Tisseel Kit

1. Name Of The Medicinal Product

TISSEEL KIT

2. Qualitative And Quantitative Composition

Each TISSEEL Kit contains 4 vials. The active ingredients are:

TISSEEL Powder for Sealer Protein Solution, Human, Vapour Heated

After reconstitution of the powder, 1 ml of TISSEEL Solution contains:

Total protein 100 - 130 mg of which 75 - 115 mg is Fibrinogen.

Aprotinin Solution, Solvent for TISSEEL Powder

Aprotinin, bovine 3000 KIU¹/ml

Thrombin Powder for Thrombin Solution, Human, Vapour Heated

After reconstitution of the powder, 1 ml of Thrombin Solution contains:

500 IU² of Thrombin in 45-55 mg of Total protein.

Calcium Chloride Solution, Solvent for Thrombin Powder

Ca²⁺ 40 µmol/ml

3. Pharmaceutical Form

Powders and solvents for fibrin sealant.

One TISSEEL KIT contains all the substances required for the preparation of the two fibrin sealant components and the kit for reconstitution and application (for details see Section 6.5. Nature and Contents of Containers).

4. Clinical Particulars

4.1 Therapeutic Indications

Tisseel is intended to complement good surgical technique in achieving haemostasis, or obtaining a watertight seal of the dura mater.

TISSEEL KIT is used as an adjunct to haemostasis in cardiopulmonary bypass surgery when control of bleeding by conventional surgical techniques including sutures, ligatures, and cautery is considered ineffective or impractical. Tisseel Kit is used as an adjunct to dural sealing when control of cerebrospinal fluid (CSF) leakage by conventional neurosurgical techniques including sutures and patches is considered insufficient or impractical.

4.2 Posology And Method Of Administration

4.2.1 Posology

The required dose of TISSEEL Solution depends on the size of the surface to be covered. It is also dependent on the application method chosen.

As a guideline for the covering of surfaces one TISSEEL KIT 1.0 (i.e. 1 ml TISSEEL Solution plus 1 ml Thrombin Solution) will be sufficient for an area of at least 10 cm².

When the fibrin sealant is applied by spray application the same quantity will be sufficient to coat an area of 25 cm² to 100 cm², depending on the individual case.

To avoid undue pressure on the brain, spinal cord and/or cranial or spinal nerves, formation of excess granulation tissue and to ensure gradual absorption of the solidified fibrin sealant, only a thin layer of the TISSEEL-Thrombin Solution, or the individual components, should be applied.

To obtain an air and watertight seal, Tisseel must be applied directly to the site of dural incontinuity and/or along the dura sutures in a thin, even layer. Tisseel Fibrin Sealant alone can withstand high hydrostatic pressure. However, since the sealant may be resorbed after seven days, it must be used in conjunction with dural, muscle or fat graft, or a collagen fleece.

Gradual absorption of TISSEEL Sealant is desirable as wound healing progresses. To prevent premature lysis, however, absorption is slowed down by the addition of aprotinin, a natural protease inhibitor, and so the TISSEEL Powder is reconstituted with Aprotinin Solution (3000 KIU/ml).

As soon as TISSEEL Solution is mixed with Thrombin Solution the setting process starts. Due to the high thrombin concentration of 500 IU/ml a fibrin clot forms within a few seconds.

4.2.2 Methods of Administration

The fibrin sealant components can be applied by the following methods:

I) Simultaneous Application

− using the DUPLOJECT Two-Syringe Clip, Joining Piece, and Application Needle

− using the DUPLOJECT Two-Syringe Clip, Spray Set, and TISSOMAT Propellant Gas Control Unit

− using the DUPLOJECT Two-Syringe Clip and DUPLOCATH Application Catheter

II) Sequential Application

I. Simultaneous Application

The DUPLOJECT Two-Syringe Clip allows simultaneous application of equal quantities of TISSEEL Solution and Thrombin Solution so that the two components are quickly and thoroughly mixed. This is essential for TISSEEL fibrin sealant to gain optimum strength.

a) Simultaneous Application Using the DUPLOJECT Two-Syringe Clip, Joining Piece, and Application Needle:

The DUPLOJECT Two-Syringe Clip holds two identical disposable syringes and has a common plunger which ensures that equal volumes of the two components are fed through a common Joining Piece before being mixed in the Application Needle and ejected.

Operating Instructions

– Place the two syringes filled with TISSEEL Solution and Thrombin Solution into the clip. Make sure that both syringes are filled with equal volumes. Any major air bubbles should be removed.

– Firmly attach the Joining Piece to the nozzles of the two syringes. Tighten the pull strap and fasten it to the attachment point on the DUPLOJECT Two-Syringe Clip. Should the pull strap tear, use the spare Joining Piece. If none is available, further use is still possible but ensure the tightness of the connection to prevent any risk of leaking.

– Fit an Application Needle onto the Joining Piece.

Do not expel the air remaining inside the Joining Piece or Application Needle until you start actual application.

– Apply the TISSEEL-Thrombin Solution onto the recipient surface or surfaces of the parts to be sealed.

If application of the fibrin sealant components is interrupted, clogging occurs immediately in the needle. Only replace the Application Needle immediately before sealing is to be resumed. If the Joining Piece becomes clogged use the spare Joining Piece provided.

b) Simultaneous Application Using the DUPLOJECT Two-Syringe Clip, Spray Set and TISSOMAT Propellant Gas Control Unit:

In the management of extensive wound areas - for example the arrest of oozing haemorrhage - TISSEEL Solution and Thrombin Solution can be applied with this device combination.

The Spray Head is attached to the two syringe tips. By pressing the common plunger the two solutions are passed to two adjacent outlets which are encircled by the pressure gas exit. The gas flow atomises and mixes the two components which can then be sprayed simultaneously using sterile propellant gas (compressed air, nitrogen or CO₂; pressure: approx. 2-3 bar, 5-10 l/min). The volume of the solutions ejected is controlled by the DUPLOJECT plunger. The pressure and flow rate of the propellant gas are controlled with the TISSOMAT Propellant Gas Control Unit. The Spray Set must be used only in connection with the TISSOMAT Propellant Gas Control Unit.

The user is cautioned against the spray application of TISSEEL Solution and Thrombin Solution with devices produced by other manufacturers.

Note: A detailed description of this application method is included in the leaflet of the Spray Set.

c) Simultaneous Application Using the DUPLOJECT Two-Syringe Clip and DUPLOCATH Application Catheters:

In operation sites where access is difficult TISSEEL Solution and Thrombin Solution can be applied using this approach.

II. Sequential Application

For this method of application the two syringes are used separately.

Apply TISSEEL Solution to one of the surfaces to be sealed and an equal quantity of Thrombin Solution to the other; then join the two surfaces. The rapid solidification of the fibrin sealant leaves very little time for approximation and adaptation of the surfaces.

Note: Regardless of the application method chosen, allow for about 3–5 minutes of undisturbed solidification after application to ensure that the setting fibrin sealant adheres firmly to the surrounding tissue. To this end, hold the sealed parts together with continuous gentle pressure in the desired position. Avoid any manipulation of the sealed surface during this period.

In certain applications biocompatible material, such as collagen fleece, is used as a carrier substance or for reinforcement.

Solidified TISSEEL Sealant reaches its maximum strength after about 2 hours (70% after about 10 minutes).

To prevent fibrin sealant from adhering to gloves and instruments, wet these with saline before contact.

TISSEEL Sealant adhering to tissue outside the wound area should be removed (for example with a surgical knife). TISSEEL Sealant is easily identified by its whitish colour.

4.3 Contraindications

TISSEEL must not be applied intravascularly.

Known hypersensitivity against aprotinin or any other ingredients.

Tisseel Kit is not indicated for the treatment of arterial bleeding.

Injection into the nasal mucosa must be avoided, as severe allergic-anaphylactoid reactions have been observed and thromboembolic complications may occur in the area of the ophthalmic artery.

4.4 Special Warnings And Precautions For Use

4.4.1 Precautions

1. For patients with known allergic diathesis, or known hypersensitivity to medicinal products, and for patients having previously received aprotinin, careful risk/benefit assessment must be carried out. It is recommended that antihistamines should be administered to these patients prior to aprotinin application.

2. Injection of TISSEEL and/or Thrombin Solution carries a risk of anaphylactoid reactions. Intravascular and intraventricular administration carries the additional risk of a thromboembolic complication. Both complications may be life threatening. Therefore, care should be taken to ensure that TISSEEL and/or Thrombin Solution are only applied topically (See Section 4.3).

3. Fibrin Sealant may be applied as a spray using pressurised gas. Any application of pressurised gas may be associated with the risk of air embolism, gas emphysema, or tissue or organ rupture, which may be life threatening. Consequently spray application of fibrin sealant should not be carried out in enclosed body areas. The spraying of fibrin sealant should only be carried out under visual control using the TISSOMAT Propellant Gas control unit at a distance no nearer than 10 cm from the surface to be sealed.

4. The spray application for dura sealing should not be carried out in intradural sealing and reconstruction procedures or in cortical dural sealing procedure in cases in which the cerebral ventricular system was opened. This may be associated with a tensile pneuomocephalus, which is life threatening.

5. The user is cautioned against the spray application of TISSEEL Solution and Thrombin Solution with devices provided by other manufacturers. The TISSOMAT Propellant Gas Control Unit and the Spray Set are available from Baxter Healthcare Ltd.

6. Similarly to comparable products or thrombin solutions, TISSEEL may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed to the greatest possible extent before applying the sealant.

7. To prevent unnecessary application to areas adjacent to the surface to be sealed, if possible, cover all tissue adjacent to the site of sealing before applying TISSEEL and Thrombin Solutions.

8. As with any protein product, allergic type hypersensitivity reactions are possible. Signs of hypersensitivity reactions include hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the administration has to be discontinued immediately.

9. TISSEEL contains bovine protein (aprotinin). Even in the case of strict local application there is a risk of anaphylactic reaction, linked to the presence of bovine aprotinin. The risk seems higher in case of previous exposure even if it was well tolerated. Therefore, any use of aprotinin, or aprotinin-containing products, should be recorded in the patients' records.

10. It is strongly recommended that every time TISSEEL is administered to a patient, the name and batch number of the product are recorded.

11. In case of shock, current medical standards for shock treatment should be observed.

4.4.2. Warnings

TISSEEL Powder and Thrombin Powder are made from human plasma originating from plasma and whole blood collected in licensed plasmapheresis centres, blood donation centres and transfusion services across the USA and some European countries excluding the UK. Blood/plasma donations are not collected in countries where clusters of cases of nvCJD are known.

Each initial plasma pool consists of a maximum of 1660 l plasma corresponding to approximately 2100 individual donations. When medicinal products prepared from human blood or plasma are administered, infectious diseases due to the transmission of infective agents cannot be totally excluded. This also applies to pathogens of hitherto unknown nature. To reduce the risk of transmission, selection of donors and donations by suitable measures (screening plasma donors for prior exposure to certain viruses, testing donations for the presence of certain current virus infections) is performed and plasma pools are tested for viruses and viral markers. In addition, the human plasma derived components are subjected to an efficient virus inactivation process by vapour heating during the manufacturing process.

In order to minimise the risk, the following measures have been implemented: Plasma pool testing for virus genome sequences of HIV-1 and-2, HBV and HCV with the polymerase chain reaction (HIQ-PCR) ³, Non-Returning Donor-Applicant Exclusion, Inventory Hold and the Lookback Programme.

The removal/inactivation procedures used may be of limited value against parvovirus B19 and hitherto unknown viruses. The possibility of parvovirus B19 transmission must be considered particularly for immunodeficient patients and seronegative pregnant women, since they may be more severely affected.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal interaction studies have been performed.

Similar to comparable products or thrombin solutions, TISSEEL may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed to the greatest possible extent before applying the sealant.

The sealant may even be applied in fully heparinised patients (e.g. extracorporeal circulation).

4.6 Pregnancy And Lactation

No undesirable effects are known to occur associated with the application of TISSEEL during pregnancy or lactation. In line with generally recognised recommendations, medicinal products should be given during pregnancy or lactation only when strictly indicated.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Inadvertent intravascular and intraventricular administration carries the risk of thromboembolic complications. Therefore, care should be taken to ensure that TISSEEL and/or Thrombin solution is only applied topically.

Injection of TISSEEL and/or Thrombin solution carries a risk of anaphylactoid reactions. Anaphylactic or anaphylactoid reactions may occur following the repeated administration of TISSEEL, the systemic administration of aprotinin and in patients with known hypersensitivity to aprotinin. In these circumstances, prophylactic premedication with H₁ antagonists should be given. Rarely, allergic reactions may occur in patients receiving TISSEEL or aprotinin for the first time. Symptoms associated with allergic reactions include the following: flushing, urticaria, pruritus, nausea, hypotension (which may be severe), tachycardia or bradycardia and dyspnoea. In the event of a hypersensitivity reaction occurring, the administration of TISSEEL should be immediately discontinued and appropriate emergency measures taken.

Both anaphylactoid reactions and thromboembolic complications may be life threatening.

4.9 Overdose

No data are available concerning overdose with TISSEEL.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Classification

Blood and blood forming organs / antihaemorrhagics / vitamin K and other haemostatics / local haemostatics

ATC code BO2BC

The fibrin adhesion system initiates the last phase of physiological blood coagulation. Conversion of fibrinogen to fibrin occurs by the splitting of fibrinogen into fibrin monomers and fibrinopeptides. The fibrin monomers aggregate and form a fibrin clot. Factor XIIIa, which is activated from factor XIII by thrombin, crosslinks fibrin.

Calcium ions are required for both the conversion of fibrinogen and the crosslinkage of fibrin.

As wound healing progresses, increased fibrinolytic activity is induced by plasmin and decomposition of fibrin to fibrin-degradation products is initiated. Proteolytic degradation of fibrin is inhibited by aprotinin.

TISSEEL Kit is a biological two-component sealant. The components (TISSEEL Solution and Thrombin Solution) are mixed during or immediately before application (see 4.2.2. Methods of Administration). This results in a viscous TISSEEL-Thrombin Solution that quickly sets to form a white mass (TISSEEL Sealant), which firmly adheres to tissue. This process simulates the key features of the physiological coagulation process and is used to achieve haemostasis.

The process is illustrated by the following diagram:

5.2 Pharmacokinetic Properties

When the fibrin sealant components come into contact, polymerisation (fibrinogen to fibrin conversion and fibrin cross linking) starts immediately and results in the setting of the fibrin sealant within seconds.

The solidified fibrin sealant is completely absorbed in the course of wound healing.

The degradation and absorption of solidified fibrin sealant is triggered at the interface between the sealant and tissue by cells which migrate into the sealant clot, where they develop fibrinolytic activity.

The plasma proteins present in TISSEEL Kit are eliminated at the same rate as the autologous plasma proteins. Thrombin is partly adsorbed by the fibrin formed. Excess thrombin, if any, is inactivated by protease inhibitors present in blood. Released aprotinin and its metabolites are eliminated by the kidney. Its half-life in blood is known to average between 30 and 60 minutes.

5.3 Preclinical Safety Data

No preclinical safety data are available for TISSEEL Kit on acute toxicity, subacute and chronic toxicity, carcinogenicity or immune stimulation. None of the proteins contained in TISSEEL Kit, nor calcium chloride have mutagenic effects.

Animal studies in rats have not shown any local toxicity.

High doses of aprotinin injected intravenously to pregnant rats had no embryotoxic or teratogenic effect.

6. Pharmaceutical Particulars

6.1 List Of Excipients

6.1.1 Excipients of TISSEEL Powder

Glycine

Human Albumin

Trisodium Citrate

Sodium Chloride

Polysorbate 80

6.1.2 Excipients of the Aprotinin Solution

Water for Injections

6.1.3 Excipients of Thrombin Powder

Human Albumin

Sodium Chloride

Glycine

6.1.4 Excipients of the Calcium Chloride Solution

Water for Injections

6.2 Incompatibilities

TISSEEL and Thrombin Solutions can be denatured following contact with solutions containing alcohol, iodine or heavy metals.

6.3 Shelf Life

TISSEEL Kit has a shelf life of 2 years. Do not use after the expiry date.

Chemical and physical in-use stability of reconstituted TISSEEL and Thrombin Solutions has been demonstrated for 6 hours at room temperature up to 37°C (reconstituted product must not be returned to the refrigerator).

From a microbiological point of view the product should be used immediately, unless the method of reconstitution precludes the risk of microbial contamination. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special Precautions For Storage

Store at +2°C to +8°C. Do not freeze.

Store in the original container to protect from light.

May be removed from refrigeration and stored at temperatures not greater than 25 degrees C for up to six months or the pre-printed expiry date, whichever is shorter.

Once removed from refrigeration, record the expiry date on the product label.

6.5 Nature And Contents Of Container

All components are filled into glass containers conforming to EP requirements. The vials containing TISSEEL Powder are equipped with a magnetic spin propeller.

TISSEEL Kit is available in presentations of 0.5 ml, 1.0 ml, 2.0 ml, and 5.0 ml.

Each TISSEEL Kit contains the following:

1 vial containing TISSEEL Powder;

1 vial containing Thrombin Powder;

1 vial containing Aprotinin Solution;

1 vial containing Calcium Chloride Solution;

1 kit for reconstitution and application

Kit for Reconstitution and Application

Each kit contains one single-sterile set of devices for reconstitution under non-sterile conditions, and one double sterile set of devices for application under sterile conditions.

The set for reconstitution includes 2 disposable needles plus one blue-scaled disposable syringe and one black-scaled disposable syringe.

The set for application includes 2 disposable needles plus one blue-scaled disposable syringe and one black-scaled disposable syringe, one DUPLOJECT Two-Syringe Clip, 2 Joining Pieces and 4 Application Needles.

For details on reconstitution and application see the following section.

The sets of devices are sterile and non-pyrogenic in unopened and undamaged packages. Sterilised by exposure to ethylene oxide.

For single use only. Do not re-sterilise.

CE ₀₂₉₇

6.6 Special Precautions For Disposal And Other Handling

Preparation of Components

The rubber stoppers of all vials should be disinfected prior to reconstitution of the fibrin sealant components.

I. Preparation of TISSEEL Solution (First Component)

TISSEEL Powder is dissolved with the Aprotinin Solution to form TISSEEL Solution.

There are two ways of reconstituting TISSEEL Powder:

− Using the FIBRINOTHERM warming and stirring device.

− In a waterbath at a temperature of 37°C.

Reconstitution Using the FIBRINOTHERM device:

The FIBRINOTHERM device maintains a constant temperature of 37°C. It also shortens the dissolution time of the TISSEEL Powder due to the spin propeller contained in each TISSEEL Powder vial. The propeller is rotated by a magnet within the FIBRINOTHERM device.

Place the vials containing the TISSEEL Powder and Aprotinin Solution into the appropriate openings of the FIBRINOTHERM device and switch on using the red switch. When the FIBRINOTHERM device has reached a temperature of 37°C the red indication lamp goes out. Allow about 10 minutes for warming.

Transfer the Aprotinin Solution into the vial containing the TISSEEL Powder using one needle and the blue-scaled syringe included in the single-sterile kit for reconstitution.

Place the TISSEEL Powder vial into the largest opening of the FIBRINOTHERM device (if necessary, use adaptors). Turn on the stirrer using the green switch and stir the contents for 8 - 10 minutes.

Note: Keep the TISSEEL Solution at 37°C without stirring if it is not used immediately. To ensure homogeneity switch on the stirrer of the FIBRINOTHERM device shortly before drawing up the TISSEEL Solution into the blue-scaled syringe included in the double sterile kit for application.

Reconstitution Using Water-Bath:

Warm the vials containing the TISSEEL Powder and the Aprotinin Solution for about 10 minutes in a water-bath at a temperature of 37°C. (Avoid heating beyond 40°C.)

Transfer the Aprotinin Solution into the vial containing the TISSEEL Powder using one needle and the blue-scaled syringe included in the single-sterile kit for reconstitution.

Return the TISSEEL Powder vial to the water-bath at 37°C for one minute.

Swirl briefly but avoid excessive frothing. Then return the vial to the water-bath and check periodically for complete dissolution (see note).

Note: Always check that the TISSEEL Powder is fully dissolved: reconstitution is complete as soon as no undissolved particles are detectable when holding the vial against the light. If particles are present keep the vial at 37°C for a few more minutes and agitate the solution as before.

Keep the TISSEEL Solution at 37°C if it is not used immediately. To ensure homogeneity swirl briefly before drawing up the solution into the blue-scaled syringe included in the double sterile kit for application.

Withdraw the reconstituted TISSEEL Solution from the vial under sterile conditions.

II. Preparation of Thrombin Solution (Second Component)

Transfer the contents of the Calcium Chloride Solution vial into the Thrombin Powder vial. Use the second needle and the black-scaled syringe provided in the single-sterile kit for reconstitution.

Swirl briefly to dissolve the powder and then keep the Thrombin Solution at 37°C until used.

Prior to use draw up the Thrombin Solution from the vial using the second needle and the black-scaled syringe provided in the double-sterile kit for application.

Note: Syringes and needles used for the reconstitution of one component must not be re-used for the dilution of Aprotinin Solution or the reconstitution of the other component, as this would lead to solidification of the latter component in the vial or syringe.

7. Marketing Authorisation Holder

Baxter Healthcare Ltd.,

Caxton Way,

Thetford,

Norfolk,

UK,

IP24 3SE.

8. Marketing Authorisation Number(S)

PL 00116/0321

9. Date Of First Authorisation/Renewal Of The Authorisation

31^st May 2000

10. Date Of Revision Of The Text

21^st January 2005

TISSEEL, DUPLOCATH, DUPLOJECT, FIBRINOTHERM TISSOMAT, IMMUNO and HIQ-PCR are trademarks of Baxter AG, Vienna, Austria. BAXTER and HYLAND are trademarks of BAXTER International Inc.

[1] KIU = Kallidinogenase Inactivator Unit

[2] One International Unit (IU) of Thrombin is defined as the activity contained in 0.0853 mg of the First International Standard for Human Thrombin or the First International Standard for Alpha Thrombin Human.

[3] HIQ-PCR is a quality-assured PCR testing programme for genome equivalents of HIV-1 and -2, HBV, and HCV. HIQ-PCR stands for Hyland Immuno Quality-Assured Polymerase Chain Reaction.

Timoptol-LA 0.25 and 0.5% w / v Gel-Forming Eye Drops Solution

1. Name Of The Medicinal Product

TIMOPTOL®-LA 0.25% w/v Gel-Forming Eye Drops Solution

TIMOPTOL®-LA 0.5% w/v Gel-Forming Eye Drops Solution

2. Qualitative And Quantitative Composition

Each millilitre of 0.25% w/v solution contains an amount of timolol maleate equivalent to 2.5 mg/ml timolol.

Each millilitre of 0.5% w/v solution contains an amount of timolol maleate equivalent to 5 mg/ml timolol.

3. Pharmaceutical Form

Sterile gel-forming eye drops solution.

4. Clinical Particulars

4.1 Therapeutic Indications

A beta-adrenoreceptor blocker used topically in the reduction of elevated intra-ocular pressure in various conditions including the following: patients with ocular hypertension; patients with chronic open-angle glaucoma including aphakic patients; some patients with secondary glaucoma.

4.2 Posology And Method Of Administration

Invert the closed container and shake once before each use. It is not necessary to shake the container more than once.

Recommended therapy is one drop 0.25% solution in each affected eye once a day.

If clinical response is not adequate, dosage may be changed to one drop 0.5% solution in each affected eye once a day.

If needed, 'Timoptol'-LA may be used with other agent(s) for lowering intra-ocular pressure. Other topically applied medication should be administered not less than 10 minutes before 'Timoptol'-LA. The use of two topical beta-adrenergic blocking agents is not recommended (see section 4.4 'Special warnings and precautions for use').

Intra-ocular pressure should be reassessed approximately four weeks after starting treatment because response to 'Timoptol'-LA may take a few weeks to stabilise.

Transfer from other agents: When transferring a patient from 'Timoptol' to 'Timoptol'-LA, discontinue 'Timoptol' after a full day of therapy, starting treatment with the same concentration of 'Timoptol'-LA on the following day.

When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with 'Timoptol'-LA the next day with one drop of 0.25% 'Timoptol'-LA in each affected eye once a day. The dosage may be increased to one drop of 0.5% solution in each affected eye once a day if the response is not adequate.

When transferring a patient from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent and add one drop of 0.25% 'Timoptol'-LA in each affected eye once a day. On the following day, discontinue the previous agent completely, and continue with 'Timoptol'-LA. If a higher dosage of 'Timoptol'-LA is required, substitute one drop of 0.5% solution in each affected eye once a day (see section 5.1 'Pharmacodynamic properties').

Paediatric use: is not currently indicated.

Use in the elderly: there has been wide-experience with the use of timolol maleate in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.

4.3 Contraindications

Bronchial asthma, history of bronchial asthma or severe chronic obstructive pulmonary disease; sinus bradycardia, second- or third-degree AV block, overt cardiac failure, cardiogenic shock; and hypersensitivity to any component of this product or other beta-blocking agents. 'Timoptol'-LA should not be used in patients wearing contact lenses as it has not been studied in these patients.

4.4 Special Warnings And Precautions For Use

Like other topically applied ophthalmic drugs, this drug may be absorbed systemically and adverse reactions seen with oral beta-blockers may occur.

Cardiac failure should be adequately controlled before beginning therapy with 'Timoptol'-LA. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates monitored.

Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure, are potential complications of therapy with 'Timoptol'-LA.

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when 'Timoptol'-LA is given to patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoreceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy involving beta-blockade should be gradual.

The dispenser of 'Timoptol'-LA contains benzododecinium bromide as a preservative. In a clinical study, the time required to eliminate 50% of the gellan solution from the eye was up to 30 minutes.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. 'Timoptol'-LA has little or no effect on the pupil. When 'Timoptol'-LA is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

Transient blurred vision following instillation may occur, generally lasting from 30 seconds to 5 minutes, and in rare cases up to 30 minutes or longer. Blurred vision and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.

Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container (see section 6.6 'Special precautions for disposal and other handling').

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Risk from anaphylactic reactions: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although 'Timoptol' alone has little or no effect on pupil size, mydriasis has occasionally been reported when 'Timoptol' is given with epinephrine (adrenaline). The potential for mydriasis exists from concomitant therapy with 'Timoptol'-LA and epinephrine.

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

The potential exists for hypotension, atrioventricular (AV) conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium-channel blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium-channel blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker.

The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging AV conduction time.

Oral calcium-channel antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.

Intravenous calcium-channel blockers should be used with caution in patients receiving beta-adrenergic blocking agents.

Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g.quinidine, SSRIs) and timolol.

Oral-β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

4.6 Pregnancy And Lactation

Use in pregnancy: 'Timoptol'-LA has not been studied in human pregnancy. The use of 'Timoptol'-LA requires that the anticipated benefit be weighed against possible hazards.

Breast-feeding mothers: Timolol is detectable in human milk. Because of the potential for adverse reactions to 'Timoptol'-LA in infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Transient blurred vision following instillation may occur, generally lasting from 30 seconds to 5 minutes, and in rare cases, up to 30 minutes or longer. Blurred vision and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.

4.8 Undesirable Effects

Side effects

'Timoptol'-LA is usually well tolerated. The most frequent drug-related complaint in clinical studies was transient blurred vision (6.0%), lasting from 30 seconds to 5 minutes following instillation.

The following possibly, probably, or definitely drug-related adverse reactions occurred with frequency of at least 1% in parallel active treatment controlled clinical trials:

Ocular: burning and stinging, discharge, foreign body sensation, itching.

The following side effects reported with 'Timoptol', either in clinical trials or since the drug has been marketed, are potential side effects of 'Timoptol'-LA. Additional side effects have been reported in clinical experiences with systemic timolol maleate, and may be considered potential effects of ophthalmic timolol maleate

Special senses:

ocular: signs and symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity and dry eyes. Tinnitus, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, and ptosis. Choroidal detachment following filtration surgery (see section 4.4 'Special warnings and precautions for use').

Cardiovascular:

ocular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud's phenomenon, cold hands and feet.

systemic: AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.

Respiratory:

ocular: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough.

systemic: rales

Body as a whole:

ocular: headache, asthenia, fatigue, chest pain.

systemic: extremity pain, decreased exercise tolerance.

Integumentary:

ocular: alopecia, psoriasiform rash or exacerbation of psoriasis.

systemic: pruritis, sweating, exfoliative dermatitis.

Hypersensitivity:

ocular: signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash.

Nervous system/psychiatric:

ocular: dizziness, depression, insomnia, nightmares, memory loss, paraesthesia.

systemic: vertigo, local weakness, diminished concentration, increased dreaming.

Neuromuscular:

ocular: increase in signs and symptoms of myasthenia gravis.

Digestive:

ocular: nausea, diarrhoea, dyspepsia, dry mouth.

systemic: vomiting.

Urogenital:

ocular: decreased libido, Peyronie's disease.

systemic: impotence, micturition difficulties.

Immunologic:

ocular: systemic lupus erythematosus.

Endocrine:

systemic: hyperglycaemia, hypoglycaemia.

Musculoskeletal:

systemic: arthralgia.

Haematological:

systemic: non-thrombocytopenic purpura.

4.9 Overdose

There have been reports of inadvertent overdosage with 'Timoptol' resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see section 4.8 'Undesirable effects' - Side effects).

If overdosage occurs, the following measures should be considered:

1. Symptomatic bradycardia: atropine sulphate, 0.25 to 2 mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.

2. Hypotension: a sympathomimetic pressor agent such as dopamine, dobutamine or norepinephrine (noradrenaline) should be used. In refractory cases, the use of glucagon has been reported to be useful.

3. Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.

4. Acute cardiac failure: conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon, which has been reported useful.

5. Heart block (second

Timolol does not dialyse readily.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group

Beta-adrenergic receptor blocking agent.

Mechanism of action

The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established. A fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.

'Timoptol'-LA is an ophthalmic formulation comprising timolol maleate, which reduces intra-ocular pressure, whether or not associated with glaucoma, and a new delivery vehicle. Gellan solution contains a highly purified anionic heteropolysaccharide derived from gellan gum. Aqueous solutions of gellan gum form a clear transparent gel at low polymer concentrations in the presence of cations. When 'Timoptol'-LA contacts the precorneal tear film, it becomes a gel. Gellan gum increases the contact time of the drug with the eye.

Pharmacodynamics

In parallel active treatment controlled, double-masked, multiclinic studies in patients with untreated elevated intra-ocular pressure of greater than 22 mmHg in one or both eyes, 0.25% and 0.5% 'Timoptol'-LA administered once daily had an intra-ocular pressure-lowering effect equivalent to the same concentration of 'Timoptol' administered twice daily (see table below).

For the five independent comparative studies listed in the table below, the entrance criterion was an intra-ocular pressure of greater than 22 mmHg in one or both eyes after a washout period of one week for most antiglaucoma medications and up to three weeks for ophthalmic beta-adrenergic antagonists. The dosage used was one drop of 'Timoptol'-LA in each affected eye once daily versus one drop of 'Timoptol' in each affected eye twice daily.

Mean change in intra-ocular pressure (mmHg) from baseline at trough (immediately before the morning dose) for the final week of the double-masked study

Concentration	'Timoptol'-LA (n)	'Timoptol' (n)	Week
0.25%	-5.8 (94)	-5.9 (96)	12
0.25%	-6.0 (74)	-5.9 (73)	12
0.50%	-8.3 (110)*	-8.2 (111)*	12
0.50%	-5.6 (189)	-6.3 (94)	24
0.50%	-6.4 (212)	-6.1 (109)	24

*The baseline intra-ocular pressure was elevated in comparison to the other studies due to the higher intra-ocular pressure of patients with pseudoexfoliative glaucoma.

Onset of action of timolol maleate is usually rapid, occurring approximately 20 minutes after topical application to the eye.

Maximum reduction of intra-ocular pressure occurs in two to four hours with 'Timoptol'-LA. Significant lowering of intra-ocular pressure has been maintained for 24 hours with both 0.25% and 0.5% 'Timoptol'-LA.

As compared with 0.5% 'Timoptol' administered twice daily, in three clinical studies 0.5% 'Timoptol'-LA administered once daily reduced mean heart rate less and produced bradycardia less frequently (see section 4.4 'Special warnings and specialprecautions for use'). At trough (24 hours post-dose 'Timoptol'-LA, 12 hours post-dose 'Timoptol'), the mean reduction in heart rate was 0.8 beats/minute for 'Timoptol'-LA and 3.6 beats/minute for 'Timoptol'; whereas at two hours post-dose, the mean reduction was comparable (3.8 beats/minute for 'Timoptol'-LA and 5 beats/minute for 'Timoptol').

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity.

Unlike miotics, timolol maleate reduces intra-ocular pressure with little or no effect on accommodation or pupil size. Thus, changes in visual acuity due to increased accommodation are uncommon, and the dim or blurred vision and night blindness produced by miotics are not evident. In addition, in patients with cataracts the inability to see around lenticular opacities when the pupil is constricted by miotics is avoided. When changing patients from miotics to 'Timoptol'-LA, refraction may be necessary after the effects of the miotic have passed.

As with other antiglaucoma drugs, diminished responsiveness to timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies of 'Timoptol' in which 164 patients were followed for at least three years, no significant difference in mean intra-ocular pressure was observed after initial stabilisation. This indicates that the intra-ocular pressure-lowering effects of timolol maleate is well maintained.

5.2 Pharmacokinetic Properties

Onset of action of timolol maleate is usually rapid, occurring approximately 20 minutes after topical application to the eye.

Maximum reduction of intra-ocular pressure occurs in two to four hours with 'Timoptol'-LA. Significant lowering of intra-ocular pressure has been maintained for 24 hours with both 0.25% and 0.5% 'Timoptol'-LA. In a study of plasma timolol concentrations, the systemic exposure to timolol was less when normal healthy volunteers received 0.5% 'Timoptol'-LA once daily than when they received 0.5% 'Timoptol' twice daily.

5.3 Preclinical Safety Data

No adverse ocular effects were observed in monkeys and rabbits administered 'Timoptol'-LA topically in studies lasting 12 months and one month, respectively. The oral LD₅₀ of timolol is 1,190 and 900 mg/kg in female mice and female rats, respectively. The oral LD₅₀ of gellan gum is greater than 5,000 mg/kg in rats.

In a two-year oral study of timolol maleate in rats there was a statistically significant (p^*). Similar differences were not observed in rats administered oral doses equivalent to 25 or 100 times the maximum recommended human oral dose.

In a lifetime oral study in mice, there were statistically significant (p

The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.

In oral studies of gellan gum administered to rats for up to 105 weeks at concentrations up to 5% of their diet and to mice for 96-98 weeks at concentrations up to 3% of their diet, no overt signs of toxicity and no increase in the incidence of tumours was observed.

Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell-transformation assay (up to 100 mcg/ml). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant (p

Gellan gum was devoid of mutagenic potential when evaluated in vivo (mouse) in micronucleus assay using doses up to 450 mg/kg. In addition, gellan gum in concentrations up to 20 mg/ml was not detectably mutagenic in the following in-vitro assays:

(1) unscheduled DNA synthesis in rat hepatocytes assay, (2) V-79 mammalian cell mutagenesis assay, and (3) chromosomal aberrations in Chinese hamster ovary cells assay.

In Ames tests, gellan gum (in concentrations up to 1,000 mcg/plate, which is its limit of solubility) did not induce a twofold or greater increase in revertants relative to the solvent control. It is therefore not detectably mutagenic.

^*The maximum recommended daily oral dose of timolol is 60 mg. One drop of 0.5% 'Timoptol'-LA contains about 1/300 of this dose, which is about 0.2 mg.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Gellan gum, trometamol, mannitol E421, and water for injection. Benzododecinium bromide (0.012%) is added as preservative.

6.2 Incompatibilities

None known.

6.3 Shelf Life

The shelf life is 24 months. After opening the shelf life is 28 days.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not freeze. Store bottle in the outer carton.

6.5 Nature And Contents Of Container

The OCUMETER Plus ophthalmic dispenser consists of a translucent high-density polyethylene container with a sealed dropper tip, a flexible fluted side area, which is depressed to dispense the drops, and a two-piece assembly. The two-piece cap mechanism punctures the sealed dropper tip upon initial use, then locks together to provide a single cap during the usage period. Tamper evidence is provided by a safety strip on the container label. The OCUMETER Plus ophthalmic dispenser contains 2.5 ml of solution.

'Timoptol'-LA Gel-Forming Eye Drops Solution is available in single bottles containing 2.5 ml of solution.

6.6 Special Precautions For Disposal And Other Handling

Invert the container and shake once before each use. It is not necessary to shake the container more than once.

Discard 28 days after opening.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK.

8. Marketing Authorisation Number(S)

0.25% PL 0025/0310

0.5% PL 0025/0311

9. Date Of First Authorisation/Renewal Of The Authorisation

Granted: 2 April 1996/Renewed: 2 April 2001

10. Date Of Revision Of The Text

February 2008

LEGAL CATEGORY

POM.

® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited 2008. All rights reserved.

SPC.TOTX.06.UK.2343 F.T. 060608

TYSABRI 300 mg concentrate for solution for infusion

TYSABRI 300 mg concentrate for solution for infusion

natalizumab

Read all of this leaflet carefully before you start using this medicine.

In addition to this leaflet you will be given a Patient Alert Card, which contains important safety information that you need to know before you are given TYSABRI (pronounced tie-SA-bree) and during treatment with TYSABRI.

• Keep this leaflet and the Patient Alert Card. You may need to read them again.


• It is important that you keep the Alert Card with you during treatment and for six months after the last dose of TYSABRI, since side effects may occur even after you have stopped treatment.


• If you have any further questions, ask your doctor or pharmacist.


• This leaflet will explain about side effects that some patients experience on TYSABRI. If you have any worrying side effects, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

In this leaflet:

• 1. What TYSABRI is and what it is used for


• 2. Before you use TYSABRI


• 3. How to use TYSABRI


• 4. Possible side effects


• 5. How to store TYSABRI


• 6. Further information

What Tysabri Is And What It Is Used For

TYSABRI is used to treat multiple sclerosis (MS).

The symptoms of MS vary from patient to patient, and you may experience some or none of them.

Symptoms can include; walking problems, numbness in the face, arms or legs, problems seeing things, tiredness, feeling off-balance or light headed, bladder and bowel problems, difficulty in thinking and concentrating, depression, acute or chronic pain, sexual problems, and stiffness and muscle spasms. When the symptoms flare up, it is called a relapse (also known as an exacerbation or an attack). When a relapse occurs, you may notice the symptoms suddenly, within a few hours, or slowly progressing over several days. Your symptoms will then usually improve gradually (this is called a remission).

MS causes inflammation in the brain that damages the nerve cells. In TYSABRI the active ingredient is natalizumab, a protein similar to your own antibodies. It stops the cells that cause inflammation from going into your brain. This reduces nerve damage caused by MS.

In clinical trials, TYSABRI approximately halved the progression of the disabling effects of MS and also decreased the number of MS attacks by about two-thirds. However, TYSABRI cannot repair the damage that has already been caused by MS. When you receive TYSABRI you might not notice any improvement, but TYSABRI may still be working to prevent your MS becoming worse.

It is important to continue with your medicine for as long as you and your doctor decide that it is helping you.

Before You Use Tysabri

Before you start treatment with TYSABRI, it is important that you and your doctor have discussed the benefits you would expect to receive from this treatment and the risks that are associated with it.

Do not use TYSABRI

• If you are allergic (hypersensitive) to natalizumab or any of the other ingredients of TYSABRI (see section 6 for the ingredients).


• If your doctor has told you that you have PML (progressive multifocal leukoencephalopathy). PML is a rare infection of the brain.


• If your doctor tells you that you have a serious problem with your immune system (due to disease for example, leukaemia or HIV or due to a medicine you are taking or have previously taken).


• If you are taking medicines that cannot be used with TYSABRI (see Using other medicines, below).


• If you have cancer (unless it is a type of skin cancer called basal cell carcinoma).


• If you are under 18 years of age.

Take special care with TYSABRI

There have been cases of a rare brain infection called PML (progressive multifocal leukoencephalopathy) that have occurred in patients who have been given TYSABRI. PML may lead to severe disability or death. The risk of PML appears to increase the longer that you are on treatment especially if you have been on treatment for more than two years. It is not known if the chance of getting PML continues to rise, remains the same, or falls after you have been on TYSABRI for more than three years. In patients with PML a reaction known as IRIS (Immune Reconstitution Inflammatory Syndrome) is likely to occur after treatment for PML, as TYSABRI is removed from your body. IRIS may lead to your condition getting worse, including worsening of brain function.

The symptoms of PML may be similar to an MS relapse (e.g. weakness or visual changes). Therefore, if you believe your MS is getting worse or if you notice any new symptoms, it is very important that you speak to your doctor as soon as possible.

Speak with your partner or caregivers and inform them about your treatment. Symptoms might arise that you might not become aware of by yourself, such as changes in mood or behaviour, memory lapses, speech and communication difficulties, which your doctor may need to investigate further to rule out PML.

You will also find this information in the Patient Alert Card you have been given by your doctor. It is important that you keep this Alert Card and show it to your partner or caregivers.

Serious infections may occur with TYSABRI. If you develop any infection, or if you develop symptoms like an unexplained fever, severe diarrhoea, prolonged dizziness / headache / stiff neck, weight loss, or listlessness, or other symptoms potentially associated with an infection whilst receiving TYSABRI, speak to your doctor as soon as possible and show the Patient Alert Card and this package leaflet to him.

You will also find this information in the Patient Alert Card you have been given by your doctor. It is important that you keep this Alert Card.

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines you may have obtained without a prescription. You may not be able to use TYSABRI with some medicines that affect your immune system.

Pregnancy and breast-feeding

You should not use TYSABRI if you are pregnant unless you have discussed this with your doctor. Be sure to tell your doctor immediately if you are pregnant, think you may be pregnant, or if you are planning to become pregnant.

Do not breast-feed whilst using TYSABRI. You should discuss with your doctor whether you choose to breast-feed or to use TYSABRI.

Ask your doctor or pharmacist for advice before taking any other medicine with TYSABRI.

Driving and using machines

TYSABRI is not expected to have an effect on your ability to drive or to operate machines. If you are concerned, discuss this with your doctor.

How To Use Tysabri

TYSABRI will be prepared and given to you by a doctor.

Information for medical or healthcare professionals on how to prepare and administer TYSABRI is provided at the end of this leaflet.

The adult dose is 300 mg given once every 4 weeks.

TYSABRI must be diluted before it is given to you. It is given as a drip into a vein (by intravenous infusion), usually in your arm. This takes about 1 hour.

A few patients have had an allergic reaction to TYSABRI. Your doctor will check for allergic reactions during the infusion and for 1 hour afterwards.

It is important to continue with your medicine for as long as you and your doctor decide that it is helping you. Continuous dosing with TYSABRI is important, especially during the first few months of treatment. This is because patients who received one or two doses of TYSABRI and then had a gap in treatment of three months or more, were more likely to have an allergic reaction when resuming treatment.

If you miss your dose of TYSABRI

If you miss your usual dose of TYSABRI, arrange with your doctor to receive it as soon as you can.

You can then continue to receive your dose of TYSABRI every 4 weeks.

Possible Side Effects

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

If you have any worrying side effects, including any not listed in this leaflet, please tell your doctor, nurse or pharmacist as soon as possible.

Speak to your doctor or nurse immediately if you notice any of the following:

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

• Itchy rash (hives)


• Swelling of your face, lips or tongue


• Difficulty breathing


• Chest pain or discomfort


• Increase or decrease in your blood pressure (your doctor or nurse will notice this if they are monitoring your blood pressure).

Signs of a possible liver problem:

• Yellowing of your skin or the whites of your eyes


• Unusual darkening of the urine.

TYSABRI can also have other side effects.

Side effects are listed below by how commonly they have been reported in clinical trials:

Common side effects that may occur in less than 10 in 100 patients:

• Urinary tract infection


• Sore throat and runny or blocked up nose


• Shivering


• Itchy rash (hives)


• Headache


• Dizziness


• Feeling sick (nausea)


• Being sick (vomiting)


• Joint pain


• Fever


• Tiredness.

Uncommon side effects that may occur in less than 1 in 100 patients:

• Severe allergy (hypersensitivity).

Rare side effects that may occur in less than 1 in 1000 patients:

• Unusual infections (so-called “Opportunistic infections”)


• Progressive multifocal leukoencephalopathy (PML), a rare brain infection.

What to do if your MS gets worse or you notice new symptoms

There have been reports of a rare brain infection called PML (progressive multifocal leukoencephalopathy) that have occurred in patients who have been given TYSABRI. PML usually leads to severe disability or death.

The symptoms of PML may be similar to an MS relapse.

• Therefore, if you believe your MS is getting worse or if you notice any new symptoms, it is important that you speak to your doctor as soon as possible.


• Discuss your treatment with your partner or caregivers. They might see new symptoms that you might not notice such as changes in mood or behaviour, memory lapses, speech and communication difficulties, which your doctor may need to investigate further to rule out PML.


• Show the Alert Card and this package leaflet to any doctor involved with your treatment, not only to your neurologist.

Serious infections may occur with TYSABRI. The symptoms of infections include:

• an unexplained fever


• severe diarrhoea


• shortness of breath


• prolonged dizziness


• headache


• stiff neck


• weight loss


• listlessness.

• Speak to your doctor as soon as possible if you think you have an infection.


• Show the Alert Card and this package leaflet to any doctor involved with your treatment, not only to your neurologist.

You will also find this information in the Patient Alert Card you have been given by your doctor.

Will TYSABRI always work?

In a few patients who use TYSABRI, over time the body’s natural defence may stop TYSABRI from working properly (the body develops antibodies to TYSABRI). Your doctor can decide whether TYSABRI is not working properly for you by testing your blood and will stop TYSABRI, if necessary.

How To Store Tysabri

Keep out of the reach and sight of children.

Unopened vial:

Store in a refrigerator (2°C to 8°C).

Do not freeze.

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

Do not use TYSABRI after the expiry date stated on the label and carton.

Diluted solution:

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

Do not use TYSABRI if you notice particles in the liquid and/or the liquid in the vial is discoloured.

Further Information

What TYSABRI contains

Each 15 ml vial of concentrate contains 300 mg 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 clear, colourless to slightly cloudy liquid. Each carton contains one glass vial.

TYSABRI must be diluted before it is given to you.

Marketing Authorisation Holder

Elan Pharma International Ltd.

Monksland

Athlone

County Westmeath

Ireland

Manufacturer

Biogen Idec B.V.

Robijnlaan 8

NL-2132 Hoofddorp

The Netherlands

Biogen Idec Denmark Manufacturing ApS

Biogen Idec Allé 1

DK-3400 Hillerød

Denmark

For any further information about this medicine, please contact the local representative of the Marketing Authorisation Holder. This information is provided at the end of the leaflet.

United Kingdom

Biogen Idec Limited

Tel:+44 (0) 1628 50 1000

This leaflet was last approved in 05/2010.

Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu/.