Timolol GFS (timolol maleate ophthalmic gel forming solution) is a non-selective beta-adrenergic receptor inhibitor. Its chemical name is (-)-1-(tert -butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided at the levo-isomer. The nominal optical rotation of timolol maleate is: [α] 25º in 0.1N HCl (C=5%) = -12.2º
Its molecular formula is C13H24N4O3S·C4H404 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol GFS is a colorless to nearly colorless, slightly opalescent, and slightly viscous, is supplied as a sterile, isotonic, buffered, aqueous topical ophthalmic solution of timolol maleate in two dosage strengths. Timolol GFS has a pH of approximately 6.9 and an osmolality of approximately 290 mOsmol/kg. Each mL of Timolol GFS 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of Timolol GFS 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: xanthan gum, tromethamine, boric acid, mannitol, polysorbate-80, and purified water. Preservative: benzododecinium bromide 0.012%.
Xanthan gum is a purified high molecular weight polysaccharide gum produced from the fermentation by bacterium Xanthomonas campestris. An aqueous solution of xanthan gum, in the presence of tear protein (lysozyme), forms a gel. Upon contact with the precorneal tear film, Timolol GFS forms a gel that is subsequently removed by the flow of tears.
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. Timolol GFS, when applied topically to the eye, has the action of reducing elevated, as well as normal, intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss and optic nerve damage. The precise mechanism of the ocular hypotensive action of Timolol GFS is not clearly established at this time. Tonography and fluorophotometry studies of Timolol GFS in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies, a slight increase in outflow facility was also observed. Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function beta-adrenergic receptor inhibitors may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function. Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activities. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.
Because in some patients the intraocular pressure-lowering response to Timolol GFS may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Timolol GFS. If the patient’s intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered.
Following topical ocular administration of timolol to humans, low concentrations of drug are found in plasma. After bilateral administration of a 0.5% timolol maleate solution to healthy volunteers, maximum plasma concentrations were generally below 5 ng/mL. Dosages higher than one drop of 0.5% Timolol GFS once daily have not been studied.
Pharmacokinetic studies in humans using this gel forming solution formulation were not performed. However, systemic uptake from a gel matrix is expected to be slower than from a non-gel forming solution based on studies using other gel forming solutions. The maximum plasma timolol concentration from the gel forming drop is not expected to exceed those of the 0.5% timolol maleate solution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose. In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps, and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which postmortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin, which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at oral doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests, the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose-response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.
In controlled, double-masked, multicenter clinical studies, Timolol GFS administered once daily was compared to equivalent concentrations of TIMOPTIC* (timolol maleate ophthalmic solution) [Merck and Co., Inc.] administered twice daily. Timolol GFS once daily was shown to be equally effective in lowering intraocular pressure as the equivalent concentration of TIMOPTIC administered twice daily.
The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of Timolol GFS. Repeated observations over a three-month study period indicate that the intraocular pressure-lowering effect of Timolol GFS was consistent. The results from the clinical trials are shown in the following figures.
Timolol GFS administered once daily had a safety profile similar to that of an equivalent concentration of TIMOPTIC administered twice daily. Due to the physical characteristics of the formulation, transient blurred vision was reported more frequently in patients administered Timolol GFS [see Adverse Reactions (6) ]. Timolol GFS has not been studied in patients wearing contact lenses.