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Mechanism of Action
COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma, by reducing aqueous humor secretion. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage.
Dorzolamide hydrochloride is an inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. The combined effect of these two agents administered as COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) b.i.d. results in additional intraocular pressure reduction compared to either component administered alone, but the reduction is not as much as when dorzolamide t.i.d. and timolol b.i.d. are administered concomitantly (see Clinical Studies).
When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in RBCs and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of binding to CA-II. The parent drug forms a single N-desethyl metabolite, which inhibits CA-II less potently than the parent drug but also inhibits CA-I. The metabolite also accumulates in RBCs where it binds primarily to CA-I. Plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15nM). Dorzolamide binds moderately to plasma proteins (approximately 33%).
Dorzolamide is primarily excreted unchanged in the urine; the metabolite also is excreted in urine. After dosing is stopped, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.
To simulate the systemic exposure after long-term topical ocular administration, dorzolamide was given orally to eight healthy subjects for up to 20 weeks. The oral dose of 2 mg b.i.d. closely approximates the amount of drug delivered by topical ocular administration of dorzolamide 2% t.i.d. Steady state was reached within 8 weeks. The inhibition of CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for a pharmacological effect on renal function and respiration in healthy individuals.
In a study of plasma drug concentrations in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/mL.
Clinical studies of 3 to 15 months duration were conducted to compare the IOP-lowering effect over the course of the day of COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol (b.i.d.) and 2.0% dorzolamide (b.i.d. and t.i.d.). The IOP-lowering effect of COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) b.i.d. was greater (1-3 mmHg) than that of monotherapy with either 2.0% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) b.i.d. was approximately 1 mmHg less than that of concomitant therapy with 2.0% dorzolamide t.i.d. and 0.5% timolol b.i.d.
Open-label extensions of two studies were conducted for up to 12 months. During this period, the IOP-lowering effect of COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) b.i.d. was consistent during the 12 month follow-up period.
Last reviewed on RxList: 7/20/2010
This monograph has been modified to include the generic and brand name in many instances.
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