5.1 Sulfonamide Hypersensitivity

Dorzolamide hydrochloride ophthalmic solution contains dorzolamide, a 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 a 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 a concurrent corneal disease or a disruption of the ocular epithelial surface.

5.3 Corneal 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 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 allergic-type 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 considering 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.

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.

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.

8.1 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 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 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 Cmax 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 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 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 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 patients.

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.

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 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 (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 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 twice daily closely approximates the amount of drug delivered by topical ocular administration of dorzolamide 2% three times daily. 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.

13.1 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. Papillomas were not seen in rats given oral doses of 1 mg/kg/day. These doses represent estimated plasma Cmax levels in rats, 138 and 7 times higher than the lower limit of detection in human plasma following ocular administration, respectively.

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. 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 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 or monkeys dosed topically to the eye for one year. An oral dose of 2 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.