Latanomol(+Timolol)

Uses

This preparation is used for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufftciently responsive to β-blockers, prostaglandins or other IOP lowering agents.

This medicine contains two active ingredients, Latanoprost and Timolol Maleate. Latanoprost is a prostaglandin analogue. It works by increasing the drainage of aqueous humour out of the eyeball. This decreases the pressure within the eye. Timolol is a beta-blocker. This medicine block beta-receptors in various parts of the body. Blocking the beta receptors in the eye reduces the amount of aqueous humour that is produced. Timolol therefore reduces the inflow of aqueous humour into the eyeball and so decreases the pressure within the eyeball.

Latanomol(+Timolol) is also used to associated treatment for these conditions: Increased Intra Ocular Pressure (IOP), Ocular Hypertension, Open Angle Glaucoma (OAG)Increased Intra Ocular Pressure (IOP), Migraine, Ocular Hypertension, Open Angle Glaucoma (OAG)

How Latanomol(+Timolol) works

Elevated intraocular pressure leads to an increased risk of glaucomatous visual field loss. The higher the intraocular pressure, the higher the risk of damage to the optic nerve and loss of visual field. Latanoprost selectively stimulates the prostaglandin F2 alpha receptor and this results in a decreased intraocular pressure (IOP) via the increased outflow of aqueous humor, which is often implicated in cases of elevated intraocular pressure. Possible specific mechanisms of the abovementioned increased aqueous outflow are the remodeling of the extracellular matrix and regulation of matrix metalloproteinases. These actions result in higher tissue permeability related to humor outflow pathways, which likely change outflow resistance and/or outflow rates.

Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure.

The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis.

Dosage

Latanomol(+Timolol) dosage

Adult or elderly: The recommended adult (including the elderly) dosage of is one drop in the affected eye(s) once daily. If one dose is missed, treatment should continue with the next dose as normal.

Children: Safety and effectiveness in children has not been established. This is therefore is not recommended for use in children.

Side Effects

This combination is generally well tolerated. The most frequent findings of increased iris pigmentation were in patients with green-brown, yellow-brown and blue/grey/brown irides. In patients with homogeneously blue, grey, green or brown eyes, the change was only rarely seen. Darkening, thickening and lengthening of the eye lashes have been reported. The most frequently reported undesirable effects in clinical trials were irritation of the eye, including stinging, burning and ,itching, eye hyperaemia, corneal disorders, coniunctivitis blepharitis, eye pain, headache and skin rash.

Toxicity

The oral LD50 in the rat is > 50 mg/kg.

An overdose of latanoprost is not expected to result in dangerous patient outcomes, however, conjunctival or episcleral hyperemia may occur.An intravenous infusion of 3 μg/kg of latanoprost in healthy volunteers led to mean plasma concentrations of 200 times higher than a normally administered therapeutic dose and no adverse effects were noted. One study suggested that an overdose of latanoprost lead to cystoid macular edema after a large, unintended overdose. This resolved within 4 weeks after 4 weeks following treatment with nepafenac 0.3% eye drops in addition to oral acetazolamide. Contact the local poison control center for updated guidance on the management of a latanoprost overdose.

The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse.

Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment.

Precaution

This preparation should be used with caution in patients with macular edema, aphakic patients, pseudophakic parients with a torn posterior lens capsule or in patients with known risk factors for macular edema.It should be administered with caution in patients subjected to spontaneous hypoglycaemia or to diabetic patients who are receiving insulin or oral hypoglycaemic agents.Caution should also be exercised to patients wearing contact lenses or drive and use machines.

Interaction

No specific interaction studies have been performed with this preparation. Patients who are receiving treatment with this preparation and an oral β-adrenergic blocking agent should be observed for potential additive effects of β-blockade, both systemic and on lntraocular pressure The concomitant use of two topical β-adrenergic blocking agents is not recommended. Although this preparation alone has little or no effect on pupil size, mydriasis has occasionally been reported when Timolol is given with epinephrine. β-blockers may increase the hypoglycemic effect of antidiabetic agents. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with Benzalkonium chloride, the preservative used in this preparatlon. If such drugs are used they should be administered with an interval of at least 5 minutes between applications. Similarly, several contact lens soakinq solutions contain thimerosal.

Volume of Distribution

The volume of distribution of latanoprost is 0.16 ± 0.02 L/kg. The activated acid form of latanoprost can be measured in aqueous humor in the initial 4 hours post-administration, and it is measured in the plasma only for 1 hour following ophthalmic administration. This drug is more lipophilic than its parent prostaglandin and easily penetrates the cornea. It has been shown to cross the placenta in rats.

1.3 - 1.7 L/kg

Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung.

Elimination Route

This drug is rapidly absorbed in the cornea as an isopropyl ester prodrug and is then activated by the process of hydrolysis. A small amount of this drug is systemically absorbed. The Cmax of latanoprost in the systemic circulation is reached after 5 minutes and is measured to be 53 pg/mL. The Cmax in the aqueous humor is attained within 2 hours after administration. and has been estimated to be 15-30 ng/mL.

The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5% , indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers.

The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration.

Half Life

The elimination half-life of latanoprost from the plasma is about 17 minutes. The elimination half-life of latanoprost from the eye is estimated at 2–3 hours.

Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers.

Clearance

The systemic clearance of latanoprost is 7 mL/min/kg.

One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers.

Elimination Route

After hepatic beta-oxidation, the metabolites of latanoprost are primarily found to be excreted by the kidneys. About 88% of the latanoprost dose is recovered in the urine after topical administration. About 15% of a dose is reported to be excreted in the feces.

Timolol and its metabolites are mainly found excreted in the urine.

Pregnancy & Breastfeeding use

No reproduction toxicity studies have been conducted with this combination.This combination should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Latanoprost and its metabolites may pass into breast milk. Timolol maleate has been detected in human milk following ocular administration. Because of the potential serious adverse reactions in nursing infants, Latanomol(+Timolol) should be used with caution in nursing women.

Contraindication

This combination is contraindicated in patients with Known hypersensitivity to Latanoprost, Timolol and benzalkonium chloride or any other ingredient in the product. This combination is also contraindicated for the following conditions such as reactive airway disease including bronchial asthma, history of bronchial asthma or severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, or cardiogenic shock.

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Acute Overdose

There is no human data available on over dosage with this preparation.Symptoms of systemic Timolol over dosage are bradycardia, hypotenslon, bronchospasm, and cardiac arrest. If such symptoms occur,treatment should be symptomatic and supportive. The ocular effects of Latanoprost administered at high doses are not known. If overdose with this preparation occurs, treatment should be symptomatic.

Storage Condition

Store at 2-8° C. For opened bottles, may store below 25° C.

Innovators Monograph

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