Lanotan® t

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LANOTAN T (LANOTAN T)

Composition:

Active substances: latanoprost, timolol;

1 ml of the preparation contains latanoprost 0.05 mg, timolol maleate equivalent to 100 % timolol 5 mg;

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

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless liquid.

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

Pharmacological properties.

Pharmacodynamics.

Lanotan® T contains two active substances: latanoprost and timolol maleate. 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 affect intraocular blood circulation. Long-term administration of latanoprost in monkeys that had undergone extracapsular lens extraction showed no effect on retinal vasculature 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 (nonselective) β1- and β2-adrenergic receptor blocker without significant direct sympathomimetic activity, direct myocardial depressant effect, or membrane-stabilizing activity. Timol0l 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 enhanced cyclic 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 local ocular blood flow after prolonged administration.

Lanotan® T produces a significantly greater reduction in mean daily intraocular pressure compared to monotherapy with either latanoprost or timolol when administered once daily. In well-controlled, double-masked, six-month clinical trials, the degree of intraocular pressure reduction achieved with the combined medicinal product containing latanoprost and timolol maleate was compared to that achieved with monotherapy using latanoprost or timolol in patients with intraocular pressure levels of 25 mm Hg. After an initial period of timolol treatment for 2–4 weeks (average reduction in intraocular pressure was 5 mm Hg from baseline), additional mean reductions in diurnal intraocular pressure of 3.1, 2.0, and 0.6 mm Hg were observed after 6 months of treatment with the combined medicinal product, latanoprost, and timolol (twice daily), respectively. The intraocular pressure-lowering effect of the combined medicinal product was maintained during subsequent 6-month open-label extension studies. Evening administration of the drug 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 combined preparation is insufficiently effective, separate administration of timolol twice daily and latanoprost once daily may be effective, as confirmed during clinical trials.

The onset of action of Lanotan® T occurs within 1 hour, and the maximum effect lasts from 6 to 8 hours. Adequate reduction of intraocular pressure persists for up to 24 hours with repeated administration.

Pharmacokinetics.

Latanoprost

Absorption

Latanoprost is a prodrug in the form of an isopropyl ester, which 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, is hydrolyzed during passage through the cornea.

Distribution

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; 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 is 45%. Latanoprost acid is 87% bound to plasma proteins.

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 and are excreted predominantly in urine.

Timolol

Absorption and distribution

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).

Metabolism

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

Elimination

Metabolites are excreted in urine as unchanged timolol.

Lanotan® T.

No pharmacological interactions between latanoprost and timolol were observed, despite an almost twofold increase in latanoprost acid concentration in aqueous humor 1–4 hours after administration of the combined medicinal product 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 substance or to any other component 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 heart failure; cardiogenic shock.

Interaction with other medicinal products and other forms of interaction.

No specific interaction studies between Lanotan® T and other drugs have been conducted.

Paradoxical increases in intraocular pressure have been reported following concomitant use of two prostaglandin analog medications. Therefore, concomitant 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 beta-blocker ophthalmic solutions are administered concomitantly with oral calcium channel blockers, beta-adrenergic blockers, antiarrhythmic agents (including amiodarone), cardiac glycosides, parasympathomimetics, or guanethidine.

Enhanced systemic beta-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 effects of beta-blockade may be potentiated when Lanotan® T is administered to patients already receiving oral beta-blockers. Concomitant use of two or more topically acting beta-blockers is not recommended.

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

Use of beta-blockers may lead to exacerbation of hypertension following abrupt withdrawal of clonidine.

Beta-blockers may enhance the hypoglycemic effect of antidiabetic agents. Beta-blocker therapy may mask the symptoms of hypoglycemia.

Special precautions for use.

Systemic effects.

Like other ophthalmic medicinal products for topical use, Lantitan® T is systemically absorbed. Since the product contains the beta-adrenergic agent timolol, the same types of adverse reactions affecting the pulmonary, cardiovascular, and other systems as with systemic beta-adrenergic receptor blockers may occur. The frequency of systemic adverse reactions after topical application is lower than after systemic administration of the drug. Measures to reduce systemic absorption are described in the section "Method of administration and dosage".

Cardiac disorders.

The necessity of beta-blocker therapy should be carefully evaluated in patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal's angina, heart failure) and hypotension, 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 prolong excitation time, they should be administered 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 administration of timolol have been reported.

Vascular disorders.

The drug should be used with caution in the treatment of 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 cases due to bronchospasm in patients with asthma, have been reported with the use of some ophthalmic beta-blockers. Lantitan® T 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 potential risk of using the drug.

Hypoglycemia/diabetes.

Beta-blockers should be prescribed with caution to patients in whom spontaneous hypoglycemia may occur or to patients with unstable diabetes mellitus, as beta-blockers may mask the symptoms of hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal disorders.

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

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 close 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.

While receiving beta-blockers, patients with a history of atopic disorders or severe anaphylactic reactions to various allergens may react more intensely to re-exposure to these allergens and may not respond to usual doses of epinephrine used to treat anaphylactic reactions.

Choroidal detachment.

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

Surgical anesthesia.

Ophthalmic beta-blocker drugs may block the systemic effects of beta-adrenergic agonists, such as epinephrine. If a patient is taking timolol, this should be communicated 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.

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

Ocular effects.

Latanoprost may gradually increase the amount of brown pigment in the iris, thereby changing eye color. As with latanoprost eye drops, pigmentation enhancement was observed in 16–20% of all patients treated with the combination 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, the brown pigmentation around the pupil of the treated 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 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 after discontinuation of treatment has 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 eyelashes or hair, as well as misdirected growth of eyelashes. Eyelash changes are reversible after discontinuation of treatment.

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.

There is no confirmed experience with the use of latanoprost in inflammatory, neovascular, chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, or pigmentary glaucoma. Latanoprost has no or minimal effect on the pupil, but there is no confirmed experience with its use in acute angle-closure glaucoma. Therefore, until sufficient experience is available, latanoprost is recommended to be used 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 herpetic keratitis caused by herpes simplex virus and in patients with a history of recurrent herpetic keratitis associated with the use of prostaglandin analogs.

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

Use of contact lenses.

Lantitan® T 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. With frequent and prolonged use of Lantitan® T in patients with dry eye or conditions associated with corneal damage, close monitoring is required. Contact lenses may absorb benzalkonium chloride; therefore, lenses must be removed before instilling Lantitan® T and may be reinserted after 15 minutes (see section "Method of administration and dosage").

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 an urgent need for timolol, this drug should not be prescribed during pregnancy. Methods to reduce systemic absorption are described in the section "Method of administration and dosage".

Epidemiological studies have not shown teratogenic effects; however, a risk of intrauterine growth retardation has been demonstrated with systemic use of beta-blockers. In addition, signs and symptoms of beta-adrenergic receptor blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycemia) have been observed in newborns whose mothers received beta-blockers during pregnancy. If Lantitan® T is used in pregnant women during the third trimester, the newborn should be closely monitored during the first days of life.

Therefore, Lantitan® T should not be used during pregnancy.

Lactation (breastfeeding).

Beta-blockers pass into breast milk. However, therapeutic doses of timolol in eye drops are insufficient for the amount excreted into breast milk to cause clinical symptoms of beta-adrenergic receptor blockade in the newborn. Methods to reduce systemic absorption are described in the section "Method of administration and dosage".

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

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.

Lantitan® T has a minor influence on the ability to drive or operate machinery. Instillation of eye drops may cause transient visual disturbances. Until vision is normalized, patients should not drive or operate machinery.

Method of Administration and 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.

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

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

If the patient applies 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 severity of systemic adverse effects and increased efficacy of local drug action.

Children

The safety and efficacy of Lanotan® T in children have not been established.

Overdose

There are no data on overdose of latanoprost with timolol in the form of eye drops in humans.

Symptoms

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

Treatment

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

The following information may be helpful in case of accidental oral ingestion. Studies have shown that timolol is not completely removed by dialysis. If necessary, gastric lavage should be performed. Latanoprost 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, hot flushes, and increased sweating. These manifestations were mild to moderate in severity and resolved spontaneously within 4 hours after completion of the infusion.

Adverse reactions

Most adverse effects associated with the use of latanoprost occur in the eye. Data from studies on the use of the combination of latanoprost and timolol for ophthalmic application indicate that iris pigmentation increased in 16–20% of patients, which may be permanent.

In an open-label 5-year safety study of latanoprost, iris pigmentation occurred in 33% of patients. Other ocular adverse effects are generally transient and dose-dependent. With timolol use, the most serious adverse effects are systemic and include bradycardia, arrhythmia, congestive heart failure, bronchospasm, and allergic reactions.

Like other topically acting 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 incidence of systemic adverse reactions after topical administration of ophthalmic agents is lower than with systemic administration. These adverse reactions are consistent with those typical of beta-blocking ophthalmic agents.

Adverse effects associated with the use of the fixed combination ophthalmic medicinal product containing latanoprost and timolol maleate observed during clinical trials are listed below.

Adverse effects are categorized by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

Adverse reactions observed during clinical trials with the fixed combination ophthalmic medicinal product containing latanoprost and timolol maleate are listed below.

Table 1

System organ class	Very common (≥1/10)	Common ≥ 1/100 - < 1/10	Uncommon ≥ 1/1 000 - < 1/100
Nervous system disorders			Headache
Eye disorders	Increased pigmentation of the iris	Eye pain, eye irritation (including burning, stinging, itching, foreign body sensation)	Corneal disorder, conjunctivitis, blepharitis, ocular hyperemia, blurred vision, increased lacrimation
Skin and subcutaneous tissue disorders			Rash, pruritus

Additional adverse effects specific to individual components of Lanotan® T have been reported in spontaneous reports and in the literature during clinical studies.

Adverse reactions observed during clinical studies with the use of latanoprost in the form of eye drops.

Table 2

System organ class	Adverse reactions
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 erosion; 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; ocular pseudopemphigoid conjunctivitis*, eyelid skin darkening
Cardiac disorders	Angina pectoris; unstable angina; palpitations
Respiratory, thoracic and mediastinal disorders	Asthma, asthma exacerbation, dyspnea
Gastrointestinal disorders	Uncommon – 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.

Adverse reactions observed during clinical trials with timolol maleate in the form of eye drops.

Table 3

System organ class	Adverse reactions
Immune system disorders	Systemic allergic reactions, including anaphylactic reaction, angioedema, urticaria, localized and generalized rashes, pruritus
Metabolism and nutrition disorders	Hypoglycemia
Psychiatric disorders	Memory loss, insomnia, depression, nightmares
Nervous system disorders	Cerebrovascular disorders; cerebral ischemia, dizziness, exacerbation of symptoms and signs of myasthenia gravis, paresthesia, headache, syncope
Eye disorders	Retinal detachment after trabeculectomy, corneal erosion, keratitis, diplopia, decreased corneal sensitivity, symptoms and signs of eye irritation (e.g. burning sensation, eye pricking, itching, lacrimation and redness), dryness of the conjunctiva, 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	Feeling of cold 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 in some patients with significant corneal damage during the use of eye drops containing phosphate.

Shelf life. 2 years.

Shelf life after first opening of the container is 28 days at a temperature not exceeding 25 °C.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in a light-protected place at a temperature of 2 to 8 °C.

Keep out of reach of children.

Packaging. 2.5 mL in a bottle. 1 bottle in a carton.

Prescription status. Prescription only.

Manufacturer: JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.