ADVERSE REACTIONS SECTION.


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 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 Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-332-1088 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 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 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 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 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 tw - ear study of dorzolamide hydrochloride administered orally to male and female Spragu e- Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 g kg/day. Papillomas were not seen in rats iven oral doses of m / g/da y. These doses represent estimated plasma ma 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 max 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 max 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.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. Dorzolamide hydrochloride ophthalmic solutionis indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.. Dorzolamide hydrochloride ophthalmic solution is carbonic anhydrase inhibitor indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. 1).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Carbonic anhydrase (CA) is an enz yme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon di oxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as number of isoenz m es, the most active being carbonic anhydrase II (C A-II), found primarily in red blood cells (RBCs), but also in other tissues. Inhibition of carbonic an yd rase in the cilia ry processes of the eye decreases aqueous hu mor 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).Dorzolamide hydrochloride ophthalmic solution contains dorzolamide hydrochloride, an inhibitor of human carbonic anh ydrase II. Following topical ocular administration, dorzolamide hydrochloride ophthalmic solution reduces elevated intraocular pressure. Elevated intraocular pressure is major risk factor in the patho genesis of optic nerve da mage and glaucomatous visual field loss.. 12.3 Pharmacokinetics. hen topically applied, dorzolamide reaches the y stemic circulation. To assess the potential for ystemic carbonic anhydrase inhibition following topical administrati on, 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 A-II less potently than the parent drug but also inhibits A-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 quantitat ion (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 rapid decline of drug concentration initially, followed by slower elimination phase with hal f-life of about four onths.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 A-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 dorzolamide hydrochloride ophthalmic solution was demonstrated in clinical studies in the treatment of elevated intraocular pressure in patients with glaucoma or ocular hypertension (baseline IOP >= 23 mmHg). The IO P-lowering effect of dorzolamide hydrochloride ophthalmic solution was approximately to mmHg throughout the day and this was consistent in clinical studies of up to one year duration.The efficacy of dorzolamide hydrochloride ophthalmic solution when dosed less frequently than three times day (alone or in co mbination with other products) has not een established.In one year clinical study, the effect of dorzolamide hydrochloride ophthalmic solution 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.

CONTRAINDICATIONS SECTION.


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).

DESCRIPTION SECTION.


11 DESCRIPTION. Dorzolamide hydrochloride ophthalmic solution, USP is carbonic anhydrase inhibitor formulated for topical ophthalmic use.Dorzolamide hydrochloride USP 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 25 (C=1, water) ~ -17. 405Its molecular formula is 10H 16N 2O 4S 3oHCl and its structural formula is: Dorzolamide hydrochloride USP 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.Dorzolamide hydrochloride ophthalmic solution USP is supplied as sterile, isotonic, buffered, clear, colorless to nearly colorless and slightly viscous solution. The pH of the solution is approximately 5.6, and the osmolarity is 260 to 330 mOsM. Each mL of dorzolamide hydrochloride ophthalmic solution 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride USP). Inactive ingredients are Mannitol, Hydroxyethyl cellulose, Sodium hydroxide, Tri Sodium citrate dihydrate, and water for injection. Benzalkonium chloride 0.0075% is added as preservative.. structure.

DOSAGE & ADMINISTRATION SECTION.


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 lo wer intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be ad ministered 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).

DOSAGE FORMS & STRENGTHS SECTION.


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

DRUG INTERACTIONS SECTION.


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) Potential additive effect of oral carbonic anhydrase inhibitor with dorzolamide hydrochloride ophthalmic solution. 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 ystemic 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 re commended.. 7.2High-Dose Salicylate Therapy. Although aci d-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 inh ibitors 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.

GERIATRIC USE SECTION.


8.5 Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Dorzolamide hydrochloride ophthalmic solution, USP 2% is supplied in an LDPE white opaque cylindrical shape, screw type neck dispenser bottle closed with LDPE white opaque cone shaped open nozzle and an HDPE orange color cone shaped cap as follows.NDC 42571-141-26, 10 mL in 10 mL capacity bottle.StorageStore dorzolamide hydrochloride ophthalmic solution at 15 to 30C (5 to 86F). Protect from light.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Sulfonamide Reactions Dorzolamide hydrochloride ophthalmic solution 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 Conditions Advise 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 Solutions Instruct 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 Therapy If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. Contact Lens Use Advise patients that dorzolamide hydrochloride ophthalmic solution 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 dorzolamide hydrochloride ophthalmic solution administration. When to Seek Physician Advice Advise patients that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physicians advice.Manufactured by:Micro Labs LimitedBangalore 560 099, India.Manufactured for:Micro Labs USA Inc.Basking Ridge, NJ 07920.

LACTATION SECTION.


8.2 Lactation. Risk Summary There are no data on the presence of dorzolamide hydrochloride ophthalmic solution in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers 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). 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.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Carbonic anhydrase (CA) is an enz yme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon di oxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as number of isoenz m es, the most active being carbonic anhydrase II (C A-II), found primarily in red blood cells (RBCs), but also in other tissues. Inhibition of carbonic an yd rase in the cilia ry processes of the eye decreases aqueous hu mor 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).Dorzolamide hydrochloride ophthalmic solution contains dorzolamide hydrochloride, an inhibitor of human carbonic anh ydrase II. Following topical ocular administration, dorzolamide hydrochloride ophthalmic solution reduces elevated intraocular pressure. Elevated intraocular pressure is major risk factor in the patho genesis of optic nerve da mage and glaucomatous visual field loss.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In tw - ear study of dorzolamide hydrochloride administered orally to male and female Spragu e- Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 g kg/day. Papillomas were not seen in rats iven oral doses of m / g/da y. These doses represent estimated plasma ma 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 max 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 max 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.

OVERDOSAGE SECTION.


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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Rx Only NDC 42571-141-26 Dorzolamide HCl Ophthalmic Solution, USP 2% Dorzolamide Equivalent (Dorzolamide HCl 22.3 mg/mL) FOR OPHTHALMIC APPLICATION IN THE EYE 10 mL MICRO LABS NDC 42571-141-26 Dorzolamide HCl Ophthalmic Solution, USP 2% Dorzolamide Equivalent (Dorzolamide HCl 22.3 mg/ mL) FOR TOPICAL APPLICATION IN THE EYE Rx only 10 mL MICRO LABS container label. carton label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness of dorzolamide hydrochloride ophthalmic solution ave been demonstrated in pediatric patients in 3- onth, ulticenter, doubl e- asked, activ e-treatment-controlled trial.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. hen topically applied, dorzolamide reaches the y stemic circulation. To assess the potential for ystemic carbonic anhydrase inhibition following topical administrati on, 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 A-II less potently than the parent drug but also inhibits A-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 quantitat ion (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 rapid decline of drug concentration initially, followed by slower elimination phase with hal f-life of about four onths.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 A-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.

PREGNULLNCY SECTION.


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 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. Data Animal Data Developmental 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 UNCLASSIFIED SECTION.


5.1 Sulfonamide Hypersensitivity. Dorzolamide hydrochloride ophthalmic solution 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 dorzolamide hydrochloride ophthalmic solution. 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)].

USE IN SPECIFIC POPULATIONS SECTION.


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 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. Data Animal Data Developmental 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 Summary There are no data on the presence of dorzolamide hydrochloride ophthalmic solution in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers 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). 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 dorzolamide hydrochloride ophthalmic solution ave been demonstrated in pediatric patients in 3- onth, ulticenter, doubl e- asked, activ e-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 L m in). Because dorzolamide and its metabolite are excreted predominantly by the kidney, dorzolamide hydrochloride ophthalmic solution 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 patient.

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) 5.1 Sulfonamide Hypersensitivity. Dorzolamide hydrochloride ophthalmic solution 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 dorzolamide hydrochloride ophthalmic solution. 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)]. 5.2 Bacterial 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.. 5.3 Corneal Endothelium. Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma e branes of the corneal endothelium. There is an increased potential for developing corneal ede ma in patients with low endothelial cell counts. Caution should be used when prescribing dorzolamide hydrochloride ophthalmic solution to this group of patients.. 5.4 Allergic Reactions. In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide hydrochloride ophthalmic solution. Many of these reactions had the clinical appearance and course of an allergi c- ype reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, dorzolamide hydrochloride ophthalmic solution should be discontinued and the patient evaluated before consider ing restarting the drug [see Adverse Reactions (6)]. 5.5 Acute Angle-Closure Glaucoma. The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents.