Timoptol-Xe 2.5 mg/ 5.0 mg Sterile Ophthalmic Gellan Solution

TIMOPTOL-XE u00ae is indicated for the reduction of elevated intraocular pressure in patients with:

• ocular hypertension
• chronic open-angle glaucoma
• aphakia and glaucoma
• secondary glaucoma (some cases)
• narrow angles and a history of spontaneous or iatrogenically induced narrow-angle closure in the opposite eye in whom reduction of intraocular pressure is necessary (see section 4.4)

Posology

The usual starting dose is one drop of 0,25 % TIMOPTOL-XE u00ae in the affected eye(s) once a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0,5 % TIMOPTOL-XE u00ae in the affected eye(s) once a day.

If needed, concomitant therapy with other agents for lowering intraocular pressure may be given with TIMOPTOL-XE u00ae. The use of two topical beta-adrenergic blockers is not recommended (see section 4.4).

Other topically applied medications should be administered no less than 10 minutes before TIMOPTOL-XE u00ae.

How to Transfer Patients from Other Therapy

When a patient is transferred from TIMOPTOL u00ae to TIMOPTOL-XE u00ae, TIMOPTOL u00ae should be discontinued after proper dosing on one day, and treatment with the same concentration of TIMOPTOL-XE u00ae started on the following day.

When a patient is transferred from another topical ophthalmic beta-adrenergic blocker, that medicine should be discontinued after proper dosing on one day and treatment with TIMOPTOL-XE u00ae started on the following day with 1 drop of 0,25 % TIMOPTOL-XE u00ae in the affected eye once a day. The dose may be increased to one drop of 0,5 % TIMOPTOL-XE u00ae once a day if the clinical response is not adequate.

When a patient is transferred from a single anti-glaucoma agent, other than a topical ophthalmic beta-adrenergic blocker, continue the medicine and add one drop of 0,25 % TIMOPTOL-XE u00ae to each affected eye once a day. On the following day, discontinue the previously used anti-glaucoma medicine and continue TIMOPTOL-XE u00ae. If a greater response is required, substitute one drop of 0,5 % TIMOPTOL-XE u00ae for the 0,25 dosage. When changing patients from miotics to TIMOPTOL-XE u00ae, refraction may be necessary after the effects of the miotic have passed.

Method of administration

Invert the closed container and shake once before each use. It is not necessary to shake the container more than once. When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption may be reduced. This may result in an increase in local activity.

TIMOPTOL-XE u00ae is contraindicated in patients with:

• Reactive airway disease, including bronchial asthma or a history of bronchial asthma, or chronic obstructive pulmonary disease
• Sinus bradycardia, heart block, including sino-atrial block, sick sinus syndrome sino-atrial block, second or third degree atrioventricular block, not controlled with pace-maker, overt cardiac failure, uncontrolled cardiac failure; cardiogenic shock
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Concomitant use with calcium-channel antagonists in patients with impaired cardiac function
• Advanced peripheral arterial insufficiency
• Raynaudu2019s syndrome

Timoptol-XE u00ae should not be used in patients wearing contact lenses as it has not been studied in these patients.

TIMOPTOL-XE u00ae is absorbed systemically and the same types of cardiovascular, pulmonary and other adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2. Prolonged use may be followed with a decreased response.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions. Cardiac complications, including death in association with cardiac failure, have been reported following administration of beta-adrenergic blocking agents. Cardiac failure should be adequately controlled before beginning therapy with TIMOPTOL-XE u00ae. In patients with a history of cardiac disease, signs of cardiac failure should be sought and pulse rates should be monitored. Due to its negative effect on conduction time, TIMOPTOL-XE u00ae should not be given to patients with first degree heart block.

Respiratory disorders

Respiratory complications, including death due to bronchospasm in patients with asthma have been reported following administration of beta-adrenergic blocking agents. These are potential complications of therapy with TIMOPTOL-XE u00ae.

Vascular disorders

Patients with peripheral arterial insufficiency or circulatory disturbance/disorders (e.g. severe forms of Raynaudu2019s disease or Raynaudu2019s syndrome) should be treated with caution (see section 4.3).

Hypoglycaemia/diabetes

TIMOPTOL-XE u00ae should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents. TIMOPTOL-XE u00ae may mask the signs and symptoms of acute hypoglycaemia and the bodyu2019s response to hypoglycaemia.

Masking of hyperthyroidism

TIMOPTOL-XE u00ae may mask certain clinical signs of hyperthyroidism (e.g. tachycardia). Patients suspected of developing hyperthyroidism should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents, such as TIMOPTOL-XE u00ae, which might precipitate a thyroid storm (see section 4.3).

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

Other beta-blocking agents

Patients who are already receiving an oral beta-adrenergic blocking medicine(s) and who are given TIMOPTOL-XE u00ae should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta blockade. The use of TIMOPTOL-XE u00ae plus another topical beta-adrenergic blocking medicine is not recommended (see section 4.5).

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

In patients with angle-closure glaucoma, the immediate objective of treatment is to re-open the angle. This requires constricting the pupil with a miotic. Timolol maleate has little or no effect on the pupil. Should TIMOPTOL-XE u00ae be used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used together with a miotic and not on its own.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy such as TIMOPTOL-XE u00ae after surgical and other filtration procedures. TIMOPTOL-XE u00ae has not been studied in patients wearing contact lenses (see section 4.3).

The dispenser of TIMOPTOL-XE u00ae 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.

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of epinephrine (adrenaline). The anaesthesiologist should be informed when the patient is receiving timolol.

The most frequent medicine related side effects are transient blurred vision, which may last from 30 seconds to 5 minutes and in rare cases up to 30 minutes or longer, following instillation. Blurred vision and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle. Ensure that vision is clear before driving a motor vehicle or operating machinery.

Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection), they should immediately seek their physicianu2019s advice concerning the continued use of the present multidose container (see section 4.2). 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.

Anaphylactic Reactions

While using TIMOPTOL-XE u00ae, 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, whether accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.

Paediatric population

Safety and efficacy of TIMOPTOL-XE u00ae has not been established in children.

No specific medicine interaction studies have been performed with timolol. There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, rauwolfia alkaloids, parasympathomimetics, guanethidine.

Mydriasis resulting from concomitant therapy with epinephrine (adrenaline) has been reported. The potential for mydriasis exists from concomitant therapy with TIMOPTOL-XE u00ae and epinephrine (adrenaline).

Close observation of the patient is recommended when TIMOPTOL-XE u00ae is administered to patients receiving catecholamine-depleting medication such as rauwolfia derivatives or antidysrhythmics and parasympathomimetics, because of the possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Hypotension, atrioventricular (AV) conduction disturbances and left ventricular failure may occur in patients receiving TIMOPTOL-XE u00ae when an oral calcium-channel blocker is added to the treatment regimen (see section 4.3). 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 TIMOPTOL-XE u00ae and digoxin with a calcium antagonist (for example 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 TIMOPTOL-XE u00ae.

Oral beta-adrenergic blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. Therefore, if clonidine and TIMOPTOL-XE u00ae are co-administered, TIMOPTOL-XE u00ae should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta blocker therapy, the introduction of beta-adrenergic blocking agent should be delayed for several days after clonidine administration has stopped. Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs including fluoxetine and paroxetine) and TIMOPTOL-XE u00ae.

Pregnancy

There are no adequate data for the use of timolol in pregnant women. TIMOPTOL-XE u00ae should not be used during pregnancy. To reduce the systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If TIMOPTOL-XE u00ae is administered until delivery, the neonate should be carefully monitored during the first days of life.

Breastfeeding

Timolol is secreted in human milk. Women on TIMOPTOL-XE u00ae should not breastfeed their infants. A decision for breastfeeding mothers, either to stop taking TIMOPTOL-XE u00ae or stop nursing, should be based on the importance of the medicine to the mother.

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, refractive changes, diplopia, ptosis, frequent episodes of mild and transient blurred vision and fatigue may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.

Like other topically applied ophthalmic medicines, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. The most frequent medicine-related complaint in clinical studies was transient blurred vision (6,0 %), lasting from 30 seconds to 5 minutes following instillation. Diminished responsiveness to TIMOPTOL-XE u00ae after prolonged therapy has been reported.

The following adverse reactions have been reported with ocular administration of TIMOPTOL-XE u00ae. Additional adverse reactions have been reported in clinical experiences with systemic timolol, and may be considered potential effects of ophthalmic timolol. Also listed are adverse reactions seen within the class of ophthalmic beta-blockers and may potentially occur with TIMOPTOL-XE u00ae.

Very Common ( u2265 1/10) Common ( u2265 1/100 to <1/10) Uncommon ( u2265 1/1 000 to <1/100) Rare (u2265 1/10 000 to <1/1 000) Not known

Blood and lymphatic system disorders

Systemic non-thrombocytopenic purpura

Immune system disorders

Ocular systemic lupus erythematosus, signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash pruritis

Systemic anaphylactic reaction

Metabolism and nutrition disorders

Ocular hypoglycaemia

Systemic hyperglycaemia, masking of the signs and symptoms of acute hypoglycaemia (see section 4.4)

Psychiatric disorders

Ocular depression insomnia, nightmares, memory loss hallucination

Systemic impaired concentration, increased dreaming nightmares, and other psychiatric disturbances (e.g. anxiety and nervousness)

Nervous system disorders

Ocular headache syncope, dizziness cerebrovascular accident, cerebral ischaemia, increase in signs and symptoms of myasthenia gravis, paraesthesia

Systemic vertigo, local weakness

Eye disorders

Ocular transient blurred vision (lasting from 30 seconds to 5 minutes following instillation) burning and stinging, conjunctival injection, discharge, foreign body sensation, and itching. Signs and symptoms of ocular irritation visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases) diplopia, ptosis, choroidal detachment following filtration surgery or other filtration procedures (see section 4.4) corneal erosion

Very Common ( u2265 1/10) Common ( u2265 1/100 to <1/10) Uncommon ( u2265 1/1 000 to <1/100) Rare (u2265 1/10 000 to <1/1 000) Not known (e.g. burning, stinging, itching, tearing, redness) conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity, and dry eyes

Ear and labyrinth disorders

Ocular tinnitus

Cardiac disorders

Ocular bradycardia dysrhythmia, heart block, congestive heart failure, palpitation, cardiac arrest, oedema, chest pain

atrial fibrillation, atrioventricular block, cardiac failure

Systemic AV block (2nd- or 3rd- degree), sino-atrial block, pulmonary oedema, worsening of peripheral arterial insufficiency (including Raynaudu2019s phenomenon, intermittent claudication), worsening of angina pectoris, vasodilation

Vascular disorders

Ocular hypotension, claudication, Raynaudu2019s phenomenon, cold hands and feet

Respiratory, thoracic, and mediastinal disorders

Ocular dyspnoea bronchospasm (predominantly in patients with pre-existing bronchospastic disease such as asthma or COPD), respiratory failure, cough

Systemic rales

Gastrointestinal disorders

Ocular nausea, dyspepsia

Systemic abdominal pain, vomiting

Skin and subcutaneous tissue disorders

Ocular alopecia, psoriasiform rash or exacerbation of psoriasis skin rash

Systemic sweating, exfoliative dermatitis

Musculoskeletal and connective tissue disorders

Ocular myalgia

Systemic arthralgia, myalgia, extremity pain

Reproductive system and breast disorders

Ocular Peyronieu2019s disease, decreased libido sexual dysfunction such as impotence

Systemic micturition difficulties, impotence

General disorders and administration site conditions

Ocular asthenia, fatigue

Systemic extremity pain, decreased exercise tolerance, local weakness

Investigations

Systemic increases in blood urea, serum potassium, serum uric acid and triglycerides and decreases in haemoglobin, haematocrit and HDL-cholesterol

Post-marketing Experience

The following adverse effects have been reported but a causal relationship to therapy with TIMOPTOL-XE u00ae has not been established.

Metabolism and nutrition disorders

Anorexia

Nervous system disorders

CNS effects (e.g. behavioural changes including confusion, hallucinations, disorientation and somnolence)

Eye disorders

Aphakic cystoid macular oedema

Cardiac and vascular disorders

Hypertension

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Gastro-intestinal disorders

Retroperitoneal fibrosis

Overdosage with TIMOPTOL-XE u00ae has resulted in systemic effects similar to those seen with systemic beta-adrenergic blockers e.g. dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (also see section 4.8). The following specific therapeutic measures should be considered:

1. Symptomatic bradycardia: Administer atropine sulphate intravenously in a dosage of 0,25 to 2 mg to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride should be cautiously administered. In refractory cases the use of a transvenous cardiac pacemaker may be considered.
2. Heart block (second or third degree): Treatment is symptomatic and supportive.
3. Hypotension: Use sympathomimetic pressor medication therapy, such as dopamine, dobutamine or levarterenol. In refractory cases the use of glucagon hydrochloride has been reported to be useful.
4. Acute cardiac failure: Conventional therapy with digoxin, 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 hydrochloride, which has been reported to be useful.
5. Bronchospasm: Additional therapy with aminophylline may be considered. Timolol does not dialyse readily.