Dorzolamide Eye Drops BP Product Monograph

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TABLE OF CONTENTS

TABLE OF CONTENTS .................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................... 3

1 INDICATIONS ...................................................................................................... 3

1.1 Pediatrics ..................................................................................................... 3 1.2 Geriatrics ..................................................................................................... 3

2 CONTRAINDICATIONS ....................................................................................... 3

3 DOSAGE AND ADMINISTRATION ..................................................................... 3

3.1 Recommended Dose and Dosage Adjustment ............................................ 3 3.2 Missed Dose ................................................................................................ 4

4 OVERDOSAGE .................................................................................................... 4

5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............. 4

6 WARNINGS AND PRECAUTIONS ...................................................................... 5

6.1 Special Populations ..................................................................................... 6 6.1.1 Pregnant Women ..................................................................................... 6 6.1.2 Breast-feeding .......................................................................................... 6 6.1.3 Pediatrics .................................................................................................. 6 6.1.4 Geriatrics .................................................................................................. 6

7 ADVERSE REACTIONS ...................................................................................... 7

7.1 Adverse Reaction Overview ........................................................................ 7 7.2 Clinical Trial Adverse Reactions .................................................................. 7 7.3 Post-Market Adverse Reactions .................................................................. 7

8 DRUG INTERACTIONS ....................................................................................... 8

8.1 Overview ...................................................................................................... 8 8.2 Drug-Drug Interactions ................................................................................ 8 8.3 Drug-Lifestyle Interactions ........................................................................... 8

9 ACTION AND CLINICAL PHARMACOLOGY ..................................................... 8

9.1 Mechanism of Action ................................................................................... 8 9.2 Pharmacokinetics ........................................................................................ 9

10 STORAGE, STABILITY AND DISPOSAL ......................................................... 10

11 PHARMACEUTICAL INFORMATION................................................................ 11

12 CLINICAL TRIALS ............................................................................................. 11

12.1 Trial Design and Study Demographics ................................................... 11

13 NON-CLINICAL TOXICOLOGY ......................................................................... 13

14 SUPPORTING PRODUCT MONOGRAPHS ...................................................... 14

PATIENT MEDICATION INFORMATION ..................................................................... 15

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Dorzolamide Eye Drops BP (dorzolamide hydrochloride) ophthalmic solution 2% is indicated in the treatment of elevated intraocular pressure in patients with:

• ocular hypertension
• open-angle glaucoma

1.1 Pediatrics

Pediatrics (<18 years of age): Safety and effectiveness in children have not been established. No data are available to Health Canada; therefore, an indication for pediatric use has not been authorized

1.2 Geriatrics

Geriatrics (> 65 years of age): No overall differences in effectiveness or safety were observed between these patients and younger adult patients, but greater sensitivity of some older individuals to the product cannot be ruled out. See WARNINGS AND PRECAUTIONS – Special Populations – Geriatrics.

2 CONTRAINDICATIONS

Dorzolamide Eye Drops BP is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see the DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

• Dorzolamide hydrochloride has not been studied in patients with severe renal impairment

  (CrCl < 0.5 mL/s). Because dorzolamide hydrochloride and its metabolite are excreted predominantly by the kidney, Dorzolamide Eye Drops BP is not recommended in such patients.

• There is a potential for an additive effect with the known systemic effects of carbonic anhydrase inhibition in patients receiving oral carbonic anhydrase inhibitor and Dorzolamide Eye Drops BP. The concomitant administration of dorzolamide hydrochloride and oral carbonic anhydrase inhibitors has not been studied and is not recommended.

3 DOSAGE AND ADMINISTRATION

3.1 Recommended Dose and Dosage Adjustment

Adults (>18 years of age): When used as monotherapy, the dose is one drop of Dorzolamide Eye Drops BP (dorzolamide hydrochloride) ophthalmic solution 2% in the affected eye(s) three times daily.

When used as adjunctive therapy with an ophthalmic beta-blocker, the dose is one drop of Dorzolamide Eye Drops BP in the affected eye(s) two times daily.

When substituting Dorzolamide Eye Drops BP for another ophthalmic antiglaucoma agent, discontinue the other agent after proper dosing on one day, and start Dorzolamide Eye Drops BP on the next day.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.

Pediatrics (<18 years of age): Safety and effectiveness in children have not been established. An indication for pediatric use has not been authorized

3.2 Missed Dose

If a dose is missed, it should be applied as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped and the next dose should be taken as usual.

4 OVERDOSAGE

For management of a suspected drug overdose, contact your regional poison control centre.

No data are available in humans in regard to overdosage by accidental or deliberate ingestion. The most common signs and symptoms to be expected with overdosage of dorzolamide are electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects (see ADVERSE REACTIONS).

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

Significant lethality was observed in female rats and mice after single oral doses of dorzolamide hydrochloride of 11 369 mg/m² or 1 927 mg/kg (24 000 times the maximum recommended human ophthalmic dose) and 3 960 mg/m² or 1 320 mg/kg (16 000 times the maximum recommended human ophthalmic dose), respectively.

5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Dorzolamide Eye Drops BP Ophthalmic Solution is supplied as a sterile, slightly opalescent, nearly colorless, slightly viscous solution of dorzolamide hydrochloride. Each mL of Dorzolamide Eye Drops BP 2% contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride).

Dorzolamide Eye Drops BP (dorzolamide hydrochloride) sterile ophthalmic solution is a slightly opalescent, nearly colorless, slightly viscous solution supplied in a 10 mL (with 5 mL fill volume) LDPE ophthalmic dispenser, with a sealed dropper tip.

Ophthalmic Solution Dorzolamide Eye Drops BP 2%, equivalent to 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) per mL; in 10 mL dispensers (with 5 mL fill volume).

6 WARNINGS AND PRECAUTIONS

General

Dorzolamide Eye Drops BP (dorzolamide hydrochloride) is a 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, including severe reactions such as Stevens- Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide hydrochloride has not been studied in patients with acute angle-closure glaucoma.

Driving and Operating Machinery

Possible side effects such as visual disturbances may affect the ability to drive and use machines.

Hepatic/Biliary/Pancreatic

Hepatic Impairment

Dorzolamide hydrochloride has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

Immune

Immunology and Hypersensitivity

In clinical studies, local ocular adverse effects, primarily conjunctivitis and eyelid reactions, were reported with chronic administration of dorzolamide hydrochloride. Some 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, discontinuation of treatment with Dorzolamide Eye Drops BP should be considered.

Monitoring and Laboratory Tests

Dorzolamide hydrochloride was not associated with clinically meaningful electrolyte disturbances.

Ophthalmologic Corneal Edema

There is an increased risk of developing irreversible corneal edema in a subset of glaucoma patients with endothelial abnormalities including cellular density and/or morphology. In this group of patients evaluation of the cornea with particular attention to the corneal endothelium is recommended prior and during treatment with Dorzolamide Eye Drops BP.

Corneal Edema and Irreversible Corneal Decompensation

Corneal edema and irreversible corneal decompensation has been reported in patients with pre- existing chronic corneal defects and/or a history of intraocular surgery while using dorzolamide. Dorzolamide Eye Drops BP should be used with caution in such patients.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., dorzolamide) after filtration procedures.

Management of eyes with chronic or recurrent choroidal detachment should include stopping all forms of aqueous suppressant therapy and treating endogenous inflammation vigorously.

Contact Lenses

Dorzolamide hydrochloride has not been studied in patients wearing contact lenses. The preservative in Dorzolamide Eye Drops BP Ophthalmic Solution, benzalkonium chloride, may be absorbed by soft contact lenses. Patients should be instructed to remove their lenses before application of the drops and not to re-insert the lenses earlier than 15 minutes after use.

6.1 Special Populations

6.1.1 Pregnant Women

There are no adequate and well-controlled studies in pregnant women. Dorzolamide Eye Drops BP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

6.1.2 Breast-feeding

It is not known whether dorzolamide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Dorzolamide Eye Drops BP in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain of 5 to 7% in offspring at an oral dose of 7.5 mg/kg/day (94 times the maximum recommended human ophthalmic dose) were seen during lactation. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings), secondary to lower fetal body weight, was noted at 7.5 mg/kg/day (94 times the maximum recommended human ophthalmic dose).

6.1.3 Pediatrics

Pediatrics (<18 years of age): Safety and effectiveness in children have not been established, therefore, an indication for pediatric use has not been authorized.

6.1.4 Geriatrics

Geriatrics (> 65 years of age): Of the total number of patients in clinical studies of dorzolamide hydrochloride, 44% were 65 years of age and over, while 10% were 75 years of age and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals to the product cannot be ruled out.

In a clinical study of dorzolamide hydrochloride ophthalmic solution, 48% of all patients were over the age of 65, while 12% were over 75 years of age. No statistical analysis was performed based upon age, but greater sensitivity of some older individuals to the product cannot be ruled out.

7 ADVERSE REACTIONS

7.1 Adverse Reaction Overview

In long-term studies of 1108 patients treated with dorzolamide hydrochloride as monotherapy or as adjunctive therapy with an ophthalmic beta-blocker, the most frequent cause of discontinuation (approximately 3%) from treatment with dorzolamide hydrochloride was drug-related ocular adverse effects, primarily conjunctivitis and eyelid reactions (see WARNINGS AND PRECAUTIONS).

In clinical studies, the most common ocular complaints were burning and stinging, blurred vision, itching and tearing. Bitter taste was also frequently reported. If these local symptoms were considered clinically important by investigators they also appear as adverse experiences in the listing below.

For dorzolamide hydrochloride ophthalmic solution the most frequently reported ocular drug related adverse events were burning and stinging 38%, taste perversion 13%, conjunctival injection 5%, comeal erosion 4%, follicular conjunctivitis 3%, and blurred vision 3%.

7.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse experiences that were reported during clinical studies as drug-related (possibly, probably, or definitely) in 1-5% of patients on dorzolamide hydrochloride were in decreasing order of frequency:

Ocular:

Burning and stinging, conjunctivitis, eyelid inflammation, eye itching, eyelid irritation.

Systemic:

Headache, bitter taste, nausea, asthenia/fatigue.

Iridocyclitis and rash were each reported rarely. There was one report of urolithiasis.

7.3 Post-Market Adverse Reactions

The following adverse reactions have been reported in post-marketing experience:

Hypersensitivity: Signs and symptoms of local reactions including palpebral reactions and systemic allergic reactions including angioedema, bronchospasm, urticaria and pruritus.

Nervous System: Dizziness, paresthesia.

Ocular: Pain, redness, superficial punctate keratitis, transient myopia (which resolved upon discontinuation of therapy), eyelid crusting, choroidal detachment following filtration surgery, corneal edema in glaucoma patients with endothelial abnormalities including cellular density and/or morphology.

Skin/Mucous Membranes: Contact dermatitis, epistaxis, throat irritation, dry mouth, Stevens- Johnson syndrome, toxic epidermal necrolysis.

Urogenital: Urolithiasis.

8 DRUG INTERACTIONS

8.1 Overview

Specific drug interaction studies have not been performed with dorzolamide hydrochloride ophthalmic solution. In clinical studies, dorzolamide hydrochloride was used concomitantly with the following medications without evidence of adverse interactions: timolol ophthalmic solution, betaxolol ophthalmic solution and systemic medications, including ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including ASA, and hormones (e.g. estrogen, insulin, thyroxine).

8.2 Drug-Drug Interactions

The following drug interaction has been associated with the dorzolamide component of Dorzolamide Eye Drops BP or with other sulfonamides:

Acid-base Disturbances: Dorzolamide Eye Drops BP is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride was not associated with acid-base disturbances. However, 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 Eye Drops BP.

8.3 Drug-Lifestyle Interactions

Possible side effects such as visual disturbances may affect the ability to drive and use machines (see ADVERSE REACTIONS).

9 ACTION AND CLINICAL PHARMACOLOGY

9.1 Mechanism of Action

Dorzolamide Eye Drops BP (dorzolamide hydrochloride) is a carbonic anhydrase inhibitor formulated for topical ophthalmic use.

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).

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 2% contains dorzolamide hydrochloride, a potent inhibitor of human carbonic anhydrase II. Following topical ocular administration, dorzolamide hydrochloride ophthalmic solution 2% reduces elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Unlike miotics, dorzolamide hydrochloride ophthalmic solution 2% reduces intraocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction. Unlike topical beta-blockers, dorzolamide hydrochloride ophthalmic solution 2% has minimal or no effect on pulse rate or blood pressure.

Topically applied beta-adrenergic blocking agents also reduce IOP by decreasing aqueous humor secretion but by a different mechanism of action. Studies have shown that when dorzolamide hydrochloride ophthalmic solution 2% is added to a topical beta-blocker, additional reduction in IOP is observed; this finding is consistent with the reported additive effects of beta-blockers and oral carbonic anhydrase inhibitors.

9.2 Pharmacokinetics

Absorption: Unlike oral carbonic anhydrase inhibitors, topically-applied Dorzolamide Eye Drops BP exerts its effects at substantially low doses and therefore with less systemic exposure. When applied topically, dorzolamide reaches the systemic circulation.

Distribution: 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 selective binding to CA-II while extremely low concentrations of free drug in plasma are maintained.

Metabolism: The parent drug forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent drug but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%).

Elimination: Dorzolamide is excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs in a non-linear manner, 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 maximum 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 4 mg/day closely approximates the maximum amount of dorzolamide delivered by topical ocular administration of dorzolamide hydrochloride 2% t.i.d. Dorzolamide and metabolite reached steady state by 4 and 13 weeks, respectively, and the following observations were noted:

• In plasma, concentrations of dorzolamide and metabolite were generally below the assay limit of quantitation (15nM) indicating almost no free drug or metabolite;

• In RBCs, dorzolamide concentrations approached the binding capacity of CA-II (20-25

  μM) and metabolite concentrations approached 12-15 μM, well below the binding capacity of CA-I (125-155 μM);

• In RBCs, inhibition of CA-II activity and total carbonic anhydrase activity was below the degree of inhibition anticipated to be necessary for a pharmacological effect on renal function and respiration.

10 STORAGE, STABILITY AND DISPOSAL

Dorzolamide Eye Drops BP Ophthalmic Solution:

Store at 15°C-30°C. Protect from light. Once opened, the bottle may be stored at 15°C-30°C for up to 40 days. Discard unused portion 40 days after opening.

PART II: SCIENTIFIC INFORMATION

11 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: dorzolamide hydrochloride

Chemical name: (4S, 6S)-4-(Ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulphonamide 7,7-dioxide hydrochloride. Dorzolamide hydrochloride is optically active.

Molecular formula and molecular mass: C₁₀H₁₇ClN₂O₄S₃, 360.9 g/mol

Structural formula:

Physicochemical properties:

Description: Dorzolamide hydrochloride is a white to off-white, free flowing crystalline powder, which is soluble in water, slightly soluble in methanol and very slightly soluble in anhydrous ethanol and has a melting point of about 283-285.5°C.

The specific rotation is α^25° (C=1, water) = ~ -17°. 405

12 CLINICAL TRIALS

12.1 Trial Design and Study Demographics

The efficacy of dorzolamide hydrochloride as monotherapy in patients with glaucoma or ocular hypertension (baseline IOP >23 mmHg) was demonstrated in clinical studies of up to one-year duration. The IOP-lowering effect of dorzolamide hydrochloride was demonstrated throughout the day and this effect was maintained during long-term administration.

In a small study, patients were treated for a total of twelve days. Patients (N=18) who received dorzolamide hydrochloride 2% t.i.d. for the last seven days of the study experienced the following mean percent reductions in IOP: 21% at morning trough (prior to first dose), 22% at peak (two hours post-dose), 18% at afternoon trough (eight hours post-dose) and 19% at the end of the day (four hours after the afternoon dose).

The efficacy of dorzolamide hydrochloride as monotherapy was further demonstrated in two large clinical trials. In a one-year controlled trial (N=523), dorzolamide hydrochloride 2% t.i.d. (N=313) was compared with betaxolol 0.5% (N=107) and timolol 0.5% (N=103) administered b.i.d. At the end of the trial, the mean percent reductions in IOP at peak and afternoon trough (for dorzolamide hydrochloride), respectively, were as follows: dorzolamide hydrochloride = 23% and 17%; betaxolol = 21% and 15%; timolol =25% and 20%. The mean percent reductions in IOP at peak did not differ significantly among treatment groups. At afternoon trough, the mean percent reduction in IOP for timolol was significantly greater (p < 0.05) than either dorzolamide hydrochloride or betaxolol, but no significant difference was observed between dorzolamide hydrochloride and betaxolol.

In a dose-response study (N=333), dorzolamide hydrochloride was compared with placebo during a six-week phase, followed by one year of treatment with dorzolamide hydrochloride. At six weeks, patients on dorzolamide hydrochloride 2% t.i.d. (N=86) had mean percent reductions in IOP at morning trough and peak of 13% and 16%, respectively, which were significantly greater (p < 0.01) than those observed with placebo. During extension treatment (N=160) with dorzolamide hydrochloride 2% t.i.d. as monotherapy for up to one year, efficacy was consistent with the six week findings; mean percent reductions in IOP from prestudy at morning trough and peak were 15% and 18%, based on last evaluation on monotherapy.

Adjunctive Therapy to Beta-Blockers

The efficacy of dorzolamide hydrochloride as adjunctive therapy in patients with glaucoma or ocular hypertension (IOP ≥ 22 mmHg while receiving ophthalmic beta-blockers) was demonstrated in clinical studies of up to one-year duration. The IOP-lowering effect of dorzolamide hydrochloride as adjunctive therapy was demonstrated throughout the day and this effect was maintained during long-term administration.

In a one-week placebo-controlled study (N=32), when patients (N=16) on timolol 0.5% b.i.d. had dorzolamide hydrochloride 2% b.i.d. added to their treatment regimen, they experienced the following additional mean percent reductions in IOP: 17% at morning trough, 21% at peak (one hour post- dose), 13% at evening trough (twelve hours post-dose).

In a six-month dose-comparison study (N=261) in patients receiving timolol 0.5% b.i.d., the additive ocular hypotensive effect of dorzolamide hydrochloride 2% b.i.d. (N=89) was compared to that of pilocarpine 2% q.i.d (N=44). Both drugs showed comparable efficacy as adjunctive therapy over the six-month treatment period. The following additional mean percent reductions in IOP at morning trough and peak (two hours post-dose) were observed at six months: dorzolamide hydrochloride =13% and 11%; pilocarpine = 10% and 10%.

Finally, over the course of one year in the beta-blocker comparison study described under Clinical Trials (N=523), a subset of 59 patients receiving timolol or betaxolol required additional medication for IOP reduction.

Dorzolamide hydrochloride 2% b.i.d. was added and at the end of the study these patients had experienced additional mean percent reductions at peak (two hours post-dose) of 14 to 19%, and eight hours post-dose of 13 to 14%.

13 NON-CLINICAL TOXICOLOGY

Acute Toxicity

The oral LD₅₀ of the drug is 1 320 mg/kg (3 960 mg/m²) in mice and 1 927 mg/kg (11 369 mg/m²) in female rats.

Chronic Toxicity

In repeated oral dose toxicity studies of dorzolamide hydrochloride in rodents, dogs and monkeys, the following effects were noted.

An increased incidence of urothelial hyperplasia was noted in rats and mice. This is a class- effect of carbonic anhydrase inhibitors (CAIs) specific to rodents and is secondary to increased urinary sodium, potassium, pH and crystals.

Another class effect of CAIs seen only in rodents was renal papillary cytoplasmic granularity associated with potassium depletion in the kidney. No-effect levels for these microscopic changes were not observed. However, these findings are rodent specific and not seen in monkeys at oral doses up to 50 mg/kg/day (625 times the maximum recommended human ophthalmic dose).

Metabolic acidosis and the related gastric mucous neck cell hyperplasia were seen in dogs and monkeys. In dogs, the gastric change was seen at a dose as low as 0.2 mg/kg/day in a one-month study, but disappeared with continued dosing and was absent at one year at a dose as high as 2 mg/kg/day. In monkeys in a one-month study, the gastric change was seen at a dose of 50 mg/kg/day orally, but no effects were seen at 10 mg/kg/day orally, or when 0.4 mg/kg/day (~5 times the maximum recommended human ophthalmic dose) was applied topically to the eye for one year.

Another high dose phenomenon observed in dogs and monkeys (doses ≥ 1.5 mg/kg/day and 50 mg/kg/day, respectively) in short term studies was decreased remodeling of bone, probably as a result of inhibition of carbonic anhydrase in osteoclasts. Longer term studies in dogs showed the change was transient.

Marginal nonprogressive decreases in some erythroid parameters were seen in dogs and monkeys at dorzolamide plasma levels of 50 ng/mL in dogs and 1660 ng/mL in monkeys. The plasma levels of dorzolamide in humans given the maximum recommended ophthalmic dose are generally ≤ 5 ng/mL.

Carcinogenicity

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 (250 times the maximum recommended human ophthalmic dose). Papillomas were not seen in rats given oral doses equivalent to approximately twelve times the maximum recommended human ophthalmic dose. 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 (~900 times the maximum recommended human ophthalmic dose).

The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class- effect of carbonic anhydrase inhibitors in rats and is secondary to increased urinary sodium, potassium, pH and crystals, all changes induced by carbonic anhydrase inhibitors. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria and sodium salts of diverse compounds that are inert when given as calcium salts.

No changes in bladder urothelium were seen in dogs given oral dorzolamide for one year at 2 mg/kg/day or monkeys given oral dorzolamide for one month at 50 mg/kg/day (the urothelial changes in the bladder occurred with oral dosing in rats within one month). In addition, monkeys dosed topically to the eye with 0.4 mg/kg/day (~5 times the maximum recommended human ophthalmic dose) for one year had no urothelial changes in the bladder.

Mutagenicity

Dorzolamide hydrochloride was devoid of mutagenic potential when evaluated in the following 5 tests: (1) in vivo (mouse) in the cytogenetic assay at doses up to 500 mg/kg/day (6 250 times the maximum recommended human ophthalmic dose); (2) in vitro in the chromosomal aberration assay; (3) in the alkaline elution assay; (4) in the V-79 assay (doses up to 10 µM); and (5) in the Ames test, in which the highest concentration of dorzolamide hydrochloride used, 10 000 µg/plate, did not result in a two-fold or greater increase in revertants with tester strains of S. typhimurium and E. coli.

Reproduction

In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on males or females at doses up to 188 or 94 times, respectively, the maximum recommended human ophthalmic dose.

Development

There were no treatment-related fetal malformations in developmental toxicity studies with dorzolamide hydrochloride in rats at oral doses up to 10 mg/kg/day (125 times the maximum recommended human ophthalmic dose). Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥ 2.5 mg/kg/day (31 times the maximum recommended human ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred only at doses that caused metabolic acidosis with resultant decreased body weight gain in dams and decreased fetal weights. These malformations, seen only at maternotoxic doses, appear to be a class-effect related to a combination of electrolyte and acid-base changes: decreased venous HCO_3-, decreased venous pH and decreased serum potassium.

No treatment- related malformations were seen at 1.0 mg/kg/day (13 times the maximum recommended human ophthalmic dose). Acetazolamide, an oral carbonic anhydrase inhibitor, causes skeletal malformations in rats and rabbits by a similar mechanism.

In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain of 5 to 7% in offspring at an oral dose of 7.5 mg/kg/day (94 times the maximum recommended human ophthalmic dose), were seen during lactation. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings), secondary to lower fetal body weight, was noted at 7.5 mg/kg/day (94 times the maximum recommended human ophthalmic dose).

14 SUPPORTING PRODUCT MONOGRAPHS

TRUSOPT^® (sterile ophthalmic solution, dorzolamide 2% weight/volume), submission control 241417, Product Monograph, Elvium Life Sciences. (Aug 26, 2020).