Duoprost

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DUOPROST

Composition:

Active substances: latanoprost, timolol;

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

Excipients: sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate dodecahydrate, sodium chloride, benzalkonium chloride, sodium hydroxide, hydrochloric acid 1M, purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: the solution is practically clear and practically free from visible particles.

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

Pharmacological properties.

Pharmacodynamics.

The medicinal product Duoprost contains two active substances: latanoprost and timolol maleate. Both components reduce elevated intraocular pressure through different mechanisms of action; their additive effect results in a more pronounced reduction of intraocular pressure compared to monotherapy with either component alone. Latanoprost, a prostaglandin F2α analogue, is a selective agonist of prostaglandin FP receptors, which 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 have a significant effect on aqueous humor production or on the blood-aqueous barrier or 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 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, has no direct depressive effect on the myocardium, and lacks 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 likely involves inhibition of adenosine monophosphate (AMP) synthesis stimulated by endogenous adrenergic beta-receptor stimulation.

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.

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

Available data suggest that evening administration 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 fixed-combination product 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 Duoprost occurs within 1 hour, and the maximum effect lasts from 6 to 8 hours. Adequate intraocular pressure reduction lasts up to 24 hours with repeated administration.

Pharmacokinetics.

Latanoprost

Absorption

Latanoprost is a prodrug 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 agents entering the aqueous humor, is hydrolyzed during passage through the cornea.

Distribution

Studies in volunteers showed 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; 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

Ocular metabolism of latanoprost acid 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 (animal studies) 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.

Fixed-dose combination of latanoprost and timolol

No pharmacological interactions between latanoprost and timolol have been observed, despite nearly a twofold increase in latanoprost acid concentration in aqueous humor 1–4 hours after administration of latanoprost/timolol 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 beta-blockers or topical prostaglandin analogs.

Contraindications.

• Hypersensitivity to the active substance or to any other component 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 the interaction of the medicinal product Duoprost with other medicinal products 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 resulting in arterial hypotension and/or marked bradycardia when beta-blockers in the form of ophthalmic drops are administered concomitantly with oral calcium channel blockers, beta-blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, or guanethidine.

Enhanced systemic beta-blockade (including 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 Duoprost is administered to patients already receiving oral beta-blockers. The use of two or more topically acting beta-blockers is not recommended.

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

The use of beta-blockers may lead to exacerbation of hypertension in response to sudden withdrawal of clonidine.

Beta-blockers may potentiate 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 administration, Duoprost is absorbed systemically. Since the medicinal product contains the beta-adrenergic agent timolol, the same types of adverse reactions affecting the pulmonary, cardiovascular, and other systems as with systemic beta-blockers may occur. The frequency of systemic adverse reactions after topical administration is lower than with 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 beta-blocker therapy in patients with cardiovascular disorders (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 beta-blockers prolong conduction time, they should be used cautiously in patients with first-degree heart block.

Cases of cardiovascular reactions, some of which were fatal due to heart failure, have been reported following timolol administration.

Vascular disorders

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

Respiratory disorders

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

Hypoglycemia/diabetes

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

Beta-blockers may also mask signs of hyperthyroidism.

Corneal disorders

Ophthalmic beta-blocker medicinal products may cause dry eyes; therefore, these products should be used with caution in patients with corneal disease.

Other beta-blockers

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

Anaphylactic reactions

Patients with atopic disorders or a history of severe anaphylactic reactions to various allergens may exhibit heightened reactivity upon repeated exposure to allergens and may not respond to usual doses of adrenaline used to treat anaphylactic reactions while receiving beta-blockers.

Choroidal detachment

Cases of choroidal detachment have been reported during therapy 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

The concomitant use of two topical beta-blockers or two topical prostaglandin analogues is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Effects on the eye

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 Duoprost 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, brown pigmentation around the pupil of the treated eye spreads concentrically toward the periphery, but the entire iris or parts 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 gradually and may go unnoticed for several months or years. This change is not associated with any symptoms or pathological developments.

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

Treatment does not affect nevi or freckles of the iris.

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.

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

Changes of eyelids and eyelashes

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

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

Glaucoma

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 aphakia, or in pigmentary glauopenia. 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 more experience is gained, latanoprost should 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 herpes simplex keratitis or in patients with a history of recurrent herpetic keratitis associated with prostaglandin analogue use.

Macular edema

Cases of macular edema, including cystoid macular edema, have been reported with latanoprost use. These cases occurred primarily in aphakic patients, pseudophakic patients with posterior capsule rupture, or patients with known risk factors for macular edema. Duoprost should be used with caution in such patients.

Use of contact lenses

Duoprost 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. Careful monitoring is required in patients with dry eye or corneal disorders during frequent and prolonged use of Duoprost. Contact lenses may absorb benzalkonium chloride; therefore, lenses must be removed before instillation of Duoprost and may be reinserted 15 minutes after instillation (see section "Dosage and administration").

Use during pregnancy or breastfeeding.

Fertility

Animal studies have not shown any effects of latanoprost or timolol on male or female reproductive function.

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. This medicinal product 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 beta-blocker use. 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 during pregnancy. If Duoprost is used during the third trimester of pregnancy, close monitoring of the newborn is required during the first days of life.

Therefore, Duoprost should not be used during pregnancy.

Lactation period

Timolol maleate has been detected in human breast milk after oral and ocular administration. Beta-blockers penetrate into breast milk. However, therapeutic doses of timolol in eye drops are unlikely to result in sufficient concentrations in breast 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, Duoprost should not be used in breastfeeding women.

Ability to influence the ability to drive and use machines.

Duoprost has a minor influence on the ability to drive or operate machinery. Instillation of eye drops may cause transient visual disturbances. Driving and operating machinery should be avoided until vision has normalized.

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 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 the eye drops. Lenses may be reinserted only 15 minutes after administration of the drops.

If more than one topical ophthalmic medicinal product 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, systemic absorption of the drug is reduced. This may help reduce the intensity of systemic adverse effects and increase the local efficacy of the drug.

Children

The safety and efficacy of Duoprost in children (under 18 years of age) have not been established.

Overdose

There are no data on latanoprost/timolol overdose in humans.

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

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

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

In case of accidental 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 cause 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.

Side effects

Most adverse effects associated with latanoprost are ocular. Data from the extended phase of the main clinical study with the medicinal product Duoprost indicate that iris pigmentation increased in 16–20% of patients, which may be irreversible. During a 5-year open-label safety study of latanoprost, iris pigmentation occurred in 33% of patients (see section "Special precautions"). Other ocular adverse effects are generally 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 ophthalmic agents for local use, 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 following local administration of ophthalmic beta-blockers is lower than with systemic administration. The listed adverse reactions are typical for ophthalmic beta-blocker preparations.

Adverse effects observed during clinical trials with the medicinal product Duoprost are listed below.

Adverse effects 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).

Nervous system: uncommon — headache.

Eye disorders: very common — increased pigmentation of the iris; common — eye irritation (including burning, stinging, itching, foreign body sensation), eye pain; uncommon — eye redness, conjunctivitis, blurred vision, increased lacrimation, blepharitis, corneal disorders, conjunctival disorders.

Skin and subcutaneous tissue disorders: uncommon — skin rash, pruritus.

Latanoprost.

Infections and infestations: herpetic keratitis.

Nervous system disorders: dizziness.

Eye disorders: changes in eyelashes and vellus hair of the eyelids (increased length, thickness, number, and pigmentation); punctate keratitis; periorbital edema; iritis/uveitis; macular edema, including cystoid macular edema; dryness of the ocular mucosa; keratitis, corneal edema and erosions; trichiasis; iris cyst; photophobia; periorbital changes and eyelid changes due to deepening of the upper eyelid sulcus; eyelid edema; localized skin reaction of the eyelids; conjunctival pseudopemphigoid*; darkening of the palpebral skin.

Cardiovascular system disorders: angina pectoris, unstable angina; worsening of angina symptoms; palpitations.

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

Musculoskeletal, connective tissue and bone disorders: joint pain, muscle pain.

General disorders: chest pain.

Gastrointestinal disorders: nausea**, vomiting**.

* May occur due to the presence of benzalkonium chloride as a preservative.

** Observed in the post-marketing period with uncommon frequency.

Timolol.

Immune system disorders: systemic allergic reactions, including anaphylactic reaction, angioedema, urticaria, localized and generalized rashes, pruritus.

Metabolism and nutrition disorders: hypoglycemia.

Psychiatric disorders: depression, memory loss, insomnia, nightmares, hallucinations.

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

Eye disorders: symptoms and signs of eye irritation (burning sensation, stinging, itching, lacrimation, redness), blepharitis, keratitis, blurred vision, as well as choroidal detachment following trabeculectomy (see section "Special precautions"), decreased corneal sensitivity, dry eye, corneal erosion, ptosis, refractive changes, diplopia.

Ear and labyrinth disorders: tinnitus.

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

Vascular disorders: arterial hypotension, Raynaud's phenomenon, coldness in hands and feet.

Respiratory, thoracic and mediastinal disorders: bronchospasm (mainly in patients with pre-existing bronchospastic disease), dyspnea, cough.

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

Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis, skin rashes.

Musculoskeletal and connective tissue disorders: myalgia.

Reproductive system and breast disorders: 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 solutions containing phosphate.

Shelf life. 3 years.

Storage conditions. Store at 2–8 °C in a protected from light place.

Store at a temperature not exceeding 25 °C and use within 4 weeks after first opening of the bottle. Keep out of reach of children.

Packaging. 2.5 ml in a polyethylene dropper bottle. 1 dropper bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer. K.T. Rompharm Company S.R.L.

Manufacturer's address and place of business.
Str. Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm 1 and Rompharm 2 buildings.