Latamolol

Latanoprost, timolol.

1 mL of eye drop solution contains Latanoprost 50 mcg, Timolol maleate 6.83 mg equivalent to timolol 5 mg.
Excipients/Inactive Ingredients: Benzalkonium chloride, Sodium chloride, Sodium dihydrogen phosphate monohydrate, Anhydrous disodium phosphate, Sodium hydroxide solution, Hydrochloric acid solution and water for injection.

Pharmacology: Pharmacodynamics: Latamolol consists of two components: latanoprost and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone.
Latanoprost is a prostanoid selective FP receptor agonist which is believed to reduce the intraocular pressure by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP the greater the likelihood of optic nerve damage and visual field loss.
Timolol is a nonselective β-adrenergic blocking agent. Timolol does not have substantial intrinsic sympathomimetic, parasympathomimetic, or local anesthetic activity.
Following topical application to the eye, timolol reduces both elevated and normal intraocular pressure (IOP) in patients with or without open-angle (chronic simple, noncongestive) glaucoma or ocular hypertension. Timolol reduces IOP with little or no effect on accommodation or pupillary size. In patients with elevated IOP, timolol reduces mean IOP by about 25-33%. The drug appears to be equally effective in light- and dark-colored eyes.
The exact mechanism by which β-blockers, including timolol, reduce IOP has not been clearly defined. Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect. β-adrenergic blocking agents may block endogenous catecholamine-stimulated increases in cyclic adenosine monophosphate (AMP) concentrations within the ciliary processes and subsequent formation of aqueous humor. Timolol appears to cause little or no change in aqueous humor outflow facility.
Pharmacokinetics: Latanoprost: Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about 2 hours after topical administration.
Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost could be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration.
Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterase in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
Excretion: The elimination of the acid of latanoprost from human plasma was rapid (t_½ = 17 minutes) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively.
Timolol: The degree of systemic absorption of timolol after topical application to the eye has not been fully elucidated; however, some absorption can apparently occur, since adverse systemic effects have occurred following ophthalmic instillation of the drug. Following topical administration of timolol 0.5% solution twice daily to the eye in a limited number of individuals, mean peak plasma concentrations were 0.46 or 0.35 ng/mL following the morning or afternoon dose, respectively. Following topical application to the eye of 0.25 or 0.5% solution of the drug, reduction in IOP usually occurs within 15-30 minutes, reaches a maximum within 1-5 hours, and persists about 24 hours.
Toxicology: Preclinical safety data: Mutagenicity and carcinogenicity: Latanoprost was not mutagenic in microbial (Ames), mouse lymphoma, or in mouse micronucleus tests; however, chromosome aberrations were observed in vitro with human lymphocytes.
No evidence of carcinogenic potential was observed in mice or rats given latanoprost by oral gavage in dosage up to 170 mcg/kg daily (approximately 2800 times the recommended maximum human dose) for 20 or 24 months, respectively. In vitro and in vivo studies evaluating unscheduled DNA synthesis in rats receiving latanoprost were negative.

Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers, prostaglandin analogues, or other IOP-reducing agents and in whom combination therapy is appropriate.

Adults (including the elderly): One eye drop in the affected eye(s) once daily.
Pediatric population: Safety and effectiveness in children and adolescents has not been established.
Dosage adjustment in hepatic/renal impairment: Latanoprost has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.
Method of administration: 1. Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.
2. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.
3. When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.

No data are available in humans with regard to overdose with the product. If ocular over dosage occurs, flush eye(s) with water or normal saline.
Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac arrest. If such symptoms occur the treatment should be symptomatic and supportive. Studies have shown that timolol does not dialyse readily.
Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic side effects are known if latanoprost is overdosed. If accidentally ingested, effort to decrease further absorption may be appropriate (gastric lavage).

Latamolol is contraindicated in patients with: Hypersensitivity to latanoprost, timolol, benzalkonium chloride or any component of the formulation; Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease (COPD); Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure or cardiogenic shock.

Systemic effects: Like other topically applied ophthalmic agents, Latamolol is absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption see Dosage & Administration.
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.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Cardiac reactions, and rarely, death in association with cardiac failures have been reported following administration of timolol.
Vascular disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory disorders: Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. Latamolol should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
Hypoglycemia/diabetes: Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia. Furthermore, beta-blockers may also mask the signs of hyperthyroidism.
Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking agents: The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the 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 (see Interactions).
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 and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.
Choroidal detachment: Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Surgical anesthesia: Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.
Concomitant therapy: Timolol may interact with other drugs see Interactions.
The use of two local beta-blockers or two local prostaglandins is not recommended.
Ocular effects: Latanoprost may gradually change eye colour by increasing the amount of brown pigment in the iris. This effect has predominantly been seen in patients with mixed coloured irides, i.e. green-brown, yellow-brown or blue/grey-brown, and is due to increased melanin content in the stromal melanocytes of the iris. The change in iris colour occurs slowly and may not be noticeable for several months to years and it has not been associated with any symptom or pathological changes. No further increase in brown iris pigment has been observed after discontinuation of treatment, but the resultant colour change may be permanent. Neither naevi nor freckles of the iris have been affected by the treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed but patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation ensues.
Before treatment is instituted patients should be informed of the possibility of a change in eye colour. Unilateral treatment can result in permanent heterochromia.
There is no documented experience with latanoprost in inflammatory, neovascular, or chronic angle closure glaucoma, in open angle glaucoma of pseudophakic patients and in pigmentary glaucoma.
Latanoprost has no or little effect on the pupil but there is no documented experience in acute attacks of closed angle glaucoma. Therefore it is recommended that the product should be used with caution in these conditions until more experience is obtained.
Latanoprost should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.
Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema. The product should be used with caution in these patients.
Use of contact lenses: Latamolol contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic product, may cause eye irritation and is known to discolour soft contact lenses. Close monitoring is required with frequent or prolonged use of the product in dry eye patients, or in conditions where the cornea is compromised. Contact lenses may absorb benzalkonium chloride and these should be removed before applying Latamolol but may be reinserted after 15 minutes (see Dosage & Administration).
Effects on ability to drive and use machine: Instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machine.
Use in Children: Safety and efficacy in children have not been established.
Use in the Elderly: Latanoprost: No overall differences in safety or efficacy have been observed between geriatric and younger patients. Results from phase III clinical studies indicate that age does not appear to affect IOP response to latanoprost.
Timolol: Safety and efficacy were similar in patients 65 years of age or older compared with younger patients, however, the possibility that some older patients may exhibit increased sensitivity to the preparation cannot be ruled out.

Pregnancy: Pregnancy category C.
Reproduction studies of latanoprost have been performed in rats and rabbits an incidence of 4 of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum human dose.
There are no adequate data from the use of latanoprost in pregnant women. 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 (see Dosage & Administration).
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 the product is administered until delivery, the neonate should be carefully monitored during the first days of life. Consequently, the product should not be used during pregnancy (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Breast-feeding: Latanoprost 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, see Dosage & Administration.
Latanoprost and its metabolites may pass into breast milk. The product should therefore not be used in women who are breast-feeding.
Fertility: Neither Latanoprost nor timolol have been found to have any effect on male or female fertility in animal studies.

Nervous system disorders: Uncommon: Headache.
Eye disorders: Very common: Increased iris pigmentation.
Common: Eye irritation (including stinging, burning and itching), eye pain.
Uncommon: Eye hyperaemia, conjunctivitis, vision blurred, lacrimation increased, blepharitis, corneal disorders.
Skin and subcutaneous tissue disorders: Uncommon: Skin rash, pruritus.
Additional adverse events have been reported specific to the use of the individual components of Latamolol in either clinical studies, spontaneous reports or in the available literature.
For latanoprost, these are: Infections and infestations: Herpetic keratitis.
Nervous system disorders: Dizziness.
Eye disorders: Eyelash and vellus hair changes (increased length, thickness, pigmentation, and number), punctate epithelial erosions, periorbital oedema, iritis/uveitis, macular oedema (in aphakic, pseudophakic patients with torn posterior lens capsules or in patients with known risk factors for macular oedema), dry eye, keratitis, corneal oedema and erosions, misdirected eyelashes sometimes resulting in eye irritation, iris cyst, photophobia, periorbital and lid changes resulting in deepening of the eyelid sulcus.
Cardiac disorders: Aggravation of angina in patients with pre-existing disease, palpitations.
Respiratory, thoracic and mediastinal disorders: Asthma, asthma aggravation, dyspnoea.
Skin and subcutaneous tissue disorders: Darkening of palpebral skin.
Musculoskeletal and connective tissue disorders: Joint pain, muscle pain.
General disorders and administration site conditions: Chest pain.
For timolol, these are: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritus, anaphylactic reaction.
Metabolism and nutrition disorders: Hypoglycaemia.
Psychiatric disorders: Insomnia, depression, nightmares, memory loss.
Nervous system disorders: Syncope, cerebrovascular accident, cerebral ischaemia, increase in signs and symptoms of myasthenia gravis, dizziness, paresthesia, and headache.
Eye disorders: Signs and symptoms of ocular irritation (e.g., burning, stinging, itching, tearing and redness), blepharitis, keratitis, blurred vision and choroidal detachment following filtration surgery (see Precautions), decreased corneal sensitivity, dry eyes, corneal erosion, ptosis, diplopia.
Ear and labyrinth disorders: Tinnitus.
Cardiac disorders: Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest.
Vascular disorders: Hypotension, Raynaud's phenomenon, cold hands and feet.
Respiratory, thoracic and mediastinal disorders: Bronchospasm (predominately in patients with pre-existing bronchospastic disease), dyspnoea, cough.
Gastrointestinal disorders: Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.
Skin and subcutaneous tissue disorders: Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash.
Musculoskeletal and connective tissue disorders: Myalgia.
Reproductive system and breast disorders: Sexual dysfunction, decreased libido.
General disorders and administration site conditions: Asthenia/fatigue.
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

Latanoprost: Thimerosal: In vitro studies indicate that precipitation occurs when ophthalmic products containing thimerosal are admixed with latanoprost ophthalmic solution. If latanoprost ophthalmic solution is administered to a patient who is receiving an ophthalmic product that contains thimerosal, an interval of at least 5 minutes should elapse between administration of latanoprost ophthalmic solution and the other ophthalmic product.
Timolol: Systemic β-adrenergic blocking agents: The possibility of an additive effect on IOP and/or systemic β-adrenergic blockade should be considered in patients who are receiving a systemic β-adrenergic blocking agent and topical timolol concomitantly.
Catecholamine-depleting drugs: When topical timolol is administered concomitantly with a catecholamine-depleting drug (e.g. reserpine), the patient should be observed closely for possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, and/or postural hypotension.
Other cardiovascular drugs: Concomitant administration of β-adrenergic blocking agent and a calcium-channel blocking agent and a cardiac glycoside may have additive effects on prolonging AV conduction. Because AV conduction disturbances, left ventricular failure, and/or hypotension may occur, caution should be exercised if timolol and a calcium-channel blocking agent are used concomitantly, and such concomitant use should be avoided in patients with impaired cardiac function. Severe bradycardia (e.g., 36 bpm), which was associated with a wandering pacemaker in one patient, and transient asystole have been reported when ophthalmic timolol and oral verapamil were used concomitantly. A single IV dose of atropine was effective in managing serious bradycardia in at least one patient. Verapamil should be used with extreme caution in patients receiving ophthalmic timolol; when therapy with a calcium-channel blocking agent is indicated (e.g. for angina) in such patients, an agent with minimal effects on SA node and cardiac conduction (e.g. nifedipine) should be used if possible.
Sinus bradycardia, which reported upon rechallenge, has been reported when ophthalmic timolol and oral quinidine were used concomitantly. This interaction has been attributed to inhibition of timolol metabolism (via the cytochrome P-450 [CYP] 2D6 isoenzyme) by quinidine. Although oral β-adrenergic blocking agents may exacerbate rebound hypertension that may occur following discontinuance of clonidine, such an effect has not been reported in patients receiving ophthalmic timolol.

Incompatibilities: No information.

Store at 2-8°C in refrigerator.

Antiglaucoma Preparations

S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.

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