Timoptic-XE (Timolol Maleate Ophthalmic) - Description and Clinical Pharmacology

DESCRIPTION

TIMOPTIC‑XE [Registered trademark of MERCK & CO., Inc.
COPYRIGHT© 1993, 2003 MERCK & CO., Inc.
All rights reserved] (timolol maleate ophthalmic gel forming solution) is a non-selective beta-adrenergic receptor blocking agent. 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 as the levo-isomer. The optical rotation of timolol maleate is:

           25°
[α]                      in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°).
          405 nm

Its molecular formula is C₁₃H₂₄N₄O₃S•C₄H₄O₄and 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.

TIMOPTIC‑XE Sterile Ophthalmic Gel Forming Solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths. The pH of the solution is approximately 7.0, and the osmolarity is 260-330 mOsm. Each mL of TIMOPTIC‑XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of TIMOPTIC‑XE 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: GELRITE gellan gum, tromethamine, mannitol, and water for injection. Preservative: benzododecinium bromide 0.012%.

GELRITE is a purified anionic heteropolysaccharide derived from gellan gum. An aqueous solution of GELRITE, in the presence of a cation, has the ability to gel. Upon contact with the precorneal tear film, TIMOPTIC‑XE forms a gel that is subsequently removed by the flow of tears.

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

TIMOPTIC‑XE, when applied topically on 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 TIMOPTIC‑XE is not clearly established at this time. Tonography and fluorophotometry studies of TIMOPTIC [Registered trademark of MERCK & CO., Inc.
COPYRIGHT© 1993, 2003 MERCK & CO., Inc.
All rights reserved] (timolol maleate ophthalmic solution) 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 blockade 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 activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

Pharmacokinetics

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following once daily administration of TIMOPTIC‑XE 0.5% in the morning. The mean peak plasma concentration following this morning dose was 0.28 ng/mL.

Clinical Studies

In controlled, double-masked, multicenter clinical studies, comparing TIMOPTIC‑XE 0.25% to TIMOPTIC 0.25% and TIMOPTIC‑XE 0.5% to TIMOPTIC 0.5%, TIMOPTIC‑XE administered once a day was shown to be equally effective in lowering intraocular pressure as the equivalent concentration of TIMOPTIC administered twice a day. The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of TIMOPTIC‑XE. Repeated observations over a period of six months indicate that the intraocular pressure-lowering effect of TIMOPTIC‑XE was consistent. The results from the largest U.S. and international clinical trials comparing TIMOPTIC‑XE 0.5% to TIMOPTIC 0.5% are shown in Figure 1.

Figure 1: Mean IOP and Std Deviation (mm Hg) by Treatment Group

TIMOPTIC‑XE 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, there was a higher incidence of transient blurred vision in patients administered TIMOPTIC‑XE. A slight reduction in resting heart rate was observed in some patients receiving TIMOPTIC‑XE 0.5% (mean reduction 24 hours post-dose 0.8 beats/minute, mean reduction 2 hours post-dose 3.8 beats/minute). (See ADVERSE REACTIONS.)

TIMOPTIC‑XE has not been studied in patients wearing contact lenses.