Merck introduces Trusopt in the U.S.

WEST POINT, Pa.--(BUSINESS WIRE)--June 9, 1995--Merck & Co. Inc. Friday announced that Trusopt(R) (dorzolamide hydrochloride ophthalmic solution), the first carbonic anhydrase inhibitor (CAI) made in a topical, or eyedrop, formulation, is now available by prescription.

Trusopt is a new eyedrop for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma and has been proven effective in the consistent lowering of intraocular pressure in most patients. Trusopt is contraindicated in patients who are hypersensitive to any component of this product.

While oral CAIs have long been used to reduce elevated eye pressure in glaucoma patients, these medications generally have had poor patient acceptance due to side effects and their use has been limited. Because Trusopt is applied as an eyedrop, it lowers intraocular pressure while avoiding many of the side effects often associated with oral CAI medications.

Trusopt is a long-awaited breakthrough in the treatment of elevated eye pressure which, in clinical trials, provided consistent lowering of elevated eye pressure throughout the day in studies of up to one year," said Michael Kass, M.D., professor of ophthalmology, Washington University School of Medicine, St. Louis.

"Research and development of topical CAIs has been ongoing for the past 40 years, and Trusopt is an excellent new alternative for treating glaucoma patients and others with elevated eye pressure."

Effective in Clinical Trials

Trusopt has been shown in clinical trials to reduce elevated eye pressure when used alone. In a six-week controlled clinical study of 295 patients with elevated eye pressure, 87 patients treated with Trusopt as monotherapy had average peak eye pressure reductions of 16 percent. In a 48-week double-masked study of 523 patients with elevated eye pressure, Trusopt demonstrated consistent lowering of elevated eye pressure throughout the study.

Additional studies have demonstrated that Trusopt provides additional lowering of elevated eye pressure when used in combination with other topical ophthalmic drugs prescribed for reducing intraocular pressure. Sometimes two or more drug therapies are needed at the same time in treating glaucoma and elevated eye pressure.

"The efficacy and systemic safety profile for Trusopt will provide more options for treating glaucoma patients and others with elevated intraocular pressure," according to Dr. Kass. "Alone, it's an effective alternative for most patients who can't take other types of medicines to lower their eye pressure. In addition, Trusopt can be a first choice for add-on therapy.

Tolerability

Trusopt has been evaluated in more than 1,400 people in controlled and uncontrolled clinical studies. Of these, 1,108 patients were treated in long-term studies of up to 12 months. Just 5 percent of these patients discontinued treatment due to side effects.

"The low discontinuation rate is encouraging because side effects often cause patients to stop using their medication as prescribed, Dr. Kass said. The minor, transient side effects associated with administering the medication were acceptable for most of the patients using Trusopt.

The most common side effects associated with the use of Trusopt in clinical studies were temporary burning, stinging or other discomfort in one third of patients immediately after applying the medication. Bitter taste was reported by one-quarter of the patients. In 10 to 15 percent of patients, superficial punctate keratitis (SPK) was observed.

This reversible, painless inflammation of the cornea may be related to preservatives used in most ophthalmic preparations. Indications of allergic reaction, primarily conjunctivitis, and lid reactions occurred in 10 percent of patients. Blurred vision, tearing, dryness of the eyes or light sensitivity occurred in 1 to 5 percent of patients. Most of these reactions were quickly reversible once treatment was stopped.

Because Trusopt is a sulfonamide and is absorbed systemically, the same types of adverse reactions that are attributable to oral CAIs and other sulfonamides may occur. Patients should be cautioned to be aware of any unusual or allergic reactions and to discontinue use and contact a doctor if they occur.

As evidence of its excellent systemic safety profile in clinical trials, no acid-base disturbances or electrolyte imbalances were reported in patients taking Trusopt. In addition, the use of Trusopt was associated with minimal or no effect on heart rate or blood pressure.

Trusopt should not be taken while patients are wearing soft contact lenses and is not recommended for those patients taking oral CAIs such as acetazolamide or dichlorphenamide.

Trusopt will be available in an easy-to-use 5 ml or 10 ml plastic ophthalmic dispenser with a controlled drop tip. The dosage is one drop three times daily in the affected eye(s).

Merck's catalog price to pharmacies will be $16.80 per 5 ml bottle. As with all eye medications, patients taking Trusopt should not allow the tip of the dispenser to come into contact with the eye and should handle the container carefully to avoid bacterial infection.

Glaucoma Takes Heavy Toll

According to the non-profit educational association Prevent Blindness America, glaucoma is a leading cause of irreversible blindness in the U.S., affecting between 2 and 3 million Americans. It is more common in older individuals, and those of African-American heritage are at greater risk. Glaucoma can cause progressive loss of vision and, if left untreated, can lead to permanent blindness.

Because glaucoma develops gradually and without symptoms, medical experts recommend annual eye examinations. Increased eye pressure is often present in patients who have open-angle glaucoma, the most common form of this disease. This increased eye pressure associated with glaucoma can often be controlled by medication.

Increased intraocular pressure is estimated to affect up to 10 million Americans, but many are unaware that they have it and don't receive appropriate medical attention. While increased eye pressure leads to glaucoma-like damage in about 1 to 3 percent of patients annually, it is unknown whether pressure-lowering therapy prevents or delays the subsequent onset of glaucoma.

Merck & Co. Inc. is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health. The Merck-Medco Managed Care Division manages pharmacy benefits for more than 40 million Americans, encouraging the appropriate use of medicines and providing disease management programs.

Through these complementary capabilities, Merck works to improve quality of life and lower overall healthcare costs. -0- Full prescribing information for Trusopt is attached.

TRUSOPT(R) (Dorzolamide Hydrochloride Ophthalmic Solution) Sterile Ophthalmic Solution 2%

DESCRIPTION

TRUSOPT(a) (Dorzolamide Hydrochloride Ophthalmic Solution) is a carbonic anhydrase inhibitor formulated for topical ophthalmic use.

Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6- methyl-4H-thieno(2,3-b)thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. Its empirical formula is C10H16N2O4S3 HCl.

Dorzolamide hydrochloride has a molecular weight of 360.9 and a melting point of about 275 degrees C. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.

TRUSOPT Sterile Ophthalmic Solution is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride. The pH of the solution is approximately 5.6. Each mL of TRUSOPT 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride). Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.

CLINICAL PHARMACOLOGY Mechanism of Action

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in other tissues. 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. The result is a reduction in intraocular pressure (IOP).

TRUSOPT Ophthalmic Solution contains dorzolamide hydrochloride, an inhibitor of human carbonic anhydrase II. Following topical ocular administration, TRUSOPT reduces elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

Pharmacokinetics/Pharmacodynamics

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 TRUSOPT 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.

Clinical Studies

The efficacy of TRUSOPT was demonstrated in clinical studies in the treatment of elevated intraocular pressure in patients with glaucoma or ocular hypertension (baseline IOP greater than or equal to 23 mmHg). The IOP-lowering effect of TRUSOPT was approximately 3 to 5 mmHg throughout the day and this was consistent in clinical studies of up to one year duration. The efficacy of TRUSOPT when dosed less frequently than three times a day (alone or in combination with other products) has not been established.

INDICATIONS AND USAGE

TRUSOPT Ophthalmic Solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

CONTRAINDICATIONS

TRUSOPT is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS

TRUSOPT is a sulfonamide and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration with TRUSOPT. 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.

PRECAUTIONS

General

Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. The effect of continued administration of TRUSOPT on the corneal endothelium has not been fully evaluated.

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. TRUSOPT has not been studied in patients with acute angle- closure glaucoma.

TRUSOPT has not been studied in patients with severe renal impairment (CrCl less than 30 mL/min). Because TRUSOPT and its metabolite are excreted predominantly by the kidney, TRUSOPT is not recommended in such patients.

TRUSOPT has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of TRUSOPT. Many of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, TRUSOPT should be discontinued and the patient evaluated before considering restarting the drug. (See ADVERSE REACTIONS.)

There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and TRUSOPT. The concomitant administration of TRUSOPT and oral carbonic anhydrase inhibitors is not recommended.

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

The preservative in TRUSOPT Ophthalmic Solution, benzalkonium chloride, may be absorbed by soft contact lenses. TRUSOPT should not be administered while wearing soft contact lenses.

Information for Patients

TRUSOPT is a sulfonamide and although administered topically is absorbed systemically. Therefore the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration. Patients should be advised that if serious or unusual reactions or signs of hypersensitivity occur, they should discontinue the use of the product (see WARNINGS).

Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physician's advice.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients also should be advised that if they develop an intercurrent ocular condition (e.g., trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.

Drug Interactions

Although acid-base and electrolyte disturbances were not reported in the clinical trials with TRUSOPT, these disturbances have been reported with oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving TRUSOPT. Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose). Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose. No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day -900 times the recommended human ophthalmic dose).

The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class-effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts.

No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (-5 times the recommended human ophthalmic dose) for one year.

The following tests for mutagenic potential were negative: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.

In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at doses up to 188 or 94 times, respectively, the recommended human ophthalmic dose.

Pregnancy

Teratogenic Effects. Pregnancy Category C. Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of greater than or equal to 2.5 mg/kg/day (31 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights. No treatment-related malformations were seen at 1.0 mg/kg/day (13 times the recommended human ophthalmic dose). There were no treatment-related fetal malformations in developmental toxicity studies with dorzolamide hydrochloride in rats at oral doses up to 10 mg/kg/day (125 times the recommended human ophthalmic dose). There are no adequate and well-controlled studies in pregnant women. TRUSOPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain of 5 to 7% in offspring at an oral dose of 7.5 mg/kg/day (94 times the recommended human ophthalmic dose) were seen during lactation. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings), secondary to lower fetal body weight, was noted.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TRUSOPT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Of the total number of patients in clinical studies of TRUSOPT, 44% were 65 years of age and over, while 10% were 75 years of age and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals to the product cannot be ruled out.

ADVERSE REACTIONS

In clinical studies, the most frequent adverse events associated with TRUSOPT were ocular burning, stinging, or discomfort immediately following ocular administration (approximately one-third of patients). Approximately one-quarter of patients noted a bitter taste following administration. Superficial punctate keratitis occurred in 10-15% of patients and signs and symptoms of ocular allergic reaction in approximately 10%. Events occurring in approximately 1-5% of patients were blurred vision, tearing, dryness, and photophobia. Other ocular events and systemic events were reported infrequently, including headache, nausea, asthenia/fatigue; and, rarely, skin rashes, urolithiasis, and iridocyclitis.

OVERDOSAGE

Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible central nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

Significant lethality was observed in female rats and mice after single oral doses of dorzolamide hydrochloride 1927 mg/kg and 1320 mg/kg, respectively.

DOSAGE AND ADMINISTRATION

The dose is one drop of TRUSOPT Ophthalmic Solution in the affected eye(s) three times daily.

TRUSOPT may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.

HOW SUPPLIED

TRUSOPT Ophthalmic Solution is a slightly opalescent, nearly colorless, slightly viscous solution.

No. 3519 -- TRUSOPT Ophthalmic Solution 2% is supplied in OCUMETER(a), a white, opaque, plastic ophthalmic dispenser with a controlled drop tip as follows:

NDC 0006-3519-03, 5 mL

NDC 0006-3519-10, 10 mL

TRUSOPT(R)

(Dorzolamide Hydrochloride Ophthalmic Solution) 7879000

NDC 0006-3519-34, 3 x 5 mL

Storage

Store TRUSOPT Ophthalmic Solution at 15-30 degrees C (59-86 degrees F). Protect from light. -0- Trusopt is the Merck trademark for dorzolamide hydrochloride ophthalmic solution 2%. -0- Issued December 1994 Printed in USA (a) Registered trademark of MERCK & CO. Inc., Whitehouse Station, NJ, USA

COPYRIGHT (C) MERCK & CO., Inc., 1994 All rights reserved

CONTACT: Merck & Co. Inc., West Point

Michael Seggev, 215/652-6931