Each mL of eye drop solution contains: Latanoprost 50 mcg and Timolol maleate 6.83 mg equivalent to timolol 5 mg.
Excipients/Inactive Ingredients: Benzalkonium chloride, Sodium chloride, Sodium dihydrogen phosphate monohydrate, Disodium phosphate anhydrous, Sodium hydroxide solution, Hydrochloric acid solution and water for injection.
Pharmacology: Pharmacodynamics: Latanoprost: 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: 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 (t1/2 = 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: Latanoprost: 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.
1 drop into affected eye(s) once daily.
Method of Administration: Remove contact lenses prior to administration; wait 15 minutes before reinserting if using products containing benzalkonium chloride. Separate administration of other ophthalmic agents by 5 minutes.
If ocular overdosage occurs, flush eye(s) with water or normal saline.
Hypersensitivity to latanoprost, timolol, benzalkonium chloride, or any component of the formulation; reactive airway disease including severe chronic obstructive pulmonary disease (COPD) and presence or history of bronchial asthma; sinus bradycardia, second-/third-degree atrioventricular block, overt cardiac failure or cardiogenic shock.
Latanoprost: Ocular pigment changes: Latanoprost has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris and periorbital tissue (eyelid) and increased pigmentation and growth of eyelashes. These changes may be permanent. Pigmentation is expected to increase as long as latanoprost is administered. After discontinuation of latanoprost, pigmentation of the iris is likely to be permanent while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The effects of increased pigmentation beyond 5 years are not known.
Latanoprost sterile ophthalmic solution may gradually change eye color, increasing the amount of brown pigment in the iris by increasing the number of melanosomes (pigment granules) in melanocytes. The long-term effects on the melanocytes and the consequences of potential injury to the melanocytes or deposition of pigment granules to other areas of the eye are currently unknown. The change in iris color occurs slowly and may not be noticeable for several months to years. Patients should be informed of the possibility of iris color change.
Eyelid skin darkening has also been reported in association with the use of latanoprost.
Latanoprost may gradually change eyelashes and vellus hair; these changes include increased length, thickness, pigmentation, and number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation treatment.
Patients who are expected to receive treatment in only 1 eye should be informed about the potential for increased brown pigmentation of the iris, periorbital tissue, and eyelashes in the treated eye and thus, heterochromia between the eyes. They should also be advised of the potential for a disparity between the eyes in length, thickness, or number of eyelashes. These changes in pigmentation and lash growth may be permanent.
Other forms of glaucoma: There is limited experience with latanoprost in the treatment of angle closure, inflammatory or neovascular glaucoma.
Infections: There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These container has been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
Contact lenses: Contact lenses should be removed prior to the administration of latanoprost, and may be reinserted 15 minutes after administration.
Active intraocular inflammation (iris/uveitis): Latanoprost should be used with caution in patients with a history of intraocular inflammation (iris/uveitis) and should generally not be used in patients with active intraocular inflammation.
Macular edema, including cystoid macular edema: Macular edema, including cystoid macular edema, 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 edema. Latanoprost should be used with caution in patients who do not have an intact posterior capsule or who have known risk factors for macular edema.
Timolol: Systemic absorption: It may be absorbed systemically. The same adverse reactions found with systemic β-blockers may occur with topical use. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in asthmatics, and rarely, death associated with cardiac failure, have been reported with topical β-blockers.
Cardiovascular: Timolol may decrease resting and maximal exercise heart rate even in healthy subjects.
Non-allergic bronchospasm: Patients with a history of chronic bronchitis, emphysema, etc, should receive β-blockers with caution; they may block bronchodilation produced by catecholamine stimulation of β2-receptors.
Major surgery: Withdrawing β-blockers before major surgery is controversial. Beta-receptor blockade impairs the heart's ability to respond to β-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia. Some patients on β-blockers have had protracted severe hypotension during anesthesia. Difficulty restarting and maintaining heartbeat has been reported. In elective surgery, gradual withdrawal of β-blockers may be appropriate.
Diabetes mellitus: Administer with caution to patients subject to spontaneous hypoglycemia or to diabetic patients (especially labile diabetics). Beta-blocking agents may mask signs and symptoms of acute hypoglycemia.
Thyroid: Beta-adrenergic blocking agents may mask clinical signs of hyperthyroidism (eg. tachycardia). Manage patients suspected of developing thyrotoxicosis carefully to avoid abrupt withdrawal of β-blockers, which might precipitate thyroid storm.
Cerebrovascular insufficiency: Because of potential effects of β-blockers on blood pressure and pulse, use with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop, consider alternative therapy.
Angle-closure glaucoma: The immediate objective is to reopen the angle, requiring constriction of the pupil with a miotic. These agents have little or no effect on the pupil. When they are used to reduce elevated IOP in angle-closure glaucoma, use with miotic.
Muscle weakness: Beta-blockade may potentiate muscle weakness consistent with certain myasthenic symptoms (eg. diplopia, ptosis, generalized weakness). Timolol has increased muscle weakness in some patients with myasthenic symptoms or myasthenia gravis.
Long-term therapy: In long-term studies (2 and 3 years), no significant difference in mean IOP were observed after initial stabilization.
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 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.
Use in Pregnancy: Category C.
Latanoprost: Reproduction studies 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 and well-controlled studies in pregnant women. Latanoprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Timolol: There are no adequate and controlled studies to date using timolol ophthalmic solution in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Use in Lactation: Latanoprost: It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when latanoprost is administered to a nursing woman.
Timolol: Timolol is distributed into milk following oral or ophthalmic administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate epithelial keratopathy, dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain, lid edema, lid erythema, and photophobia.
Bradycardia; arrhythmia; hypotension; syncope; heart block; cerebral vascular accident; cerebral ischemia; heart failure; palpitation; cardiac arrest, dizziness; depression; fatigue; lethargy; hallucinations; confusion, ocular irritation including conjunctivitis; blepharitis; keratitis; blepharoptosis; decreased corneal sensitivity; visual disturbances including refractive changes; diplopia; ptosis. Bronchospasm (mainly in patients with preexisting bronchospastic disease); respiratory failure; dyspnea, aggravation of myasthenia gravis; alopecia; nausea; localized and generalized rash; urticarial; impotence; decreased libido; masked symptoms of hypoglycemia in diabetics; diarrhea.
Thimerosal, β-adrenergic blocking agent, catecholamine-depleting drugs, calcium-channel blocking agent (e.g. verapamil), quinidine.
Incompatibilities: No information.
Store below 2-8°C in refrigerator.
S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.