TIMOLOL GFS- timolol maleate solution, gel forming, extended release
Sandoz Inc
1 INDICATIONS AND USAGE
Timolol GFS 0.25% and 0.5% are indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
2 DOSAGE AND ADMINISTRATION
Instill one drop of Timolol GFS (either 0.25% or 0.5%) in the affected eye(s) once daily. It may be used alone or in combination with other intraocular pressure lowering medications.
3 DOSAGE FORMS AND STRENGTHS
5 mL size bottle filled with 2.5 mL or 5 mL of 0.25% or 0.5% sterile ophthalmic gel forming solution
4 CONTRAINDICATIONS
Timolol GFS is contraindicated in patients with:
� bronchial asthma
� history of bronchial asthma
� severe chronic obstructive pulmonary disease
� sinus bradycardia
� second or third degree atrioventricular block
� overt cardiac failure
� cardiogenic shock
� hypersensitivity to any component of this product.
DESCRIPTION
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-thia diazol-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:
[?] 25� in 0.1N HCl (C=5%) = -12.2�
405 nm
Its molecular formula is C13 H24 N4 O3 S�C4 H4 O4
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.
12 CLINICAL PHARMACOLOGY
12.1 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.
Pharmacodynamics
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.
