Lapronext combo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LaproNext combi (LaproNext combi)

Composition:

Active substances: latanoprost, timolol;

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

Excipients: benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate anhydrous, sodium hydroxide or hydrochloric acid diluted, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical characteristics: clear, colorless solution.

Pharmacotherapeutic group. Antiglaucoma preparations 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 that reduces intraocular pressure 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 humans. Latanoprost does not significantly affect aqueous humor production or the blood-aqueous barrier, nor does it affect intraocular blood circulation. Long-term administration of latanoprost in monkeys that had undergone extracapsular lens extraction did not affect retinal vessels, according to fluorescein angiography data. 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 blocker of beta1- and beta2-adrenergic receptors, lacking significant direct sympathomimetic activity, direct myocardial depressant effects, 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 is likely due to inhibition of the enhanced cyclic AMP synthesis caused by endogenous stimulation of beta-adrenergic receptors.

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

It is known from dose-finding studies that the combined medicinal product demonstrated a significantly greater reduction in mean daily intraocular pressure compared to monotherapy with either latanoprost or timolol administered once daily. The degree of intraocular pressure reduction with the combined product was compared to that achieved with monotherapy using latanoprost and timolol in patients with intraocular pressure of at least 25 mm Hg or higher. After an initial period of treatment with timolol for 2–4 weeks (mean reduction in intraocular pressure was 5 mm Hg from baseline), an additional reduction in mean daily intraocular pressure of 3.1, 2.0, and 0.6 mm Hg was observed after 6 months of treatment with the combined product, latanoprost, and timolol (twice daily), respectively. The effect of reducing elevated intraocular pressure with the combined product was maintained during subsequent 6-month open-label extension studies.

Administration of the medicinal product in the evening 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 in cases of insufficient efficacy of the combined product, separate administration of timolol twice daily and latanoprost once daily may be effective, as confirmed in clinical studies.

The onset of action of the medicinal product occurs within 1 hour, and the maximum effect lasts 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. Prodrugs are well absorbed through the cornea, and like all drugs entering the aqueous humor, they are hydrolyzed 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 mainly 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, the systemic bioavailability of latanoprost is 45%. Latanoprost acid is 87% bound to plasma proteins.

Metabolism of latanoprost acid in the eye is minimal. 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 about 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 of latanoprost and timolol.

No pharmacological interactions between latanoprost and timolol have been observed, despite an almost twofold increase in latanoprost acid concentration in aqueous humor 1–4 hours after administration of the combined product compared to monotherapy.

Clinical characteristics.

Indications.

Reduction of intraocular pressure in patients with open-angle glaucoma and elevated intraocular pressure when the response to treatment with topical beta-blockers or prostaglandin analogues is inadequate.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Reactive respiratory diseases, including bronchial asthma (including in medical history), severe chronic obstructive pulmonary disease.

Sinus bradycardia; sick sinus syndrome; sinoatrial block; second- or third-degree atrioventricular block not controlled by a pacemaker; clinically manifest heart failure; cardiogenic shock.

Interaction with other medicinal products and other forms of interaction.

No specific studies on interactions with other drugs have been conducted.

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

There is a potential for additive effects leading to the development of arterial hypotension and/or marked bradycardia when beta-blockers in the form of ophthalmic 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 concomitant use with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol.

The effect on intraocular pressure or known systemic beta-blockade effects may be potentiated when the drug is used concomitantly in patients already receiving oral beta-blockers. Concomitant use of two or more locally acting adrenergic beta-blockers is not recommended.

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

Beta-blockers may cause a hypertensive reaction in response to abrupt withdrawal of clonidine.

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

Special precautions for use.

Systemic effects

Like other topically applied ophthalmic medicinal products, LaproNext Combi is absorbed systemically. Since the product contains the beta-adrenergic component timolol, the same types of adverse reactions affecting the cardiovascular, pulmonary and other systems as with systemic beta-blockers may occur. The frequency of systemic adverse reactions after topical administration as eye drops is lower than after systemic administration of the drug. Measures to reduce systemic absorption are described in the section "Dosage and administration".

Cardiac disorders

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

Since beta-blockers have a negative effect on conduction time, they should be prescribed with caution to patients with first-degree heart block.

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

Vascular disorders

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

Respiratory disorders

Adverse reactions affecting the respiratory system, including fatal outcomes due to bronchospasm in patients with asthma, have been reported with the use of some ophthalmic beta-blockers. LaproNext Combi 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 treatment.

Hypoglycemia/diabetes

Beta-blockers should be prescribed with caution in patients who may develop spontaneous hypoglycemia or in patients with unstable diabetes mellitus, as beta-blockers may mask the symptoms and signs of acute hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal disorders

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

Other beta-blockers

The effect on intraocular pressure or known systemic beta-blocking effects may be enhanced when timolol is used concomitantly in patients already receiving systemic beta-blockers. Such patients require careful monitoring. The concomitant use of two locally acting beta-blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Anaphylactic reactions

Patients with a history of atopic disorders or severe anaphylactic reactions to various allergens may exhibit an intensified response to re-exposure to these allergens while receiving beta-blockers 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 treatment aimed at suppressing aqueous humor formation (e.g., with timolol, acetazolamide) following trabeculectomy.

Surgical anesthesia

Ophthalmic beta-blocker medicinal products may block the systemic effects of beta-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 (see section "Interaction with other medicinal products and other forms of interaction").

Other prostaglandin analogues

Concomitant use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Change in iris pigmentation

Latanoprost may gradually increase the amount of brown pigment in the iris and thereby change eye color. As with the use of latanoprost eye drops, increased iris pigmentation was observed in 16–20% of all patients treated with the drug 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 occurs due to 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 treatment with latanoprost in clinical trials.

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.

No further darkening of the iris was observed after discontinuation of treatment, but the color changes that occurred may be permanent.

Treatment does not affect iris nevi or freckles.

Accumulation of pigment 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 developing a change in eye color. Treatment of one eye may result in permanent heterochromia.

Changes in eyelids and eyelashes

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

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 hairs, as well as misdirected eyelash growth. Eyelash changes are reversible after discontinuation of treatment.

Glaucoma

There is no confirmed experience with the use of latanoprost in inflammatory, neovascular, or chronic angle-closure glaucoma, open-angle glaucoma in aphakic patients, or pigmentary glaucone. Latanoprost has little or no effect on the pupil of the eye, but there is no confirmed experience with its use in acute attacks of angle-closure glaucoma. Therefore, until more experience is gained, latanoprost is recommended to be prescribed with caution in these conditions.

Herpetic keratitis

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

Macular edema

Cases of macular edema, including cystoid macular edema, have been reported with the use of latanoprost. Such cases have mainly been reported in aphakic patients, pseudophakic patients with posterior capsule tear, or patients with known risk factors for macular edema. LaproNext Combi should be prescribed with caution to such patients.

Preservative

LaproNext Combi contains benzalkonium chloride, commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause punctate keratitis and/or toxic ulcerative keratopathy. Benzalkonium chloride may cause irritation. It discolors soft contact lenses. Careful monitoring is required in patients with dry eye or corneal disorders who require frequent and prolonged use of the product.

Contact lenses

Contact lenses may absorb benzalkonium chloride; therefore, lenses should be removed before instillation of the product and may be reinserted 15 minutes later (see section "Dosage and administration").

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 for humans is unknown.

Timolol

There are no adequate data on the use of timolol in pregnant women. Unless clearly necessary, timolol should not be prescribed during pregnancy. Methods 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 beta-blockers. In addition, signs and symptoms of beta-adrenergic blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycemia) have been observed in newborns whose mothers received beta-blockers before delivery. If the drug is used in pregnant women close to delivery, the newborn should be closely monitored during the first days of life.

Therefore, LaproNext Combi should not be used during pregnancy.

Lactation

Beta-blockers pass into breast milk. However, therapeutic doses of timolol in eye drops are insufficient to result in clinically significant levels in breast milk to cause beta-blockade symptoms in the newborn. Methods to reduce systemic absorption are described in the section "Dosage and administration".

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

Fertility

Animal studies have not shown any effect of latanoprost or timolol on male or female fertility.

Ability to influence reaction speed when driving or operating machinery

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

Method of Administration and Dosage

Dosage

Adults, including elderly patients

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

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

Method of Administration

Contact lenses must be removed before instilling the eye drops. Lenses may be reinserted only 15 minutes after drop administration.

If more than one topical ophthalmic medicinal product is prescribed for a patient, the agents should be administered with at least a 5-minute interval between them.

If the patient uses nasolacrimal occlusion or closes the eyelids for 2 minutes after instillation, systemic absorption of the drug is reduced. This may lead to a reduction in the intensity of systemic adverse effects and an increase in the local efficacy of the drug.

Children

The safety and efficacy of the drug in children and adolescents have not been established.

Overdose

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

Symptoms

Symptoms of systemic overdose of timolol: bradycardia, arterial hypotension, bronchospasm, cardiac arrest. Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been observed with latanoprost overdose.

Treatment

If such symptoms occur, symptomatic and supportive therapy should be administered.

The following information may be helpful in case of accidental oral ingestion of LaproNext Combo.

Studies have shown that timolol is not completely eliminated by dialysis.

If necessary, gastric lavage should be performed.

Lataprost is extensively metabolized during the first pass through the liver. Intravenous infusion at a dose of 3 mcg/kg in healthy volunteers did not produce any symptoms, whereas 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 without treatment within 4 hours after completion of the infusion.

Adverse Reactions

Most adverse effects associated with latanoprost administration are ocular. Data indicate that when latanoprost and timolol are used in combination, increased pigmentation of the iris occurs in 16–20% of patients, which may be permanent. It is known that iris pigmentation occurs in 33% of patients receiving latanoprost. Other ocular adverse effects are usually transient and dose-dependent. The most serious adverse effects associated with timolol 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 observed with systemic beta-blockers. The frequency of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration. The listed adverse reactions are consistent with those typical of ophthalmic beta-blocking agents.

Adverse reactions associated with the use of the latanoprost/timolol combination observed during clinical trials are listed below.

Adverse reactions are categorized by 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).

Central nervous system: uncommon – headache.

Ocular: very common – increased pigmentation of the iris; common – eye pain, ocular irritation (including burning, stinging, itching, foreign body sensation); uncommon – corneal disorder, conjunctivitis, blepharitis, ocular hyperemia, blurred vision, increased lacrimation.

Skin and subcutaneous tissue: uncommon – skin rash, pruritus.

Additional adverse reactions specific to individual components of the drug have been reported in clinical trials, spontaneous reports, and the literature.

For latanoprost

Infections and infestations: herpetic keratitis.

Central nervous system: dizziness.

Ocular: changes in eyelashes and vellus hair of the eyelids (increased length, thickness, pigmentation, and number of lashes); punctate keratitis, periorbital edema; iritis; uveitis; macular edema, including cystoid macular edema; dry eye; keratitis; corneal edema; corneal erosions; trichiasis; iris cyst; photophobia; changes in periorbital area and eyelids due to deepening of the eyelid sulcus; eyelid edema; localized skin reaction on eyelids, conjunctival pseudopemphigoid*, darkening of eyelid skin.

Cardiovascular system: 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.

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

For 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 loss, insomnia, depression, nightmares.

Nervous system disorders: cerebral circulation disorders; cerebral ischemia, dizziness, exacerbation of symptoms and signs of myasthenia gravis, paresthesia, headache, syncope.

Ocular: choroidal detachment following trabeculectomy (see section "Special precautions for use"), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, symptoms and signs of ocular irritation (e.g., burning sensation, stinging, itching, lacrimation, redness), dry eye, ptosis, blepharitis, blurred vision.

Ear and labyrinth disorders: tinnitus.

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

Vascular disorders: coldness 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, psoriasiform 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.

Isolated cases of corneal calcification have been reported with the use of phosphate-containing ophthalmic solutions in some patients with significant corneal damage.

Reporting of 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 through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After first opening, use within 4 weeks.

Storage conditions. Store in the original packaging at 2–8 °C.

Keep out of reach of children.

After first opening, store the bottle in its original packaging, protected from light, at a temperature not exceeding 25 °C.

Packaging. 2.5 mL in a dropper bottle; 1 dropper bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

RAFARM SA / RAFARM SA.

Manufacturer's address and place of business.

Thesi Pousi-Xatzi Agiou Louka, Paiania (Attiki), TK 19002, PO Box 37, Greece / Thesi Pousi-Xatzi Agiou Louka, Paiania Attiki, TK 19002, TO 37, Greece.