1 mL of eye drop solution contains dorzolamide hydrochloride 22.26 mg equivalent to dorzolamide 20 mg.
Excipients/Inactive Ingredients: Mannitol, Sodium citrate dihydrate, Hydroxyethylcellulose, Benzalkonium chloride, Sodium hydroxide solution and water for injection.
Pharmacology: Pharmacodynamics: Dorzolamide is carbonic anhydrase inhibitors for ophthalmic use. 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 carbonic dioxide and the dehydration of carbonic acid. In human, CA exists as a number of isoenzymes, the most active being CA-II, found primary in red blood cells (RBCs), but also in other tissues. Inhibition of CA in the ciliary processes of the ye 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 reduce elevated IOP by inhibiting CA-II. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.
Pharmacokinetics: When topically applied, dorzolamide reach the systemic circulation and accumulate in RBCs during chronic dosing as a result of binding to CA-II. Extensive distribution into RBCs yields a long half-life, approximately 3.5 to 4 months. The parent drugs form a single N-desethyl metabolite that inhibit CA-II less potently than the parent drug, but also inhibits CA-I. The metabolite also accumulates in RBCs, where it binds primary to CA-I. Plasma protein binding is moderate (approximately 33%) for dorzolamide. This agent is primary excreted unchanged in the urine, and the metabolite also is excreted in urine.
Toxicology: Preclinical safety data: 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 males 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 divers 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 reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at dose of 15 and 7.5 mg/kg/day, respectively. These doses represent estimated plasma C max levels in rats, 104 and 52 times higher than the lower limit of detection in human plasma following ocular administration, respectively.
Elevated intraocular pressure (IOP): Treatment of elevated IOP in patients with ocular hypertension or open-angle glaucoma.
Children and adults: Reduction of intraocular pressure: 1 drop in the affected eye(s) 3 times/day.
Dosage adjustment in hepatic impairment: No dosage adjustment provided in manufacturer's labeling (has not been studied); use with caution.
Dosage adjustment in renal impairment: Not recommended in patients with severe renal function impairment (creatinine clearance less than 30 mL/min).
Administration: If more than 1 ophthalmic drug is being used, administer the drugs at least 10 minutes apart.
Usage instructions: 1. Before using this medicine for the first time, make sure the safety strip on the front of the bottle is intact. There is a small gap between the bottle and the cap in an unopened bottle.
2. After tearing off the safety strip the cap can be removed.
3. To open the bottle, unscrew the cap by turning as indicated by the arrows on the top of the cap. The cap must not be pulled directly up and away from the bottle. Pulling the cap directly up would prevent your dispenser from operating properly.
4. The patient must tilt his/her head back and pull his/her lower eyelid down slightly to form a "pocket" between the eyelid and the eye.
5. The bottle should be inverted and pressed lightly with the thumb or index finger until a single drop is dispensed into the eye. The dropper tip must not touch the eye or eyelid.
6. If drop dispensing is difficult for the patient after opening for the first time, the patient should replace the cap on the bottle, tighten it and then remove it by turning the cap in the opposite direction as indicated by the arrows on the top of the cap.
7. If necessary, steps 4 and 5 should be repeated with other eye.
8. The cap should be replaced and bottle should be closed securely immediately after use. The arrow on the left side of the cap must be aligned with the arrow on the left side of the bottle label for proper closure. The cap must not be tightened excessively because the bottle and cap may get damaged.
9. The dispenser tip is designed to provide a single drop; due to that the hole of the dispenser tip must not be enlarged.
10. After dispensing all doses, a small amount of the medicine will remain in the bottle.
Electrolyte imbalance, development of an acidotic state and possible CNS effect may occur. Monitor serum electrolyte levels (particularly potassium) and blood pH levels. Significant lethality was observed in female rats and mice after single oral dose of 1927 and 1320 mg/kg of dorzolamide, respectively.
Hypersensitivity to dorzolamide or any component of this product.
Systemic effect: Dorzolamide is sulphonamides and, although administered topically, are absorbed systemically. Therefore, the same types of adverse reactions attributable to systemic sulphonamides may occur with topical administration of this agent. Fatalities have occurred, although rarely, because of severe reactions to sulphonamides including Steven-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulphonamide is re-administered regardless of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.
Corneal endothelium effects: Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. The effect of continued administration of dorzolamide on the corneal endothelium has not been fully evaluated.
Acute angle-closure glaucoma: The management of patients with acute angle-closure glaucoma therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide have not been studied in patients with acute angle-closure glaucoma.
Ocular effects: Local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide. 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, discontinue the drug and evaluate the patients before considering restarting the drug.
Concomitant oral carbonic anhydrase inhibitors: There is a potential for an additive effect on the known systemic effects of CA inhibition in patients receiving an oral CA inhibitor and dorzolamide. Concomitant administrative of ophthalmic and oral CA inhibitors is not recommended.
Bacterial keratitis: There have been reports of bacterial keratitis associated with the use of topical ophthalmic products in multiple-dose containers. 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. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
Contact lenses: The preservative used in this product, benzalkonium chloride, may be absorbed by soft contact lenses. Do not administer these agents while wearing soft contact lenses; reinsert lenses 15 minutes or longer after drug administration.
Effects on ability to drive and use machine: No information.
Use in Children: Safety and efficacy in children have not been established.
Use in Elderly: Of all the patients in dorzolamide clinical studies, 44% were 65 years of age or older, and 10% were 75 years of age or older. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals to the product cannot be rules out.
Pregnancy: Category C.
Maternal toxicity and significant increase in the number of fetal variations (eg. malformations of the vertebral bodies) was seen in animals at dose greater than 20 times the recommended human ophthalmic dose. These malformations occured at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights. There are no adequate and well controlled studies in pregnant woman. Use during pregnancy only if the potential benefit justifies the risk to the fetus.
Lactation: In lactating rats, decrease in body weight gain were seen in offspring with these agents at oral doses greater than 94 times the recommended human ophthalmic dose. A slight delay in postnatal development (incisor eruption, vaginal canalization, and eye openings), secondary to lower fetal body weight, also was noted with dorzolamide.
It is not known whether this drug is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Ocular burning, stinging or discomfort immediately following administration (approximately 33%); bitter taste following administration (approximate 25%); superficial punctate keratitis (10% to 15%); signs and symptoms of ocular allergic reactions (approximately 10%); blurred vision, tearing, dryness, photophobia (approximately 1% to 5%); headache, nausea, asthenia/fatigue (infrequent); skin rashes, urolithiasis, iridocyclitis (rare), dyspnea (frequency not known), foreign body sensation in eye (frequency not known).
Although acid-base and electrolyte disturbances were not reported in the clinical trials with dorzolamide, this disturbance has been reported with oral CA inhibitor and have, in some instances, resulted in drug interactions (eg. toxicity associated with high-dose salicylate therapy). Therefore, consider the potential for such drug interactions in patients receiving either of these agents.
Incompatibilities: No information.
S01EC03 - dorzolamide ; Belongs to the class of carbonic anhydrase inhibitors. Used in the treatment of glaucoma.
Ophth soln 20 mg/mL (sterile, slightly opalescent, nearly colorless, slightly viscous) x 1's.