ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most frequently reported adverse reactions associated with TRUSOPT were ocular burning, stinging, or discomfort immediately following ocular administration (approximately one-third of patients). Approximately one-quarter of patients noted 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 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 TRUSOPT were ocular burning, stinging, or discomfort immediately following ocular administration (approximately one-third of patients). Approximately one-quarter of patients noted 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 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 3-month, double-masked, active-treatment-controlled, multicenter study in pediatric patients, the adverse reactions profile of TRUSOPT was comparable to that seen in adult patients.. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of TRUSOPT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 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. Papillomas were not seen in rats given oral doses of mg/kg/day. These doses represent estimated plasma Cmax levels in rats, 138 and times higher than the lower limit of detection in human plasma following ocular administration, respectively.No treatment-related tumors were seen in 21-month study in female and male mice given oral doses up to 75 mg/kg/day. This dose represents an estimated plasma Cmax level in mice, 582 times higher than the lower limit of detection in human plasma following ocular administration.The increased incidence of urinary bladder papillomas seen in the high-dose male rats is 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 mg/kg/day or monkeys dosed topically to the eye for one year. An oral dose of mg/kg/day in dogs represents an estimated plasma Cmax level, 137 times higher than the lower limit of detection in human plasma following ocular administration. The topical ophthalmic dose in monkeys was approximately equivalent to the human topical ophthalmic dose.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 fertility studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at doses of 15 and 7.5 mg/kg/day, respectively. These doses represent estimated plasma Cmax levels in rats, 103 and 52 times higher than the lower limit of detection in human plasma following ocular administration, respectively.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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 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 reduction in intraocular pressure (IOP).TRUSOPT contains dorzolamide hydrochloride, an inhibitor of human carbonic anhydrase II. Following topical ocular administration, TRUSOPT reduces elevated intraocular pressure. Elevated intraocular pressure is major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.. 12.3 Pharmacokinetics. 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 result of binding to CA-II. The parent drug forms 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 (15 nM). 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 rapid decline of drug concentration initially, followed by slower elimination phase with 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 mg twice daily closely approximates the amount of drug delivered by topical ocular administration of dorzolamide 2% three times daily. Steady state was reached within weeks. The inhibition of CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for pharmacological effect on renal function and respiration in healthy individuals.

CLINICAL STUDIES SECTION.

14 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 >= 23 mmHg). The IOP-lowering effect of TRUSOPT was approximately to 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 day (alone or in combination with other products) has not been established.In one year clinical study, the effect of TRUSOPT 2% three times daily on the corneal endothelium was compared to that of betaxolol ophthalmic solution twice daily and timolol maleate ophthalmic solution 0.5% twice daily. There were no statistically significant differences between groups in corneal endothelial cell counts or in corneal thickness measurements. There was mean loss of approximately 4% in the endothelial cell counts for each group over the one year period.

DESCRIPTION SECTION.

11 DESCRIPTION. TRUSOPT(R) (dorzolamide hydrochloride ophthalmic solution) is 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. The specific rotation is25(C=1, water) ~ -17.405Its empirical formula is C10H16N2O4S3HCl and its structural formula is:Dorzolamide hydrochloride has molecular weight of 360.9 and melting point of about 264C. It is white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.TRUSOPT is supplied as sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride. The pH of the solution is approximately 5.6, and the osmolarity is 260-330 mOsM. Each mL of TRUSOPT 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 preservative.. Chemical Structure.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Potential additive effect of oral carbonic anhydrase inhibitor with TRUSOPT. (7.1)Potential acid-base and electrolyte disturbances. (7.2). Potential additive effect of oral carbonic anhydrase inhibitor with TRUSOPT. (7.1). Potential acid-base and electrolyte disturbances. (7.2). 7.1Oral Carbonic Anhydrase Inhibitors. There is 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.. 7.2High-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 TRUSOPT.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Instructions for Use).Sulfonamide ReactionsTRUSOPT is 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. Advise patients that if serious or unusual reactions including severe skin reactions or signs of hypersensitivity occur, they should discontinue the use of the product [see Warnings and Precautions (5.1)].Intercurrent Ocular ConditionsAdvise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physicians advice concerning the continued use of the present multidose container.Handling Ophthalmic SolutionsInstruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.Instruct patients 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.Concomitant Topical Ocular TherapyIf more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.Contact Lens UseAdvise patients that TRUSOPT contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following TRUSOPT administration.When to Seek Physician AdviceAdvise patients that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physicians advice.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 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. Papillomas were not seen in rats given oral doses of mg/kg/day. These doses represent estimated plasma Cmax levels in rats, 138 and times higher than the lower limit of detection in human plasma following ocular administration, respectively.No treatment-related tumors were seen in 21-month study in female and male mice given oral doses up to 75 mg/kg/day. This dose represents an estimated plasma Cmax level in mice, 582 times higher than the lower limit of detection in human plasma following ocular administration.The increased incidence of urinary bladder papillomas seen in the high-dose male rats is 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 mg/kg/day or monkeys dosed topically to the eye for one year. An oral dose of mg/kg/day in dogs represents an estimated plasma Cmax level, 137 times higher than the lower limit of detection in human plasma following ocular administration. The topical ophthalmic dose in monkeys was approximately equivalent to the human topical ophthalmic dose.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 fertility studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at doses of 15 and 7.5 mg/kg/day, respectively. These doses represent estimated plasma Cmax levels in rats, 103 and 52 times higher than the lower limit of detection in human plasma following ocular administration, respectively.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. 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 result of binding to CA-II. The parent drug forms 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 (15 nM). 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 rapid decline of drug concentration initially, followed by slower elimination phase with 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 mg twice daily closely approximates the amount of drug delivered by topical ocular administration of dorzolamide 2% three times daily. Steady state was reached within weeks. The inhibition of CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for pharmacological effect on renal function and respiration in healthy individuals.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies in pregnant women with TRUSOPT.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 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 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 to 4% and 15 to 20%, respectively.DataAnimal DataDevelopmental toxicity studies were conducted in pregnant rabbits administered dorzolamide hydrochloride orally during the period of organogenesis from gestation days 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 mg/kg/day. The rabbit doses of and 2.5 mg/kg/day represent estimated plasma Cmax 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 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 Cmax level in rats 52 times higher than the lower limit of detection in human plasma following ocular administration. The developmental NOAEL was mg/kg/day. The maternal LOAEL was mg/kg/day, based on reduced body weight gain. The maternal NOAEL was 0.1 mg/kg/day. The rat doses of and 0.1 mg/kg/day represent estimated plasma Cmax levels in rats approximately 8.0 times and approximately equal (1x), respectively to the lower limit of detection in human plasma following ocular administration.

SPL PATIENT PACKAGE INSERT SECTION.

INSTRUCTIONS FOR USETRUSOPT(R) (TRU-sopt)(dorzolamide hydrochloride ophthalmic solution) 2%Before using your TRUSOPTBefore using your TRUSOPT for the first time, make sure the safety strip on the front of the bottle is unbroken. gap between the bottle and the cap is normal for an unopened bottle. See Figure A.Figure AStep 1. Wash your hands.Step 2. Tear off the safety strip to break the seal. See Figure B.Figure BStep 3. Unscrew the cap by turning in the direction of the arrows on the top of the cap. Do not pull the cap directly up and away from the bottle. Pulling the cap directly up will keep your TRUSOPT dispenser from working the right way. See Figure C.Figure CGiving your TRUSOPT dropsStep 4. Tilt your head back and pull your lower eyelid down slightly to form pocket between your eyelid and your eye. See Figure D.Figure DStep 5. Turn your TRUSOPT dispenser upside down and press lightly with your thumb or index finger over the Finger Push Area until single drop is placed in your eye. Do not touch your eye or eyelid with the dropper tip. See Figure E.Figure EStep 6. If the medicine does not drop easily from the TRUSOPT dispenser after you open it for the first time, replace the cap on the bottle and tighten. Do not over tighten. Remove the cap by turning the cap in the direction of the arrows on the top of the cap. See Figure F. This should make the hole on the dispenser tip larger. Do not try to make the hole of the dispenser tip larger in any other way. The dispenser tip is made to provide single drop. Repeat Steps and to give your TRUSOPT drop.Figure FStep 7. If your doctor has told you to use TRUSOPT drops in both eyes, repeat Steps and 5.After using your TRUSOPTStep 8. Replace the cap by turning it until it is firmly touching your TRUSOPT dispenser. The arrow on the left side of the cap must be lined up with the arrow on the left side of the TRUSOPT dispenser label for it to be closed correctly. Do not over tighten or you may damage the TRUSOPT dispenser and cap. See Figure G.Figure GAfter you have used all of your TRUSOPT doses, there will be some TRUSOPT medicine left in the dispenser. Do not try to remove the extra medicine from the TRUSOPT dispenser. Throw away your TRUSOPT dispenser in your household trash.How should store TRUSOPTStore TRUSOPT between 59F to 86F (15C to 30C)Protect from lightAfter opening, TRUSOPT can be used until the expiration date on the bottleSafely throw away medicine that is out of date or no longer needed.Keep TRUSOPT and all medicines out of the reach of children.Important information about using TRUSOPTIf you have any eye or skin reactions, especially conjunctivitis or eyelid reactions to TRUSOPT, stop using it and call your doctor right away.If you have eye surgery or have problem such as trauma or infection of your eye while using TRUSOPT, 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 TRUSOPT, use the medicines at least minutes before or after you use TRUSOPT.TRUSOPT contains benzalkonium chloride which may be absorbed by soft contact lenses. If you wear contact lenses, remove them before you use your TRUSOPT. You can place your contact lenses back into your eyes 15 minutes after using your TRUSOPT.This Instructions for Use has been approved by the U.S. Food and Drug Administration.. Store TRUSOPT between 59F to 86F (15C to 30C). Protect from light. After opening, TRUSOPT can be used until the expiration date on the bottle. Safely throw away medicine that is out of date or no longer needed.. If you have any eye or skin reactions, especially conjunctivitis or eyelid reactions to TRUSOPT, stop using it and call your doctor right away.. If you have eye surgery or have problem such as trauma or infection of your eye while using TRUSOPT, 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 TRUSOPT, use the medicines at least minutes before or after you use TRUSOPT.. TRUSOPT contains benzalkonium chloride which may be absorbed by soft contact lenses. If you wear contact lenses, remove them before you use your TRUSOPT. You can place your contact lenses back into your eyes 15 minutes after using your TRUSOPT.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies in pregnant women with TRUSOPT.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 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 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 to 4% and 15 to 20%, respectively.DataAnimal DataDevelopmental toxicity studies were conducted in pregnant rabbits administered dorzolamide hydrochloride orally during the period of organogenesis from gestation days 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 mg/kg/day. The rabbit doses of and 2.5 mg/kg/day represent estimated plasma Cmax 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 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 Cmax level in rats 52 times higher than the lower limit of detection in human plasma following ocular administration. The developmental NOAEL was mg/kg/day. The maternal LOAEL was mg/kg/day, based on reduced body weight gain. The maternal NOAEL was 0.1 mg/kg/day. The rat doses of and 0.1 mg/kg/day represent estimated plasma Cmax 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 SummaryThere are no data on the presence of TRUSOPT 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 mothers clinical need for TRUSOPT and any potential adverse effects on the breast-fed child from TRUSOPT. Dorzolamide is present in the milk of lactating rats (see Data).DataAnimal DataLactating 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 TRUSOPT have been demonstrated in pediatric patients in 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.. 8.6Renal 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, TRUSOPT is not recommended in such patients.Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Sulfonamide Hypersensitivity (5.1)Bacterial Keratitis (5.2)Corneal Endothelium (5.3)Allergic Reactions (5.4)Acute Angle-Closure Glaucoma (5.5). Sulfonamide Hypersensitivity (5.1). Bacterial Keratitis (5.2). Corneal Endothelium (5.3). Allergic Reactions (5.4). Acute Angle-Closure Glaucoma (5.5). 5.1Sulfonamide Hypersensitivity. TRUSOPT contains dorzolamide, sulfonamide; and although administered topically, it is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of 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 sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Contraindications (4)].. 5.2Bacterial Keratitis. 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 concurrent corneal disease or disruption of the ocular epithelial surface. 5.3Corneal Endothelium. Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing TRUSOPT to this group of patients.. 5.4Allergic Reactions. 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 (6)].. 5.5Acute Angle-Closure Glaucoma. The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents.