Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution Sterile Ophthalmic Solution

DORZOLAMIDE HYDROCHLORIDE-TIMOLOL MALEATE OPHTHALMIC SOLUTION STERILE OPHTHALMIC SOLUTION- dorzolamide hydrochloride and timolol maleate solution
ALVOGEN INC.

47781-136-34-label47781-136-34-cartonstructure-1structure-2figure-1figure-2figure-3

DESCRIPTION

Dorzolamide hydrochloride – timolol maleate (dorzolamide hydrochloride-timolol maleate ophthalmic solution) is the combination of a topical carbonic anhydrase inhibitor and a topical beta- adrenergic receptor blocking agent.

Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6- methyl-4H-thieno[2,3-b]thiopyran]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is:

[a] 25°C (C=1, water) = ~ -17°
.405 nm

Its empirical formula is C10H16N2O4S3•HCl and its structural formula is:

structure-1

Dorzolamide hydrochloride has a molecular weight of 360.91. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.

Timolol maleate is described chemically as: (-)-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:

[a] 25°C in 1N HCl (C = 5) = -12.2° (-11.7° to -12.5°) .405 nm

Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:

structure-2
(click image for full-size original)

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 maleate is stable at room temperature.

Dorzolamide hydrochloride – timolol maleate is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution. The pH of the solution is approximately 5.65, and the osmolarity is 242-323 mOsM. Each mL of dorzolamide hydrochloride – timolol maleate contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (6.83 mg timolol maleate). Inactive ingredients are sodium citrate, hydroxyethyl cellulose, sodium hydroxide, mannitol, and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.

CLINICAL PHARMACOLOGY

Mechanism of Action
Dorzolamide hydrochloride – timolol maleate 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 dorzolamide hydrochloride – timolol maleate 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).

Pharmacokinetics/Pharmacodynamics

Dorzolamide Hydrochloride
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.

Timolol Maleate
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
Clinical studies of 3 to 15 months duration were conducted to compare the IOP-lowering effect over the course of the day of dorzolamide hydrochloride – timolol maleate 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 dorzolamide hydrochloride – timolol maleate 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 dorzolamide hydrochloride – timolol maleate 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 dorzolamide hydrochloride – timolol maleate b.i.d. was consistent during the 12 month follow-up period.

INDICATIONS AND USAGE

Dorzolamide hydrochloride – timolol maleate is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers (failed to achieve target IOP determined after multiple measurements over time). The IOP-lowering of dorzolamide hydrochloride – timolol maleate b.i.d. was slightly less than that seen with the concomitant administration of 0.5% timolol b.i.d. and 2.0% dorzolamide t.i.d. (see CLINICAL PHARMACOLOGY, Clinical Studies).

CONTRAINDICATIONS

Dorzolamide hydrochloride – timolol maleate is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

WARNINGS

Systemic Exposure
Dorzolamide hydrochloride – timolol maleate contains dorzolamide, a sulfonamide, and timolol maleate, a beta-adrenergic blocking agent; and although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides and/or systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate (see CONTRAINDICATIONS). Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.

In Patients Without a History of Cardiac Failure continued depression of the myocardium with betablocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, dorzolamide hydrochloride – timolol maleate should be discontinued.

Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which dorzolamide hydrochloride – timolol maleate is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta blockingagents, including dorzolamide hydrochloride – timolol maleate.

Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta adrenergicallymediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

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