Travoprost/Timolol

Uses

This Sterile Ophthalmic Solution is used for the treatment of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to single therapy with prostaglandin analogue or topical beta blocker.

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

How Travoprost/Timolol works

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.

Travoprost, a prostaglandin F2α analogue, is a highly selective full agonist which has a high affinity for the prostaglandin FP receptor, and facilitates reductions in intraocular pressure by increasing the outflow of aqueous humour via trabecular meshwork and uveoscleral pathways . Reduction of the intraocular pressure in man starts about 2 hours after administration and maximum effect is reached after 12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding 24 hours with a single dose .

Dosage

Travoprost/Timolol dosage

Instill one drop in the conjunctival sac of the affected eye(s) once daily at about the same time each day, preferably in the evening.

Side Effects

No serious adverse reactions are reported. Most frequently reported side effects are ocular hyperemia.

Toxicity

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.

No cases of overdose have been reported for travoprost . A topical overdose is not likely to occur or to be associated with toxicity . A topical overdose of travoprost may be flushed from the eye(s) with lukewarm water . Treatment of a suspected oral ingestion is symptomatic and supportive .

Travoprost has harmful pharmacological effects on pregnancy and/or the fetus/new-born child. Travoprost should not be used during pregnancy unless clearly necessary . The medication subsequently must not be used in women of childbearing age/potential unless adequate contraceptive measures are in place .

It is unknown whether travoprost from the eye drops is excreted in human breast milk. Animal studies have shown excretion of travoprost and metabolites in breast milk . The use of travoprost by breast-feeding mothers is not recommended .

There are no data on the effects of TRAVATAN on human fertility . Animal studies showed no effect of travoprost on fertility at doses more than 250 times the maximum recommended human ocular dose .

Use in patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use .

No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients .

Travoprost has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 ml/min) [L514. No dosage adjustment is necessary for these patients .

Precaution

For ophthalmic use only. Patients should remove their contact lenses prior to instilling this preparation and should not insert their lenses until 15 minutes after instillation of the preparation.

Interaction

Although Timolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timolol Maleate and epinephrine has been reported occasionally. Drug interactions of Timolol Maleate have been noticed with concomitant administration of beta-adrenergic blocking agents (both oral and topical), calcium antagonists, catecholamine-depleting drugs, digitalis, quinidin, clonidine, injectable epinephrine.

Reduced therapeutic effect with NSAIDs.

Volume of Distribution

1.3 - 1.7 L/kg

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

Given the data currently available, it has been recorded that travoprost free acid is moderately distributed into body tissues with a volume of distribution of 2.6 L/kg in rats .

Elimination Route

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.

Travoprost is systemically absorbed through the cornea . In humans, peak plasma concentrations of travoprost free acid were low (25 pg/mL or less) and occurred within 30 minutes following topical ocular administration of one drop of 0.004% travoprost ophthalmic solution .

Half Life

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

The terminal elimination half-life of travoprost free acid is determined to be approximately 45 minutes, although studies demonstrated half-life values that ranged from 17 to 86 minutes .

Clearance

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.

Data regarding the clearance of travoprost is not readily available or accessible.

Elimination Route

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

Less than 2% of the topical ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free acid . Moreover, elimination from plasma is rapid, resulting in concentrations below the limit of quantitation (< 10 pg/mL) by one hour .

Furthermore, in rats, 95% of a subcutaneous radiolabeled dose was eliminated within 24 hours . The major route of elimination was via the bile (61%) with the remainder excreted by the kidneys .

Pregnancy & Breastfeeding use

Use in pregnancy: There are no adequate and well-controlled studies in pregnant women. It should not be used during pregnancy.

Use in lactation: Caution should be exercised when Travoprost/Timolol Maleate is administered to a nursing mother.

Contraindication

Contraindicated in patients who are hypersensitive to Travoprost, Timolol or any of the components of Travoprost/Timolol Maleate.

Special Warning

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

Use in elderly patients: No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Acute Overdose

There have been reports of inadvertent overdosage with Timolol Ophthalmic Solution 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.

Storage Condition

Store in a cool, dry place, away from heat and direct light. Keep out of the reach of children. Do not use more than 4 weeks after opening the bottle

Innovators Monograph

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