Dorzotimol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DORZOTYMOL® (DORZOTYMOL®)

Composition:

Active substances: dorzolamide and timolol;

5 ml of solution contains dorzolamide hydrochloride 0.11125 g, equivalent to 0.10001 g of dorzolamide, and timolol maleate 0.03416 g, equivalent to 0.02499 g of timolol;

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

Pharmaceutical form.

Eye drops, solution.

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

Pharmacotherapeutic group.

Agents used in ophthalmology. Anti-glaucoma preparations and miotics. Beta-adrenoreceptor blockers. Timolol, combinations.

ATC code S01E D51.

Pharmacological properties.

Pharmacodynamics.

Dorzotimol**®** contains two components – dorzolamide and timolol. Both components reduce intraocular pressure by decreasing the secretion of aqueous humor, but they act through different mechanisms.

Dorzolamide is a potent inhibitor of human carbonic anhydrase II. By inhibiting carbonic anhydrase in the ciliary body, it reduces aqueous humor secretion by slowing the formation of bicarbonate ions, thereby decreasing the concentration of sodium and fluid.

Timolol is a non-selective beta-adrenergic receptor blocker. The precise mechanism by which timolol reduces intraocular pressure is not fully understood, although fluorescein studies and tomographic imaging suggest a reduction in aqueous humor production. However, in some studies a slight increase in outflow has been observed. The combined effect of dorzolamide and timolol results in a greater reduction of intraocular pressure than either component alone.

Topical administration of Dorzotimol**®** ophthalmic solution reduces elevated intraocular pressure, regardless of whether this elevation is associated with glaucoma. Elevated intraocular pressure is the major risk factor in the pathogenesis of optic nerve damage and visual field loss due to glaucoma. Intraocular pressure is reduced without the typical side effects of miotic agents, such as night blindness, accommodative spasm, and pupillary constriction.

Pharmacokinetics.

Unlike systemic carbonic anhydrase inhibitors, dorzolamide acts directly on the eye when administered topically, even in small doses, thereby minimizing its systemic effects. Clinical studies have shown that intraocular pressure can be reduced in this manner without disturbing acid-base and electrolyte balance, as commonly occurs with systemic carbonic anhydrase inhibitors.

Dorzolamide enters the systemic circulation even after 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. With prolonged use, dorzolamide accumulates in erythrocytes due to selective binding to carbonic anhydrase type II, while remaining in very low concentrations in plasma in free form. One N-desethyl metabolite is formed from the active substance, which inhibits carbonic anhydrase type II less potently than the parent compound, but also inhibits the less active isoenzyme (carbonic anhydrase type I). This metabolite also accumulates in erythrocytes, where it initially binds primarily to carbonic anhydrase type I. Dorzolamide is approximately 33% bound to plasma proteins. It is primarily excreted unchanged in urine. The metabolite is also excreted in urine. After discontinuation of the drug, dorzolamide is eliminated nonlinearly from erythrocytes, characterized by an initial rapid decline in concentration followed by a slow phase with an elimination half-life of approximately 4 months.

During studies measuring plasma concentrations of the active substance in 6 patients, systemic effects of timolol were observed after topical administration of 0.5% timolol ophthalmic solution twice daily. The mean maximum plasma concentration after the morning dose was 0.46 ng/mL and 0.35 ng/mL after the afternoon dose.

Clinical Characteristics.

Indications.

Dorzotimol**®** is used to treat elevated intraocular pressure in patients with:

• open-angle glaucoma;
• pseudoexfoliative glaucoma;

as adjunctive therapy to beta-blocker treatment or as monotherapy when treatment with beta-blockers has been unsuccessful or beta-blockers are contraindicated.

Contraindications.

Dorzotimol**®** eye drops are contraindicated in patients:

• with hypersensitivity to either or both active substances or to any of the excipients;
• with reactive respiratory diseases, including bronchial asthma, history of bronchial asthma, or severe obstructive pulmonary disease;
• with sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, severe heart failure, or cardiogenic shock;
• with severe renal impairment (creatinine clearance <30 mL/min) and hyperchloremic acidosis.

Interaction with other medicinal products and other forms of interactions.

Concomitant use of Dorzotimol**®** is not recommended with:

• oral carbonic anhydrase inhibitors;
• other topical beta-adrenergic blockers.

During clinical trials, Dorzotimol**®** was administered concomitantly with the following medications, and no adverse interactions were observed with ACE inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid, and hormones (e.g., estrogen, insulin, thyroxine).

However, there is a potential for additive effects and arterial hypotension and/or pronounced bradycardia when timolol maleate is used concomitantly with oral calcium channel blockers, drugs that reduce catecholamine production, beta-adrenergic receptor blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, narcotics, and monoamine oxidase inhibitors.

Cases of systemic effects of beta-blockers (e.g., bradycardia, depression) have been reported with concomitant use of CYP2D6 inhibitors (quinidine, selective serotonin reuptake inhibitors) and timolol.

Although the effect on the pupil during monotherapy with Dorzotimol**®** is minimal or absent, isolated cases of mydriasis have been reported with concomitant use of timolol maleate and adrenaline.

Beta-blockers may enhance the hypoglycemic effect of antidiabetic agents.

Withdrawal of clonidine may lead to rebound hypertension, which may be further exacerbated by concomitant use of beta-blockers.

Special precautions for use.

Reactions affecting the cardiovascular and respiratory systems.

Like all topically administered ophthalmic medicinal products, the product may also be systemically absorbed. Timolol is a beta-blocker, therefore all adverse effects observed with systemic administration of beta-blockers, including exacerbation of Prinzmetal's angina, exacerbation of severe circulatory disorders and arterial hypotension, and heart failure, may occur with local application. Patients with cardiovascular disorders should be monitored for signs of worsening condition and adverse reactions. Reactions affecting the respiratory system and heart have been reported with timolol use, including a fatal case of bronchospasm in a patient with asthma, as well as rare fatal cases associated with heart failure. Development of respiratory reactions due to bronchospasm in patients with asthma has been reported after administration of certain ophthalmic beta-blockers. Dorzotimol should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease, and only if the expected benefit outweighs the potential risk.

Patients with severe peripheral vascular disorders or circulatory disturbances (i.e., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Hepatic impairment

The use of Dorzotimol**®** in patients with impaired liver function has not been studied; therefore, it should be used with caution in such patients.

Immunological and hypersensitivity reactions

Like all topically administered ophthalmic medicinal products, the product may also be systemically absorbed. Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, adverse effects observed with systemic administration of sulfonamide drugs may also occur with topical application. If signs of acute reactions or hypersensitivity occur, the drug should be discontinued.

Local ocular adverse events similar to those observed with dorzolamide eye drops have been reported. In the event of such reactions, discontinuation of Dorzotimol**®** should be considered.

Patients with atopy or acute anaphylactic reactions to various allergens may exhibit increased sensitivity to accidental, diagnostic, or therapeutic exposure to such allergens when taking beta-blockers. It is also possible that such patients may not respond to usual doses of adrenaline administered during anaphylactic reactions. The anaesthesiologist should be informed that the patient is receiving timolol.

Anesthesia during surgical procedures.

Ophthalmic beta-blockers may block the systemic effects of beta-agonists, such as adrenaline. The anaesthesiologist should be informed that the patient is receiving timolol.

Discontinuation of treatment

As with systemic administration of a beta-blocker, topical timolol should be tapered gradually in patients with coronary heart disease.

Additional effects of beta-blockers

Beta-blocker therapy may mask certain symptoms of hypoglycaemia in diabetic patients and in patients with hypoglycaemia. Beta-blockers should be used with caution in patients prone to spontaneous hypoglycaemia or in patients with labile diabetes.

Beta-blocker therapy may mask certain symptoms of hyperthyroidism. Abrupt discontinuation of beta-blocker therapy may exacerbate or precipitate new symptoms. Beta-blocker therapy may exacerbate symptoms of myasthenia gravis.

Ophthalmic beta-blockers may cause dry eyes. Patients with corneal disorders should be treated with caution.

Additional effects of carbonic anhydrase inhibition

Oral administration of carbonic anhydrase inhibitors has been associated with urolithiasis due to disturbances in acid-base balance, particularly in patients with a history of kidney stones. Although acid-base imbalances have not been observed with the use of Dorzotimol**®** eye drops, isolated cases of urolithiasis have been reported.

Since Dorzotimol**®** contains a systemically absorbed topically acting carbonic anhydrase inhibitor, patients with a history of kidney stones have an increased risk of developing urolithiasis.

Other

Patients with acute angle-closure glaucoma require additional medications along with those used to reduce intraocular pressure. The use of Dorzotimol**®** in patients with acute angle-closure glaucoma has not been studied.

Cases of corneal edema and irreversible corneal decompensation have been reported in patients with chronic corneal disease or those who have undergone ocular surgery and were treated with dorzolamide. Dorzolamide for topical use should be administered with caution in these patients.

Corneal epithelial breakdown has been observed in patients using medications to prevent tearing after filtration surgery.

Cases of timolol unresponsiveness have been reported with prolonged ophthalmic use. In clinical studies monitoring 164 patients for at least 3 years, no statistically significant difference in mean intraocular pressure was observed after initial stabilization.

Use of contact lenses

Dorzotimol**®** eye drops contain the preservative benzalkonium chloride, which may cause eye irritation. Contact lenses should be removed before instillation of the drops and not reinserted earlier than 15 minutes afterwards. Benzalkonium chloride is known to discolor contact lenses.

Use during pregnancy or breastfeeding.

The product is not to be used during pregnancy.

It is not known whether dorzolamide is excreted in breast milk. Timolol is excreted in breast milk. Therefore, breastfeeding should be discontinued during treatment.

E**ffect on ability to drive and use machines.

In some patients, adverse events such as blurred vision may occur, which could affect their ability to drive or operate machinery.

Administration and Dosage

For monotherapy, it is recommended to instill 1 drop of Dorzotimol® into the conjunctival sac of the affected eye twice daily. When using several ophthalmic agents locally, a 10-minute interval between applications should be maintained. Nasolacrimal occlusion or closing the eyelids for 2 minutes after instillation reduces systemic absorption. This may lead to a reduction in systemic adverse effects and increased local activity.

Patients should be advised to wash their hands before use 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 may lead to ocular infections. Use of a contaminated solution may result in severe ocular damage with subsequent loss of vision.

Elderly patients

The recommended dosage applies also to elderly patients.

Children

This medicinal product is not recommended for use in children.

Administration instructions

Instill 1 drop into the medial canthus of each affected eye. Immediately after instillation, gently press on the lacrimal sac area to reduce the possibility of systemic absorption of Dorzotimol®.

Overdose

There are no data on overdose with the combination of timolol and dorzolamide following oral administration.

Symptoms

Reports of accidental overdose with timolol eye drops describe systemic effects similar to those observed with systemic administration of beta-blockers, such as blurred vision, headache, shallow breathing, bradycardia, bronchospasm, and cardiac arrest. The most common symptoms expected in dorzolamide overdose include electrolyte imbalance, acidosis, and effects on the central nervous system.

Following accidental oral ingestion, somnolence has been reported.

With topical application, nausea, blurred vision, headache, fatigue, abnormal dreams, and dysphagia have been observed.

Data on dorzolamide overdose following oral administration are limited. Somnolence has been reported after oral intake. With topical use, nausea, blurred vision, headache, fatigue, abnormal dreams, and dysphagia have been reported.

Treatment

Treatment of overdose should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that timolol is not removed by dialysis.

Adverse Reactions

Adverse effects observed during clinical studies were those previously reported with dorzolamide and/or timolol.

A total of 1035 patients participated in clinical trials. Approximately 2.4% discontinued treatment due to ocular adverse reactions and about 1.2% due to local allergic or hypersensitivity reactions (e.g. eyelid inflammation and conjunctivitis).

The following adverse reactions have been observed during clinical studies and in the post-marketing period, with the following frequencies:

Very common: ≥ 1/10;
Common: ≥ 1/100 to < 1/10;
Uncommon: ≥ 1/1,000 to < 1/100;
Rare: ≥ 1/10,000 to < 1/1,000;
Frequency not known: cannot be estimated based on available data.

Immune system disorders:

Rare: systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylactic reaction.

Musculoskeletal and connective tissue disorders:

Timolol maleate, eye drops, solution.

Rare: systemic lupus erythematosus.

Nervous system disorders:

Dorzolamide, eye drops, solution.

Common: headache.

Rare: dizziness, paresthesia.

Timolol maleate, eye drops, solution.

Common: headache.

Uncommon: dizziness.

Rare: loss of consciousness, paresthesia, symptoms of myasthenia gravis, decreased libido, hemorrhagic stroke, cerebral ischemia.

Psychiatric disorders:

Timolol maleate, eye drops, solution.

Uncommon: depression.

Rare: insomnia, nightmares, memory loss.

Frequency not known: hallucinations.

Eye disorders:

Combination of timolol and dorzolamide

Very common: stinging and burning.

Common: conjunctival infection, blurred vision, corneal erosion, ocular pruritus, lacrimation.

Dorzolamide, eye drops, solution.

Common: eyelid inflammation, eyelid irritation.

Uncommon: iridocyclitis.

Rare: ocular irritation, including redness, eye pain, eyelid scaling, transient myopia (resolves after discontinuation of treatment), corneal edema, decreased intraocular pressure, uveitis ablation (after filtration surgery).

Frequency not known: foreign body sensation in the eye.

Timolol maleate, eye drops, solution.

Common: ocular irritation symptoms, including blepharitis, keratitis, decreased corneal sensitivity, dry eye.

Uncommon: visual disturbances, including changes in refraction (due to cessation of miotic therapy in some cases).

Rare: ptosis, diplopia, uveitis ablation (after filtration surgery).

Not known: pruritus, lacrimation, redness, blurred vision, corneal erosion.

Ear and labyrinth disorders:

Timolol maleate, eye drops, solution.

Rare: tinnitus.

Cardiovascular disorders:

Timolol maleate, eye drops, solution.

Uncommon: bradycardia, syncope.

Rare: arterial hypotension, chest pain, palpitations, edema, arrhythmia, congestive heart failure, heart block, cardiac arrest, cerebral ischemia, claudication, Raynaud's phenomenon, cold sensation in hands and feet.

Dorzolamide, eye drops, solution.

Frequency not known: palpitations, tachycardia, arterial hypertension.

Respiratory, thoracic and mediastinal disorders:

Combination of timolol and dorzolamide

Common: sinusitis.

Rare: dyspnea, respiratory failure, rhinitis, bronchospasm.

Dorzolamide, eye drops, solution.

Rare: epistaxis.

Frequency not known: dyspnea.

Timolol maleate, eye drops, solution.

Uncommon: dyspnea.

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), cough.

Gastrointestinal disorders:

Combination of timolol and dorzolamide.

Very common: taste disturbances.

Dorzolamide, eye drops, solution.

Common: nausea.

Rare: throat irritation, dry mouth.

Timolol maleate, eye drops, solution.

Uncommon: nausea, dyspepsia.

Rare: diarrhea, dry mouth.

Skin and subcutaneous tissue disorders:

Combination of timolol and dorzolamide.

Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Dorzolamide, eye drops, solution.

Rare: rash.

Timolol, eye drops, solution.

Rare: alopecia, psoriasiform rash or exacerbation of psoriasis.

Renal and urinary disorders:

Combination of timolol and dorzolamide.

Uncommon: urolithiasis.

Reproductive system and breast disorders:

Timolol maleate, eye drops, solution.

Rare: Peyronie's disease, decreased sexual drive.

General disorders:

Dorzolamide, eye drops, solution.

Uncommon: asthenia/weakness.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children. Store at temperatures not exceeding 30°C. After opening, 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.

Manufacturer's address and place of business.

Svilno 20, 51000 Rijeka, Croatia