carcinoma).
  • If you are under the age of 18.

Precautions for use What you need to know before taking Tysabri

Talk to your doctor before using TYSABRI.

Infections

There have been cases of a rare brain infection called progressive multifocal leukoencephalopathy (PML) in patients taking TYSABRI. PML can cause severe disability or be fatal.

  • Symptoms of PML can be similar to those of an MS relapse (i.e. weakness or changes in vision). Therefore, if you think your MS is getting worse or if you notice any new symptoms, it is very important that you see your doctor as soon as possible.
  • Talk to your partner or caregiver about therapy and tell them about the treatment. Symptoms may occur that you may not be aware of yourself, such as mood or behavior changes, memory lapses, speech and communication difficulties, which may need to be further evaluated by your doctor to rule out the possibility of PML.
  • You will also find this information on the Patient Alert Card that your doctor gave you. It is important that you keep this Alert Card and show it to your partner or caregiver.

PML is associated with an uncontrolled increase in JC virus in the brain, although the reasons for this increase occurring in some of the patients treated with TYSABRI are not known. The JC virus is a common virus that infects many people without normally causing observable disease.

Before starting treatment with TYSABRI, your doctor may do a blood test to check if it contains antibodies to the JC virus. These antibodies are a sign that he has been infected with the JC virus.

The risk of developing PML with TYSABRI is higher:

  • if there are antibodies to JC virus in the blood. o The risk of PML is higher in patients with JC virus antibodies than in patients without JC virus antibodies. o If you do not have JC virus antibodies, your doctor may repeat the test at regular intervals to check for any changes.
  • if the treatment is prolonged, especially beyond two years. It is not known whether the likelihood of developing PML continues to increase, remains the same, or decreases after treatment with TYSABRI for more than four years.
  • if you have previously taken a medicine called an immunosuppressant. These medicines reduce the activity of the immune system.

If you have all three of the risk factors listed above, the likelihood of developing PML is higher. Before you start taking TYSABRI and after taking TYSABRI for more than two years, you should discuss with your doctor whether TYSABRI is the right treatment for you.

Patients who experience PML are likely to have a reaction called immune reconstitution inflammatory syndrome (IRIS) after treatment for PML, as TYSABRI is removed from the body. IRIS can cause conditions to worsen, including worsening. of brain function.

Allergic reactions

Some patients have experienced an allergic reaction to TYSABRI. Your doctor will check for any allergic reactions that may occur during the infusion and for the next hour.

Does TYSABRI always work?

In a small number of patients using TYSABRI, over time the body's natural defenses can prevent TYSABRI from working properly (the body produces antibodies to TYSABRI). Your doctor will be able to determine if TYSABRI is not working as it should by taking a blood test and will stop taking the medicine if necessary.

Interactions Which drugs or foods may change the effect of Tysabri

Tell your doctor if you are taking, have recently taken or might take any other medicines.

  • You should not use TYSABRI if you are taking other medicines to treat multiple sclerosis such as beta interferons or glatiramer acetate.
  • You may not be able to use TYSABRI if you are taking or have ever taken medicines that affect the immune system, e.g. mitoxantrone or cyclophosphamide.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

  • Do not use TYSABRI if you are pregnant unless you have talked to your doctor. Tell your doctor immediately if you are pregnant, if you think you are pregnant or if you are planning to become pregnant.
  • Do not breast-feed while being treated with TYSABRI. Ask your doctor for advice in deciding whether to breast-feed or to use TYSABRI.

Driving and using machines

No studies on the effect of TYSABRI on the ability to drive and use machines have been conducted. However, if you experience dizziness, a common side effect, you should not drive or use machines.

TYSABRI contains

Sodium phosphate, monobasic, monohydrate; Sodium phosphate, dibasic, heptahydrate

Sodium chloride, Polysorbate 80 (E433), Water for injections.

After dilution, the medicinal product contains 17.7 mmol (406 mg) sodium in each dose. To be kept in mind for patients on a low-sodium diet.

Dosage and method of use How to use Tysabri: Dosage

TYSABRI will be given to you by a doctor who specializes in treating MS. Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor.

  • The recommended adult dose is 300 mg given once every 4 weeks.
  • Before administration, TYSABRI must be diluted. It is given into a vein with a drip (an "intravenous infusion), usually in the arm. The infusion lasts about 1 hour.
  • Information for doctors and healthcare professionals on how to prepare and administer TYSABRI is provided at the end of this package leaflet.
  • It is important that you continue the treatment for as long as you and your doctor feel that this is of benefit to you. Continuous use of TYSABRI is important, especially during the first months of treatment. The reason is that patients who received one or two doses of TYSABRI and then stopped treatment for three months or more were more likely to develop a allergic reaction if treatment is resumed.

Overdose What to do if you have taken too much Tysabri

If you forget to take TYSABRI

If you miss your usual dose of TYSABRI, please agree with your doctor to get it as soon as possible. You will then need to continue to receive the TYSABRI dose every 4 weeks.

Always use this medicine exactly as described in this leaflet or as directed by your doctor. If in doubt, consult your doctor

For more information on using TYSABRI, ask your doctor.

Side Effects What are the side effects of Tysabri

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious infections can occur with TYSABRI. Symptoms of an infection include:

an unexplained fever

  • severe diarrhea
  • breathing difficulties
  • prolonged dizziness
  • headache
  • stiff neck
  • weight loss
  • apathy

Tell your doctor or nurse immediately if you notice any of the following signs:

Signs of allergy to TYSABRI, during the infusion or shortly after:

  • urticaria
  • swelling of the face, lips or tongue
  • breathing difficulties
  • chest pain or discomfort
  • increase or decrease in blood pressure (which will be noticed by your doctor or nurse if your blood pressure is monitored).

Signs of a possible liver problem:

  • yellowing of the skin or whites of the eyes
  • unusual dark colored urine.

TYSABRI can also have other side effects.

Undesirable effects are listed below according to the frequency with which they were reported during clinical trials.

Common side effects that may affect up to 1 in 10 people

  • urinary tract infection
  • sore throat and nasal hypersecretion or congestion
  • chills
  • urticaria
  • headache
  • dizziness
  • nausea
  • He retched
  • joint pains
  • fever
  • tiredness

Uncommon side effects that may affect up to 1 in 100 people:

  • severe allergy (hypersensitivity)? Progressive multifocal leukoencephalopathy (PML).

Rare side effects which may affect up to 1 in 1000 people:

  • unusual infections (so-called "opportunistic infections").

Contact your doctor as soon as possible if you think you have an infection.

Show the Patient Alert Card and this leaflet to any doctor involved in your therapy, not just the neurologist.

You will also find this information on the Patient Alert Card that your doctor gave you.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Unopened vial:

Store in the refrigerator (2? C - 8? C).

Do not freeze.

Keep the vial in the outer carton to protect the medicine from light.

Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

Diluted solution:

After dilution, immediate use is recommended. If not used immediately, the diluted solution should be stored at 2 ° C to 8 ° C and administered within 8 hours of dilution.

Do not use this medicine if you notice particles in the liquid and / or if the liquid in the vial has a "discolouration".

What TYSABRI contains

The active ingredient is natalizumab. Each 15 ml vial of concentrate contains 300 mg of natalizumab (20 mg / ml).

The other ingredients are:

Sodium phosphate, monobasic, monohydrate

Sodium phosphate, dibasic, heptahydrate

Sodium chloride

Polysorbate 80 (E433)

Water for injections.

What TYSABRI looks like and contents of the pack

TYSABRI is a colorless and clear or slightly opalescent liquid.

Each carton contains a glass vial.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Tysabri can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TYSABRI 300 MG CONCENTRATE FOR SOLUTION FOR INFUSION

▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate contains 20 mg of natalizumab.

Natalizumab is a recombinant humanized anti-α4-integrin antibody produced in a mouse cell line by recombinant DNA technology.

After dilution (see section 6.6), the solution for infusion contains approximately 2.6 mg / ml of natalizumab.

Excipient with known effects

TYSABRI contains 2.3 mmol (52 mg) sodium in each bottle. After dilution in 100 ml of sodium chloride 9 mg / ml (0.9%) solution the medicinal product contains 17.7 mmol (406 mg) of sodium.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Colorless, clear or slightly opalescent solution.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

TYSABRI is indicated as monotherapy disease-modifying in high activity relapsing-remitting multiple sclerosis in the following patient groups:

• Adult patients 18 years of age and older with high disease activity despite interferon beta or glatiramer acetate therapy. These patients are defined as patients who have failed to respond to a complete and adequate course of therapy (usually , at least one year of treatment) with a beta interferon or glatiramer acetate. Patients must have had at least 1 relapse in the previous year while on therapy and must have at least 9 T2 hyperintense lesions on brain magnetic resonance imaging (MRI) or at least 1 Gadolinium-enhancing lesion. A patient non-responder it can also be defined as a patient who has an unchanged or increased relapse rate compared to the previous year or who has severe relapses.

Or

• Adult patients 18 years of age and older with rapidly evolving severe relapsing remitting multiple sclerosis, defined by two or more disabling relapses in one year and with 1 or more Gadolinium-enhancing lesions on brain MRI or a significant increase in lesion load in T2 compared to a previous MRI performed recently.


04.2 Posology and method of administration

Treatment with TYSABRI should be initiated and continuously supervised by a physician experienced in the diagnosis and treatment of neurological diseases, in centers where prompt access to MRI is possible.

Patients treated with TYSABRI should be given the Patient Alert Card and provided information about the risks of TYSABRI (see also the package leaflet inside the package). After 2 years of treatment, patients should be informed again about the risks of TYSABRI, in particular about the increased risk of progressive multifocal leukoencephalopathy (PML), and both patients and caregivers should be educated to recognize the early signs and symptoms of PML.

Means must be available to treat hypersensitivity reactions and access to MRI.

Patients can switch directly from interferon beta or glatiramer acetate therapy to natalizumab, provided they do not show signs of major treatment-related abnormalities, eg. neutropenia. If treatment-related abnormalities are present, they will need to return to normal before starting treatment with natalizumab.

Some patients may have been exposed to immunosuppressive drugs (e.g. mitoxantrone, cyclophosphamide, azathioprine). Such medicinal products can cause prolonged immunosuppression, even after discontinuing their administration. Therefore, before initiating therapy with TYSABRI (see also section 4.4), the physician should ensure that such patients are not immunocompromised.

Dosage

Adults

TYSABRI 300 mg should be administered as an intravenous infusion once every 4 weeks.

Continuation of treatment should be carefully considered in patients who show no evidence of therapeutic benefit after 6 months.

The 2-year safety and efficacy data of natalizumab are from double-blind controlled studies. After 2 years, continuation of therapy should only be considered after a reassessment of the possible benefits and risks. Patients should be re-informed about risk factors for PML, ie duration of treatment, use of immunosuppressive drugs prior to TYSABRI administration and the presence of anti-JCV antibodies (see section 4.4).

Re-administration

The efficacy of re-administration of the product has not been established, for safety see section 4.4.

Older people

TYSABRI is not recommended in patients over 65 years of age due to a lack of data in this patient population.

Renal and hepatic impairment

No studies have been conducted to investigate the effects of renal or hepatic impairment.

The drug elimination mechanism and the results from population pharmacokinetic studies suggest that no dosage adjustment is necessary in patients with renal or hepatic impairment.

Pediatric population

TYSABRI is contraindicated in children and adolescents below 18 years of age (see section 4.3).

Method of administration

For intravenous use.

For instructions on dilution of the medicinal product before administration, see section 6.6.

After dilution (see section 6.6), the infusion should be administered over approximately 1 hour and patients should be observed both during the infusion and for 1 hour after the end of the infusion for any signs. and symptoms of hypersensitivity reactions.

TYSABRI must not be given as a 'bolus injection.


04.3 Contraindications

Hypersensitivity to natalizumab or to any of the excipients listed in section 6.1.

Progressive multifocal leukoencephalopathy (PML).

Patients at increased risk of opportunistic infections, including immunocompromised patients (including those treated with concomitant immunosuppressive therapies or those immunocompromised by previous therapies, e.g. mitoxantrone or cyclophosphamide, see also sections 4.4 and 4.8).

Combination with beta interferons or glatiramer acetate.

Active malignant tumors diagnosed with the exception of patients with basal cell skin cancer.

Children and adolescents under the age of 18.


04.4 Special warnings and appropriate precautions for use

Progressive multifocal leukoencephalopathy (PML)

Use of TYSABRI has been associated with an increased risk of PML, an opportunistic infection caused by the JC virus, which can be fatal or cause severe disability. Because of this increased risk of developing PML, the specialist and patient need to reassess the risks and benefits of TYSABRI on an individual basis.

Both patients and caregivers should be trained to recognize the early signs and symptoms of PML.

The following risk factors are associated with an increased risk of PML.

• Presence of anti JCV antibodies

• Duration of treatment, in particular exceeded 2 years. Experience with patients who have followed TYSABRI treatment for more than 4 years is limited, therefore the risk of PML in these patients cannot be assessed.

• Use of immunosuppressive drugs prior to administration of TYSABRI.

The presence of anti-JCV antibodies characterizes different levels of PML risk in patients treated with TYSABRI. Anti-JCV antibody positive patients have a higher risk of developing PML than anti-JCV antibody negative patients. Patients with all three risk factors for PML (i.e. they are positive for anti-JCV antibodies and have been on TYSABRI therapy for more than 2 years and have previously received immunosuppressive therapy) have a significantly higher risk of PML . In patients with all three risk factors, treatment with TYSABRI should only be continued if the benefits outweigh the risks. Regarding the quantification of PML risk in the various patient subgroups, please consult the Information and Management Guidelines for physicians.

Anti-JCV antibody testing provides supportive information for risk stratification of treatment with TYSABRI. It is recommended that anti-JCV antibody testing in serum be performed prior to initiation of TYSABRI therapy or in patients receiving TYSABRI that have not been tested for the presence of antibodies. Patients negative for anti-JCV antibodies may still be at risk for PML for reasons such as a new JCV infection, fluctuation in antibody status, or a false negative test result. recommends repeating the test every 6 months in patients negative for JCV antibodies. The anti-JCV antibody test (ELISA) should not be used for the diagnosis of PML. The anti-JCV antibody test should not be used. performed during plasmapheresis nor before two weeks after its execution, due to the removal of antibodies from the serum.

Before starting TYSABRI therapy, a recent MRI (usually done within the last 3 months) should be available for reference. MRI should be repeated on an annual basis so that the reference MRI is up to date. Patients should be monitored at regular intervals throughout the duration of treatment. After 2 years of treatment all patients should be re-informed about the risk of developing PML with TYSABRI.

If PML is suspected, treatment should be suspended until PML has been ruled out.

The physician should evaluate the patient to determine if these symptoms are indicative of neurological dysfunction and possibly if they are typical of MS or if they suggest the presence of PML.In case of doubt, further evaluation should be considered, including preferably a contrast MRI (to compare with pre-treatment MRI), cerebrospinal fluid (CSF) examination for JC virus DNA and repetition of neurological examinations, as described in the Information and Guidelines for Physicians for the Management of Patients with Multiple Sclerosis (see Educational Support). Once the physician has ruled out the presence of PML (by repeating clinical, imaging and / or laboratory investigations if clinical suspicion persists), natalizumab can be resumed.

Physicians should be particularly alert to symptoms that may suggest PML and which may go unnoticed by the patient (eg, cognitive or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment. they are subjected to, as they may notice symptoms that the patient is not aware of.

PML has been reported after discontinuation of TYSABRI in patients who did not have signs suggestive of PML at the time of discontinuation. For approximately six months after discontinuing TYSABRI treatment, both patients and physicians should continue to monitor for any new signs or symptoms that may be indicative of PML.

If a patient develops PML, treatment with TYSABRI should be permanently discontinued.

After reconstitution of the immune system in immunocompromised patients with PML, an improvement in outcome was observed.

PML and IRIS (Immune Reconstitution Inflammatory Syndrome)

IRIS syndrome occurs in almost all patients with PML after discontinuation or active removal of TYSABRI, e.g. by plasmapheresis (see section 5.2). IRIS syndrome is thought to result from the restoration of immune function in patients with PML, a condition that can cause severe neurological complications and be fatal. Careful monitoring should be conducted for the onset of IRIS, which in TYSABRI-treated patients with PML typically occurred within a few days to several weeks after plasmapheresis. Appropriate treatment of associated inflammation should also be undertaken while the patient recovers from PML (see the Information and Management Guidelines for Physicians for more information).

Infections including other opportunistic infections

Other opportunistic infections have been reported with the use of TYSABRI, mainly in patients with immunocompromised Crohn's disease or with other important concomitant conditions, however an increased risk of other opportunistic infections in patients treated with TYSABRI but not currently cannot be excluded. have such concomitant conditions Opportunistic infections have also been detected in MS patients treated with TYSABRI monotherapy (see section 4.8).

TYSABRI increases the risk of developing encephalitis and meningitis caused by the herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the post-marketing setting in patients with multiple sclerosis receiving Tysabri therapy (see section 4.8). If herpes encephalitis or meningitis occurs, TYSABRI therapy should be discontinued and appropriate therapy for herpes encephalitis or meningitis administered.

Prescribers should be aware of the possibility that other opportunistic infections may occur during therapy with TYSABRI and therefore should take these into account in the differential diagnosis of infections occurring in patients treated with TYSABRI. If opportunistic infection is suspected, treatment with TYSABRI should be suspended until such infection has been ruled out through further investigation.

If a patient receiving TYSABRI develops an opportunistic infection, TYSABRI treatment should be permanently discontinued.

Training support

All physicians intending to prescribe Tysabri should ensure that they are familiar with the Information and Guidelines for Physicians for the Management of Patients with Multiple Sclerosis.

Physicians should inform patients of the benefits and risks of TYSABRI therapy and provide them with a Patient Alert Card. Patients should be instructed to inform their doctor that they are taking TYSABRI if they develop any infections.

Physicians should inform patients of the "importance of" uninterrupted use, particularly during the initial months of treatment (see hypersensitivity).

Hypersensitivity

Hypersensitivity reactions, including serious systemic reactions, have been associated with TYSABRI (see section 4.8). These reactions usually occurred during the infusion or in the first hour after completion of the infusion. The risk of hypersensitivity was greatest with the first infusions and in patients re-exposed to TYSABRI after a short initial exposure (one or two infusions) and a prolonged period (three months or more) without treatment. However, the risk of hypersensitivity reactions must be considered during all infusions.

Patients should be observed during the infusion and for the next hour (see section 4.8). Means must be available to treat hypersensitivity reactions.

At the first symptoms or signs of hypersensitivity, administration of TYSABRI should be discontinued and appropriate therapy initiated.

Patients who have previously experienced a hypersensitivity reaction should permanently discontinue treatment with TYSABRI.

Concomitant or previous immunosuppressive therapies

The safety and efficacy of TYSABRI, in combination with other immunosuppressive and antineoplastic treatments, have not been fully established. Concomitant use of these agents with TYSABRI may increase the risk of infections, including opportunistic infections, and is contraindicated (see paragraph 4.3).

Patients previously treated with immunosuppressive drugs have an increased risk of developing PML. Particular caution should be exercised with patients previously treated with immunosuppressive drugs and sufficient time should be allowed for immune function to resume. Before starting treatment with TYSABRI, the physician should evaluate each individual case to determine if an immunocompromised state exists (see section 4.3).

In Phase 3 clinical trials in MS, concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infections. Short courses of corticosteroids associated with TYSABRI may be used.

Immunogenicity

Flare-ups of the disease or infusion-related reactions may indicate the development of antibodies to natalizumab. In these cases, the presence of antibodies should be assessed and if these are confirmed by a subsequent test, performed after at least 6 weeks, treatment must be performed. be discontinued, because the presence of persistent antibodies is associated with a substantial reduction in the efficacy of TYSABRI and an increased incidence of hypersensitivity reactions (see section 4.8).

Since patients who have had a short initial exposure to TYSABRI and a prolonged period without treatment have a higher risk of developing anti-natalizumab antibodies and / or hypersensitivity upon re-treatment, it is necessary to evaluate the presence of antibodies and whether are still present in a confirmatory test performed after at least 6 weeks, the patient should not undergo further treatment with Tysabri.

Hepatic events

Serious spontaneous adverse reactions of liver damage have been reported in the post-marketing setting. Such liver damage can arise at any time during treatment, even after the first dose. In some cases the reaction appeared again when treatment with TYSABRI was restarted. Some patients with a "previous history of liver test abnormalities have experienced" exacerbation of liver test abnormalities during TYSABRI therapy. Patients should be monitored as needed for evidence of impaired liver function and instructed to seek medical attention for signs and symptoms that suggest liver damage, such as jaundice and vomiting. In cases of significant hepatic injury, treatment with TYSABRI should be discontinued.

Discontinuation of treatment with TYSABRI

If a decision is made to discontinue treatment with natalizumab, the physician should be aware that natalizumab remains in the blood and exerts pharmacodynamic effects (eg an increase in lymphocyte counts) for approximately 12 weeks after the last dose. Administration of other therapies during this interval will result in concomitant exposure to natalizumab. For medicinal products such as interferon and glatiramer acetate, concomitant exposure of similar duration was not associated with safety risks in clinical studies. There are no data available on concomitant exposure to immunosuppressive drugs in MS patients. Use of such drugs shortly after the discontinuation of natalizumab administration may result in an additional immunosuppressive effect. This should be carefully considered on a case-by-case basis, and a period of wash-out for natalizumab. Short courses of steroids used to treat relapses have not been associated with an increase in infections in clinical trials.

Sodium content in TYSABRI

TYSABRI contains 2.3 mmol (or 52 mg) sodium in each bottle. After dilution in 100 ml of 9% saline (9 mg / ml), this medicinal product contains 17.7 mmol (406 mg) of sodium for each dose. To be kept in mind for patients on a low-sodium diet.


04.5 Interactions with other medicinal products and other forms of interaction

TYSABRI is contraindicated in combination with beta interferons or glatiramer acetate (see section 4.3).

Immunizations

In a randomized open-label study with 60 patients with relapsed MS, there was no significant difference in the humoral immune response to a booster antigen (tetanus toxoid), while a slightly slowed and reduced humoral immune response to a neoantigen (hemocyanin of Megathura crenulata, KLH) in patients treated with TYSABRI for 6 months compared with the untreated control group. Live vaccines have not been studied.


04.6 Pregnancy and breastfeeding

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3).

Data from clinical trials, a prospective pregnancy registry, post-marketing cases and available literature do not suggest an effect of TYSABRI exposure on pregnancy outcomes.

The completed TYSABRI prospective pregnancy registry contained 355 pregnancies with available outcomes. There were 316 live births, and on 29 of them birth defects were reported. Sixteen of the 29 were classified as major defects. The defect rate corresponds to the rates reported in other pregnancy registries involving MS patients. There is no evidence of a specific pattern of birth defects associated with TYSABRI.

Cases published in the literature report transient mild to moderate thrombocytopenia and anemia seen in infants born to women exposed to TYSABRI in their third trimester of pregnancy. Therefore, it is recommended that neonates of women exposed to TYSABRI during the third trimester of pregnancy are monitored for possible haematological abnormalities.

Should a patient become pregnant during treatment with TYSABRI, consideration should be given to discontinuing therapy. A benefit-risk assessment of the use of TYSABRI in pregnancy should take into account the clinical condition of the patient and the possible return of disease activity after discontinuation of TYSABRI.

Feeding time

TYSABRI is excreted in breast milk. The effect of natalizumab on the health of newborns and infants is unknown. Breast-feeding should be discontinued during treatment with TYSABRI.

Fertility

In a study with doses higher than the human dose, a reduction in fertility was observed in female guinea pigs; natalizumab had no effect on male fertility. It is considered unlikely that natalizumab at the maximum recommended dose will affect the degree of fertility in humans.


04.7 Effects on ability to drive and use machines

No studies on the effects of TYSABRI on the ability to drive and use machines have been performed. However, as dizziness is a commonly reported adverse reaction, patients experiencing this adverse reaction are advised not to drive or operate machinery until it is resolved.


04.8 Undesirable effects

Summary of the safety profile

In placebo-controlled studies involving 1617 multiple sclerosis patients treated with natalizumab for up to 2 years (placebo: 1135), adverse events leading to discontinuation of therapy were observed in 5.8% of patients. treated with natalizumab (placebo: 4.8%) In the 2 years the study was conducted, 43.5% of patients treated with natalizumab experienced adverse reactions (placebo: 39.6%) 1.

1 An adverse reaction judged to be related to therapy by the investigating physician.

In placebo-controlled clinical trials in multiple sclerosis patients treated with natalizumab at the recommended dose, the highest incidence of adverse reactions was reported for infusion-associated dizziness, nausea, urticaria and stiffness.

Summary of adverse reactions

The following are adverse reactions reported for natalizumab with an incidence greater than 0.5% compared to placebo.

Reactions are reported according to conventional terminology recommended in the MedDRA System Organ Classes. The frequencies are expressed according to the following classes:

Common (≥ 1/100,

Within each frequency class, adverse reactions are reported in order of decreasing severity. Infections and infestations common Urinary tract infection Nasopharyngitis Disorders of the immune system common Urticaria Uncommon Hypersensitivity Nervous system disorders common Headache Uncommon Dizziness, Progressive multifocal leukoencephalopathy (PML) Gastrointestinal disorders common Vomiting, Nausea Musculoskeletal and connective tissue disorders common Arthralgia General disorders and administration site conditions common Stiffness, Pyrexia, Fatigue

Immunogenicity

In 2-year controlled clinical trials, anti-natalizumab antibodies were detected in 10% of patients in MS patients. Persistent anti-natalizumab antibodies (2 positive tests performed 6 weeks apart) developed in approximately 6% of patients. In a further 4% of patients, antibodies were detected on one occasion. Persistence of antibodies has been associated with a substantial decrease in efficacy of TYSABRI and an increased incidence of hypersensitivity reactions. Other infusion-related reactions associated with the presence of persistent antibodies included stiffness, nausea, vomiting and flushing (see section 4.4).

If, after about 6 months of therapy, the presence of persistent antibodies is suspected, due to both a decreased efficacy of the product and the presence of infusion-related reactions, these can be detected and confirmed by a second test, 6 weeks after the first positive test. Since treatment efficacy may be reduced in patients with persistent antibodies or the incidence of hypersensitivity or infusion-related reactions may increase, treatment should be discontinued in patients who develop persistent antibodies.

Infections, including PML and opportunistic infections

In 2-year controlled clinical trials in MS patients, the infection rate was approximately 1.5 per patient-year in both natalizumab and placebo treated patients. The nature of the infections was usually similar in both patient groups A single case of diarrhea has been reported in clinical trials in MS patients cryptosporidium. Cases of additional opportunistic infections, some of which were fatal, have been reported in other clinical studies. Most patients did not discontinue natalizumab therapy during infections that resolved with adequate therapy.

In clinical trials, herpes infections (varicella-zoster virus, herpes simplex virus) were observed slightly more frequently in patients treated with natalizumab than in those treated with placebo. In post-marketing experience, serious, life-threatening and sometimes fatal cases of encephalitis and meningitis caused by herpes simplex or varicella zoster have been reported in multiple sclerosis patients receiving TYSABRI. The duration of TYSABRI therapy prior to onset. ranged from several months to several years (see section 4.4).

Cases of PML have been reported in clinical trials, post-marketing observational studies and post-marketing passive surveillance. PML usually causes severe disability or can be fatal (see section 4.4).

Hepatic events

Spontaneous reactions of severe liver damage, elevated liver enzymes and hyperbilirubinaemia have been reported in the post-marketing setting (see section 4.4).

Anemia and haemolytic anemia

Rare severe cases of anemia and haemolytic anemia have been reported in patients treated with TYSABRI in post-marketing observational studies.

Malignant tumors

No differences in incidence rates or the nature of malignancies were observed between patients treated with natalizumab and those treated with placebo during 2 years of treatment. However, observation for a longer treatment period is required before being able to rule out any effect of natalizumab on malignant tumors. See section 4.3.

Effects on laboratory investigations

In controlled clinical trials lasting 2 years in MS patients, treatment with TYSABRI is associated with an increase in the number of circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. An increase in neutrophils was not observed. Increases from baseline in lymphocytes, monocytes, eosinophils, and basophils ranged from 35% to 140% for individual cell types, but mean counts remained within normal ranges. Slight decreases in hemoglobin (mean decrease 0.6 g / dl), hematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 x 106 / l) were observed during treatment with TYSABRI. . Within 16 weeks after the last administration of TYSABRI, all values ​​generally returned to their pre-treatment values ​​and changes were not associated with clinical symptoms. Cases of eosinophilia (cell counts) have also been reported in post-marketing experience. eosinophils> 1500 / mm3) without clinical symptoms. In cases where TYSABRI therapy was discontinued, eosinophil levels have normalized.

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. . Website: www.agenziafarmaco.gov.it/it/responsabili.


04.9 Overdose

No cases of overdose have been reported.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: substances with selective immunosuppressive action.

ATC code: L04AA23.

Pharmacodynamic effects

Natalizumab is a selective inhibitor of the adhesion molecule and binds to the α4 subunit of human integrins which is highly expressed on the surface of all leukocytes except neutrophils. Specifically, natalizumab binds to the α4β1 integrin, thus blocking the ' interaction with its complementary receptor, VCAM-1 (vascular cell adhesion molecules-1), and with the osteopontin and CS-1 ligands (connecting segment-1), an alternative fibronectin splice domain. Natalizumab blocks the interaction of integrin α4β7 with MadCAM-1 (mucosal adressin cell adhesion molecules-1). The alteration of these molecular interactions prevents the migration of mononuclear leukocytes through the endothelium to the inflamed parenchymal tissue. A further mechanism of action of natalizumab may consist in the suppression of inflammatory reactions taking place in diseased tissues, by inhibiting the interaction of leukocytes expressing α4 with their ligands in the extracellular matrix and on parenchyma cells. Thus natalizumab it can suppress the inflammatory activity present in the diseased area and inhibit further migration of immune system cells into the inflamed tissues.

In MS, lesions are thought to occur when activated T cells cross the blood-brain barrier. The migration of leukocytes across the blood-brain barrier presupposes an "interaction between the adhesion molecules" of the inflammatory cells and the endothelial cells of the vascular wall. The interaction between α4β1 and its targets represents an important component of pathological inflammation of the brain and the alteration of these interactions results in a decrease in inflammation. Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 of endothelial cells and probably glial cells are overactivated near the inflammation sites. "interaction of α4β1 with VCAM-1, CS-1 and osteopontin which mediates the migration and firm adhesion of leukocytes to the brain parenchyma and can perpetuate the inflammatory cascade in CNS tissue. Blocking the molecular interactions of α4β1 with its targets reduces the inflammatory activity present in the brain, in MS patients, and inhibits further recruitment of immune system cells and their migration to inflamed tissue, thereby reducing formation or the extent of MS lesions.

Clinical efficacy

The efficacy of monotherapy was evaluated in a 2-year, randomized, double-blind, placebo-controlled study (Study AFFIRM), conducted in patients with relapsing-remitting MS who had experienced at least one clinical relapse in the previous year. entered the study and had a score of 0 to 5 on the Kurtzke Expanded Disability Status Scale (EDSS). The median age of the patients was 37 years with a median disease duration of approximately 5 years. Patients were randomized to receive, in a 2: 1 ratio, TYSABRI 300 mg (n = 627) or placebo (n = 315) every 4 weeks for up to 30 infusions overall. Neurological evaluations were performed every 12 weeks and at times of suspected relapse. Evaluations of T1-weighted Gadolinium-enhancing (Gd) lesions and T2-weighted hyperintense lesions were performed annually by magnetic resonance imaging (MRI).

The characteristics and results of the study are presented in the following table.

AFFIRM study: Main features and results Drawing Monotherapy; randomized, double-blind, placebo-controlled, parallel-group study lasting 120 weeks Subjects SMRR (according to McDonald's criteria) Treatment Placebo / Natalizumab 300 mg i.v. every 4 weeks Endpoint at one year Relapse rate Two-year endpoint Progression of the EDSS Secondary endpoints Variables derived from the rate of relapses / variables derived from MRI Subjects Placebo Natalizumab Randomized 315 627 Which completed 1 year 296 609 Which have completed 2 years 285 589 Years of age, median (range) 37 (19-50) 36 (18-50) MS duration in years, median (range) 6,0 (0-33) 5,0 (0-34) Time since diagnosis, in years, median (range) 2,0 (0-23) 2,0 (0-24) Number of relapses in the previous 12 months, median (range) 1,0 (0-5) 1,0 (0-12) EDSS-baseline, median (range) 2 (0-6,0) 2 (0-6,0) RESULTS Annual relapse rate After one year (primary endpoint) 0,805 0,261 After two years 0,733 0,235 One year Rate ratio 0.33 95% CI 0.26; 0.41 Two years Rate ratio 0.32 95% CI 0.26; 0.40 Without relapses After a year 53% 76% After two years 41% 67% Disability Percentage of progressions1 (confirmed after 12-weeks; main outcome) 29% 17% Hazard ratio 0.58, 95% CI 0.43; 0.73, p Percentage of progressions1 (confirmed after 24-weeks) 23% 11% Hazard ratio 0.46, 95% CI 0.33; 0.64, p RM (0-2 years) Median of the percentage change in the volume of T2 hyperintense lesions +8,8% -9.4% (p Mean number of new or recently enlarged T2 hyperintense lesions 11,0 1.9 (p Mean number of T1 hypointense lesions 4,6 1.1 (p Average number of Gd-enhancing lesions 1,2 0.1 (p 1 Disability progression was defined as an increase of at least 1.0 point on EDSS from an initial EDSS value> = 1.0 maintained for at least 12 or 24 weeks or as an increase of at least 1, 5 points on the EDSS compared to an initial value of the EDSS = 0 maintained for 12 or 24 weeks.

In the subgroup of patients indicated for the treatment of rapidly evolving relapsing-remitting MS (patients with 2 or more relapses and 1 or more Gd + lesions) the annual relapse rate was 0.282 in the TYSABRI group (n = 148) and 1,455 in the placebo group (n = 61) (p risk index for disability progression was 0.36 (95% CI: 0.17, 0.76) p = 0.008. These results were derived from an analysis post hoc and must be interpreted with caution. No information is available on the severity of relapses prior to inclusion of patients in the study.

The European Medicines Agency has deferred the obligation to submit the results of studies with TYSABRI in one or more subsets of the pediatric population in multiple sclerosis (see section 4.2 for information on pediatric use).


05.2 "Pharmacokinetic properties

Following repeated intravenous administration of a 300 mg dose of natalizumab to MS patients, the mean maximum observed serum concentration was 110 ± 52 μg / mL. The mean concentrations of natalizumab allo steady-state during the dosing period it ranged from 23 mcg / mL to 29 mcg / mL. The expected time to reach it steady-state was about 36 weeks.

A population pharmacokinetic analysis was conducted on samples from over 1100 MS patients treated with doses ranging from 3 to 6 mg / kg natalizumab. Of these, 581 patients received a fixed dose of 300 mg as monotherapy. mean ± SD at steady-state was 13.1 ± 5.0 mL / h, with a mean ± SD half-life of 16 ± 4 days. The analysis investigated the effects on the pharmacokinetics of selected covariates such as body weight, age, gender, hepatic and renal function and the presence of anti-natalizumab antibodies. It was observed that only body weight and the presence of anti-natalizumab antibodies influenced the availability of natalizumab. Body weight affected clearance in a less than proportional manner. that a 43% change in body weight resulted in a 31 - 34% change in clearance. The change in clearance was not clinically significant. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold, in line with the reduced serum concentrations of natalizumab observed in patients with persistent antibodies (see section 4.8).

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

The effect of plasmapheresis on natalizumab clearance and pharmacodynamics was evaluated in a study involving 12 MS patients. The estimated total elimination of natalizumab after 3 plasmaphereses (over 5-8 days) was approximately 70. -80%. This value is comparable to approximately 40% obtained in previous studies, in which measurements were conducted after the discontinuation of natalizumab for an observation period of similar length. The impact of plasmapheresis on restoration of lymphocyte and consequently its clinical usefulness are unknown.


05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In line with natalizumab's pharmacological activity, the altered lymphocyte activity resulted in both an increase in white blood cells and an increase in spleen weight in most studies. in vivo. These changes were reversible and did not appear to have had any adverse toxicological consequences.

In studies performed in mice, growth and metastasis of melanoma and lymphoblastic leukemia cells did not increase after administration of natalizumab.

No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human chromosomal aberration assays. Natalizumab showed no effect in the assays in vitro of proliferation / toxicity with α4-integrin positive tumor lines.

In a study with doses higher than the human dose, a reduction in fertility was observed in female guinea pigs; Natalizumab had no effect on male fertility.

The effect of natalizumab on reproduction was evaluated in 5 studies: 3 in guinea pigs and 2 in monkeys cynomolgus. These studies did not reveal any teratogenic effects or on the growth of offspring. In a study in guinea pigs, a slight reduction in offspring survival was noted. In a study in monkeys, the number of abortions was doubled in monkeys treated with natalizumab, 30 mg / kg, compared to the comparable control group. This was the result of a "high incidence of abortions in the treated groups in the first cohort, which was not observed in the second cohort. No effect on the abortion rate was observed in any other study. A study in monkeys." cynomolgus showed mild natalizumab-associated fetal changes which included mild anemia, reduced platelet count, increased spleen volume, decreased liver and thymus weight. These changes were associated with an increase in splenic extramedullary hematopoiesis, thymus atrophy and a decrease in hepatic hematopoiesis. Platelet counts were also decreased in births to mothers treated with natalizumab until delivery, however there was no evidence of anemia in such offspring. All changes were observed at higher than human dosages and returned to normal after the elimination of natalizumab.

Low levels of natalizumab have been found in the breast milk of some monkeys cynomolgus treated with natalizumab until delivery.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Sodium phosphate, monobasic, monohydrate

Sodium phosphate, dibasic, heptahydrate

Sodium chloride

Polysorbate 80 (E433)

Water for injections


06.2 Incompatibility

TYSABRI must not be mixed with other medicinal products except those mentioned in section 6.6.


06.3 Period of validity

4 years.

Diluted solution

After dilution with sodium chloride 9 mg / ml (0.9%) solution, immediate use is recommended. If not used immediately, the diluted solution should be stored at 2 ° C to 8 ° C and administered within 8 hours of dilution. In-use storage times and conditions prior to use are the responsibility of the user.


06.4 Special precautions for storage

Concentrated

Store in a refrigerator (2 ° C - 8 ° C).

Do not freeze.

Keep the vial in the outer carton to protect the medicine from light.

For storage conditions of the medicinal product after dilution, see section 6.3.


06.5 Nature of the immediate packaging and contents of the package

15 ml of concentrate in a vial (Type I glass) with a stopper (bromobutyl rubber) and a seal (aluminum) with a flip off cap. Pack size of one vial per carton.


06.6 Instructions for use and handling

Instructions for Use:

1. Before dilution and administration, inspect the vial of TYSABRI for the absence of particles. If there are particles and / or if the liquid in the vial does not appear colorless, clear or slightly opalescent, the vial should not be used.

2. To prepare the TYSABRI solution for intravenous (IV) infusion, use aseptic technique. Remove the flip-off cap from the vial. Insert the syringe needle into the vial through the center of the rubber stopper and withdraw 15 ml of concentrate for solution for infusion.

3. Add the 15 ml of concentrate for solution for infusion to 100 ml of sodium chloride 9 mg / ml (0.9%) solution for injection. Gently invert the TYSABRI solution to mix thoroughly. Don't shake.

4. TYSABRI must not be mixed with other medicinal products or diluents.

5. Visually inspect the diluted medicinal product prior to administration for the absence of particles and discolouration. Do not use the product if it appears discolored or if there are suspended particles.

6. The diluted medicinal product should be used as soon as possible and within 8 hours of dilution. If the diluted medicinal product is stored at 2 ° C to 8 ° C (do not freeze), allow the solution to return to room temperature prior to infusion.

7. The diluted solution should be infused intravenously over 1 hour at a rate of approximately 2 ml / minute.

8. After completion of the infusion, flush the intravenous line with sodium chloride 9 mg / ml (0.9%) solution for injection.

9. Each vial is for single use only.

10. Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

Biogen Idec Limited, Innovation House, 70 Norden Road, Maidenhead, Berkshire, SL6 4AY United Kingdom

08.0 MARKETING AUTHORIZATION NUMBER

A.I.C. 037150012

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 27 June 2006

Date of most recent renewal: June 27, 2011

10.0 DATE OF REVISION OF THE TEXT

11/2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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