Dorzolamide is a carbonic anhydrase inhibitor ophthalmic solution indicated in the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. A related carbonic anhydrase inhibitor, acetazolamide, has poor penetration when applied to the cornea, and thus is only administered systemically. Dorzolamide represents the culmination of a decade of research for an effective topical carbonic anhydrase inhibitor. Dorzolamide proved to be the most potent inhibitor in the group studied, showing good tolerability and effective lowering of IOP. Since dorzolamide is not a beta-blocker, bradycardia and/or hypotension are less likely. Dorzolamide is a sulfonamide derivative and should not be administered to patients with sulfonamide hypersensitivity. Dorzolamide 2% ophthalmic solution was approved by the FDA in 1994.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Ophthalmic Administration
-Before the initial use, make sure the safety strip on the front of the bottle is unbroken. Once confirmed, tear off the safety strip to break the seal.
-Wash hands before each use.
-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; doing so will keep the dispenser from working properly.
-Care should be taken to avoid contamination. Do not touch the tip of the dropper to the eye, fingertips, or other surfaces.
-Tilt the head back slightly and pull the lower eyelid down with the index finger to form a pouch.
-Turn dispenser upside down and press lightly with the thumb and index finger over the "Finger Push Area". Squeeze the prescribed number of drops into the pouch and gently close eyes for 1 to 2 minutes. Do not blink.
-Replace the cap by turning it until it is firmly touching the dispenser. The arrow on the left side of the cap must be lined up with the arrow on the left side of the dispenser label for it to be closed correctly; DO NOT over tighten.
-Remove contact lenses prior to administration. Contact lenses may placed back into the eye 15 minutes post-dose.
-The solution may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.
Carbonic anhydrase activity has been observed in the corneal endothelium, but the effect of long-term administration of dorzolamide has not been evaluated. The adverse reactions have not been evaluated beyond one-year of treatment and study in clinical trials.
Choroidal detachment has been reported with administration of dorzolamide following filtration surgery.
The most frequently reported adverse reactions with ophthalmic dorzolamide in adults are localized reactions and include ocular irritation, reported in approximately one-third of patients and manifested as burning, stinging, or discomfort. These effects are generally transient and occur immediately after administration. In a 3 month, controlled multicenter study in pediatric patients, the adverse event profile was comparable to that seen in adult patients. About 25% of patients reported dysgeusia, or a bitter taste, after ophthalmic instillation. Dorzolamide produced superficial punctate keratitis in 10 to 15% of patients, with 10% of patients reporting some type of allergic ocular reaction. Incidence of bacterial keratitis has been attributed to inadvertent contamination of multi-dose containers. Adverse reactions reported by 1 to 5% of patients include blurred vision, excessive lacrimation, photophobia, conjunctivitis, lid reactions, eye redness, and xerophthalmia.
Patients with low corneal endothelial cell counts are at increased risk for the development of corneal edema after the administration of dorzolamide.
The possibility of systemic adverse reactions to dorzolamide is small, but there have been reports of headache, nausea, asthenia, and fatigue. Reactions that present with even lower frequency include dizziness, paresthesias, ocular pain, transient myopia, eyelid crusting, dyspnea, skin rash, iridocyclitis, and urolithiasis. Contact dermatitis, xerostomia (dry mouth), epistaxis, and throat irritation have been reported during post-market surveillance, and were reported in less than 1% during clinical trials.
Signs and symptoms of systemic allergic reactions (anaphylactoid reactions) have been reported in less than 1% of patients in clinical trials, and in clinical practice, with ophthalmic administration of dorzolamide including: anaphylactoid reactions, bronchospasm, pruritus, angioedema, urticaria, and localized and generalized rash (unspecified).
Dorzolamide is a sulfonamide and can be absorbed systemically. Sulfonamides can produce severe, possibly fatal, reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Although not reported with dorzolamide, administration of sulfonamides by any route can precipitate a possibly severe reaction in sulfonamide-sensitive patients. The use of dorzolamide should be discontinued if there is any sign of these reactions or a hypersensitivity reaction.
Patients with low corneal endothelial cell counts are at increased risk for the development of corneal edema. Dorzolamide should be used cautiously in these patients.
Dorzolamide should not be administered to patients with carbonic anhydrase inhibitor hypersensitivity. Since dorzolamide is a sulfonamide derivative, it should not be used in patients with sulfonamide hypersensitivity. Topical administration of dorzolamide can result in systemic absorption. Although not reported with dorzolamide, administration of sulfonamides by any route can precipitate a possibly severe reaction in sulfonamide-sensitive patients.
The management of patients with acute closed-angle glaucoma requires therapeutic interventions in addition to ocular hypotensive agents.
Dorzolamide is formulated with the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Remove contact lenses before administering the ophthalmic solution. Contact lenses may be reinserted 15 minutes post-dose.
The use of multiple dose containers of ophthalmic products has been associated with bacterial keratitis. Inadvertent contamination of the product may occur if the patient has an ocular infection, or corneal abrasion. If there is any damage to the ocular epithelial surface, dorzolamide should be used with caution.
Dorzolamide should be used with caution in patients with hepatic disease. There have been no studies on safe use in patients with hepatic impairment.
Dorzolamide is primarily excreted by the kidney, with a prolonged terminal half-life. Use of dorzolamide is not recommended in patients with renal impairment. No evaluations have been made as to safe use in patients with a CrCl less than 30 mL/min. Adverse effects due to dorzolamide are generally more frequent and likely to be severe among geriatric patients. The manufacturer states that no overall differences in the safety or effectiveness of dorzolamide have been observed between elderly and younger patients.
There are no adequate and well-controlled studies of dorzolamide use in human pregnancy. Dorzolamide caused fetal vertebral malformations when administered orally to rabbits at 2.5 mg/kg/day (37 times higher than the lower limit of detection in human plasma following ocular administration). Dorzolamide administered during the period of organogenesis was not teratogenic in rabbits dosed up to 1 mg/kg/day (15 times higher than the lower limit of detection in human plasma following ocular administration). Dorzolamide hydrochloride administered orally to rats during late gestation and lactation caused growth delays in offspring at 7.5 mg/kg/day (52 times higher than the lower limit of detection in human plasma following ocular administration). Growth was not delayed at 1 mg/kg/day (8 times higher than the lower limit of detection in human plasma following ocular administration). Systemic absorption of dorzolamide is low following topical administration; plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15 nM).
There are no data on the presence of dorzolamide in human milk, the effects on the breastfed infant, or the effects on milk production. Dorzolamide was present in the milk of lactating rats following oral administration. However, systemic absorption of dorzolamide is low following topical administration; plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15 nM). The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for dorzolamide and any potential adverse effects on the breast-fed child from dorzolamide.
Safety and IOP-lowering effects of dorzolamide have been established in pediatric patients; however, safety and efficacy of treatment beyond 3 months in duration have not been established in this population. Dorzolamide was shown to be generally well-tolerated and effective in neonates, infants, and children 1 week to younger than 6 years with elevated intraocular pressure or glaucoma in a 3-month, multicenter, double-masked, active-treatment-controlled trial.
For the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma:
Ophthalmic dosage:
Adults: Instill 1 drop of a 2% solution into the affected eye(s) 3 times daily.
Adolescents, Children, Infants, and Neonates 1 week to 17 years: Instill 1 drop of a 2% solution into the affected eye(s) 3 times daily. NOTE: The safety and efficacy of treatment durations longer than 3 months has not been established in pediatric patients.
Maximum Dosage Limits:
-Adults
3 drops/day per affected eye.
-Geriatric
3 drops/day per affected eye.
-Adolescents
3 drops/day per affected eye.
-Children
3 drops/day per affected eye.
-Infants
3 drops/day per affected eye.
-Neonates
1 week and older: 3 drops/day per affected eye.
Younger than 1 week: Safety and efficacy have not been established
Patients with Hepatic Impairment Dosing
Specific dosage guidelines are not available; it appears that no dosage adjustment is needed. Dorzolamide should be used with caution in patients with hepatic impairment; data are lacking in these patients.
Patients with Renal Impairment Dosing
CrCl 30 mL/min or greater: Specific dosage guidelines are not available.
CrCl less than 30 mL/min: Dorzolamide has not been studied in these patients. Because dorzolamide and its metabolites are excreted primarily by the kidney, use is not recommended in these patients.
*non-FDA-approved indication
There are no drug interactions associated with Dorzolamide products.
Dorzolamide is a highly specific inhibitor of an isoenzyme of carbonic anhydrase, CA-II. 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). Following administration of dorzolamide to the eye, intraocular pressure is lowered, reducing the risk of nerve damage and visual field loss in patients with pathologic elevations of intraocular pressure. The plateau of the dosage curve occurred with the 2% concentration. Dorzolamide appears to have no clinically significant biochemical or hematologic effects when administered topically to the eye.
Dorzolamide is administered as an ophthalmic solution. Dorzolamide accumulates in RBCs, where it binds strongly to CA-II, and weakly to CA-I. The metabolite has less affinity for CA-II and is less selective than dorzolamide, but also binds to CA-I. Total carbonic anhydrase activity inhibition is 81 to 88% (94 to 96% in RBCs). Steady state concentrations in RBCs were reached after four weeks. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide and the metabolite are primarily excreted unchanged in the urine. Systemically-absorbed 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.
-Route-Specific Pharmacokinetics
Other Route(s)
Ophthalmic Route
Following topical administration to the eye, there is some systemic absorption of dorzolamide; however, plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15 nM).
-Special Populations
Renal Impairment
Patients with a moderate impairment of renal function (CrCl 30 to 60 mL/min) had higher concentration of metabolite in RBCs. Studies have not been undertaken to determine the effect of dorzolamide in patients with impaired renal function.