Xalo-pharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XALO-PHARM (XALO-PHARM)

Composition:

Active substances: 1 ml of the preparation contains latanoprost 0.05 mg; timolol 5 mg;

Excipients: sodium chloride, sodium dihydrogen phosphate anhydrous, sodium hydrogen phosphate anhydrous, benzalkonium chloride, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless solution, free from visible particles.

Pharmacotherapeutic group. Anti-glaucoma agents and miotics. Beta-blocking agents. Timolol combinations. ATC code S01ED51.

Pharmacological Properties.

Pharmacodynamics.

The medicinal product contains two active substances: latanoprost and timolol. Both components reduce elevated intraocular pressure through different mechanisms of action, and their combined effect results in a more pronounced reduction of intraocular pressure compared to monotherapy with either component alone.

Latanoprost, a prostaglandin F2α analog, is a selective agonist of prostaglandin FP receptors, reducing intraocular pressure by enhancing the outflow of aqueous humor. The primary mechanism of action involves increased uveoscleral outflow. Additionally, slightly enhanced outflow (reduced outflow resistance in the trabecular meshwork) has been reported in humans. Latanoprost does not significantly affect aqueous humor production or the blood-aqueous barrier, nor does it influence intraocular blood circulation. Long-term administration of latanoprost in monkeys, who had undergone extracapsular lens extraction, did not affect retinal blood vessels, as assessed by fluorescein angiography. Latanoprost did not induce fluorescein leakage in the posterior segment of the eye in pseudophakic patients during short-term treatment.

Timolol is a (non-selective) β1 and β2 adrenergic receptor blocker without significant direct sympathomimetic activity, direct myocardial depressant effect, or membrane-stabilizing activity. Timolol reduces intraocular pressure by decreasing aqueous humor production in the ciliary epithelium. The exact mechanism of action is not fully established, but it likely involves inhibition of enhanced adenosine monophosphate (AMP) synthesis caused by endogenous stimulation of β-adrenergic receptors.

Timolol does not significantly affect the permeability of the blood-aqueous barrier to plasma proteins. In rabbits, timolol did not affect ocular blood flow after prolonged administration.

Clinical dose-finding studies have shown that the combined medicinal product produces a significantly greater reduction in mean daily intraocular pressure compared to monotherapy with either latanoprost or timolol when administered once daily. Data indicate that the degree of intraocular pressure reduction with the combined preparation is comparable to that achieved with monotherapy using latanoprost and timolol in patients with baseline intraocular pressure of at least 25 mm Hg or higher. After an initial 2–4 week period of treatment with timolol (mean reduction in intraocular pressure of 5 mm Hg from baseline), additional mean reductions in daily intraocular pressure of 3.1, 2.0, and 0.6 mm Hg were observed after 6 months of treatment with the combination product, latanoprost, and timolol (twice daily), respectively. The intraocular pressure-lowering effect of the combination product was maintained throughout subsequent 6-month open-label extension studies.

Available data suggest that evening administration of the product may be more effective in reducing intraocular pressure than morning administration. However, when considering recommendations for morning or evening dosing, the patient’s lifestyle and likely compliance should be taken into account.

It should be noted that if the combination product is insufficiently effective, separate administration of timolol twice daily and latanoprost once daily may be effective, as confirmed in clinical studies.

The effect of the medicinal product begins within 1 hour, with maximum effect lasting from 6 to 8 hours. Adequate reduction of intraocular pressure lasts up to 24 hours with repeated administration.

Pharmacokinetics.

Lataprost. Latanoprost is a prodrug, an isopropyl ester that is essentially inactive but becomes biologically active latanoprost acid after hydrolysis by esterases in the cornea. The prodrug is well absorbed through the cornea and, like all drugs entering the aqueous humor, undergoes hydrolysis while passing through the cornea. Data indicate that maximum concentration in aqueous humor (approximately 15–30 ng/mL) is reached about 2 hours after topical administration of latanoprost as monotherapy. After topical administration in monkeys, latanoprost is distributed primarily in the anterior segment of the eye, conjunctiva, and eyelids.

Plasma clearance of latanoprost acid is 0.4 L/h/kg; the volume of distribution is low—0.16 L/kg—resulting in a short plasma half-life (17 minutes). After topical ophthalmic administration, systemic bioavailability of latanoprost is 45%. Latanoprost acid is 87% bound to plasma proteins.

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 and are excreted predominantly in urine.

Timolol. Maximum concentration of timolol in aqueous humor is reached approximately 1 hour after topical administration of eye drops. A portion of the dose is systemically absorbed; maximum plasma concentration is 1 ng/mL, reached 10–20 minutes after topical administration of one drop in each eye once daily (300 µg/day). The plasma half-life of timolol is approximately 6 hours. Timolol is extensively metabolized in the liver. Metabolites are excreted in urine along with a small amount of unchanged timolol.

Combination product. No pharmacological interactions between latanoprost and timolol have been observed, despite nearly a two-fold increase in latanoprost acid concentration in aqueous humor after combination therapy compared to monotherapy.

Clinical characteristics.

Indications.

Reduction of intraocular pressure in patients with open-angle glaucoma and elevated intraocular pressure when there is an insufficient response to treatment with topical β-blockers or topical prostaglandin analogs.

Contraindications.

• Hypersensitivity to the active substance or to any of the other components of the medicinal product;
• Respiratory diseases, including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease;
• 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 interactions with other drugs have not been conducted.

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

There is a potential for additive effects leading to arterial hypotension and/or marked bradycardia when β-blockers in the form of ophthalmic solutions are used concomitantly with oral calcium channel blockers, catecholamine-depleting agents, β-adrenergic blockers, antiarrhythmic agents (including amiodarone), cardiac glycosides, parasympathomimetics, or guanethidine.

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

The effect on intraocular pressure or known systemic β-blocking effects may be intensified when administered concomitantly to patients already receiving oral β-blockers. The use of two or more topically acting β-blockers is not recommended.

In isolated cases, mydriasis has been reported due to concomitant use of ophthalmic β-blockers and adrenaline (epinephrine).

The use of β-blockers may lead to an exacerbation of hypertension following abrupt withdrawal of clonidine.

β-blockers may potentiate the hypoglycemic effect of antidiabetic agents. β-blocker therapy may mask the symptoms of hypoglycemia.

Special precautions for use.

Systemic effects.

Like other ophthalmic medicinal products for topical administration, the medicinal product is absorbed systemically. Since the product contains the β-adrenergic agent timolol, the same types of adverse reactions involving the pulmonary, cardiovascular, and other systems as with systemic β-blockers may occur. The frequency of systemic adverse reactions after topical administration is lower than after systemic administration of the drug. Measures to reduce systemic absorption are described in the section "Dosage and administration".

Cardiac disorders.

Careful consideration should be given to the necessity of β-blocker therapy in patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal's angina, heart failure) and hypotension, and alternative treatments should be considered. Patients with cardiovascular disorders should be monitored for signs of worsening of these conditions and adverse reactions.

Since β-blockers prolong excitation time, they should be used with caution in patients with first-degree heart block.

Cases of cardiovascular adverse reactions and isolated fatal cases due to heart failure after timolol administration have been reported.

Vascular system disorders.

The medicinal product 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 system disorders.

Adverse reactions involving the respiratory system, including fatal cases due to bronchospasm in patients with asthma, have been observed with the use of some ophthalmic β-blockers. The medicinal product should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and should be prescribed only when the potential benefit outweighs the potential risk of using the drug.

Hypoglycemia / diabetes mellitus.

β-blockers should be used with caution in patients in whom spontaneous hypoglycemia may occur and in patients with unstable diabetes mellitus, as β-blockers may mask the symptoms of hypoglycemia.

β-blockers may also mask the signs of hyperthyroidism.

Corneal disorders.

Ophthalmic β-blocker medicinal products may cause dry eyes; therefore, these products should be prescribed with caution to patients with corneal disease.

Other β-blockers.

The effect on intraocular pressure or known systemic β-blocking effects may be enhanced when timolol is used concomitantly in patients already receiving systemic β-blockers. Such patients require close monitoring. The concomitant use of two locally acting β-blockers is not recommended.

Anaphylactic reactions.

During β-blocker therapy, patients with a history of atopic disorders or severe anaphylactic reactions to various allergens may have an intensified response upon re-exposure to these allergens and may not respond to the usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment.

Cases of choroidal detachment have been reported during therapy aimed at suppressing intraocular fluid production (e.g., with timolol, acetazolamide) following trabeculectomy.

Surgical anesthesia.

Ophthalmic β-blocker medicinal products may block the systemic effects of β-adrenergic agonists, such as adrenaline. If a patient is taking timolol, this should be communicated to the anesthesiologist.

Concomitant therapy.

Timolol may interact with other medicinal products.

The use of two topical β-blockers or two topical prostaglandins is not recommended.

Ocular effects.

Latanoprost may gradually increase the amount of brown pigment in the iris, thereby changing eye color. As with latanoprost eye drops, increased pigmentation was observed in 16–20% of all patients treated with the combination product for 1 year (based on photographs). This effect is predominantly observed in patients with mixed iris color, e.g., green-brown, yellow-brown, or blue/green-brown, and results from increased melanin content in the stromal melanocytes of the iris. Typically, brown pigmentation around the pupil of the affected eye spreads concentrically toward the periphery, but the entire iris or part of it may become more intensely brown. Such changes were rarely observed in patients with uniformly blue, green, gray, or brown eyes during 2 years of latanoprost treatment.

The change in iris color occurs slowly and may go unnoticed for several months or years. This change is not associated with the development of any symptoms or pathological changes.

Further darkening of the iris after discontinuation of treatment has not been observed, but the color changes that have occurred may be permanent.

Skin darkening of the eyelids, which may be reversible, has been reported with the use of latanoprost.

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

Treatment does not affect iris nevi or freckles.

Pigment accumulation in the trabecular meshwork or elsewhere in the anterior chamber of the eye has not been observed, but patients should be examined regularly. Depending on the clinical picture, treatment may be discontinued if increased iris pigmentation is observed.

Before initiating treatment, patients should be informed about the possibility of eye color changes. Treatment of one eye may result in permanent heterochromia.

There is no confirmed experience with the use of latanoprost in inflammatory, neovascular, chronic angle-closure, or congenital glaucoma, in open-angle glaucoma in patients with pseudophakia, or in pigmentary glaucoma. Latanoprost has little or no effect on the pupil, but there is no confirmed experience with its use in acute angle-closure glaucoma. Therefore, until more experience is available, latanoprost should be prescribed with caution in these conditions.

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

Macular edema, including cystoid macular edema, has been reported with the use of latanoprost. Such cases have been primarily reported in aphakic patients, pseudophakic patients with posterior capsule rupture, or patients with known risk factors for macular edema. The medicinal product should be prescribed with caution in such patients.

Use of contact lenses.

The medicinal product contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. Benzalkonium chloride has been reported to cause punctate keratitis and/or toxic ulcerative keratopathy, may cause eye irritation, and is known to discolor soft contact lenses. Close monitoring is required in patients with dry eye mucosa or conditions associated with corneal damage during frequent and prolonged use of the product. Contact lenses may absorb benzalkonium chloride; therefore, lenses must be removed before instillation of the product and may be reinserted 15 minutes later.

Use during pregnancy or breastfeeding.

Pregnancy.

Latanoprost.

There are no adequate data on the use of latanoprost in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Timolol.

There are no adequate data on the use of timolol in pregnant women. In the absence of a clear medical need, this medicinal product should not be prescribed during pregnancy. Measures to reduce systemic absorption are described in the section "Dosage and administration".

Epidemiological studies have not shown teratogenic effects, but a risk of intrauterine growth retardation has been demonstrated with systemic use of β-blockers. Additionally, newborns whose mothers received β-blockers before delivery have shown symptoms of β-adrenergic receptor blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycemia). If the medicinal product is used in pregnant women close to delivery, the newborn should be closely monitored during the first days of life.

Therefore, the medicinal product should not be used during pregnancy.

Breastfeeding period.

Timolol maleate has been detected in human milk after oral and ocular administration. β-blockers penetrate into breast milk. However, the therapeutic doses of timolol in eye drops are insufficient for the amount that penetrates into milk to cause clinical symptoms of β-adrenergic receptor blockade in the newborn. Measures to reduce systemic absorption are described in the section "Dosage and administration".

Latanoprost and its metabolites may pass into breast milk; therefore, the medicinal product should not be used in women who are breastfeeding.

Fertility.

Animal studies have shown no evidence that latanoprost or timolol affect reproductive function in males or females.

Ability to influence reaction speed when driving or operating machinery.

Instillation of eye drops may cause transient visual disturbances. Until vision is normalized, patients should not drive or operate machinery.

Dosage and Administration

Adults, including elderly patients

The recommended dose is 1 drop in the affected eye(s) once daily.

If a dose is missed, treatment should be continued with the next scheduled dose. The dose must not exceed 1 drop in the affected eye(s) once daily.

Contact lenses must be removed prior to instillation of eye drops. Lenses may be reinserted only 15 minutes after drop administration.

If more than one ophthalmic medicinal product is prescribed, the agents should be administered with an interval of at least 5 minutes between applications.

Application of nasolacrimal occlusion or having the patient close the eyelids for 2 minutes after instillation reduces systemic absorption of the drug. This may reduce the incidence of systemic adverse effects and increase the local efficacy of the medication.

Children

The safety and efficacy of this medicinal product in children and adolescents have not been established.

Overdose

There are no data on overdose of the drug in humans.

Symptoms of systemic overdose with timolol: bradycardia, hypotension, bronchospasm, cardiac arrest. If such symptoms occur, symptomatic and supportive therapy should be administered. Studies have shown that timolol is not completely removed by dialysis.

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been observed in cases of latanoprost overdose.

The following information may be helpful in case of accidental ingestion of latanoprost.

Treatment: if necessary, perform gastric lavage.

Symptomatic treatment: latanoprost is extensively metabolized during first-pass liver metabolism. Intravenous infusion at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms; however, administration of 5.5–10 mcg/kg was associated with nausea, abdominal pain, dizziness, fatigue, flushing, and increased sweating. These manifestations were mild to moderate in severity and resolved spontaneously within 4 hours after completion of the infusion, without requiring specific treatment.

Adverse Reactions

Most adverse reactions associated with latanoprost use are ocular. Data indicate that when latanoprost and timolol are used in combination, iris pigmentation intensification occurred in 16–20% of patients, which may be permanent. It is known that iris pigmentation occurred in 33% of patients treated with latanoprost. Other ocular adverse reactions are generally transient and dose-dependent. With timolol use, the most serious adverse reactions are systemic and include bradycardia, arrhythmia, congestive heart failure, bronchospasm, and allergic reactions.

Like other topically applied ophthalmic agents, timolol is absorbed into the systemic circulation. This may lead to systemic adverse effects similar to those seen with systemic β-blockers. The frequency of systemic adverse reactions following topical administration of ophthalmic drugs is lower than with systemic administration. The listed adverse reactions correspond to those typical for β-blocker ophthalmic preparations.

Adverse reactions associated with the use of the combined medicinal product.

Adverse effects are grouped according to frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), and very rare (< 1/10000).

From the nervous system: uncommon – headache.

From the eye organs: very common – increased pigmentation of the iris; common – eye irritation (including burning, stinging, and itching), eye pain; uncommon – eye redness, conjunctivitis, blurred vision, increased lacrimation, blepharitis, corneal disorder, conjunctival disorders, pseudorefractive error.

From the skin and its appendages: uncommon – skin rash, pruritus, hypertrichosis, skin disorders.

Vascular disorders: hypertension.

Infections and infestations: infections, sinusitis, upper respiratory tract infections.

From the musculoskeletal, connective tissue, and bone system: arthritis.

For latanoprost.

Infections and infestations: herpetic keratitis.

From the nervous system: dizziness.

From the eye organs: changes in eyelids and eyelashes (increased length, thickness, number, and intensified pigmentation); punctate epithelial erosion; periorbital edema; iritis/uveitis; macular edema (in aphakic patients, pseudophakic patients with posterior capsule tear, or patients with known risk factors for macular edema); dryness of the ocular mucosa; keratitis, corneal edema and erosions; misdirected eyelashes, which may cause eye irritation; iris cysts; photophobia; changes in periorbital area and eyelid due to deepening of the eyelid sulcus; foreign body sensation, gritty feeling in the eye, conjunctival pseudopemphigoid*, darkening of eyelid skin.

From the cardiovascular system: worsening of angina pectoris, palpitations.

From the respiratory system, thoracic and mediastinal organs: asthma, asthma exacerbation, dyspnea.

From the skin and subcutaneous tissue: darkening of eyelid skin area, localized skin reaction on eyelids.

From the musculoskeletal, connective tissue, and bone system: joint pain, muscle pain.

From the gastrointestinal tract: uncommon – nausea, vomiting.

General disorders: chest pain.

* May occur due to the presence of the preservative benzalkonium chloride in the medicinal product.

For timolol.

From the immune system: systemic allergic reactions, including angioedema, urticaria, localized and generalized rashes, pruritus, anaphylactic reaction.

From metabolism and nutrition: hypoglycemia.

From the psyche: depression, memory impairment, insomnia, nightmares, hallucinations.

From the nervous system: syncope, cerebrovascular disorders, cerebral ischemia, exacerbation of symptoms and signs of myasthenia, dizziness, paresthesia, headache.

From the eye organs: eye irritation symptoms (burning sensation, stinging, itching, lacrimation, redness), blepharitis, keratitis, visual blurring, as well as choroidal detachment after trabeculectomy, decreased corneal sensitivity, dry eyes, corneal erosion, ptosis, diplopia.

From the auditory organs: tinnitus.

From the cardiovascular system: bradycardia, chest pain, palpitations, edema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, heart failure.

From the vascular system: hypotension, Raynaud's phenomenon, cold sensation in hands and feet.

From the respiratory system, thoracic and mediastinal organs: bronchospasm (predominantly in patients with bronchospastic disease), dyspnea, cough.

From the gastrointestinal tract: dysgeusia, nausea, dyspepsia, diarrhea, dry mouth, abdominal pain, vomiting.

From the skin and subcutaneous tissue: alopecia, psoriatic rash or psoriasis exacerbation, skin rashes.

From the musculoskeletal system and connective tissues: myalgia.

From the reproductive system and mammary glands: sexual dysfunction, decreased libido.

General disorders: asthenia/fatigue.

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

Shelf life.

3 years.

The shelf life of the medicinal product after opening the bottle is not more than 4 weeks.

Storage conditions.

Store in the original packaging at a temperature of 2 °C to 8 °C.

After first opening, store the bottle at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

5 ml in a bottle with a dropper cap in a box.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business.

100 Shevchenka Street, city of Boryspil, Kyiv region, 08301, Ukraine.