TIOPEX timolol 1 mg / g, eye gel in single-dose container

1. Name Of The Medicinal Product

TIOPEX 1 mg/g, eye gel in single-dose container

2. Qualitative And Quantitative Composition

1 g of gel contains 1 mg of timolol as timolol maleate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye gel in single-dose container.

Opalescent, colourless to slightly yellow gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Reduction of the elevated intraocular pressure in patients with:

- ocular hypertension,

- chronic open angle glaucoma.

4.2 Posology And Method Of Administration

Ocular use.

Adults

The recommended dosage regimen is 1 drop of TIOPEX 1 mg/g in the affected eye (or eyes), once a day, in the morning.

Elderly:

There has been wide experience with the use of timolol eye drops in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.

Children and adolescents

There is no experience in children and adolescents. This eye gel is therefore not recommended in such patients.

If the ophthalmologist considers it necessary, TIOPEX 1 mg/g may be combined with one or more other anti-glaucoma treatments (local and/or systemic route of administration).

However, the combination of two beta-blocker eye drops is not recommended (see section 4.4.).

The other eye drops should be administered at least 15 minutes before TIOPEX 1 mg/g. The eye gel should be the last medication instilled.

Nonetheless, response to TIOPEX 1 mg/g may take several weeks to stabilise intraocular pressure, therefore the monitoring of the treatment should include intraocular pressure assessment after a treatment period of approximately four weeks.

Method of administration

Timolol eye gel should be instilled into the conjunctival sac.

A single-dose contains enough gel to treat both eyes.

For single use only.

Patients should be instructed:

• to avoid contact between the dropper tip and the eye or eyelids,

• to use the eye gel immediately after first opening the single-dose container and to discard the single-dose after use.

When using nasolacrimal occlusion or closing the eyelids for 3 minutes, the systemic absorption may be reduced. This may result in a decrease in systemic side effects and in an increase in local activity.

Replacement of a previous treatment:

When TIOPEX 1 mg/g is used to replace another anti-glaucoma eye drops, this eye drops should be discontinued after a full day of therapy, and TIOPEX 1 mg/g should be started the next day at the dosage of one drop in the affected eye (or eyes) once a day, in the morning.

If TIOPEX 1 mg/g is replacing a combination of anti-glaucoma treatments, only one drug should be withdrawn at a time.

If the anti-glaucoma drug being replaced is not a beta-blocker eye drops, it should be continued and one drop of TIOPEX 1 mg/g should be instilled in the affected eye (or eyes), once a day. The following day, stop taking the previous drug completely.

When TIOPEX 1 mg/g is used to replace miotic eye drops, testing of refraction may prove necessary when the effects of the miotics have disappeared.

Medical prescription should be combined with the monitoring of intraocular pressure, particularly when the treatment is initiated.

4.3 Contraindications

The contra-indications of beta-blockers administered by the general route should be borne in mind, although systemic beta-blocker effects are only rarely observed following ocular instillation:

- hypersensitivity to timolol maleate, to other beta-blockers or to any component of the drug product,

- asthma, chronic obstructive lung disease, history of asthma, bronchial hyperreactivity and severe allergic rhinitis,

- cardiac insufficiency unsatisfactorily controlled by the treatment,

- cardiogenic shock,

- second and third degree atrioventricular blocks in the absence of a pacemaker,

- Prinzmetal's angina,

- sinus disease (including sinoatrial block),

- bradycardia (< 45 to 50 beats per minute),

- Raynaud's disease and peripheral circulatory disturbances,

- untreated pheochromocytoma,

- hypotension,

- corneal dystrophies,

- combination with floctafenine (see section 4.5.),

- combination with sultopride (see section 4.5.).

4.4 Special Warnings And Precautions For Use

Ocular

As with any glaucoma treatment, regular examination of the intraocular pressure and cornea is recommended.

The use of two beta-blocker eye drops is not recommended (see section 4.2).

If TIOPEX 1 mg/g is administered to reduce intraocular pressure in patients with closed-angle glaucoma, a miotic should be used in combination.

In such patients, the immediate objective of the treatment is to reopen the angle, which requires the use of a miotic agent in order to obtain pupil constriction, since timolol maleate has little or no effect on the pupil.

Choroidal detachment accompanying ocular hypotonia, has been reported after surgical treatment of glaucoma, with administration of anti-glaucoma drugs which reduce aqueous humour secretions (timolol, acetazolamide).

Patients wearing contact lenses

There is a risk of intolerance to contact lenses due to a beta-blocker induced reduction in lacrimal secretion.

Timolol eye gel has not been studied in patients using contact lenses, and therefore the wearing of contact lenses should be avoided while using of TIOPEX 1 mg/g.

General anaesthesia

In patients undergoing elective surgery, gradual withdrawal of ocular beta-adrenergic receptor blocking agents should be discussed.

General

The warnings and precautions for use of beta-blockers administered by the general route should be borne in mind, although systemic beta-blocker effects are only rarely observed following ocular instillation.

This drug should not generally be used in combination with certain calcium antagonists (bepridil, verapamil, diltiazem) (see section 4.5.).

Concomitant treatment with systemic beta-blockers should be exercised with cautions.

Sportsmen: Sportsmen should be warned that this drug contains an active substance, which may induce a positive analytical result in anti-doping controls.

Discontinuation of therapy

Beta-blocker therapy by general route should never be withdrawn abruptly, particularly in patients suffering from angina: sudden discontinuation may give rise to severe arrhythmia, myocardial infarction or sudden death.

The dose should be reduced gradually i.e. over a period of one or two weeks.

Cardiovascular diseases

The dosage should be reduced if the rate falls below 50-55 beats per minute at rest, and if the patient presents bradycardia-related symptoms.

Given the negative dromotrope effect of beta-blockers, such agents should be administered with caution to patients presenting first-degree atrioventricular block, if the patient presents sick sinus syndrome or low blood pressure.

Cardiac failure should be ruled out before starting treatment. Patients with a history of severe cardiac disease should be monitored for early signs of possible cardiac failure.

Beta-blockers may increase the risk of rebound hypertension.

Metabolic disease

It should be used with caution in patients with metabolic acidosis.

Treated pheochromocytoma

These patients should not receive β-blocking agents without concomitant α-adrenoceptor blocking therapy.

Elderly patients, impaired renal and/or hepatic function

When such agents are administered orally in such high-risk subjects, a dosage adjustment is often necessary.

Diabetic patients

Patients should be advised to increase self-monitoring of their glucose status during the early phase of treatment.

The signs of incipient hypoglycemia may be masked, particularly tachycardia, palpitations and sweating.

Psoriasis

Beta-blockers have been reported to aggravate psoriasis and its use in this condition therefore deserves careful consideration.

Allergic reactions

In patients at risk of severe anaphylactic reactions of whatever origin, particularly with iodine-containing contrast products, anaesthesia or floctafenine (see section 4.5) or during desensitisation, beta-blockers may aggravate the reaction and make it resistant to treatment with adrenalin at usual dosages.

General anaesthesia

Beta-blockers reduce sympathetic reflex activity. Continuing treatment with a systemic beta-blocker reduces the risk of arrhythmia, myocardial ischaemia and peroperative hypertensive attacks. The anaesthetist should be informed that the patient is receiving beta-blocker therapy.

If it is deemed necessary to discontinue treatment, a 48-hour period of withdrawal is considered sufficient to allow catecholamine sensitivity to reappear.

In certain cases, systemic beta-blocker treatment cannot be interrupted:

• in patients with coronary insufficiency it is preferable to continue treatment until surgery, given the risks associated with sudden discontinuation of beta-blockers;

• in an emergency, or if discontinuation is impossible, the patient should be protected from vagal predominance by sufficient premedication with atropine, which should be repeated as required.

Anaesthesia should be with agents, which cause as little myocardial depression as possible, and blood losses should be compensated for.

Thyrotoxicosis

Beta-blockers are likely to mask certain signs of thyrotoxicosis, particularly cardiovascular.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1) Eye drops

Ophthalmological monitoring is necessary in the event of concomitant treatment with eye drops containing adrenaline (risk of mydriasis).

2) Other drugs

Although the quantity of beta-blockers, which passes into the systemic circulation is low after ocular instillation, the risk of drug interactions is still present.

It is therefore advisable to keep in mind the interactions observed with beta-blockers given by general route.

Combinations which are contraindicated

+ Floctafenine

In the event of shock or hypotension caused by floctafenine, beta-blockers attenuate compensatory cardiovascular mechanisms.

+ Sultopride

Increased risk of ventricular arrhythmia, particularly torsades de pointes.

Combinations which are not recommended

+ Bepridil

Automatism disorders (excessive bradycardia, sinus arrest), sinoatrial and atrioventricular conduction disorders and increased risk of ventricular rhythm disorders (torsades de pointes) as well as cardiac failure.

This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or in those beginning treatment.

+ Diltiazem

Automatism disorders (excessive bradycardia, sinus arrest) sinoatrial and atrioventricular conduction disorders and cardiac failure.

This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or those starting treatment.

+ Verapamil

Automatism disorders (excessive bradycardia, sinus arrest) sinoatrial and atrioventricular conduction disorders and cardiac failure (synergy of effects).

This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or those starting treatment.

Combinations requiring precautions for use

+ Amiodarone

Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).

Clinical and ECG monitoring is recommended.

+ Volatile halogenated anaesthetic agents

Reduction in compensatory cardiovascular mechanisms by beta-blockers. Betaadrenergic inhibition may be counteracted during surgery by beta-mimetics.

As a general rule, do not discontinue beta-blocker therapy, and in any event, avoid a sudden discontinuation. The anaesthetist should be advised of this treatment.

+ Potentiation of the systemic beta-blocking effects of eye gel and an increase in plasma levels of the beta-blocker have been reported when beta-blocker eye gels are combined with quinidine, probably due to the inhibition of the beta-blocker metabolism by quinidine (described for timolol).

+ Baclofen

Enhancement of hypotension risk, notably orthostatic.

Blood pressure monitoring and, if necessary, dosage adjustment of the antihypertensive.

+ Central anti-hypertensives

Significant increase in arterial pressure if treatment with a central anti-hypertensive is suddenly discontinued.

Avoid sudden withdrawal of treatment with a central anti-hypertensive. Clinical monitoring.

+ Insulin, oral hypoglycaemic agents

All beta-blockers may mask certain symptoms of hypoglycaemia: palpitations and tachycardia.

Warn the patient and, particularly at the beginning of treatment, self-monitoring of glycaemia by the patient should be increased.

+ Lidocaine

With lidocaine used intravenously: increase in plasmatic concentrations of lidocaine with a possibility of adverse neurological and cardiac side effects (reduction in hepatic clearance of lidocaine).

Clinical and ECG monitoring and possibly testing of the plasmatic concentrations of lidocaine during the combined therapy and after the beta-blocker has been withdrawn.

Adaptation if necessary of dosage regimen of lidocaine.

+ Drugs which may cause torsades de pointes (except sultopride)

Enhanced risk of ventricular arrhythmia, particularly torsades de pointes.

Clinical and ECG monitoring is recommended.

+ Propafenone

Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).

Clinical and ECG monitoring is recommended.

Combinations to be taken into account

+ Alpha-blockers intended for urological use; Anti-hypertensive alphablockers

Enhancement of hypotensive effect. Increased risk of orthostatic hypotension.

+ Amifostine

Enhancement of hypotension risk, notably orthostatic.

+ Imipraminic antidepressants; Neuroleptic

Enhancement of hypotension risk, notably orthostatic.

+ Non-steroidal anti-inflammatory drugs

Reduction in the antihypertensive effect (inhibition of vasodilator prostaglandins by NSAIDs and of water and salt retention by pyrazole NSAIDs).

+ Other bradycardial drugs

Risk of excessive bradycardia (additive effects).

+ Dihydropyridines

Hypotension, cardiac failure in patients with latent or uncontrolled cardiac insufficiency (additional negative inotropic effects). Moreover, the beta-blocker can minimise the sympathetic reflex reaction, which comes into play in the event of excessive haemodynamic repercussion.

+ Dipyridamole

With dipyridamole IV: enhancement of the anti-hypertensive effect.

+ Pilocarpine

Risk of excessive bradycardia (additive bradycardial effects).

4.6 Pregnancy And Lactation

The systemic passage of beta-blockers with ocular administration is less than with oral administration, but nevertheless exists.

Pregnancy

Studies in animals have not revealed any teratogenic effect.

Clinically, to date, no teratogenic effect has been reported, and the results of controlled prospective studies performed with some beta-blockers have not shown any malformations at birth.

Beta-blockers reduce placentary flow, and consequently, foetal death or premature delivery may occur.

In neonates born to treated mothers, beta-blockers activity persists for several days after birth and may cause bradycardia, respiratory distress and hypoglycaemia, but in general this is of no clinical consequence.

However, as a result of depressed sympathetic compensatory mechanisms, cardiac failure, requiring intensive care, may occur , with careful avoidance of intravenous fluids (risk of acute pulmonary oedema).

Therefore, this drug may be used during pregnancy if necessary. If treatment is continued until delivery, close monitoring of the neonate (for heart rate and hypoglycaemia during the first 3 to 5 days after birth) is recommended.

Breast-feeding

Timolol is excreted in human milk.

An occurrence of hypoglycaemia and bradycardia with poorly protein-bound betablockers has been described. Therefore, for safety mesure, it is preferable to avoid breast-feeding when treatment is necessary.

4.7 Effects On Ability To Drive And Use Machines

TIOPEX 1 mg/g has minor influence on the ability to drive and use machines.

No studies on the effect of this medicinal product on the ability to drive have been conducted. While driving vehicles or operating different machines, it should be taken into account that occasionally visual disturbances may occur including refractive changes, diplopia, ptosis, frequent episodes of mild and transient blurred vision and occasional episodes of dizziness or fatigue.

4.8 Undesirable Effects

Like other topically applied ophthalmic drugs, timolol gel may be absorbed systemically. Adverse reactions seen with oral beta-blockers may occur.

Immune system disorders:

Systemic lupus erythematosus.

Signs and symptoms of allergic reactions including anaphylaxis, angio-oedema, urticaria, erythematous rash.

Metabolism and nutrition disorders:

Hypoglycaemia.

Nervous system and psychiatric disorders:

Headache, dizziness, increase in signs and symptoms of myasthenia gravis.

Depression, insomnia, nightmares, libido decreased, impotence.

Eye disorders:

Signs and symptoms of eye irritation, including mild burning or stinging sensation at the beginning of treatment, conjunctival hyperaemia, conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity, and dry eyes.

Visual disturbances including blurred vision, refractive changes (due to withdrawal of miotic therapy in some cases), ptosis, diplopia, choroidal detachment (following filtration surgery).

Cardiac and vascular disorders:

Syncope, palpitations, arrhythmia, bradycardia, hypotension, cardiac insufficiency, atrioventricular block, slowing in atrioventricular conduction or intensification of an existing atrioventricular block, claudication, Raynaud's phenomenon, cold extremities.

Respiratory, thoracic, and mediastinal disorders:

Dyspnea, cough, bronchospasm (predominantly in patients with pre-existing obstructive lung disease).

Gastrointestinal disorders:

Dyspepsia, dry mouth, nausea, vomiting, diarrhea, gastralgia.

Skin and subcutaneous tissue disorders:

Alopecia.

Various skin symptoms, including urticaria, hypersensitivity reaction, angio-oedema (angioneurotic oedema), erythematous skin rash, rash psoriasiform or exacerbation of psoriasis (see section 4.4.).

General disorders and administration site conditions:

Fatigue, asthenia, chest pain.

Biologically:

Rare cases of antinuclear antibodies have been observed, only exceptionally accompanied by clinical symptoms such as lupus syndrome, which regress at treatment discontinuation.

4.9 Overdose

Although systemic absorption of beta-blockers after ocular instillation is low, the possible risk of overdosing should be borne in mind. The symptoms and management of overdose are similar to that of beta-blockers administered by the systemic route.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group : ANTIGLAUCOMA PREPARATIONS AND MIOTICS; Beta-blocking agents

ATC code: S01ED01

General:

Timolol can be characterised by three pharmacological properties:

- non-cardioselective beta-blockade,

- partial agonist potential [moderate intrinsic sympathomimetic activity (ISA)],

- non-significant membrane stabilising effect (local anaesthetic or quinidine-like).

Ocular:

- timolol maleate eye gel reduces intra-ocular pressure, whether or not this is associated with glaucoma;

- an effect is seen around 20 minutes following instillation, reaches a maximum in 1 to 2 hours and is still present after 24 hours;

- there is no effect on pupil diameter or visual acuity.

5.2 Pharmacokinetic Properties

The pharmacokinetic data arising from a comparative trial carried out on patients, suggests negligible systemic exposure, not greater than that obtained with a 0.1% timolol eye gel containing a preservative, used as a comparator in this study.

Plasmatic concentrations remain outside the quantification threshold (QL = 0.8 ng/ml) for both eye gels.

A similar level of systemic tolerance can therefore be anticipated for the two eye gels.

5.3 Preclinical Safety Data

None of the mutagenesis studies carried out in vivo and in vitro on timolol have produced any evidence of mutagenic potential. Cancerogenic potential in timolol has been shown in animals, at exposure levels much higher than those observed in clinical practice during treatment with TIOPEX 1 mg/g.

Reprotoxicity studies have not shown any teratogenic effect in mice, rats and rabbits.

In rats, a delay in ossification was observed at levels of exposure much higher than those observed in clinical practice during treatment with TIOPEX 1 mg/g. No effects on fertility were observed in rats.

In rabbits, a single or repeated instillation of TIOPEX 1 mg/g for 28 days did not cause any local or systemic intolerance, nor local anaesthetic effect.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sorbitol,

Polyvinyl alcohol,

Carbomer 974 P,

Sodium acetate trihydrate,

Lysine monohydrate,

Water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

30 months.

After opening of the single-dose container: use immediately and discard the singledose container after use.

After opening of the sachet: use the single-dose containers within 1 month.

6.4 Special Precautions For Storage

Keep the single-dose containers in the sachet and the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

10 single-dose containers (PEBD) containing 0.4 g of gel are packed in sachet (paper/aluminium), box of 3 or 9 sachets.

A pack size contains 30 (3x10) or 90 (9x10) single-dose containers.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Laboratoires THEA

12 Rue Louis Blériot

63017 Clermont-Ferrand Cedex 2

FRANCE

8. Marketing Authorisation Number(S)

PL 20162/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

16/04/2010

10. Date Of Revision Of The Text

14/10/2010