LATAMED

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LATAMED (LATAMED)

Composition:

Active substances: latanoprost, timol,ol;

1 ml of solution contains 0.05 mg of latanoprost and 5 mg of timolol (as timolol maleate);

Excipients: disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, benzalkonium chloride, sodium hydroxide or hydrochloric acid, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antiglaucoma preparations and miotics. Beta-blocking agents. Timolol combinations. ATC code S01ED51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

The medicinal product contains two active substances: latanoprost and timolol. Both components reduce elevated intraocular pressure through different mechanisms of action; 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 prostaglandin FP receptor agonist that reduces 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 affect intraocular blood circulation. Long-term administration of latanoprost in monkeys that had undergone extracapsular lens extraction showed no effect on retinal vessels, according to fluorescein angiography data. Latanoprost did not induce fluorescein leakage into the posterior segment of the eye in pseudophakic patients during short-term treatment.

Timolol is a (non-selective) beta-1 and beta-2 adrenergic receptor blocker that lacks significant direct sympathomimetic activity, direct myocardial depressant effects, and 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 stimulated cyclic AMP (adenosine monophosphate) synthesis caused by endogenous stimulation of beta-adrenergic receptors.

No significant effect of timolol on the permeability of the blood-aqueous barrier to plasma proteins has been observed. In rabbits, timolol did not affect local ocular blood flow after long-term administration.

Pharmacodynamic effects.

In dose-finding studies, the latanoprost/timolol combination demonstrated significantly greater reduction in mean diurnal intraocular pressure compared to monotherapy with either latanoprost or timolol when administered once daily. In two well-controlled, double-masked, six-month clinical trials, the degree of intraocular pressure reduction with the latanoprost/timolol combination was compared to that achieved with monotherapy using latanoprost or timolol in patients with intraocular pressure of at least 25 mmHg or higher. After an initial run-in period with timolol administration for 2–4 weeks (mean reduction in intraocular pressure was 5 mmHg from baseline), additional mean diurnal intraocular pressure reductions of 3.1, 2.0, and 0.6 mmHg were observed after 6 months of treatment with the latanoprost/timolol combination, latanoprost monotherapy, and timolol (twice daily), respectively. The intraocular pressure-lowering effect of the latanoprost/timolol combination was maintained during subsequent open-label, six-month extension studies.

Available data suggest that evening administration may be more effective in reducing intraocular pressure than morning administration. However, when considering recommendations for administering the latanoprost/timolol combination in the morning or evening, patient lifestyle and likely compliance should be taken into account.

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

The onset of action of the latanoprost/timolol combination occurs within 1 hour, with maximum effect achieved within 6–8 hours. Adequate intraocular pressure reduction lasts up to 24 hours after instillation with repeated dosing.

Pharmacokinetics.

Latanoprost.

Latanoprost is a prodrug, an isopropyl ester that is essentially inactive but becomes biologically active latanoprost acid after esterase hydrolysis in the cornea. The prodrug is well absorbed through the cornea and, like all agents entering the aqueous humor, is hydrolyzed during passage through the cornea. Studies in humans have shown that maximum concentration in the 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 at 0.16 L/kg, resulting in a short plasma half-life (17 minutes). After topical ophthalmic administration, systemic bioavailability of latanoprost acid 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) have no or only weak biological activity (animal studies) 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 some unchanged timolol.

No pharmacokinetic interactions between latanoprost and timolol have been observed, despite an almost two-fold increase in latanoprost acid concentration in aqueous humor 1–4 hours after administration of the latanoprost/timolol combination compared to monotherapy.

Clinical characteristics.

Indications.

Reduction of intraocular pressure in patients with open-angle glaucoma and elevated intraocular pressure who have an insufficient response to treatment with beta-blockers or topical prostaglandin analogs.

Contraindications.

• Hypersensitivity to the active substances and/or to any of the excipients of the medicinal product.
• Reactive respiratory tract diseases, including bronchial asthma or 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; clinically manifest cardiac failure; cardiogenic shock.

Interaction with other medicinal products and other forms of interactions.

No specific interaction studies of the latanoprost/timolol combination with other agents have been conducted.

Prostaglandins, prostaglandin analogs, or prostaglandin derivatives.

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.

Oral calcium channel blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.

There is a potential for additive effects leading to arterial hypotension and/or marked bradycardia when beta-blockers in the form of ophthalmic drops are used concomitantly with these agents.

CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine).

Enhanced systemic beta-blockade (e.g., reduced heart rate, depression) has been observed during concomitant use of these agents and timolol.

Oral beta-adrenergic receptor blockers.

The effect on intraocular pressure or known systemic beta-blocking effects may be potentiated when the latanoprost/timolol combination is used concomitantly in patients already receiving oral beta-blockers. The use of two or more topical beta-blockers is not recommended.

Adrenaline (epinephrine).

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

Clonidine.

Use of beta-blockers may lead to a hypertensive reaction in response to abrupt withdrawal of clonidine.

Antidiabetic agents.

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

Special precautions for use.

Systemic effects.

Like other ophthalmic medicinal products for topical application, the medicinal product is systemically absorbed. Since the medicinal product contains the beta-adrenergic component timolol, the same types of adverse reactions affecting the cardiovascular, pulmonary, and other systems as with systemically administered beta-blockers may occur. The frequency of systemic adverse reactions after topical administration in the form of eye drops is lower than after systemic administration. Measures to reduce systemic absorption are described in the section «Dosage and 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, heart failure) and hypotension, and consideration should be given to treatment with alternative agents. During treatment with the medicinal product, patients with cardiovascular disorders should be monitored for signs of worsening of these conditions and adverse reactions.

Since beta-adreoreceptor blockers negatively affect conduction time, they should be used with caution in 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.

Respiratory system disorders.

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

Corneal disorders.

Ophthalmic beta-blocker agents may cause dry eye; therefore, the medicinal product should be used with caution in patients with corneal disease.

Anaphylactic reactions.

During treatment with beta-blockers, patients with a history of atopic disorders or severe anaphylactic reactions to various allergens may exhibit more intense reactions upon re-exposure to these allergens and may not respond to usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment.

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

Perioperative anesthesia.

Ophthalmic beta-blocker agents 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.

Change in iris pigmentation.

Lataprost may gradually increase the amount of brown pigment in the iris, thereby changing eye color. As with latanoprost administered as eye drops, increased iris pigmentation was observed in 16–20% of all patients treated with the latanoprost/timolol combination for 1 year (based on photographs). This effect is predominantly observed in patients with mixed iris color, such as green-brown, yellow-brown, or blue/green-brown, and occurs due to increased melanin content in the stromal melanocytes of the iris. Typically, the 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 clinical trials with latanoprost.

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 has been observed after discontinuation of treatment, but the color changes that have occurred may be permanent.

The 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 eye color changes. 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 alter 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 patients with aphakia or pseudophakia, or pigmentary glaucoma. Latanoprost has little or no effect on the pupil, but there is no confirmed experience with its use during acute attacks of angle-closure glaucoma. Therefore, the medicinal product should be used with caution in such conditions until more data are available.

Macular edema.

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

Concomitant use with other beta-blockers.

The effect on intraocular pressure or known systemic beta-blocking effects may be enhanced when timolol is used in patients already receiving systemic beta-blockers. These 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 types of interactions»).

Concomitant use with other prostaglandin analogues.

The concomitant use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended (see section «Interaction with other medicinal products and other types of interactions»).

Concomitant use with other agents.

Timolol may interact with other medicinal products (see section «Interaction with other medicinal products and other types of interactions»).

Patients with severe peripheral circulation disorders.

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

Patients at risk of spontaneous hypoglycemia or patients with unstable diabetes mellitus.

The medicinal product should be used with caution in such patients, as beta-blockers may mask the symptoms and signs of acute hypoglycemia. Beta-blockers may also mask the signs of hyperthyroidism.

Patients with herpetic keratitis.

The medicinal product 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.

Patients using contact lenses.

Contact lenses may absorb the excipient benzalkonium chloride from the medicinal product; therefore, lenses must be removed before instilling eye drops and may be reinserted 15 minutes after instillation (see section «Dosage and administration»).

Warnings related to excipients.

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 alter the color of soft contact lenses. Careful monitoring is required in patients with dry eye or conditions associated with corneal damage when the medicinal product is used frequently and long-term.

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. Timolol should not be used during pregnancy unless clearly necessary. Methods to reduce systemic absorption are described in the section «Dosage and administration».

Epidemiological studies have not shown teratogenic effects; however, a risk of intrauterine growth retardation has been demonstrated with systemic administration 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 medicinal product is used in pregnant women close to delivery, the newborn should be carefully monitored during the first days of life.

Considering the above, the medicinal product should not be used during pregnancy.

Lactation period.

Beta-blockers pass into breast milk. However, therapeutic doses of timolol in eye drops are insufficient for the amount excreted into milk to cause clinical symptoms of beta-adrenergic blockade 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, the medicinal product should not be used during lactation.

Fertility.

Animal studies did not reveal any effect of latanoprost or timolol on male or female reproductive function.

Ability to affect reaction speed when driving or operating machinery.

Instillation of eye drops may cause transient visual disturbances. Driving or operating machinery should be avoided until vision is normalized.

Dosage and Administration

The medicinal product is intended for ophthalmic use.

Adults, including elderly patients.

Administer 1 drop of the medicinal product into the affected eye(s) once daily.

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

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

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

If the patient performs nasolacrimal occlusion or closes the eyelids for 2 minutes after instillation, systemic absorption of the drug is reduced. This may decrease the incidence of systemic adverse reactions and increase the efficacy of local action.

Children.

Safety and efficacy of the medicinal product in children and adolescents have not been established.

Overdose.

There is no information available on overdose.

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

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse reactions have been observed with latanoprost overdose.

The following information may be helpful in case of accidental oral ingestion of latanoprost. If necessary, perform gastric lavage. Provide symptomatic treatment. Latanoprost is extensively metabolized during the first pass through the liver. Intravenous infusion of 3 mcg/kg in healthy volunteers did not produce any symptoms; however, doses of 5.5–10 mcg/kg were 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 reactions associated with latanoprost use are ocular. Data from the extended phase of the main study on the latanoprost/timolol combination indicate that iris pigmentation increased in 16–20% of patients, which may be permanent. During a 5-year open-label safety study of latanoprost, iris pigmentation occurred in 33% of patients (see section "Special Warnings and Precautions for Use"). Other ocular adverse reactions are generally transient and dose-dependent. The most serious adverse reactions 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 systemically. This may lead to adverse reactions similar to those observed with systemic beta-blockers. The incidence of systemic adverse reactions following topical administration of ophthalmic agents is lower than with systemic administration. Listed adverse reactions include those typical for the class of ophthalmic beta-blockers.

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

Adverse reactions are categorized according to frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Nervous system disorders:

Uncommon – headache.

Eye disorders:

Very common – increased pigmentation of the iris;
Common – eye pain, eye irritation (including burning, stinging, itching, foreign body sensation);
Uncommon – corneal condition abnormalities, conjunctivitis, blepharitis, ocular hyperemia, blurred vision, increased lacrimation.

Skin and subcutaneous tissue disorders:

Uncommon – skin rash, pruritus.

During clinical trials, spontaneous reports, and literature reviews, additional adverse effects specific to individual components have been reported.

For latanoprost.

Infections and infestations: Herpetic keratitis.

Nervous system disorders: Dizziness.

Eye disorders: Changes in eyelashes and vellus hair of the eyelid (increased length, thickness, pigmentation, and number of eyelashes); 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 eyelid due to deepening of the eyelid sulcus; eyelid edema; localized skin reaction on the eyelids, conjunctival pseudopemphigoid\1, darkening of eyelid skin.

Cardiac disorders: Angina pectoris; unstable angina; palpitations.

Respiratory, thoracic and mediastinal disorders: Asthma, exacerbation of asthma, dyspnea.

Gastrointestinal disorders: Nausea (uncommon), vomiting (uncommon).

Musculoskeletal and connective tissue disorders: Myalgia; arthralgia.

General disorders and administration site conditions: Chest pain.

1 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, hallucinations.

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

Eye disorders: Detachment of the ocular choroid following trabeculectomy (see section "Special Warnings and Precautions for Use"), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, symptoms and signs of eye irritation (e.g., burning sensation, stinging, itching, lacrimation, redness), dry eye, ptosis, blepharitis, blurred vision.

Ear and labyrinth disorders: Tinnitus.

Cardiac disorders: Cardiac arrest, heart failure, atrioventricular block, congestive heart failure, chest pain, arrhythmia, bradycardia, edema, palpitations.

Vascular disorders: Cold sensation in hands and feet, 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 rashes, psoriasiform rashes, 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 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 continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

After opening the bottle, the product can be used for up to 4 weeks.

Storage conditions.

Store at 2–8 °C, protected from light and inaccessible to children.

After opening, store the bottle 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.

C.O. Rompharm Company S.R.L., Romania /
S.C. Rompharm Company S.R.L., Romania.

WORLD MEDICINE ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business.

Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov, Romania.
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.