Xaloptic combo eco

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XALOPTIC COMBI ECO (XALOPTIC COMBI ECO)

Composition:

Active substances: latanoprost, timolol;

1 ml of solution contains 50 mcg of latanoprost and 6.8 mg of timolol maleate, equivalent to 5 mg of timolol;

Excipients: polysorbate 80, sodium edetate, sodium chloride, sodium phosphate dibasic, sodium dihydrogen phosphate monohydrate, sodium hydroxide, hydrochloric acid diluted, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: colorless clear solution.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma and miotic agents. Timolol, combinations. ATC code S01ED51.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The medicinal product Xaloptic Combo Eco contains two active substances: latanoprost and timolol maleate. Both components reduce elevated intraocular pressure (IOP) through different mechanisms, and their combined effect results in a more pronounced reduction of IOP than monotherapy with either component alone.

Latanoprost is a prostaglandin F2 alpha analogue and a selective agonist of prostanoic FP receptors, which reduces IOP by enhancing the outflow of aqueous humor. The primary mechanism of action involves increased uveoscleral outflow. Additionally, a slightly enhanced outflow (reduced outflow resistance in the trabecular meshwork) has been reported in men. Latanoprost does not significantly affect aqueous humor production, the blood-ocular barrier, or intraocular blood circulation. Long-term administration of latanoprost in animals following extracapsular lens extraction did not affect retinal vessels, as assessed by fluorescein angiography. Short-term administration of latanoprost did not induce fluorescein leakage into the posterior segment of the eye in pseudophakic patients.

Timolol is a non-selective beta-1 and beta-2 adrenergic receptor blocker with no direct sympathomimetic activity and no direct myocardial depressant or membrane-stabilizing effects. Timolol reduces IOP by decreasing aqueous humor production by the ciliary epithelium.

The exact mechanism is not fully established, but likely involves inhibition of adrenergic beta-receptor-mediated stimulation of cyclic AMP (cAMP) synthesis. Timolol does not significantly affect the permeability of the blood-ocular barrier to plasma proteins. In animals, timolol did not affect ocular blood flow after long-term administration.

Pharmacodynamic Effects. Clinical Efficacy and Safety

In clinical studies, combination therapy with latanoprost and timolol maleate resulted in significantly greater reduction of mean diurnal intraocular pressure (IOP) compared to monotherapy with either latanoprost or timolol administered once daily. The IOP-lowering effect of the combination of latanoprost and timolol was compared with monotherapy using latanoprost or timolol in patients with baseline IOP of 25 mmHg or higher. After 2–4 weeks of treatment, additional mean diurnal IOP reductions of 3.1, 2.0, and 0.6 mmHg were observed after 6 months of treatment with the fixed combination of latanoprost and timolol maleate, latanoprost monotherapy, and timolol twice daily, respectively (following an initial 5 mmHg reduction with timolol monotherapy). The IOP-lowering effect of the combination was maintained throughout a 6-month open-label extension of these studies.

Available data suggest that evening administration of the drug may be more effective in reducing IOP compared to morning administration. However, when considering recommendations for morning or evening dosing, the patient's lifestyle and likely adherence to the dosing regimen should be appropriately taken into account.

It should be noted that in cases where the fixed combination is insufficiently effective, studies indicate that an unfixed regimen—timolol maleate twice daily and latanoprost once daily—may remain effective.

Onset of action with combined administration of latanoprost and timolol maleate occurs within one hour, with maximum effect achieved within six to eight hours. With repeated administration, the optimal IOP-lowering effect has been shown to last up to 24 hours after dosing.

Pharmacokinetics

Latanoprost

Absorption. Latanoprost is a prodrug in the form of an isopropyl ester, which is inactive per se but becomes biologically active after hydrolysis by esterases in the cornea to latanoprost acid. The prodrug is well absorbed through the cornea, and all of the drug reaching the aqueous humor is hydrolyzed during passage through the cornea.

Distribution. Studies in humans indicate that maximum latanoprost concentration in aqueous humor, approximately 15–30 ng/mL, is reached about 2 hours after topical administration of latanoprost monotherapy. After topical administration in monkeys, latanoprost distributes predominantly in the anterior segment of the eye, conjunctiva, and eyelids.

Latanoprost acid has a plasma clearance of 0.40 L/h/kg and a small volume of distribution of 0.16 L/kg, resulting in a short plasma half-life of 17 minutes. After topical ocular administration, the systemic bioavailability of latanoprost acid is 45%. Plasma protein binding of latanoprost acid is 87%.

Metabolism and Elimination. Metabolism of latanoprost acid in the eye is negligible. The main metabolism occurs in the liver. The primary metabolites, 1,2-dinor and 1,2,3,4-tetranor, are either inactive or have only weak biological activity in animal studies and are primarily excreted in urine.

Timolol

Absorption and Distribution. Maximum concentration of timolol in the aqueous humor of the eye is reached approximately 1 hour after topical administration of eye drops. A portion of the dose is systemically absorbed, with maximum plasma concentration of 1 ng/mL achieved 10–20 minutes after topical administration of one drop in each eye once daily (300 micrograms/day).

Metabolism. The plasma half-life of timolol is approximately 6 hours. Timolol is extensively metabolized in the liver.

Elimination. Metabolites are excreted in urine along with a small amount of unchanged timolol.

Latanoprost/Timolol

Pharmacokinetic/Pharmacodynamic Interaction. No pharmacokinetic interactions between latanoprost and timolol have been observed. However, approximately a two-fold increase in latanoprost acid concentration in aqueous humor was observed 1–4 hours after administration of the latanoprost/timolol combination compared to monotherapy with latanoprost.

Clinical characteristics

Indications

To be used for reduction of intraocular pressure in patients with open-angle glaucoma and elevated intraocular pressure when the efficacy of local treatment with beta-adrenergic blockers or prostaglandin analogs is insufficient.

Contraindications

• Hypersensitivity to the active substances or to any of the other components of the medicinal product.
• Airway hyperreactivity syndrome, including bronchial asthma in the exacerbation phase and history of severe asthma attacks, severe chronic obstructive bronchopulmonary diseases.
• Sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, cardiac failure, cardiogenic shock.

Interaction with other medicinal products and other forms of interaction

Specific studies on the interaction of Xaloptic Combi Eko with other drugs have not been conducted.

Paradoxical increase in intraocular pressure has been reported following concomitant use of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended.

There is a possibility of additive effects leading to the development of arterial hypotension and/or marked bradycardia when beta-blockers in the form of eye drops are administered concomitantly with oral calcium channel blockers, beta-adrenergic blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, or guanethidine.

Enhanced systemic beta-blockade (e.g., reduced heart rate, depression) has been observed during combined use of CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol.

Use of Xaloptic Combi Eko in patients already receiving oral beta-blockers may enhance the effect on intraocular pressure or systemic effects associated with beta-receptor blockade. Concomitant use of two locally acting beta-blockers is not recommended.

Rarely, mydriasis has been reported when ophthalmic beta-adrenergic blockers were used concomitantly with adrenaline (epinephrine).

The reaction associated with arterial hypertension upon abrupt discontinuation of clonidine may be potentiated by beta-blockers.

Beta-blockers may enhance the hypoglycemic effect of antidiabetic agents. Beta-blocker therapy may mask the signs and symptoms of hypoglycemia (see section "Special precautions").

Special precautions for use

Systemic effects

Like other ophthalmic medicinal products for local use, Xaloptic Combi Eco may undergo systemic absorption. Since it contains a beta-adrenergic receptor blocker (timolol), this medicinal product may cause the same adverse reactions in the cardiovascular and respiratory systems as systemic beta-blockers. The frequency of systemic adverse reactions after local administration is lower than after systemic administration of the drug. Measures to reduce systemic absorption are described in the section "Dosage and method of administration".

Cardiac disorders

The necessity of using beta-blockers should be carefully evaluated in patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal's angina, and heart failure), arterial hypotension, and the possibility of treatment with other drugs should be considered. Patients with cardiovascular diseases should be monitored for signs of worsening of these conditions and adverse reactions.

Since beta-blockers prolong conduction time, they should be prescribed with caution to patients with first-degree heart block.

Cases of cardiovascular reactions, including fatal outcomes due to heart failure, have been reported after timolol administration.

Vascular disorders

The drug should be used with caution in the treatment of patients with severe disorders of peripheral circulation (i.e., patients with severe forms of Raynaud's disease or Raynaud's syndrome).

Respiratory disorders

Respiratory reactions, including fatal cases due to bronchospasm in patients with asthma, have been reported with the use of some ophthalmic beta-blockers. The drug should be used with caution in the treatment of patients with mild to moderate chronic obstructive pulmonary disease (COPD) and should be prescribed only when the potential benefit of treatment outweighs the risk.

Hypoglycemia/diabetes

Beta-blockers should be prescribed with caution to patients prone to spontaneous hypoglycemia or patients with labile insulin-dependent diabetes mellitus, as they may mask the signs and symptoms of acute hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal disorders

Ophthalmic beta-blockers may cause dry eyes; therefore, these drugs should be prescribed with caution to patients with corneal disorders.

Other beta-blockers

The known effect of systemic beta-blockers on intraocular pressure may be enhanced if Xaloptic Combi Eco solution is used in patients who are already receiving oral beta-blockers. Such patients require careful monitoring. The use of two locally acting beta-blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Anaphylactic reactions

During the use of beta-blockers, patients with atopy or a history of severe anaphylactic reactions to various allergens may not respond to usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported with the use of aqueous suppressants (e.g., timolol, acetazolamide) after filtration procedures.

Surgical anesthesia

Ophthalmic beta-blockers may block the systemic effects of beta-adrenergic agonists, such as adrenaline. If a patient is taking timolol, this should be reported to the anesthesiologist.

Concomitant therapy

Timolol may interact with other drugs (see section "Interaction with other medicinal products and other forms of interaction").

Other prostaglandin analogs

Patients should not use two topical beta-blockers or two prostaglandin analogs simultaneously (see section "Interaction with other medicinal products and other forms of interaction").

Change in iris pigmentation

Latanoprost may gradually change eye color by increasing the amount of brown pigment in the iris. According to data from treatment with latanoprost eye drops, increased iris pigmentation (based on photographs) was observed in 16–20% of patients treated with latanoprost in combination with timolol for up to one year. This effect is predominantly observed in patients with mixed-color irises, i.e., green-brown, yellow-brown, or blue/brown-gray, due to an increased concentration of melanin in the stromal melanocytes of the iris. Typically, the brown pigmentation around the pupil spreads concentrically toward the periphery of the iris of the affected eye, but the entire iris or parts of it may acquire a more pronounced brown color. In clinical trials of latanoprost in patients with uniformly blue, gray, green, or brown eyes, color changes were rarely observed and only after two years of treatment.

The change in iris color occurs slowly, may be unnoticeable for several months or years, and is not associated with any symptoms or pathological changes.

Further intensification of brown iris pigmentation has not been observed after discontinuation of treatment, but the existing color change may be permanent.

Neither nevi nor freckles on the iris were altered by the therapy.

Accumulation of pigment in the trabecular meshwork or any other part of the anterior chamber of the eye has not been observed; however, patients should be examined regularly. If pigmentation increases, treatment may be discontinued.

Patients should be informed before starting treatment about the possibility of eye color change. Treatment of one eye may lead to permanent heterochromia.

Changes in eyelids and eyelashes

It is known that the use of latanoprost may cause darkening of the eyelid skin, usually reversible.

Latanoprost may gradually change the eyelashes and vellus hair around the treated eye. These changes include increased length, thickness, pigmentation, and number of eyelashes or hair, as well as misdirected growth of eyelashes. Changes in eyelashes are reversible after discontinuation of treatment.

Glaucoma

There is no documented experience with the use of latanoprost in the treatment of inflammatory, neovascular, chronic angle-closure, or congenital glaucoma, open-angle glaucoma in pseudophakic patients, or pigmentary glau游戏副本. Latanoprost has no or minimal effect on the pupil, but there is no experience with its use in acute attacks of angle-closure glaucoma. Therefore, Xaloptic Combi Eco should be used with caution in such situations until more experience with its use is accumulated.

Herpetic keratitis

Latanoprost should be used with caution in patients with a history of herpetic keratitis and should be avoided in patients with active herpes simplex virus keratitis, as well as in patients with a history of recurrent herpetic keratitis associated with the use of prostaglandin analogs.

Macular edema

Macular edema, including cystoid macular edema, may occur during the use of latanoprost. Such cases have predominantly occurred in pseudophakic patients with a ruptured posterior lens capsule or in patients with a known risk of macular edema. Xaloptic Combi Eco should be used with caution in such patients.

Contact lenses

Contact lenses should be removed before instilling Xaloptic Combi Eco, and may be reinserted 15 minutes after instillation (see section "Dosage and method of administration").

Use during pregnancy or breastfeeding

Latanoprost

There is insufficient data on the use of latanoprost in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Timolol

There is insufficient data on the use of timolol in pregnant women. This drug should not be prescribed during pregnancy unless clearly needed. Methods to reduce systemic absorption are described in the section "Dosage and method of administration".

Epidemiological studies have not shown teratogenic effects, but a risk of intrauterine growth retardation has been observed with systemic use of beta-blockers. In addition, newborns whose mothers took beta-blockers before delivery have shown signs and symptoms of beta-adrenergic receptor blockade (e.g., bradycardia, arterial hypotension, respiratory distress, and hypoglycemia). If Xaloptic Combi Eco is used in pregnant women during the pre-delivery period, the newborn should be carefully monitored during the first days of life.

Therefore, Xaloptic Combi Eco should not be used during pregnancy.

Breastfeeding period

Beta-blockers pass into breast milk. However, the therapeutic doses of timolol in eye drops are not sufficient for the amount that passes into milk to cause clinical symptoms of beta-adrenergic receptor blockade in the newborn. Methods to reduce systemic absorption are described in the section "Dosage and method of administration".

Latanoprost and its metabolites may pass into breast milk; therefore, Xaloptic Combi Eco should not be used in women who are breastfeeding.

Fertility

Animal studies have not shown any ability of latanoprost or timolol to affect reproductive function in males or females.

Ability to affect reaction speed when driving or operating machinery

The combined use of latanoprost and timolol has a minor effect on the ability to drive or operate machinery. Xaloptic Combi Eco, like other ophthalmic medicinal products, may cause transient visual blurring after instillation. Therefore, patients should wait until vision is fully restored before driving a vehicle or operating machinery.

Dosage and Administration

Recommended dosage for adults (including elderly patients)

Recommended dose: one drop in each affected eye once daily.

The dose should not exceed one drop in each affected eye once daily, as more frequent administration has been associated with reduced drug efficacy.

If a dose is missed, the next dose should be administered the following day.

Administration instructions

Contact lenses should be removed prior to instillation of the eye drops and may be reinserted only 15 minutes after administration (see section "Special precautions").

If multiple topical ophthalmic agents are prescribed, they should be administered with an interval of at least 5 minutes between each. Ophthalmic ointments should be applied last.

Pressing the nasolacrimal duct or closing the eyelids for 2 minutes after instillation of eye drops reduces systemic absorption of the drug. This may help reduce the incidence and severity of systemic adverse effects and enhance the local therapeutic effect of the medication.

Route of administration

For ophthalmic use.

Xaloptic Combi ECO is a sterile preservative-free solution.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas, or any other surfaces with the tip of the dropper bottle.

Children. The safety and efficacy of the drug in children have not been established; therefore, Xaloptic Combi is not recommended for use in pediatric patients.

Overdose

There are no data on overdose in humans with concomitant use of latanoprost and timolol.

Symptoms

Symptoms of timolol overdose following systemic administration: bradycardia, hypotension, bronchospasm, cardiac arrest.

In addition to eye irritation and conjunctival hyperemia, no other systemic adverse effects of latanoprost have been observed.

Treatment

If symptoms of overdose occur, treatment should be symptomatic and supportive.

Accidental ingestion of the drug

In case of accidental ingestion, consider the following information.

Timolol is poorly dialyzable. Gastric lavage should be performed if necessary.

Latanoprost is extensively metabolized during first-pass liver metabolism. Intravenous infusion of 3 mcg/kg in healthy volunteers did not produce any symptoms, whereas doses of 5.5–10 mcg/kg were associated with nausea, abdominal pain, dizziness, fatigue, flushing, and increased sweating. These effects were mild to moderate in severity and resolved spontaneously within 4 hours after the end of infusion without specific treatment.

Adverse Reactions

Most adverse effects associated with latanoprost use are ocular. According to available data, iris pigmentation increased in 16–20% of patients, which may be irreversible. During an open-label 5-year safety study of latanoprost, iris pigmentation occurred in 33% of patients (see section "Special Warnings and Precautions for Use"). Typically, other ocular adverse reactions are transient and dose-dependent.

The most serious adverse effects associated with timolol are systemic, including bradycardia, arrhythmia, congestive heart failure, bronchospasm, and allergic reactions.

Like other topically administered ophthalmic agents, timolol is absorbed systemically. This may result in systemic adverse effects similar to those seen with systemic beta-blockers. The frequency of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration of beta-blockers.

The listed adverse reactions correspond to the typical adverse effect profile associated with beta-blocking ophthalmic agents.

The adverse reactions listed below are categorized by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000).

Combined Use of Latanoprost and Timolol

Nervous System

Uncommon: headache.

Eye Disorders

Very common: increased pigmentation of the iris.

Common: eye pain, eye irritation (including stinging, burning, itching, foreign body sensation).

Uncommon: corneal damage, conjunctivitis, blepharitis, eye redness, blurred vision, increased lacrimation.

Skin and Subcutaneous Tissue

Uncommon: rash, pruritus.

In clinical trials, spontaneous reports, and scientific publications, adverse effects characteristic of the individual components of the medicinal product Xalacom Combo Eco have been reported.

Latanoprost

Infections and Infestations: herpes simplex keratitis.

Nervous System: dizziness.

Eye Disorders: changes in eyelashes and vellus hair of the eyelids (increased length, thickness, number, and pigmentation); punctate keratitis, periorbital edema; iritis/uveitis; macular edema, including cystoid macular edema; dry eye; keratitis; corneal edema; corneal erosion; trichiasis; iris cyst; photophobia; periorbital changes and eyelid changes leading to deepening of the eyelid crease; eyelid edema; local skin reaction on eyelids; conjunctival pseudopemphigoid+; darkening of the palpebral skin of the eyelids.

Cardiac Disorders: angina pectoris; unstable angina; palpitations.

Respiratory, Thoracic and Mediastinal Disorders: asthma; exacerbation of asthma; dyspnea.

Gastrointestinal Disorders: nausea*; vomiting*.

Musculoskeletal and Connective Tissue Disorders: myalgia, arthralgia.

General Disorders and Administration Site Conditions: chest pain.

* Adverse reaction identified in the post-marketing period and classified as "uncommon" in frequency.

• May be related to the preservative benzalkonium chloride.

Timolol

Immune System Disorders: systemic allergic reactions, including anaphylactic reaction, angioedema, urticaria, localized and generalized rash, pruritus.

Metabolism and Nutrition Disorders: hypoglycemia.

Psychiatric Disorders: memory impairment, insomnia, depression, nightmares, hallucinations.

Nervous System Disorders: cerebrovascular disorder, cerebral ischemia, dizziness, worsening of symptoms and signs of myasthenia, paresthesia, headache, syncope.

Eye Disorders: choroidal detachment after filtration surgery (see section "Special Warnings and Precautions for Use"), corneal erosion, keratitis, diplopia, reduced corneal sensitivity, signs and symptoms of eye irritation (e.g., burning, stinging, itching, lacrimation, redness), dry eyes, ptosis, blepharitis, blurred vision.

Aural and Vestibular Disorders: tinnitus.

Cardiac Disorders: cardiac arrest, heart failure, atrioventricular block, congestive heart failure, chest pain, arrhythmia, bradycardia, edema, tachycardia.

Vascular Disorders: cold sensation in hands and feet, arterial hypotension, Raynaud's phenomenon.

Respiratory, Thoracic and Mediastinal Disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), cough, dyspnea.

Gastrointestinal Disorders: abdominal pain, vomiting, diarrhea, dry mouth, dysgeusia, dyspepsia, nausea.

Skin and Subcutaneous Tissue Disorders: skin rash, psoriatic rash, exacerbation of psoriasis, alopecia.

Musculoskeletal and Connective Tissue Disorders: myalgia.

Reproductive System and Breast Disorders: sexual dysfunction, decreased libido.

General Disorders and Administration Site Conditions: asthenia/fatigue, weakness.

There have been isolated reports of corneal calcification with ophthalmic solutions containing phosphate in some patients with significant corneal damage.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or 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.

After first opening, store the bottle in the original packaging at a temperature not exceeding 25 °C: 30 days for the 2.5 ml pack; 90 days for the 7.5 ml pack.

Storage Conditions

Store in the original packaging in a refrigerator, protected from light, at a temperature between +2 and +8 °C. Do not freeze!

Keep out of reach of children.

Incompatibilities

In vitro studies have shown that mixing ophthalmic solutions containing thimerosal with drops containing the combination of latanoprost and timolol results in precipitate formation. If such products are used concomitantly with Xalacom Combo Eco eye drops, they should be administered at least five minutes apart.

Packaging

2.5 ml or 7.5 ml in a bottle.

1 bottle in a cardboard box.

Prescription Category

Prescription only.

Manufacturer

Lomapharm GmbH.

Manufacturer's Address and Place of Business

Langes Feld 5, Emmertal, Lower Saxony, 31860, Germany.