TIMOWELL Eye Drop

 Timolol Maleate Eye Drops IP 0.5 % w/v

COMPOSITION

Each ml contains:

Timolol Maleate                       IP         equ. to Timolol  5 mg

Benzalkonium Chloride             BP        0.01 % w/v

(as preservative)

Water for Injections                   BP        q.s.

 DESCRIPTION

A clear, colorless to slightly pale-yellow colored solution.

 PHARMACODYNAMIC

Pharmacotherapeutic group: Anti-glaucoma preparations and miotics, beta-blocking agents, selective.

ATC Code: S01E D01

Mechanism of action

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.

PHARMACOKINETICS

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.

Paediatric Population:

As already confirmed by adult data, 80% of each eye drop passes through the nasolacrimal system where it may be rapidly absorbed into the systemic circulation via the nasal mucosa, conjunctiva, nasolacrimal duct, oropharynx and gut, or the skin from tear overflow.

Due to the fact that the blood volume in children is smaller than that in adults a higher circulation concentration has to be taken into account. In addition, neonates have immature metabolic enzyme pathways and it may result in an increase in elimination half-life and potentiating adverse events.

Limited data show that plasma timolol levels in children after 0.25% greatly exceed those in adults after 0.5%, especially in infants and are presumed to increase the risk of side effects such as bronchospasm and bradycardia.

 THERAPEUTIC INDICATION

Timolol 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.

DOSAGE AND ADMINISTRATION

Apply one drop in the eye(s) 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, Timolol may be used with other agent(s) for lowering intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended.

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

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

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.

Paediatric Population:

Due to limited data, Timolol could only be recommended for use in primary congenital and primary juvenile glaucoma for a transitional period while a decision is made on a surgical approach and in case of failed surgery while awaiting further options.

INSTRUCTION FOR USE

Apply TIMOWELL Eye Drops in the following way:

1. Wash your hands. Tilt your head back and look at the ceiling.
2. Gently pull the lower eyelid down until there is a small pocket.
3. Turn the bottle upside down and gently press the bottle to release drops into eyes that needs treatment.
4. Let go of the lower lid, and close your eye for 30 seconds.
5. To avoid contamination, do not let the tip of dropper touch your eye or anything else.
6. Replace and tighten the cap straight after use.

 OVERDOSE

There have been reports of inadvertent overdosage with Timolol resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and cardiac arrest.

If overdosage occurs, the following measures should be considered:

• Gastric lavage, if ingested. Studies have shown that timolol does not dialyse readily.
• 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.
• 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.
• Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.
• 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.
• Heart block (second- or third-degree): isoprenaline hydrochloride or a pacemaker should be used.

 CONTRAINDICATION

• Timolol 0.5% Eye Drops, Solution is contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease; sinus bradycardia; second- and third-degree atrioventricular block; overt cardiac failure; and cardiogenic shock.
• Hypersensitivity to the active substance or to any of the excipients.

WARNING AND PRECAUTIONS

• It is not for injection.
• Do not use the eye drop with contact lenses.
• After application keep the eyelid closed for two minutes & close the lacrimal duct with the finger for two minutes.
• Patients who are receiving a beta-adrenergic blocking agent orally and Timolol 0.5% should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta blockade.
• Patients should not receive two topical ophthalmic beta-adrenergic blocking agents concurrently.
• Muscle Weakness.
• In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Timolol has little or no effect on the pupil.
• Consideration may be given to the gradual withdrawal of beta-adrenergic blocking agents prior to general anesthesia as beta-blockade reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli.
• When Timolol is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used with a miotic and not alone.

PREGNANCY, LACTATION AND FERTILITY

Pregnancy

There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary.

To reduce the systemic absorption.

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 timolol eye drops is administered until delivery, the neonate should be carefully monitored during the first days of life.

Lactation

Beta- blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption.

 Fertility

Timolol have not been found to have any effect on male or female fertility in animal studies.

DRUG INTERACTION

The interactions known for beta-blockers when used orally may also occur with the use of Timolol eye drops.

Although Timolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timolol and epinephrine has been reported occasionally.

Close observation of the patients 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-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.

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-channel blocker is added to the treatment regimen. The nature of any cardiovascular adverse effects 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.

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.

Beta-blockers may increase the hypoglycaemic effect of anti-diabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia.

 ADVERSE EFFECTS

Objective and subjective symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and so on.

PRESENTATION

TIMOWELL Eye Drops are supplied in 5 ml sterilized opaque plastic container with nozzle and cap.

STORAGE AND OTHER INFORMATION

Store at temperature below 30 °C. Keep this medicine out of the sight and reach of children. Do not touch the dropper tip or other dispensing tip to any surface since this may contaminate the solution. Use the solution within one month after opening the container.