Dorzolamide hydrochloride

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DORZOLAMIDE HYDROCHLORIDE (DORZOLAMIDE HYDROCHLORIDE)

Composition:

Active substance: dorzolamide hydrochloride;

1 ml of solution contains dorzolamide hydrochloride equivalent to dorzolamide 20 mg;

Excipients: benzalkonium chloride solution, anhydrous citric acid, mannite (E 421), hypromellose, concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Anti-glaucoma preparations and miotics. Carbonic anhydrase inhibitors. Dorzolamide. ATC code S01E C03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Carbonic anhydrase (CA) is an enzyme present in many tissues of the body, including ocular tissues. In the human body, carbonic anhydrase exists in the form of several isoenzymes, among which carbonic anhydrase-II (CA-II) is the most active form, primarily present in erythrocytes and other tissues. Inhibition of carbonic anhydrase in the ciliary body of the eye reduces the secretion of aqueous humor. As a result, intraocular pressure (IOP) decreases.

The medicinal product Dorzolamide Hydrochloride contains dorzolamide hydrochloride, a potent inhibitor of carbonic anhydrase type II. After topical administration, dorzolamide reduces IOP, whether associated or not associated with glaucoma. Elevated intraocular pressure is the main risk factor for optic nerve damage or visual field loss. Dorzolamide does not cause miosis and reduces intraocular pressure without such side effects as night blindness or accommodative spasm. The effect of the drug on pulse rate and blood pressure is minimal or absent.

Topically applied beta-adrenergic blockers also reduce intraocular pressure but have a different mechanism of action. Therefore, combined use of beta-blockers with dorzolamide provides additive reduction of IOP. These data are consistent with reports on the additive effect of combining beta-blockers with oral carbonic anhydrase inhibitors.

Pharmacokinetics

Unlike oral carbonic anhydrase inhibitor drugs, dorzolamide hydrochloride acts directly in the eye after topical application at substantially lower doses and therefore has less pronounced systemic effects. In clinical studies, this resulted in reduced intraocular pressure without concomitant disturbances in acid-base balance or changes in electrolyte parameters, which are typical of oral carbonic anhydrase inhibitors.

After topical administration, dorzolamide reaches the systemic circulation. To assess the level of systemic carbonic anhydrase inhibition following topical application, concentrations of the active substance and metabolites in plasma and erythrocytes were measured, along with the degree of inhibition of carbonic anhydrase activity in erythrocytes. With prolonged use, dorzolamide accumulates in erythrocytes due to selective binding to CA-II, while extremely low concentrations of free active substance are maintained in plasma. One N-desethylated metabolite is formed from the active substance, which inhibits CA-II to a lesser extent than the parent compound but also inhibits the less active isoenzyme CA-I. The metabolite also accumulates in erythrocytes, where it binds predominantly to CA-I. Dorzolamide is moderately bound to plasma proteins (approximately 33%) and is excreted in urine (mainly in unchanged form), as is its metabolite. After discontinuation of treatment, nonlinear elimination of dorzolamide from erythrocytes occurs, initially resulting in a rapid decline in active substance concentration, followed by a slower elimination phase with a half-life of approximately 4 months.

Following oral administration aimed at simulating maximum systemic exposure to dorzolamide after prolonged topical ophthalmic use, steady-state conditions were achieved within 13 weeks. At steady state, neither free active substance nor metabolite was practically detectable in plasma; carbonic anhydrase inhibition in erythrocytes was lower than what is considered necessary for pharmacological effects on renal function or respiration. Similar pharmacokinetic results were observed after prolonged topical use of dorzolamide.

However, in some elderly patients with renal impairment (creatinine clearance 30–60 mL/min), concentrations of the metabolite in erythrocytes were higher, although this was not accompanied by significant differences in carbonic anhydrase inhibition; clinically significant systemic adverse reactions directly related to these findings were not observed.

Clinical characteristics.

Indications.

Treatment of elevated intraocular pressure in ocular hypertension or open-angle glaucoma.

Contraindications.

• Hypersensitivity to dorzolamide or to any of the components of the medicinal product;
• severe renal impairment (creatinine clearance less than 30 mL/min);
• hyperchloremic acidosis.

Interaction with other medicinal products and other forms of interaction.

Specific studies on drug interactions with dorzolamide have not been conducted.

There have been reports of concomitant use of dorzolamide without any signs of adverse reactions due to interaction with the following agents: timolol ophthalmic solution; betaxolol ophthalmic solution; systemic medicinal products, including ACE inhibitors, calcium channel blockers, diuretics, NSAIDs (including acetylsalicylic acid), and hormones (such as estrogen, insulin, thyroxine).

During glaucoma treatment, the interaction between concomitant use of dorzolamide and miotics or adrenergic agonists has not been adequately studied.

Dorzolamide is a carbonic anhydrase inhibitor which, when administered topically, is also systemically absorbed. During treatment with this medicinal product, disturbances in acid-base balance have not been observed. However, such disturbances have been reported with oral carbonic anhydrase inhibitors, and in some cases, these disturbances occurred as a result of drug interactions (e.g., toxic reactions in patients receiving high doses of salicylates). Such an interaction should be considered when treating with dorzolamide.

Special precautions for use.

There are no data on the use of dorzolamide in patients with hepatic insufficiency; therefore, the drug should be prescribed with caution in such patients.

The treatment of patients with acute angle-closure glaucoma involves additional therapy besides the use of intraocular pressure-lowering agents. The use of dorzolamide in patients with acute angle-closure glaucoma has not been studied.

Dorzolamide contains a sulfonamide group, similar to systemic sulfonamides, and despite topical administration, it is absorbed into the systemic circulation. Therefore, when dorzolamide is used topically, adverse effects typical of sulfonamide intake may occur, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If severe reactions or hypersensitivity occur, the drug should be discontinued immediately.

The use of oral carbonic anhydrase inhibitors has been associated with the development of urolithiasis due to disturbances in acid-base balance, particularly in patients with a history of nephrolithiasis. Although acid-base imbalances have not been observed with dorzolamide, rare cases of urolithiasis have been reported. Since dorzolamide, as a topically applied carbonic anhydrase inhibitor, is systemically absorbed, patients with a history of nephrolithiasis who are using dorzolamide are at increased risk of developing urolithiasis.

If allergic reactions occur (e.g., conjunctivitis or eyelid reactions), discontinuation of the drug should be considered.

Concomitant use of dorzolamide may potentiate the known effects of oral carbonic anhydrase inhibitors. Therefore, concomitant use of oral carbonic anhydrase inhibitors and dorzolamide is not recommended.

Corneal edema and irreversible corneal decompensation have been reported with dorzolamide use in patients with pre-existing chronic corneal abnormalities and/or a history of intraocular surgery. Dorzolamide for topical use should be prescribed with caution in such patients.

Cases of ciliary body detachment associated with ocular hypotony have been reported following filtration procedures using aqueous suppressants.

Dorzolamide contains benzalkonium chloride, which may cause eye irritation. Contact lenses should be removed before instilling the solution and should not be reinserted earlier than 15 minutes after administration. Benzalkonium hydrochloride is known to discolor soft contact lenses.

Use in pediatrics.

Studies on dorzolamide have been conducted in patients with a gestational age of less than 36 weeks and up to one year of age. Dorzolamide should be used in patients with significantly immature renal tubules only after careful assessment of the benefit-risk ratio, due to the potential risk of metabolic acidosis.

Use during pregnancy or breastfeeding.

Dorzolamide should not be used during pregnancy, as adequate clinical data on its use in pregnant women are lacking.

It is unknown whether dorzolamide is excreted in human milk; therefore, it should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Since dorzolamide may cause dizziness, nausea, and visual disturbances, potentially hazardous activities requiring concentration and increased psychomotor reaction speed should be avoided during treatment, especially at the beginning of therapy.

Method of administration and dosage.

In monotherapy, 1 drop of dorzolamide is administered into the conjunctival sac of the affected eye(s) 3 times daily.

The drug may be used concomitantly with other ophthalmic medicinal products for reducing intraocular pressure.

When using more than one topical ophthalmic agent, the products should be instilled with an interval of at least 10 minutes.

When switching from other ophthalmic agents to dorzolamide, the previously used drug should be discontinued and treatment with dorzolamide started the following day.

Patients should be given appropriate instructions: to wash hands before administration and to avoid contact of the container dropper tip with the eyes or adjacent areas. Patients should also be advised that improper use may result in contamination of eye drops with bacteria, which can cause ocular infections. Use of contaminated solutions may lead to serious eye damage and subsequent vision loss.

Children. Since clinical data on the use of dorzolamide eye drops in children are limited, this drug is not recommended for use in pediatric patients.

Overdose.

Only limited data are available regarding accidental or intentional overdose following oral administration of dorzolamide hydrochloride eye drops.

Symptoms. Somnolence has been reported after oral ingestion. With topical administration, nausea, dizziness, headache, weakness, unusual dreams, and dysphagia have been reported.

Treatment is symptomatic and supportive. Electrolyte imbalance, development of acidosis, and central nervous system disturbances may occur. Monitoring of serum electrolyte levels (particularly potassium) and blood pH parameters is required.

Adverse Reactions

Nervous system disorders: headache, dizziness, paresthesia.

Ophthalmological disorders: burning and stinging sensation, superficial punctate keratitis, lacrimation, conjunctivitis, eyelid inflammation, eye itching, eyelid irritation, blurred vision, iridocyclitis, ocular irritation including redness, eye pain, eyelid scaling, transient myopia (resolves after discontinuation of treatment), corneal edema, decreased intraocular pressure, ciliary detachment following filtration surgery.

Respiratory, thoracic and mediastinal disorders: epistaxis, dyspnea.

Gastrointestinal disorders: nausea, bitter taste, throat irritation, dry mouth.

Skin and subcutaneous tissue disorders: contact dermatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, skin rash.

Renal and urinary disorders: urolithiasis.

General disorders and administration site conditions: asthenia/weakness, hypersensitivity: local reaction symptoms (palpebral reactions) and systemic allergic reactions, including angioedema, respiratory distress, rarely bronchospasm.

Laboratory test results: dorzolamide use has not been associated with clinically significant electrolyte disturbances.

Shelf life. 2 years.

Shelf life after first opening of the bottle – 4 weeks.

Storage conditions.

Store in the original packaging (to protect from light) at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

5 ml solution in a bottle, 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Alcon Parenterals (India) Limited, India / Ahlcon Parenterals (India) Limited, India.

Manufacturer's address and place of business.

SP-918, Phase-III, RIICO Industrial Area, Bhiwadi, Dist. Alwar (Rajasthan), 301 019, India / SP-918, Phase-III, RIICO Industrial Area, Bhiwadi, Dist. Alwar (Rajastan), 301 019, India.

Marketing Authorization Holder. SCAN BIOTECH LTD, India / SCAN BIOTECH LTD, India.

Address of the Marketing Authorization Holder.

E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India / E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India.