Timoptol Unit Dose 0.25% and 0.5% w / v Eye Drops Solution

T

1. Name Of The Medicinal Product

TIMOPTOL® Unit Dose 0.25% w/v Eye Drops Solution

TIMOPTOL® Unit Dose 0.5% w/v Eye Drops Solution

2. Qualitative And Quantitative Composition

'Timoptol' Unit Dose 0.25% w/v Eye Drops Solution contains timolol maleate equivalent to 0.25% w/v solution of timolol without preservative.

'Timoptol' Unit Dose 0.5% w/v Eye Drops Solution contains timolol maleate equivalent to 0.5% w/v solution of timolol without preservative.

3. Pharmaceutical Form

Eye drops solution.

Clear, colourless to light yellow, sterile eye drops.

4. Clinical Particulars 4.1 Therapeutic Indications

'Timoptol' Eye Drops Solution is a beta-adrenoreceptor blocking agent 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

Recommended therapy is one drop 0.25% solution in the affected eye twice a day.

If clinical response is not adequate, dosage may be changed to one drop 0.5% solution in each affected eye twice a day. If needed, 'Timoptol' may be used with other agent(s) for lowering intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended (see 4.4 'Special warnings and precautions for use').

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

Provided that the intra-ocular pressure is maintained at satisfactory levels, many patients can than be placed on once-a-day therapy.

Transfer from other agents

When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with 'Timoptol' the next day with one drop of 0.25% 'Timoptol' in each affected eye twice a day. The dosage may be increased to one drop of 0.5% solution in each affected eye twice 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' in each affected eye twice a day. On the following day, discontinue the previous agent completely, and continue with 'Timoptol'. If a higher dosage of 'Timoptol' is required, substitute one drop of 0.5% solution in each affected eye twice a day.

'Timoptol' Unit dose: The Unit-dose Dispenser of 'Timoptol' is free from preservative and should be used for patients who may be sensitive to the preservative benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

'Timoptol' Unit-dose is a sterile solution. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration.

Paediatric use: is not currently recommended.

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- and third-degree AV block, overt cardiac failure, cardiogenic shock; and hypersensitivity to this product or other beta-blocking agents.

4.4 Special Warnings And Precautions For Use

Like other topically applied ophthalmic drugs, 'Timoptol' 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'. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked.

Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure have been reported.

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when 'Timoptol' 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.

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

'Timoptol' has been generally well tolerated in glaucoma patients wearing conventional hard contact lenses. 'Timoptol' has not been studied in patients wearing lenses made with material other than polymethylmethacrylate (PMMA), which is used to make hard contact lenses.

The Unit-dose Dispenser of 'Timoptol' is free from preservative and should, therefore, be discarded after single use to one or both eyes.

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' has little or no effect on the pupil. When 'Timoptol' is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.

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 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 reaction: 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).

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

'Timoptol' may potentially add to the effects of oral calcium antagonists, rauwolfia alkaloids or beta-blockers, to induce hypotension and/or marked bradycardia.

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.

Oral calcium 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.

The potential exists for hypotension, AV conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium entry blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium 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.

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

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

4.6 Pregnancy And Lactation

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

Breast-feeding mothers: Timolol is detectable in human milk. A decision for breast-feeding mothers, either to stop taking 'Timoptol' or stop nursing, should be based on the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Possible side effects such as dizziness and visual disturbances may affect some patients' ability to drive or operate machinery.

4.8 Undesirable Effects

Side effects

'Timoptol' is usually well tolerated. The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulations, either in clinical trials or since the drug has been marketed. 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 burning and stinging, conjunctivitis, blepharitis, keratitis, dry eyes, and decreased corneal sensitivity. Tinnitus, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and choroidal detachment following filtration surgery (see 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: pruritus, 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, increase in signs and symptoms of myasthenia gravis, paraesthesia.

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

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.

Haematologic:

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 4.8 'Undesirable effects').

If overdosage occurs, the following measures should be considered:

1. Gastric lavage, if ingested. Studies have shown that timolol does not dialyse readily.

2. 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.

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

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

5. 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.

6. Heart block (second- or third-degree): isoprenaline hydrochloride or a pacemaker should be used.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic activity. Timolol maleate combines reversibly with the beta-adrenergic receptor, and this inhibits the usual biologic response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of the agonist which will restore the usual biological response.

Unlike miotics, 'Timoptol' reduces IOP with little or no effect on accommodation or pupil size. In patients with cataracts, the inability to see around lenticular opacities when the pupil is constricted is avoided. When changing patients from miotics to 'Timoptol' a refraction might be necessary when the effects of the miotic have passed.

Diminished response after prolonged therapy with 'Timoptol' has been reported in some patients.

5.2 Pharmacokinetic Properties

The onset of reduction in intra-ocular pressure can be detected within one-half hour after a single dose. The maximum effect occurs in one or two hours; significant lowering of IOP can be maintained for as long as 24 hours with a single dose.

5.3 Preclinical Safety Data

No adverse ocular effects were observed in rabbits and dogs administered 'Timoptol' topically in studies lasting one and two years, respectively. The oral LD50 of the drug is 1,190 and 900 mg/kg in female mice and female rats, respectively.

Carcinogenesis, mutagenesis, impairment of fertility

In a two-year oral study of timolol maleate in rats there was a statistically significant (p

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 tumors 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.

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

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 150 times the maximum recommended human oral dose.

6. Pharmaceutical Particulars 6.1 List Of Excipients

'Timoptol' Unit Dose Eye Drops Solution contains the following inactive ingredients:

Disodium phosphate dodecahydrate

(may be replaced by equivalent amounts of the dihydrate or anhydrous form)

Sodium dihydrogen phosphate dihydrate

(may be replaced by equivalent amounts of the monohydrate)

Sodium hydroxide

Water for injection

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 Years

'Timoptol' Unit Dose Eye Drops Solution should be used immediately after opening and any remaining contents should be discarded immediately after administration.

6.4 Special Precautions For Storage

Do not store above 25°C and keep in outer carton.

6.5 Nature And Contents Of Container

Both the 0.25% and the 0.5% w/v solutions are presented in:

Unit-dose Dispensers, available in cartons of 30 unit doses.

6.6 Special Precautions For Disposal And Other Handling

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% w/v Eye Drops Solution, PL0025/0210

0.5% w/v Eye Drops Solution, PL0025/0211

9. Date Of First Authorisation/Renewal Of The Authorisation

Granted: 17 March 1992

Last renewed: 21 March 2002

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.TOTUD.06.UK.2347 F.T. 080608

Timoptol Unit Dose 0.25 and 0.5 w v Eye Drops Solution

.