Dorzol®

INSTRUCTIONS for medical use of the medicinal product DORZOL® (DORZOL®)

Composition:

active substance: dorzolamide;

1 ml of the preparation contains dorzolamide hydrochloride 22.3 mg, equivalent to 20 mg of dorzolamide;

excipients: benzalkonium chloride, mannitol (E 421), sodium citrate, sodium hydroxide,
hydroxyethylcellulose, purified water.

Pharmaceutical form.

Eye drops, solution.

Main physicochemical properties: clear, colourless or almost colourless liquid.

Pharmacotherapeutic group.

Ophthalmological agents. Anti-glaucoma agents and miotics. Carbonic anhydrase inhibitors. Dorzolamide.

ATC code S01E C03.

Pharmacological properties.

Pharmacodynamics.

Carbonic anhydrase (CA) is an enzyme present in many tissues, including ocular tissues. In humans, CA exists in several isoenzymes, of which CA II is the most active. CA II is predominantly found in erythrocytes but is also present in other tissues. Inhibition of CA in the ciliary processes of the eye reduces aqueous humor secretion, primarily by slowing the formation of bicarbonate ions, followed by a reduction in sodium and fluid concentration. As a result, intraocular pressure is lowered.

Dorzolamide is a potent inhibitor of human CA II. After administration, it reduces intraocular pressure regardless of whether it is associated with glaucoma or not. Elevated intraocular pressure is the major risk factor in the pathogenesis of optic nerve damage and visual field loss in glaucoma. Intraocular pressure is reduced without the typical side effects of miotics, such as night blindness, accommodation spasm, and pupillary constriction. Dorzolamide has no effect on pulse or blood pressure, or such effects are minimal.

Topical application of beta-blockers also reduces intraocular pressure by decreasing aqueous humor production and through other mechanisms of action. Studies have shown that concomitant use of dorzolamide with a topical beta-blocker provides additional reduction in intraocular pressure. This phenomenon confirms the previously known additive effect of beta-blockers and carbonic anhydrase inhibitors.

Pharmacokinetics.

Unlike orally administered carbonic anhydrase inhibitors, topical application of dorzolamide allows the active substance to act directly on the eye, even when used in small doses, thereby minimizing systemic effects. In this way, intraocular pressure can be reduced without disrupting acid-base balance and electrolyte equilibrium, which are commonly associated with systemic carbonic anhydrase inhibitors.

Dorzolamide enters the systemic circulation even with topical application. To assess the extent of systemic carbonic anhydrase inhibition following topical administration, concentrations of the active substance and its metabolites in plasma and erythrocytes, as well as inhibition of carbonic anhydrase activity in erythrocytes, were measured. Dorzolamide accumulates in erythrocytes during prolonged use due to selective binding to CA II, while in plasma it remains in free form at very low concentrations. One N-desethyl metabolite is formed from the parent compound, which is less potent in inhibiting CA II activity than the parent substance but also inhibits the less active isoenzyme (CA I). The metabolite also accumulates in erythrocytes, where it initially binds to CA I. Dorzolamide is bound to plasma proteins (approximately 33%). It is primarily excreted in urine, mainly in unchanged form. The metabolite is also excreted in urine. After discontinuation of the drug, dorzolamide is eliminated nonlinearly from erythrocytes, with an initial rapid decline in concentration followed by a slower elimination phase with an elimination half-life of approximately 4 months.

Similar pharmacokinetic results have been obtained with long-term topical use of dorzolamide. In some elderly patients with impaired renal function and creatinine clearance (CrCl) of 30–60 mL/min, increased concentrations of metabolites in erythrocytes have been observed; however, there is no difference in the degree of carbonic anhydrase inhibition or in clinically significant systemic adverse effects.

Clinical characteristics.

Indications.

Dorzol® is used for the treatment of elevated intraocular pressure in patients with:

• ocular hypertension;
• open-angle glaucoma;
• pseudoexfoliative glaucoma;

as adjunctive therapy to beta-blockers or as monotherapy when treatment with beta-blockers has not been successful or beta-blockers are contraindicated.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients;
• severe renal impairment (CrCl < 30 mL/min);
• hyperchloremic acidosis.

Interaction with other medicinal products and other forms of interaction.

The potential for interaction of Dorzol® eye drops with other medications has not been studied.

No adverse interactions were observed during concomitant use of dorzolamide with the following agents: timolol and betaxolol eye drops, systemic medications – angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs including acetylsalicylic acid, and hormones (e.g. estrogen, insulin, and thyroxine).

The interaction of dorzolamide with miotics and adrenergic agonists during glaucoma treatment has not been fully studied.

Dorzolamide potentiates the effect of other antiglaucoma agents. Acetazolamide taken orally increases the risk of systemic adverse effects of dorzolamide. The effect of cholinesterase inhibitors such as physostigmine, galantamine, neostigmine, or pyridostigmine (commonly used in myasthenia gravis) may be reduced by dorzolamide.

Concomitant use with diuretics may lead to significant potassium loss.

Concomitant use with phenytoin may worsen the course of osteoporosis.

Salicylic acid used together with dorzolamide may lead to the development of acidosis. In addition, the preservative contained in dorzolamide eye drops (benzalkonium chloride) may interact with soft contact lenses.

Special precautions for use

Patients with acute closed-angle glaucoma require concomitant use of other medications aimed at reducing intraocular pressure. The use of Dorzol® eye drops in patients with acute closed-angle glaucoma has not been studied.

As with all topically applied ophthalmic medications, systemic absorption of the drug may occur. Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, with topical administration, adverse effects associated with systemic use of sulfonamide drugs may occur, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of acute reactions or hypersensitivity occur, administration of the drug should be discontinued.

If signs of allergic reactions (conjunctivitis, eyelid reactions) appear, consideration should be given to discontinuing the use of Dorzol® eye drops.

Treatment with oral carbonic anhydrase inhibitors is associated with an increased risk of urolithiasis due to disturbances in acid-base balance, especially in patients with a history of kidney stones. Although disturbances in acid-base balance have not been observed with the use of Dorzol® eye drops, rare cases of urolithiasis have been reported. Dorzolamide is a topically applied carbonic anhydrase inhibitor that may be systemically absorbed, and patients with a history of kidney stones are at increased risk of developing urolithiasis.

Patients receiving both oral carbonic anhydrase inhibitors and dorzolamide have an increased risk of additive systemic effects; therefore, concomitant use is not recommended.

Cases of corneal edema and irreversible corneal decompensation have been reported in patients with a prior history of chronic corneal epithelial defects and/or ocular surgery. Dorzolamide should be used with caution in such patients.

Uveitis with concomitant ocular hypotony may occur in patients treated with medications for prevention of aqueous leakage following filtration surgery.

Hepatic impairment

The use of Dorzol® in patients with impaired liver function has not been studied; therefore, the drug should be used with caution in such patients.

The eye drops contain benzalkonium chloride, which may cause eye irritation.

Direct contact with soft contact lenses should be avoided. Contact lenses must be removed prior to instillation of the medication and may be reinserted approximately 15 minutes later. The product may change the color of soft contact lenses.

Elderly patients

The recommended dosage applies also to elderly patients.

Use during pregnancy or breastfeeding

Dorzol® eye drops are not recommended during pregnancy.

Breastfeeding is not recommended during treatment with Dorzol® eye drops.

Ability to influence reaction speed when driving or operating machinery

The medicinal product may cause adverse effects such as blurred vision, dizziness, and nausea, which may impair the ability to drive or operate machinery.

During treatment, potentially hazardous activities requiring concentration and increased psychomotor reaction speed should be avoided, especially at the beginning of therapy.

Method of Administration and Dosage

It is recommended to instill 1 drop of Dorzol**®** into the conjunctival sac of the affected eye 3 times daily when used as monotherapy.

Instill 1 drop into the medial canthus of each eye. Gently press on the tear duct area immediately after instillation to reduce the possibility of systemic absorption of Dorzol**®**. Systemic absorption is reduced by applying nasolacrimal occlusion or by closing the eyelids for 2 minutes. This may lead to a reduction in systemic adverse effects and an increase in local activity.

When the medication is used as adjunctive therapy, instill 1 drop of Dorzol**®** into the conjunctival sac of the affected eye twice daily in combination with a topical beta-blocker.

When switching from another glaucoma medication to Dorzol**®** drops, discontinue the previous medication at the end of its daily dosing regimen and begin treatment with Dorzol**®** drops the following day.

If multiple ophthalmic agents are used locally, they should be administered with an interval of 10 minutes between applications.

Patients should be advised to wash their hands before using the medication and to avoid touching the eye or surrounding surfaces with the dropper tip.

Patients should also be informed that improper handling of eye drops may result in bacterial contamination of the solution, which can lead to eye infections. The use of a contaminated solution may cause severe ocular damage and subsequent vision loss.

Children

Data on the use of the medication in children are limited; therefore, it is not recommended for use in pediatric patients.

Overdose

There are no data on accidental or intentional overdose of dorzolamide taken orally.

Symptoms

Drowsiness may occur when taken orally.

With topical administration, nausea, blurred vision, headache, fatigue, abnormal dreams, and dysphagia may be observed.

Treatment

Treatment of overdose should be symptomatic and supportive.

Possible disturbances in electrolyte levels, development of acidosis, and adverse effects on the central nervous system may occur. Electrolyte levels should be monitored.

Adverse Reactions

Nervous system disorders: Headache, dizziness, paraesthesia.

Eye disorders: Stinging and burning, superficial punctate keratitis, lacrimation, conjunctivitis, eyelid inflammation, eye pruritus, eyelid irritation, blurred vision, blepharitis, iridocyclitis, irritation and redness, eye pain, eyelid desquamation, transient myopia (which resolves after discontinuation of treatment), corneal edema, ocular hypotension, uveitis following filtration surgery, foreign body sensation in the eye.

Respiratory, thoracic and mediastinal disorders: Epistaxis, sinusitis, rhinitis, dyspnea.

Gastrointestinal disorders: Nausea and bitter taste in mouth, throat irritation, dry mouth.

Skin and subcutaneous tissue disorders: Contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Cardiac disorders:
Palpitations, which may be rapid or irregular, tachycardia – frequency cannot be estimated based on available data.

Renal and urinary disorders: Urolithiasis (urinary stones).

Vascular disorders: Hypertension – frequency cannot be estimated based on available data.

General disorders and administration site conditions: Asthenia/fatigue, signs and symptoms of hypersensitivity: local-palpebral reactions, angioneurotic edema, urticaria, pruritus, rash, anaphylaxis, and rarely bronchospasm.

Investigations: Dorzolamide administration has not been associated with clinically significant electrolyte imbalances.

Shelf life. 2 years.

Storage conditions.
Keep out of reach and sight of children. Store below 30 °C. After opening the bottle, the eye drops should be used within 4 weeks.

Packaging.
5 ml solution in a dropper bottle; 1 dropper bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.
Jadran-Galenski Laboratorij d.d. / Jadran-Galenski Laboratory d.d.

Manufacturer's address.
Svilno 20, 51000 Rijeka, Croatia