Intramol

Each mL contains: Timolol (as Maleate) 5 mg, Benzalkonium chloride 0.1 mg (Preservative).
Timolol maleate is a clear ophthalmic solution.
Timolol maleate is a beta-1 and beta-2 (non-selective) adrenergic receptor-blocking agent, when applied topically to the eye, has the action of reducing elevated, as well as normal, intraocular pressure, whether or not accompanied by glaucoma.

Pharmacology: Pharmacodynamics: Ophthalmological beta-blocking agent.
Timolol is a non-selective β-adrenergic blocker, which does not possess significant intrinsic sympathomimetic or local anaesthetic (membrane-stabilising) activity. When applied topically in the eye, it reduces both elevated and normal intraocular pressure by inhibiting the production of aqueous humour. Unlike miotics, Timolol reduces intraocular pressure with little or no effect on pupil size or accommodation.
The onset of reduction in intraocular pressure following ocular administration of Timolol can be detected within 30 minutes after a single dose. The maximum effect usually occurs in one to three hours and significant lowering of intraocular pressure can be maintained for as long as 24 hours following a single dose.
If systemically absorbed, as is possible, Timolol maleate is capable of producing beta-blockade elsewhere in the body with consequent systemic effects (increased airway resistance, bradycardia, hypotension, etc.).
Pharmacokinetics: Topical instillation of 50 μl of a 0.5% solution of Timolol to the rabbit eye resulted in rapid appearance of Timolol in the aqueous humour and to a much lesser degree in the plasma. The concentration in the aqueous humour (mean of 2.47 μg/mL) peaked 30 minutes after instillation.
The plasma concentration (0.188 μg/mL) also packed at this time.
Following topical instillation in humans, the Timolol concentration in aqueous humour was 8-100 ng/mL within the first hour while the mean plasma concentration was approximately 1 ng/mL seen with therapeutic doses of oral Timolol.
Toxicology: Preclinical Safety Data: Acute Toxicity Studies: Data have been reported in a number of animal species. Oral LD50 in the mouse and rat are 1137 mg/kg and 1028 mg/kg respectively.
Chronic Toxicity Studies: No adverse effects were observed with ophthalmic topical administration of Timolol in rabbits and dogs in studies lasting one and two years respectively. In studies with oral administration in high dosed dogs and rats, bradycardia and weight increase in the heart, kidneys and liver were observed as adverse effects.
Carcinogenicity: In a life-time study in mice, Timolol increased the incidence of benign and malignant pulmonary tumours, benign uterine polyps and mammary adenocarcinomas in female mice when administered orally at doses of 500 mg/kg per day, but not at 5 to 50 mg/kg per day. In a 2-year study in rats, oral Timolol increased the incidence of adrenal phaeochromocytomas in male rats at 300 mg/kg per day but not at 25 or 100 mg/kg per day.
Mutagenicity: Timolol was not shown to be mutagenic when tested in vivo (mouse) in the micronucleus test and cytogenic assay (at doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 0.1 mg per 1 mL).
Reproduction and Fertility: Reproduction and fertility studies in rats have not shown that Timolol causes any adverse effects on male or female when administered orally at doses of up to 125 times the maximum recommended human oral dose of 30 mg. Studies in rats have shown that Timolol at doses up to 50 mg/kg/day (50 times the maximum recommended human oral dose) caused delayed foetal ossification; however, there were no adverse effects on post-natal development of offspring. Teratogenic studies in mice and rabbits have not shown that Timolol at doses up to 50 mg/kg/day causes foetal malformations. In mice, Timolol at doses of 1000 mg/kg/day (1000 times the maximum recommended human oral dose) was maternotoxic and resulted in an increased incidence of foetal resorptions.
In rabbits, Timolol at 100 mg/kg/day (100 times the maximum recommended human oral dose) increased incidence of foetal resorptions but not maternotoxicity.
Timolol maleate 0.25% eye drops have not been adequately studied in human pregnancy. Although timolol ophthalmic solution may be absorbed systematically, daily treatment with Timolol ophthalmic solution 0.25% (1 drop twice daily in both eyes) will not exceed 0.4 mg Timolol compared with the oral therapeutic dose of 20-60 mg/day. However, as a precautionary measure, it is recommended that Timolol should not be used in pregnancy unless the potential benefit to the pregnant woman exceeds the potential risk to the fetus.

Reduction of elevated intraocular pressure in conditions such as: Ocular hypertension; Chronic open-angle glaucoma (including aphakic patients); Some cases of secondary glaucoma.

Adults and Children over 12 years: Recommended therapy is one drop of Timolol ophthalmic solution in the affected eye(s) twice a day.
Elderly: Dosage need not be modified for the elderly as there has been wide experience with the use of Timolol ophthalmic solution in elderly patients.
Children below the age of 12 years: This product is currently not recommended for use.
It is recommended that therapy is initiated using Timolol 0.25% ophthalmic solution. If the clinical response is not adequate, the dosage may be increased to one drop of Timolol 0.5% ophthalmic solution in each affected eye twice daily. Intraocular pressure should be reassessed approximately four weeks after starting treatment because response to Timolol ophthalmic solution may take a few weeks to stabilize. Provided that intraocular pressure is maintained at satisfactory levels, many patients can be placed on once daily therapy.
If necessary, concomitant treatment with miotics, epinephrine and/or carbonic anhydrase inhibitors can be instituted. In order to prevent the active substance from being washed out when additional ophthalmic medication is used, an interval of at least 10 minutes between each application is recommended. The use of two topical beta-adrenergic agents is not recommended.
Transfer from topical beta-blocking agents: Discontinue use after a full day of therapy and start treatment with Timolol ophthalmic solution the next day, with one drop in each affected eye twice daily.
Transfer from a single anti-glaucoma agent other than a topical beta-blocking agent: Continue the agent and add one drop of Timolol ophthalmic solution in each affected eye twice daily. On the following day, discontinue the previous agent completely, and continue with Timolol ophthalmic solution.

No specific data are available. Overdosage is unlikely to occur as one 5 mL bottle contains 12.5 mg (Timolol ophthalmic solution 0.25%) or 25 mg (Timolol ophthalmic solution 0.5%) of Timolol maleate compared with the usual adult oral dose of 20-60 mg per day.
However, in the rare event that overdosage occurs the most common signs and symptoms to be expected following overdosage with beta-adrenergic receptor blocking agents are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. If overdosage does occur, the following measures should be considered: Gastric lavage, if ingested: Studies have shown that Timolol cannot be easily removed by haemodialysis.
Symptomatic bradycardia: Atropine sulfate, 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 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 to be useful.
Heart block (second or third degree): Isoprenaline hydrochloride or a pacemaker should be used.

Cardiogenic shock; Overt cardiac failure; Second and third degree AV block; Sinus bradycardia; Presence or history of bronchial asthma; Presence or history of severe chronic obstructive pulmonary disease; Severe peripheral circulatory disturbances (Raynaud disease); Hypersensitivity to any of the ingredients or to other beta-blocking agents.

Timolol ophthalmic solution may be absorbed systemically and adverse reactions seen with oral beta-blockers may occur. Patients who are receiving a beta-adrenergic blocking agent orally as well as Timolol ophthalmic solution 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.
Cardiac failure should be adequately controlled before beginning therapy with Timolol ophthalmic solution. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure. Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death associated with cardiac failure have been reported.
Timolol ophthalmic solution should be used with caution in patients with sick sinus syndrome, Prinzmetal's angina, untreated phaechromocytoma, metabolic acidosis, hypertension, and diabetes under treatment (Timolol may mask the signs of and response to hypoglycaemia).
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 dose of adrenaline used to treat anaphylactic reactions.
This formulation of Timolol ophthalmic solution contains Benzalkonium chloride as a preservative which may be deposited in soft contact lenses. Hence, Timolol ophthalmic solution should not be used while wearing these lenses. The lenses should be removed before instillation of the drops and not re-inserted earlier than 15 minutes after use.
When Timolol ophthalmic solution is used to reduce intraocular pressure in angle-closure glaucoma, it should be used with a miotic and not alone.
A reduction in ocular hypotensive response has been reported in some patients following prolonged therapy with Timolol ophthalmic solution.
Muscle weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
Timolol ophthalmic solution have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenia symptoms.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., Timolol, acetazolamide) after filtration procedures.
Patient should be instructed to avoid allowing the tip of the dispensing container to contact the eye 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.
Patients should be advised that if they develop any intercurrent ocular condition (e.g., trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of present multi-dose container.
There have been reports of bacterial keratitis associated with the use of topical ophthalmic products.
Effects on ability to drive and use machines: There are currently no data available on the effects of Timolol ophthalmic solution on the ability to drive or use machinery. It has to be taken into account that dizziness, fatigue, transient ocular irritation, blurred vision and lacrimation may occur occasionally.

Timolol ophthalmic solution has not been studied in human pregnancy. However, timolol may cross the placenta with the potential to cause adverse effects of beta-blockade e.g., bradycardia in foetus and neonate. Timolol ophthalmic solution should therefore not be used in pregnancy unless the potential benefit to the pregnant women justifies the potential risk to the foetus.
Timolol ophthalmic solution may be systemically absorbed and excreted in the breast milk, with the potential to cause adverse effects related to beta-blockade in the infant. Treatment during breastfeeding is therefore not recommended unless the potential benefit to the nursing mother justifies the potential risk both to the infant and to the mother.

There have been reports of bacterial keratitis associated with the use of topical ophthalmic products.
Timolol ophthalmic solution is usually well tolerated. The following adverse reactions have been reported.
Urogenital: Urination difficulties.
In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential effects of ophthalmic Timolol maleate: Digestive: Mesentric arterial thrombosis, ischaemic colitis.
Haematologic: Agranulocytosis, thrombocytopenic purpura.
Nervous System: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium and decreased performance on neuropsychometrics.
Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress.
Urogenital: Peyronie's disease.
There have been reports of a syndrome comprising psoriasis skin rash, conjunctivitis sicca, otitis and sclerosing serositis attributed to the beta-adrenergic receptor blocking agent, practolol. This syndrome has been reported with Timolol maleate.

Although Timolol ophthalmic solution has little or no effect on pupil size, mydriasis has occasionally been reported when Timolol is given with adrenaline. The effects of intraocular pressure or the known effects of systemic beta-blockade such as hypotension or bradycardia may be exaggerated when Timolol ophthalmic solution is given to patients already receiving an oral beta-blocking agent. The response of these patients should be closely monitored.
As Timolol ophthalmic solution may be absorbed systemically, the following interactions seen with oral beta-blockers may occur: Calcium channel blockers (verapamil and diltiazem): Negative effect on contractility and atrio-ventricular conduction can lead to cardiac failure and hypotension.
Digitalis glycosides: In association with calcium channel blockers may increase atrio-ventricular conduction time.
Catecholamine-depleting drugs (rauwolfia, alkaloids, reserpine, etc.): Potentiation of hypotension and/or marked bradycardia.
Clonidine: Increased risk of "rebound hypertension" on discontinuation of clonidine.
Class I antiarrhythmic drugs (e.g., disopyramide, quinidine, and amiodarone): Potentiation of bradycardia, sinus arrest and AV block.
Anaesthetic drugs: Increased risk of myocardial depression and hypotension due to blockade of cardiac response to reflex sympathetic stimuli.
Cimetidine, hydralazine, phenothiazines, and alcohol: May cause increase plasma level of Timolol.

Store at temperatures not exceeding 30°C.

Antiglaucoma Preparations

S01ED01 - timolol ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.

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