DORZOLAMIDE HYDROCHLORIDE

Dorzolamide hydrochloride ophthalmic solution is a carbonic anhydrase inhibitor formulated for topical ophthalmic use. Dorzolamide hydrochloride is described chemically as: (4 S-trans )-4-(ethylamino)-5,6-dihydro-6-methyl-4 H -thieno[2,3- b ]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is α 25° (C=1, water) = ~ -17°. 405 Its empirical formula is C 10 H 16 N 2 O 4 S 3 •HCl and its structural formula is: Dorzolamide hydrochloride has a molecular weight of 360.9 and a melting point of about 264°C. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol. Dorzolamide hydrochloride ophthalmic solution is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride. The pH of the solution is approximately 5.4 to 5.9, and the osmolarity is 260-330 mOsmoles/kg. Each mL of dorzolamide hydrochloride ophthalmic solution 2% contains 20 mg dorzolamide (equivalent to 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. Dorzolamide hydrochloride ophthalmic solution Chemical Structure

Dorzolamide hydrochloride ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Dorzolamide hydrochloride is a carbonic anhydrase inhibitor indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. ( 1 ) INSTRUCTIONS FOR USE Dorzolamide hydrochloride (dor-ZOE-la-mide HYE-droe-KLOR-ide) ophthalmic solution 2% Before using your dorzolamide hydrochloride ophthalmic solution Before using your dorzolamide hydrochloride ophthalmic solution for the first time, make sure the tamper evident ring between the bottle and the cap is unbroken. See Figure A . Figure A Step 1. Wash your hands. Step 2. Before opening the bottle for the first time, tear off the tamper evident ring to break the seal. See Figure B . Figure B Step 3. To open the bottle, unscrew the cap by turning it in the counterclockwise direction. Do not pull the cap directly up and away from the bottle. See Figure C . Figure C Giving your dorzolamide hydrochloride ophthalmic solution drops Step 4. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and your eye. See Figure D . Figure D Step 5. Turn your dorzolamide hydrochloride ophthalmic solution bottle upside down and press gently with your thumb or index finger over the middle of the bottle until a single drop is placed in your eye. Do not touch your eye or eyelid with the dropper tip. See Figure E . Figure E Step 6. If your healthcare provider has told you to use dorzolamide hydrochloride ophthalmic solution drops in both eyes, repeat Steps 4 and 5. After using your dorzolamide hydrochloride ophthalmic solution Step 7. Replace the cap by turning it clockwise direction until tight. See Figure F . Figure F After you have used all of your dorzolamide hydrochloride ophthalmic solution doses, there will be some dorzolamide hydrochloride ophthalmic solution medicine left in the dispenser. Do not try to remove the extra medicine from the dorzolamide hydrochloride ophthalmic solution dispenser. Throw away your dorzolamide hydrochloride ophthalmic solution dispenser in your household trash. How should I store dorzolamide hydrochloride ophthalmic solution? Store dorzolamide hydrochloride ophthalmic solution between 68°F to 77°F (20°C to 25°C) Protect from light. After opening, dorzolamide hydrochloride ophthalmic solution can be used until the expiration date on the bottle. Safely throw away medicine that is out of date or no longer needed. Keep dorzolamide hydrochloride ophthalmic solution and all medicines out of the reach of children. Important information about using dorzolamide hydrochloride ophthalmic solution If you have any eye or skin reactions, especially conjunctivitis or eyelid reactions to dorzolamide hydrochloride ophthalmic solution, stop using it and call your doctor right away. If you have eye surgery or have a problem such as trauma or infection of your eye while using dorzolamide hydrochloride ophthalmic solution, call your doctor right away. If you do not handle eye medicines the right way the medicine can become contaminated. If the tip of the dispenser touches your eye or areas around your eye, the tip can become contaminated with bacteria which can cause an eye infection and other serious problems including loss of eyesight. If you use other eye medicines dropped onto the eye like dorzolamide hydrochloride ophthalmic solution, use the medicines at least 5 minutes before or after you use dorzolamide hydrochloride ophthalmic solution. Dorzolamide hydrochloride ophthalmic solution contains benzalkonium chloride which may be absorbed by soft contact lenses. If you wear contact lenses, remove them before you use your dorzolamide hydrochloride ophthalmic solution. You can place your contact lenses back into your eyes 15 minutes after using your dorzolamide hydrochloride ophthalmic solution. ______________________________________________________________________________________________________________________________________________________________ This Instructions for Use has been approved by the U.S. Food and Drug Administration. Dorzolamide hydrochloride ophthalmic solution Figure A Dorzolamide hydrochloride ophthalmic solution Figure B Dorzolamide hydrochloride ophthalmic solution Figure C Dorzolamide hydrochloride ophthalmic solution Figure D Dorzolamide hydrochloride ophthalmic solution Figure E Dorzolamide hydrochloride ophthalmic solution Figure F

The dose is one drop of dorzolamide hydrochloride ophthalmic solution in the affected eye(s) three times daily. Dorzolamide hydrochloride ophthalmic solution 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 five minutes apart. The dose is one drop of dorzolamide hydrochloride ophthalmic solution in the affected eye(s) three times daily. Dorzolamide hydrochloride ophthalmic solution may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. ( 2 )

Dorzolamide hydrochloride is contraindicated in patients who are hypersensitive to any component of this product [see Warnings and Precautions (5.1) ]. Dorzolamide hydrochloride is contraindicated in patients who are hypersensitive to any component of this product. ( 4 , 5.1 )

The most frequently reported adverse reactions associated with dorzolamide hydrochloride 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 to 15% of patients and signs and symptoms of ocular allergic reaction in approximately 10%. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd., at 888-413-0949 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Controlled Clinical Trials: The most frequent adverse reactions associated with dorzolamide hydrochloride ophthalmic solution 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 to 15% of patients and signs and symptoms of ocular allergic reaction in approximately 10%. Reactions occurring in approximately 1 to 5% of patients were conjunctivitis and lid reactions [see Warnings and Precautions (5.4) ] , blurred vision, eye redness, tearing, dryness, and photophobia. Other ocular reactions and systemic reactions were reported infrequently, including headache, nausea, asthenia/fatigue; and, rarely, skin rashes, urolithiasis, and iridocyclitis. In a 3-month, double-masked, active-treatment-controlled, multicenter study in pediatric patients, the adverse reactions profile of dorzolamide hydrochloride ophthalmic solution was comparable to that seen in adult patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dorzolamide hydrochloride ophthalmic solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: signs and symptoms of systemic allergic reactions including angioedema, bronchospasm, pruritus, and urticaria; Stevens-Johnson syndrome and toxic epidermal necrolysis; dizziness, paresthesia; ocular pain, transient myopia, choroidal detachment following filtration surgery, eyelid crusting; dyspnea; contact dermatitis, epistaxis, dry mouth and throat irritation.

Potential additive effect of oral carbonic anhydrase inhibitor with dorzolamide hydrochloride. ( 7.1 ) Potential acid-base and electrolyte disturbances. ( 7.2 ) 7.1 Oral Carbonic Anhydrase Inhibitors 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 dorzolamide hydrochloride. The concomitant administration of dorzolamide hydrochloride and oral carbonic anhydrase inhibitors is not recommended. 7.2 High-Dose Salicylate Therapy Although acid-base and electrolyte disturbances were not reported in the clinical trials with dorzolamide hydrochloride ophthalmic solution, 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 dorzolamide hydrochloride ophthalmic solution.

Storage Store dorzolamide hydrochloride ophthalmic solution at 20°C to 25°C (68°F to 77°F). Protect from light. After opening, dorzolamide hydrochloride ophthalmic solution can be used until the expiration date on the bottle.