Dorzolamide Hydrochloride

1 INDICATIONS AND USAGE 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. ___ …

2 DOSAGE AND ADMINISTRATION 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 )

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing dorzolamide 2% (20 mg/mL) equivalent to 22.3 mg/mL of dorzolamide hydrochloride, USP. Ophthalmic solution containing dorzolamide 2% (20 mg/mL). ( 3 )

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

6 ADVERSE REACTIONS The most frequently reported 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%. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 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 Post-Marketing 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.

7 DRUG INTERACTIONS Potential additive effect of oral carbonic anhydrase inhibitor with Dorzolamide Hydrochloride Ophthalmic Solution. ( 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 Ophthalmic Solution. The concomitant administration of Dorzolamide Hydrochloride Ophthalmic Solution 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with Dorzolamide Hydrochloride Ophthalmic Solution. Dorzolamide caused fetal vertebral malformations when administered orally to rabbits at 2.5 mg/kg/day (37 times the clinical exposure). Dorzolamide administered during the period of organogenesis was not teratogenic in rabbits dosed up to 1 mg/kg/day (15 times the clinical exposure). Dorzolamide hydrochloride administered orally to rats during late gestation and lactation caused growth delays in offspring at 7.5 mg/kg/day (52 times the clinical exposure). Growth was not delayed at 1 mg/kg/day (8.0 times the clinical exposure). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Developmental toxicity studies were conducted in pregnant rabbits administered dorzolamide hydrochloride orally during the period of organogenesis from gestation days 6 through 18 at doses of 0.2, 1, 2.5, 5, and 10 mg/kg/day. The developmental lowest observed adverse effect level (LOAEL) was 2.5 mg/kg/day, based on vertebral malformations and decreased fetal body weight. The maternal LOAEL was 2.5 mg/kg/day, based on metabolic acidosis and reduced weight gain. The maternal and developmental no adverse effect levels (NOAELs) were 1 mg/kg/day. The rabbit doses of 1 and 2.5 mg/kg/day represent estimated plasma C max levels in rabbits 15 and 37 times higher than the lower limit of detection in human plasma following ocular administration, respectively. Dorzolamide hydrochloride was administered orally to rats during late gestation and lactation (gestation day 17 through postpartum day 20) at doses of 0.1, 1, or 7.5 mg/kg/day. The developmental LOAEL was 7.5 mg/kg/day, based on reduced birth weight, reduced weight gain, and a slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings) secondary to lower offspring body weight. This 7.5 mg/kg/day dose represents an estimated plasma C max level in rats 52 times higher than the lower limit of detection in human plasma following ocular administration. The developmental NOAEL was 1 mg/kg/day. The maternal LOAEL was 1 mg/kg/day, based on reduced body weight gain.The maternal NOAEL was 0.1 mg/kg/day. The rat doses of 1 and 0.1 mg/kg/day represent estimated plasma C max levels in rats approximately 8.0 times and approximately equal (1x), respectively to the lower limit of detection in human plasma following ocular administration. 8.2 Lactation Risk Summary There are no data on the presence of Dorzolamide Hydrochloride Ophthalmic Solution in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Dorzolamide Hydrochloride Ophthalmic Solution and any potential adverse effects on the breast-fed child from Dorzolamide Hydrochloride Ophthalmic Solution. Dorzolamide is present in the milk of lactating rats (see Data). Data Animal Data Lactating rats were dosed orally with 7.5 mg/kg/day of dorzolamide hydrochloride; dorzolamide and the N-desethyl metabolite were detected in the milk. 8.4 Pediatric Use Safety and effectiveness of Dorzolamide Hydrochloride Ophthalmic Solution have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-treatment-controlled trial. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. 8.6 Renal and Hepatic Impairment Dorzolamide has not been studied in patients with severe renal impairment (CrCl < 30 mL/min). Because dorzolamide and its metabolite are excreted predominantly by the kidney, Dorzolamide …

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

11 DESCRIPTION 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

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Dorzolamide Hydrochloride Ophthalmic Solution 2% is supplied as a 5ml and 10 ml labeled LDPE bottle with insert cap assembly comprising of orange colored screw cap over a LDPE nozzle with tamper evident LDPE dust cover sealing the bottle cap. NDC 69315-304-05, 5 mL in a 5 ml bottle NDC 69315-304-10, 10 mL in a 10 ml bottle Storage Store Dorzolamide Hydrochloride Ophthalmic Solution at 15° to 30°C (59° to 86°F)F). Protect from light. After opening, Dorzolamide Hydrochloride Ophthalmic Solution can be used until the expiration date on the bottle.