Dorzoptic combo eco

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DORZOPTIK COMBI ECO (DORZOPTIK COMBI ECO)

Composition:

Active substances: dorzolamide, timolol;

1 ml of eye drops, solution, contains 20 mg dorzolamide (as 22.26 mg dorzolamide hydrochloride) and 5 mg timolol (as 6.83 mg timolol maleate);

Excipients: hydroxyethylcellulose, mannitol (E 421), sodium citrate, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Basic physicochemical properties: clear, slightly viscous, colorless aqueous solution.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma preparations and miotics. Beta-adrenoreceptor blockers.

ATC code S01ED51.

Pharmacological Properties

Pharmacodynamics

The medicinal product contains two active substances: dorzolamide hydrochloride and timolol maleate. Each of these components reduces elevated intraocular pressure by decreasing the secretion of aqueous humor, but they have different mechanisms of action.

Dorzolamide hydrochloride is a potent inhibitor of carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary processes reduces aqueous humor secretion by slowing the formation of bicarbonate ions, which in turn decreases the transport of sodium and fluid.

Timolol maleate is a non-selective beta-adrenergic receptor blocker. The precise mechanism of timolol’s action in reducing intraocular pressure is not fully understood. Fluorometric and tonographic studies indicate that the effect of timolol is due to reduced secretion of aqueous humor. Additionally, timolol may enhance outflow of fluid.

The combined action of both components results in a greater reduction of intraocular pressure than monotherapy with either agent alone.

After topical administration, Dorzoptic Combi Eco reduces intraocular pressure regardless of whether the elevation is associated with glaucoma. Elevated intraocular pressure plays a significant role in the pathogenesis of optic nerve damage and visual field loss in glaucoma.

Dorzoptic Combi Eco reduces intraocular pressure without producing the side effects typical of miotic agents, such as night blindness, accommodative spasm, or pupillary constriction.

Pharmacodynamic effects

Clinical effects

Clinical studies lasting up to 15 months were conducted comparing the effect of dorzolamide hydrochloride combined with timolol maleate administered twice daily (specific morning and evening doses) on lowering intraocular pressure, versus 0.5% timolol and 2.0% dorzolamide used separately or in combination, in patients with glaucoma or ocular hypertension for whom combination therapy was considered appropriate and necessary in these studies. The studies included both untreated patients and patients inadequately controlled on timolol monotherapy. Most patients had been receiving topical beta-blocker monotherapy prior to enrollment. In the analysis of combined studies, the effect of dorzolamide hydrochloride and timolol maleate combination administered twice daily on reducing intraocular pressure was greater than that of monotherapy with 2% dorzolamide administered three times daily or 0.5% timolol administered twice daily. The effect of dorzolamide hydrochloride and timolol maleate combination administered twice daily on reducing intraocular pressure was equivalent to that of combined therapy with dorzolamide and timolol administered twice daily. The effect of dorzolamide hydrochloride and timolol maleate combination administered twice daily on reducing intraocular pressure was demonstrated at various time points throughout the day, and this effect was maintained during long-term use.

Pediatric patients

A three-month controlled study was conducted with the primary objective of investigating and confirming the safety of 2% ophthalmic solution of dorzolamide hydrochloride in children under 6 years of age. In this study, 30 patients aged 2 to 6 years whose intraocular pressure was not adequately controlled on monotherapy with dorzolamide or timolol received the combination of dorzolamide hydrochloride and timolol maleate in the open-label phase of the study. Efficacy in these patients has not been established. In this small group, the combination of dorzolamide hydrochloride and timolol maleate administered twice daily was generally well tolerated by 19 patients who completed the treatment period, while

11 patients discontinued treatment due to surgical intervention, change of medication, or other reasons.

Pharmacokinetics

Dorzolamide hydrochloride. After topical administration, dorzolamide penetrates into the systemic circulation. With prolonged use, dorzolamide accumulates in erythrocytes due to binding with carbonic anhydrase type II, maintaining very low concentrations of free drug in plasma. Dorzolamide is metabolized to a single N-desethyl metabolite, which is less potent in inhibiting carbonic anhydrase type II compared to the parent compound, but inhibits carbonic anhydrase type I, a less active isoenzyme. The metabolite also accumulates in erythrocytes, where it binds primarily to carbonic anhydrase type I. Approximately 33% of dorzolamide is protein-bound in plasma. Dorzolamide is excreted in urine unchanged and as metabolite. After discontinuation of the drug, dorzolamide is eliminated from erythrocytes nonlinearly, with an initial rapid decline in concentration followed by a slow elimination phase with a half-life of approximately 4 months.

When dorzolamide was administered orally to simulate maximum systemic exposure following chronic topical ophthalmic use, steady state was reached within 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; inhibition of carbonic anhydrase in erythrocytes was less than that expected to be necessary for pharmacological effects on renal or respiratory function. Similar pharmacokinetic results were obtained after continuous topical administration of dorzolamide hydrochloride. However, in some elderly patients with impaired renal function (creatinine clearance (CrCl) of 30–60 mL/min), higher concentrations of the metabolite in erythrocytes (RBCs) were observed, but significant differences in carbonic anhydrase inhibition and clinically significant systemic adverse effects were not directly associated with this finding.

Timolol maleate. After topical ocular administration, timolol is systemically absorbed. Systemic exposure to timolol was measured after topical administration of 0.5% ophthalmic solution twice daily. The maximum plasma concentration after the morning dose was 0.46 ng/mL, and after the evening dose was 0.35 ng/mL.

Clinical Characteristics

Indications

Elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical use of beta-blockers alone is insufficient.

Contraindications

• Hypersensitivity to either or both active substances or to any component of the medicinal product;
• Respiratory tract diseases, including bronchial asthma, history of bronchial asthma, or severe chronic obstructive pulmonary disease;
• Sinus bradycardia, sinoatrial node dysfunction, second- or third-degree atrioventricular block not controlled by a pacemaker, overt heart failure, cardiogenic shock;
• Severe renal impairment (creatinine clearance < 30 mL/min) or hyperchloremic acidosis.

The above contraindications are related to the active substances of the drug and are not specific to the combination.

Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been conducted with Dorzoptik Kombi Eco and other medicinal products. No adverse interactions have been observed when Dorzoptik Kombi Eco was used concomitantly with the following systemically acting drug classes: angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs (including acetylsalicylic acid), and hormones (estrogens, insulin, thyroxine).

However, there is a potential for additive effects leading to arterial hypotension and/or marked bradycardia when the ophthalmic solution is used concomitantly with orally administered calcium channel blockers, agents that reduce catecholamine production, beta-adrenergic receptor blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase inhibitors (MAO inhibitors).

When timolol is used concomitantly with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine), potentiation of systemic beta-blockade (reduced heart rate, depression) has been reported.

Although Dorzoptik Kombi Eco has minimal effect on pupil size when used as monotherapy, mydriasis has occasionally been reported with concomitant use of topical timolol maleate and epinephrine (adrenaline).

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

Orally administered beta-blockers may provoke rebound arterial hypertension upon discontinuation of clonidine.

Special precautions for use

Before applying the medicinal product, hands should be thoroughly washed.

Cardiovascular and respiratory system reactions

Like other locally acting ophthalmic preparations, timolol is systemically absorbed. Since timolol is a beta-blocker, adverse reactions affecting the cardiovascular and respiratory systems, similar to those observed with systemic administration of beta-adrenergic blockers, may occur. The frequency of systemic adverse reactions after local application of ophthalmic preparations is lower than with systemic administration. For measures to reduce systemic absorption, see section "Directions for use and dosage".

Cardiac disorders

The use of beta-blockers in patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina / Prinzmetal's angina, heart failure) and arterial hypotension should be carefully evaluated, and treatment with alternative active substances should be considered. Patients with cardiovascular disorders should be monitored for signs of worsening of these conditions and adverse reactions.

Due to its negative effect on impulse conduction time, beta-blockers should be administered with caution in patients with first-degree atrioventricular block.

Vascular disorders

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

Respiratory system disorders

Cases of respiratory reactions, including fatal bronchospasm, have been reported in asthmatic patients after administration of certain ophthalmic beta-blockers.

Dorzoptic Combi Eco should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and only if the expected benefit outweighs the potential risk.

Hepatic function impairment

Since there are no data on the use of the medicinal product in patients with impaired liver function, Dorzoptic Combi Eco should be prescribed with caution in such patients.

Immunological and hypersensitivity reactions

Like other locally acting preparations, Dorzoptic Combi Eco may be systemically absorbed. Dorzolamide, like sulfonamides, contains a sulfonamide group; therefore, adverse reactions associated with systemic administration of sulfonamide drugs, including serious reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur. If signs of severe reactions or hypersensitivity reactions appear, the use of the medicinal product should be discontinued.

Local ocular adverse reactions similar to those observed with dorzolamide hydrochloride have been reported during treatment with Dorzoptic Combi Eco. If such reactions develop, the use of Dorzoptic Combi Eco should be discontinued.

Patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to re-exposure to such allergens when taking beta-blockers and may not respond to standard doses of adrenaline in the treatment of anaphylactic reactions.

Concomitant therapy

The effect on intraocular pressure or other known systemic effects of beta-blockers may be enhanced when timolol is administered to patients already receiving systemic beta-blockers. The response to treatment in such patients should be carefully monitored. The use of two topical beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

The use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Discontinuation of treatment

As with systemically acting beta-blockers, ophthalmic timolol should be tapered gradually when discontinuation is necessary in patients with ischemic heart disease.

Additional effects of beta-blockers

Hypoglycemia / diabetes mellitus

Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia and in patients with labile diabetes mellitus, as beta-blockers may mask the symptoms of acute hypoglycemia.

Beta-blockers may also mask signs of hyperthyroidism. Abrupt discontinuation of beta-blockers may lead to worsening of symptoms.

Corneal disorders

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

Anesthesia during surgical procedures

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

Beta-blocker therapy may exacerbate symptoms in myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Treatment with oral carbonic anhydrase inhibitors has been associated with the development of urolithiasis due to acid-base imbalances, particularly in patients with a history of nephrolithiasis. Although acid-base imbalances have not been observed with Dorzoptic Combi Eco, rare cases of urolithiasis have been reported. Since Dorzoptic Combi Eco contains a carbonic anhydrase inhibitor that is systemically absorbed after topical administration, patients with a history of nephrolithiasis have an increased risk of urolithiasis when using this medicinal product.

Other special considerations

Treatment of patients with acute angle-closure glaucoma requires additional therapeutic measures beyond intraocular pressure-lowering agents. This medicinal product has not been studied in patients with acute angle-closure glaucoma.

Corneal edema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal disorders and/or a history of intraocular surgery during treatment with dorzolamide. There is a high likelihood of corneal edema development. Precautionary measures should be taken when prescribing Dorzoptic Combi Eco to such patient groups.

Ciliary detachment has been reported following filtration procedures when aqueous suppressants (e.g., timolol, acetazolamide) were administered.

As with other antiglaucomatous agents, reduced responsiveness to ophthalmic timolol maleate has been reported in some patients after prolonged treatment. However, in clinical studies involving 164 patients monitored for at least three years, no significant change in mean intraocular pressure was observed after initial pressure stabilization.

Use of contact lenses

The effect of dorzolamide with timolol in patients wearing contact lenses has not been studied. Contact lenses should be removed before instillation of the product and reinserted no earlier than 15 minutes after administration.

Chemical and physical stability has been demonstrated for 90 days at 25 ± 2°C.

From a microbiological standpoint, the medicinal product may be stored for a maximum of 90 days after opening at a temperature not exceeding 25°C. The responsibility for other storage periods and conditions during use lies with the user.

Use during pregnancy or breastfeeding

Pregnancy

Dorzoptic Combi Eco should not be used during pregnancy.

Dorzolamide

There are no adequate clinical data on the effects during pregnancy. In rabbits, dorzolamide showed teratogenic effects when administered at doses toxic to the mother.

Timolol

There are no adequate data on the use of timolol in pregnant women. Timolol should not be used during pregnancy except when clearly necessary. For measures to reduce systemic absorption, see section "Directions for use and dosage".

Epidemiological studies have not provided data indicating a risk of intrauterine growth retardation with oral administration of beta-blockers during pregnancy. However, newborns exposed to beta-blockers before delivery have shown signs of beta-blockade (such as bradycardia, arterial hypotension, respiratory distress syndrome, and hypoglycemia). If this medicinal product was used before delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding

It is unknown whether dorzolamide passes into breast milk. In studies in lactating rats receiving dorzolamide, reduced body weight in rat pups was observed.

Beta-blockers pass into breast milk. However, when therapeutic doses of timolol eye drops are used, it is unlikely that the amount excreted in breast milk would cause clinical signs of beta-blockade in the infant.

If treatment with Dorzoptic Combi Eco is necessary, breastfeeding is not recommended.

Effect on ability to drive and use machines

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Adverse reactions such as blurred vision may negatively affect the ability of some patients to drive or operate machinery.

Method of Administration and Dosage

Dorzoptic Combi Eco should be administered as 1 drop into the conjunctival sac twice daily.

If several topical ophthalmic agents are being used, they should be administered with an interval of 10 minutes between each. When switching from other ophthalmic medications to Dorzoptic Combi Eco, the latter should be initiated the day after discontinuation of the previous medication.

Patients should be advised to wash their hands thoroughly before application and to avoid touching the eye or surrounding areas with the dropper tip.

Patients should also be informed that improper handling of eye drops may allow bacteria to enter the solution, which can lead to eye infections. Use of a contaminated solution may result in severe ocular damage and subsequent vision loss.

Administration of Dorzoptic Combi Eco Eye Drops

1. Wash hands thoroughly before using the medication.
2. Do not use the drops if the packaging or bottle is damaged.
3. Ensure the tamper-evident ring on the cap is intact. Before first use, unscrew the cap: slight resistance may be felt as the safety ring breaks.
4. If the safety ring is damaged during initial opening, remove and discard it to prevent injury.
5. Tilt the head backward and gently pull down the lower eyelid to create a space between the eyeball and eyelid. Avoid contact between the dropper tip and the eye, eyelids, or fingers.
6. Gently squeeze the bottle to release one drop into the eye. Note that there may be a delay of several seconds between squeezing the bottle and the drop falling. Do not squeeze too hard. If unsure about proper administration, consult a physician, pharmacist, or nurse.
7. After instillation, press the nasolacrimal duct for approximately 2 minutes (by applying finger pressure to the inner corner of the eye near the nose), close the eyes, and keep them closed during this time. This may reduce systemic side effects and enhance local efficacy.
8. Do not touch the dropper tip to the surface of the eye or surrounding tissues.
9. If the physician has prescribed the medication for the other eye, repeat steps 5–6 and 7.
10. After use and before the next application, shake the bottle once with the tip pointing downward, without touching the dropper tip, to remove residual solution from the tip. This ensures proper delivery of subsequent doses. After instillation, replace the cap tightly on the bottle.

If a drop fails to enter the patient's eye, repeat the administration.

Children

Dorzoptic Combi Eco should not be used in children, as there is no data on efficacy and safety in pediatric patients.

Overdose

There are no data on accidental or intentional overdose following oral ingestion of Dorzoptic Combi Eco.

Symptoms

In case of timolol overdose, systemic effects typical of systemic beta-blocker overdose may occur, including dizziness, headache, dyspnea, bradycardia, bronchospasm, and cardiac arrest. The most expected symptoms of dorzolamide overdose include electrolyte imbalance, development of acidosis, and effects on the central nervous system.

There is limited information on accidental or intentional overdose with dorzolamide hydrochloride. Drowsiness has been reported after oral ingestion. With topical use, symptoms such as nausea, dizziness, headache, weakness, unusual dreams, and dysphagia have been observed.

Treatment: symptomatic and supportive. Monitor serum electrolyte levels (particularly potassium) and blood pH. Timolol is not completely removed by dialysis.

Adverse Reactions

As with other ophthalmic medicinal products administered locally, timolol is absorbed into the systemic circulation. This may cause adverse effects similar to those observed with systemic beta-blockers. The frequency of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration.

The adverse reactions listed below have been reported during use of the medicinal product Dorzoptik Combo Eco or one of its components. Frequency: 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), not known (cannot be estimated from available data).

Immune system disorders

Dorzolamide with timolol

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylactic reaction.

Timolol maleate, ophthalmic solution

Rare: signs and symptoms of allergic reactions, including angioed edema, urticaria, localized and generalized rash, anaphylactic reaction.

Not known**: pruritus.

Metabolism and nutrition disorders

Timolol maleate, ophthalmic solution

Not known**: hypoglycemia.

Psychiatric disorders

Timolol maleate, ophthalmic solution

Uncommon: depression*.

Rare: insomnia*, nightmares*, memory loss.

Not known**: hallucinations.

Nervous system disorders

Dorzolamide hydrochloride, ophthalmic solution

Common: headache*.

Rare: dizziness*, paresthesia* (skin sensory disturbances).

Timolol maleate, ophthalmic solution

Common: headache*.

Uncommon: dizziness*, syncope*.

Rare: paresthesia*, exacerbation of symptoms of myasthenia gravis, decreased libido*, cerebral circulation disorders*, cerebral ischemia.

Eye disorders

Dorzolamide with timolol

Very common: burning and stinging.

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

Dorzolamide hydrochloride, ophthalmic solution

Common: eyelid inflammation*, eyelid irritation*.

Uncommon: iridocyclitis*.

Rare: eye irritation, including redness*, eye pain*, eyelid scaling*, transient myopia (resolves upon discontinuation of treatment), corneal edema*, intraocular pressure reduction*, retinal detachment (requiring filtration surgery)*.

Not known**: foreign body sensation in the eye.

Timolol maleate, ophthalmic solution

Common: signs and symptoms of eye irritation, including blepharitis*, keratitis*, corneal hypoesthesia, dry eyes*.

Uncommon: visual disturbances, including refractive changes (in some cases due to discontinuation of miotics)*.

Rare: ptosis, diplopia, retinal detachment requiring filtration surgery* (see section "Special precautions for use").

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

Ear and labyrinth disorders

Timolol maleate, ophthalmic solution

Rare: tinnitus*.

Cardiac disorders

Timolol maleate, ophthalmic solution

Uncommon: bradycardia*.

Rare: chest pain*, palpitations*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block.

Not known**: atrioventricular block, heart failure.

Dorzolamide hydrochloride, ophthalmic solution

Not known: palpitations, tachycardia.

Vascular disorders

Timolol maleate, ophthalmic solution

Rare: arterial hypotension*, claudication, Raynaud's phenomenon*, cold sensation in hands and feet*.

Dorzolamide hydrochloride, ophthalmic solution

Not known: arterial hypertension.

Respiratory, thoracic and mediastinal disorders

Dorzolamide with timolol

Common: sinusitis.

Rare: dyspnea, respiratory failure, rhinitis, bronchospasm.

Dorzolamide hydrochloride, ophthalmic solution

Rare: epistaxis*.

Not known**: dyspnea.

Timolol maleate, ophthalmic solution

Uncommon: dyspnea.

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

Gastrointestinal disorders

Dorzolamide with timolol

Very common: dysgeusia (altered taste sensation).

Dorzolamide hydrochloride, ophthalmic solution

Common: nausea*.

Rare: throat irritation, dry mouth*.

Timolol maleate, ophthalmic solution

Uncommon: nausea*, dyspepsia*.

Rare: diarrhea, dry mouth*.

Not known**: dysgeusia (altered taste sensation), abdominal pain, vomiting.

Skin and subcutaneous tissue disorders

Dorzolamide with timolol

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

Dorzolamide hydrochloride, ophthalmic solution

Rare: rash*.

Timolol maleate, ophthalmic solution

Rare: alopecia*, psoriatic rash or exacerbation of psoriasis*.

Not known**: skin rash.

Musculoskeletal and connective tissue disorders

Timolol maleate, ophthalmic solution

Rare: systemic lupus erythematosus.

Not known**: myalgia.

Renal and urinary disorders

Dorzolamide with timolol

Uncommon: urolithiasis.

Reproductive system and breast disorders

Timolol maleate, ophthalmic solution

Rare: Peyronie's disease*, decreased libido.

Not known**: sexual dysfunction.

General disorders and administration site conditions

Dorzolamide hydrochloride, ophthalmic solution

Common: asthenia / weakness*.

Timolol maleate, ophthalmic solution

Uncommon: asthenia / weakness*.

* Adverse effect observed after use of dorzolamide with timolol.

** Additional adverse reactions observed with ophthalmic beta-blockers that may occur during use of this medicinal product.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2 years. Do not use after the expiry date stated on the packaging.

Shelf life after first opening: 90 days.

Keep the bottle tightly closed.

Storage conditions

Store at temperatures not exceeding 30 °C. Store in the original packaging.

Keep out of reach of children.

Packaging

5 mL of solution in a 5 mL polyethylene dropper bottle with a cap and tamper-evident seal. Packaged in cardboard boxes containing 1 or 3 bottles.

Prescription status

Prescription only.

Manufacturer

Rafarm S.A. /
Rafarm S.A.

Manufacturer's address and place of business

Thesi Pousi Xatzi Agiou Louka, Paiania, 190 02, Greece /
Thesi Pousi Xatzi Agiou Louka, Paiania, 190 02, Greece.