COSOTIMOL

Dorzolamide is a non-bacteriostatic sulfonamide derivative and topical carbonic anhydrase (CA) inhibitor that treats elevated intraocular pressure (IOP) associated with open-angle glaucoma and ocular hypertension.

It works by blocking an enzyme in the ciliary process that regulates ion balance and fluid pressure in the eyes.

Unlike oral

CA inhibitors, dorzolamide has negligible effects of acid-base or electrolyte disturbances and other systemic adverse effects.

First marketed in 1995, 5 dorzolamide is available in ophthalmic solutions as monotherapy marketed as Trusopt 6 or in combination with timolol as Cosopt PF.

Dorzolamide is indicated for the management of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

It can also be used in combination with timolol for the same indication in patients who are insufficiently responsive to ophthalmic beta-blockers.

Its pre-operative use was also investigated to prevent elevated intraocular pressure after neodynium yttrium aluminum garnet laser posterior capsulotomy.

Dorzolamide is a carbonic anhydrase inhibitor that reduces elevated intraocular pressure in open-angle glaucoma or ocular hypertension.

When used in combination with topic beta-adrenergic antagonists, dorzolamide has an additive effect of lowering intraocular pressure.

The peak ocular hypotensive effect of dorzolamide is observed at about 2 hours following ophthalmic administration.

Carbonic anhydrase 2 Inhibitor Carbonic anhydrase 4 Inhibitor Carbonic anhydrase 1 Inhibitor.

Dorzolamide readily penetrated into the eye in animal studies.

Upon ophthalmic administration, dorzolamide is absorbed via the cornea and stroma.

Dorzolamide is reported to be absorbed systematically following topical administration.

The systemic exposure of dorzolamide following long-term administration was assessed in healthy subjects receiving an oral dose of 2 mg dorzolamide twice daily, which equates to the ophthalmic dose of 2% dorzolamide three times daily.

In these subjects receiving the treatment for 20 weeks, the steady-state was reached within 8 weeks.

There is limited information on the volume of distribution of dorzolamide; however, the plasma concentrations of dorzolamide and its main metabolite are generally below the assay limit of quantitation, which is 15nM.

Dorzolamide accumulates in red blood cells following chronic administration as a result of binding to CA-II, which is contained in peripheral red blood cells (RBCs).

Dorzolamide is slowly metabolised to

N-desethyldorzolamide, which has a less potent pharmacological activity on CA-II and some inhibitory effect on CA-I.

Like the parent drug, N-desethyldorzolamide is also stored in RBCs, where it binds to CA-I. 1, 6 The findings of an in vitro study using liver microsomes from Sprague-Dawley rats suggest the involvement of CYP2B1, CYP2E1, and CYP3A2 in the metabolism of dorzolamide in rat liver.

Hover over products below to view reaction partners Dorzolamide N-desethyldorzolamide.

Dorzolamide is primarily excreted unchanged in the urine; however, N-desethyldorzolamide is also detected in the urine.

As the drug administration is stopped, dorzolamide stored in RBCs is washed out of RBCs in a non-linear fashion, 6 with the terminal elimination half-life of ≥120 days in RBCs.

This initial rapid decline in drug concentrations is followed by the slow elimination phase, where the elimination half-life of the drug is about >4 months.

There is limited information on the clearance rate of dorzolamide.

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The oral

LD of dorzolamide is 1927 mg/kg in rats and 1320 mg/kg in mice.

The subcutaneous

LD is >2 g/kg in both rats and mice.

Overdose may result in electrolyte imbalance, acidosis, and possibly central nervous system effects; these symptoms should be responded with appropriate supportive treatment.

It is advised that the patient's serum electrolyte (particularly potassium) levels and blood pH levels are monitored in the case of a suspected overdose.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with: Bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.

Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock.

Hypersensitivity to any component of this product. 4.1 Asthma, COPD Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease. 4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, and cardiogenic shock. 4.3 Hypersensitivity Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients who are hypersensitive to any component of this product.

& ADMINISTRATION The dose is one drop of dorzolamide hydrochloride and timolol maleate ophthalmic solution in the affected eye(s) two times daily.

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

The dose is one drop of dorzolamide hydrochloride and timolol maleate ophthalmic solution in the affected eye(s) two times daily.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP 2%/0.5% is supplied in 10mL a natural, LDPE plastic ophthalmic dispenser with a natural nozzle and a dark blue, tamper-evident cap.

NDC 71921-226-10, 10 mL in a 10 mL capacity bottle.

Store dorzolamide hydrochloride and timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) .

Protect from light.

After opening, dorzolamide hydrochloride and timolol maleate ophthalmic solution can be used until the expiration date on the bottle.

Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥ 2.5 mg/kg/day (37 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies.

These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights.

No treatment-related malformations were seen at 1 mg/kg/day (15 times the recommended human ophthalmic dose).

Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations.

Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring.

Doses of 1,000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions.

Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether dorzolamide is excreted in human milk.

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.

Because of the potential for serious adverse reactions from dorzolamide hydrochloride and timolol maleate ophthalmic solution 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.

The safety and effectiveness of dorzolamide hydrochloride ophthalmic solution and timolol maleate ophthalmic solution have been established when administered individually in pediatric patients aged 2 years and older.

Use of these drug products in these children is supported by evidence from adequate and well-controlled studies in children and adults.

Safety and efficacy in pediatric patients below the age of 2 years have not been established.

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