Dorzamed

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DORZAMED (DORZAMED)

Composition:

Active substance: dorzolamide;

1 ml of solution contains dorzolamide (as dorzolamide hydrochloride) 20 mg;

Excipients: hydroxyethylcellulose; mannitol (E 421); citric acid monohydrate; sodium hydroxide; benzalkonium chloride; sodium hydroxide; hydrochloric acid; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless, slightly viscous solution.

Pharmacotherapeutic group.

Antiglaucoma preparations and miotics. Carbonic anhydrase inhibitors. Dorzolamide.

ATC code S01E C03.

Pharmacological Properties

Pharmacodynamics

Dorzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II). Carbonic anhydrase (CA) is an enzyme present in many tissues, including ocular tissues. In humans, CA exists in several isoenzymes, the most active of which is CA-II. 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, leading to a subsequent reduction in sodium and fluid concentration, thereby lowering intraocular pressure (IOP).

After topical administration, dorzolamide reduces elevated IOP, whether associated or not associated with glaucoma. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Reduction of IOP with dorzolamide does not involve the widespread adverse reactions typical of miotics, such as night blindness, accommodative spasm, and pupillary constriction. Dorzolamide has no effect or only a minimal effect on arterial blood pressure and pulse rate.

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

The efficacy of dorzolamide, administered either as monotherapy three times daily (baseline IOP ≥ 23 mmHg) or twice daily as adjunctive therapy to topical beta-blockers (baseline IOP ≥ 22 mmHg), has been confirmed in clinical trials lasting up to one year. Whether used as monotherapy or in combination with beta-blockers, dorzolamide reduced IOP throughout the day, and this effect was maintained over a prolonged period. The efficacy of dorzolamide after long-term use as monotherapy was similar to that of betaxolol and only slightly less than that of timolol. When dorzolamide was used as adjunctive therapy to topical beta-blockers, an additional reduction in IOP was observed, comparable to that achieved with 2% pilocarpine administered four times daily.

Pharmacokinetics

Unlike oral carbonic anhydrase inhibitors, dorzolamide acts directly in the eye when administered topically, at substantially lower doses, resulting in reduced systemic effects. In clinical studies, this led to IOP reduction without the acid-base imbalances or electrolyte changes typically associated with oral carbonic anhydrase inhibitors.

After topical administration, dorzolamide enters the systemic circulation. To assess the extent of systemic carbonic anhydrase inhibition, concentrations of the active substance and its metabolites in plasma and erythrocytes, as well as inhibition of carbonic anhydrase activity in erythrocytes, were measured. With chronic administration, dorzolamide accumulates in erythrocytes due to selective binding to CA-II, while free active substance concentrations in plasma remain extremely low. Dorzolamide forms one N-desethyl metabolite, 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%). It is excreted primarily unchanged in urine; the metabolite is also excreted in urine. After discontinuation, dorzolamide is nonlinearly eliminated from erythrocytes, initially resulting in a rapid decline in concentrations, followed by a slower elimination phase with a half-life of approximately 4 months.

Following oral administration to model maximum systemic exposure 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 less than that considered necessary for pharmacological effects on renal function or respiration. Similar pharmacokinetic results were observed after prolonged topical administration of dorzolamide.

However, in some elderly patients with renal impairment (creatinine clearance [CrCl] established at 30–60 mL/min), metabolite concentrations in erythrocytes were higher, although this was not associated with significant differences in carbonic anhydrase inhibition. Clinically significant systemic adverse reactions directly related to these findings were not observed.

Clinical Characteristics

Indications

• Adjunctive therapy in the treatment with topical beta-blockers.

• Monotherapy when treatment with topical beta-blockers is insufficiently effective or contraindicated.

• Therapy of elevated intraocular pressure in:

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

Contraindications

• Hypersensitivity to the active substance or to any of the other components of the medicinal product.
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Hyperchloremic acidosis.

Interaction with other medicinal products and other forms of interaction

Specific studies on the interaction of dorzolamide with other medicinal products have not been conducted.

In clinical studies, dorzolamide was used concomitantly with timolol and betaxolol in the form of eye drops, as well as with systemically administered drugs: angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, and also with hormonal agents (e.g., estrogens, insulin, thyroxine), without any occurrence of drug interactions.

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

Special precautions for use

Dorzolamide contains a sulfonamide group and, although administered locally, undergoes systemic absorption. Therefore, when used as eye drops, adverse reactions typical of sulfonamides may occur, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). If serious adverse reactions or signs of hypersensitivity occur, the drug should be discontinued.

If allergic reactions (such as conjunctivitis, eyelid reactions) develop, discontinuation of the drug should be considered.

Dorzolamide has not been studied in patients with impaired liver function. The drug should be used with caution in such patients.

Corneal edema and irreversible corneal decompensation have been observed in patients with previously diagnosed chronic corneal defects and/or a history of intraocular surgery during treatment with dorzolamide. The drug should be used with caution in such patients.

The use of oral carbonic anhydrase inhibitors has been associated with the development of urinary stones due to water-electrolyte imbalances, particularly in patients with a history of nephrolithiasis. Although water-electrolyte imbalances have not been observed with dorzolamide use, rare cases of ureterolithiasis have been reported. Since dorzolamide is a locally acting carbonic anhydrase inhibitor that enters systemic circulation, patients with a history of nephrolithiasis are considered to be at increased risk of ureterolithiasis associated with dorzolamide use.

An enhanced systemic effect of carbonic anhydrase inhibitors may occur in patients who are concurrently taking oral carbonic anhydrase inhibitors and dorzolamide. Concomitant use of dorzolamide and oral carbonic anhydrase inhibitors has not been studied and is therefore not recommended.

Cases of choroidal detachment with concurrent intraocular hypotony have been observed during treatment with drugs that reduce aqueous humor production following filtration procedures.

In treating patients with acute angle-closure glaucoma, in addition to using agents that reduce intraocular pressure (IOP), other therapeutic measures should also be employed. The use of dorzolamide in patients with acute angle-closure glaucoma has not been studied.

The product contains the preservative benzalkonium chloride, which may cause eye irritation and discoloration of soft contact lenses. Contact lenses should be removed before instilling eye drops and not reinserted earlier than 15 minutes after administration.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of dorzolamide in pregnant women are lacking or limited. Animal studies have shown dorzolamide to have teratogenic effects at maternotoxic doses. The drug should not be used during pregnancy.

Breastfeeding period

It is unknown whether dorzolamide/metabolites are excreted in human breast milk.

Available pharmacodynamic/toxicological data from animal studies have demonstrated that dorzolamide/metabolites are excreted in breast milk. Risk to newborns/infants cannot be excluded.

The decision on whether to discontinue breastfeeding or to discontinue/abstain from using the drug should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment for the mother.

Fertility

Dorzolamide did not affect fertility in male and female animals. Data on effects on human fertility are lacking.

Ability to influence the speed of reactions while driving or operating machinery

Studies on the effect of dorzolamide on the ability to drive or operate machinery have not been conducted. During use of the drug, adverse reactions such as dizziness and visual disturbances may occur, which could affect the ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product is intended for topical administration (into the conjunctival sac).

Dosage

Monotherapy

Administer 1 drop of the medicinal product into the affected eye(s) three times daily.

Adjunctive therapy

Administer 1 drop of the medicinal product into the affected eye(s) twice daily.

If dorzolamide is to replace another topical anti-glaucoma agent, the previous medicinal product should be discontinued and dorzolamide therapy initiated the following day.

When using multiple topical ophthalmic medicinal products, they should be administered at least 10 minutes apart.

Hands should be washed before using the medicinal product. Avoid any contact between the dropper tip and the eye or surrounding surfaces during instillation. Improper handling may result in contamination of the eye drops with common bacteria causing ocular infections. Use of contaminated eye drops may lead to serious eye injury and subsequent vision loss.

Application of nasolacrimal occlusion or closure of eyelids for 2 minutes reduces systemic absorption. This may reduce systemic adverse reactions and increase local activity.

Method of Administration

1. Wash hands.
2. Open the bottle. Avoid any contact between the dropper tip and the eye, skin around the eye, or skin of the hands.
3. Tilt the head backward and pull the lower eyelid downward to form a space between the eyelid and the eyeball.
4. Turn the bottle upside down and gently squeeze its sides until one drop of the medicinal product falls into the eye.
5. Press the fingertip against the inner corner of the eye near the nose, or close the eyelids for 2 minutes. This limits the amount of medicinal product entering the bloodstream.
6. Repeat steps 3–5 for the other eye, if prescribed by a physician.
7. Close the bottle tightly.

Children

Clinical data on the use of dorzolamide in children are limited. The medicinal product should not be used in children.

Overdose

Symptoms

Data on dorzolamide overdose in humans are limited. Symptoms observed after oral intake include drowsiness; after topical administration: nausea, dizziness, headache, feeling of fatigue, unusual dreams, and dysphagia. Electrolyte disturbances, acidosis, and symptoms related to the central nervous system may also occur.

Treatment

In case of overdose, symptomatic and supportive therapy should be administered. Plasma electrolyte concentrations (particularly potassium) should be checked, and blood pH should be determined.

Side effects

Dorzolamide has been evaluated in over 1400 patients in controlled and uncontrolled clinical studies. In long-term studies involving 1108 patients receiving dorzolamide as monotherapy or as additional therapy to ophthalmic beta-blockers, the most common reason for discontinuation of treatment (in approximately 3% of cases) was ocular adverse reactions, predominantly conjunctivitis and eyelid reactions.

The adverse reactions listed below have been reported during clinical trials and post-marketing surveillance with dorzolamide use.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); unknown (frequency cannot be estimated from the available data).

Nervous system disorders:

Common – headache; rare – paraesthesia, dizziness.

Eye disorders:

Very common – burning and stinging; common – superficial punctate keratitis, lacrimation, conjunctivitis, blepharitis, eye pruritus, eye irritation, blurred vision; uncommon – iridocyclitis; rare – irritation including redness, pain, eyelid sticking, transient myopia (resolving after discontinuation of treatment), corneal edema, ocular hypotony, choroidal detachment following filtration procedures; unknown – foreign body sensation in the eye.

Cardiac disorders:

Unknown – palpitations, tachycardia.

Vascular disorders:

Unknown – arterial hypertension.

Respiratory, thoracic and mediastinal disorders:

Rare – epistaxis; unknown – dyspnea.

Gastrointestinal disorders:

Common – nausea, bitter taste; rare – throat irritation, dry mouth.

Skin and subcutaneous tissue disorders:

Rare – contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Renal and urinary disorders:

Rare – nephrolithiasis.

General disorders and administration site conditions:

Common – asthenia/fatigue; rare – hypersensitivity reactions, including local manifestations (palpebral reactions) and systemic manifestations (angioneurotic edema, urticaria, pruritus, rash, dyspnea); very rare – bronchospasm.

Investigations:

Dorzolamide did not cause clinically significant disturbances in electrolyte balance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

5 years.

After opening the bottle, the product can be used for up to 28 days.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging and in a place inaccessible to children.

Packaging

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

Prescription status

Prescription only.

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.