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Composition:


active ingredients: Travoprost, timolol;


1 ml of the solution contains Travoprost 40 MCG, timolol 5 mg (in the form of timolol maleate);


excipients: polyquad, propylene glycol, mannitol (e 421), boric acid, sodium chloride, polyethoxylated castor oil, hydrogenated 40 (HCO-40), sodium hydroxide and/or hydrochloric acid (for pH regulation), purified water.


Dosage form.


Eye drops.


Basic physical and chemical properties: transparent, colorless to light yellow solution.


Pharmacotherapeutic group. Anti-glaucoma drugs and myotics.


ATX code S01E D51.


Pharmacological properties.


Pharmacodynamics. Duotrav® contains two active ingredients: Travoprost and timolol maleate. These two substances reduce intraocular pressure due to a complementary mechanism of action and a combined effect that leads to an additional decrease in intraocular pressure (IOP) compared to the effect that is achieved when using either of these components as monotherapy.


Travoprost, an analog of prostaglandin F2A, is its complete agonist, has high selectivity and a high degree of affinity with prostaglandin FP receptors, it reduces intraocular pressure by increasing the outflow of intraocular fluid along the trabecular network and uveoscleral pathway. A decrease in intraocular pressure in humans begins 2 hours after administration of the drug, and the maximum effect is achieved after 12 hours. A significant reduction in IOP persists for 24 hours after a single application.


Timolol is a non-selective beta-adrenergic receptor blocker that does not have significant sympathomimetic and local anesthetic (membrane-stabilizing) activity, as well as a direct inhibitory effect on the myocardium. Tonographic and fluorometric studies have confirmed that its main effect in humans is associated with a decrease in the formation of intraocular fluid and a slight increase in its outflow.


Secondary pharmacology


Travoprost significantly increased blood circulation of the optic disc in rabbits 7 days after its topical introduction into the eye (1.4 MCG 1 time per day).


Clinical Pharmacology


In a twelve-month controlled clinical trial in patients with open-angle glaucoma or ocular hypertension and an average IOP value of 25 to 27 mm Hg.the average reduction in IOP under the action of Duotrav®, which was applied once in the morning, ranged from 8 to 10 mm Hg.during the study, it was demonstrated that the decrease in IOP under the action of the combination of latanoprost 50 mcg/ml + timolol 5 mg/mL did not exceed the similar effect of Duotrav®.


During a three-month controlled clinical trial in patients with open-angle glaucoma or ocular hypertension and with an average IOP value of 27 to 30 mm Hg.the average reduction in IOP under the action of Duotrav®, which was applied once in the morning, ranged from 9 to 12 mm Hg.St., which is 2 mmHg.St. exceeded the effect of Travoprost 40 mcg/ml, which was administered once in the evening, and by 2-3 mm Hg.St – - the effect of timolol 5 mg/mL, which was administered twice a day. During the study, there was a statistically significant decrease in the average value of morning IOP (8 am, i.e. 24 hours after the last dose of Duotrav®) compared to that of Travoprost.


In two three-month controlled clinical trials in patients with open-angle glaucoma or ocular hypertension and an average IOP value of 23 to 26 mm Hg.the average reduction in IOP under the action of Duotrav®, which was applied once in the morning, ranged from 7 to 9 mm Hg.the average reduction in IOP was not insignificant, although it was quantitatively lower than in those who received Travoprost 40 mcg/ml once in the evening and timolol 5 mg/mL once in the morning as concomitant therapy.


During a six-week controlled clinical trial in patients with open-angle glaucoma or ocular hypertension and an average IOP value of 24 to 26 mm Hg.the average reduction in IOP when using Duotrav® with polyquaternium-1 as a preservative 1 time a day, in the morning, was 8 mm Hg.St. TA had the same indicator as when using Duotrav® with benzalkonium chloride as a preservative.


The inclusion criteria were the same for all studies, with the exception of the input IOP criterion and response to previous IOP reduction therapy. The clinical development of Duotrav® involved both patients who had not previously used any drugs, and patients who had already completed a certain course of therapy. Insufficient response to monotherapy was not an inclusion criterion.


The data obtained confirm that administration of the drug in the evening may have some advantage in reducing IOP. When recommending the use of the dose of the drug in the morning, and not in the evening, it is necessary to take into account the convenience for the patient and his discipline.


Preclinical safety data


Experiments on monkeys have shown that the introduction of Duotrav® twice a day causes an increase in the eye gap, as well as an increase in pigmentation, similar to that observed with the introduction of prostaglandins into the eye.


Duotrav® with polyquaternium-1 preservative resulted in minimal toxic effects on the eye surface on human corneal cell cultures and after topical application in rabbit eyes compared to the use of Duotrav® with benzalkonium chloride as a preservative.


Travoprost


Topical administration of Travoprost at a concentration of 0.012% or higher in the right eye of monkeys twice a day for one year did not cause systemic toxicity.


Studies of toxic effects on reproductive function were conducted in rats, mice and rabbits with systemic use. The data obtained were associated with the activity of the FP receptor agonist in the uterus, which was manifested by early embryo mortality, impaired fetal implantation, and toxic effects on the fetus. In pregnant rats, systemic administration of Travoprost during organogenesis at doses 200 times higher than therapeutic doses led to an increase in the number of cases of malformations. Low levels of radioactivity were measured in the amniotic fluid and fetal tissues of pregnant female rats treated with 3h-Travoprost. Studies of reproductive function and development have shown a significant effect on fetal death, with a high percentage of such cases in female rats and mice (180 pg/mL and 30 pg/mL in blood plasma, respectively) at doses 1.2 – 6 times higher than therapeutic (more than 25 pg/ml).


Timolol


Preclinical data indicate that there is no risk to humans when using timolol, as evidenced by pharmacological safety studies, repeated dose toxicity studies, genotoxicity, and carcinogenic potential. Studies of the toxic effect of timolol on reproductive function have shown delayed fetal bone formation in rats in the absence of undesirable effects on postnatal development (exceeding the clinical dose by 7,000 times) and increased fetal resorption in rabbits (exceeding the clinical dose by 14,000 times).


Pharmacokinetics. Travoprost and timolol are absorbed through the cornea. Travoprost refers to prodrugs that undergo rapid essential hydrolysis in the cornea to active free acid. After a single administration of Duotrav® (with polyquaternium-1 as a preservative) to healthy volunteers (N = 22) for 5 days, free acid was not quantified in plasma samples from most participants (94.4 %) and was generally not observed 1 hour after administration. When measured (>0.01 ng/mL, quantification limit), the concentration ranged from 0.011 to 0.03 ng/mL. The average established timolol concentration Cmax after a single dose of Duotrav® was 1.34 ng/mL, and Tmax was approximately 0.69 hours.


Travoprost free acid can be quantified in intraocular fluid during the first 5 hours in animals, and in human plasma – only during the first hour after administration of Duotrav® into the eye. Timolol can be detected in human intraocular fluid and blood plasma 12 hours after administration of Duotrav® into the eye.


Metabolism is the main route of elimination of both Travoprost and active free acid. The pathways of systemic metabolism are parallel to the pathways of endogenous prostaglandin F2A metabolism, which are characterized by the reduction of the 13-14 double bond, oxidation of the 15-hydroxyl group, and breaks in the B-oxidative upper side chain.


Timolol is metabolized in two ways. The first pathway is associated with the formation of an ethanolamine side chain in the thiodiazole ring, and the second is associated with the formation of an ethanol side chain in morpholinazote and another similar side chain with a carbonyl group adjacent to nitrogen. The plasma half-life of timolol is 4 hours after instillation of Duotrav® in the eye.


Travoprost in the form of free acid and its metabolites are mainly excreted by the kidneys. Less than 2% of the ophthalmic dose of Travoprost in the form of free acid is observed in the urine after application to the eye. Timolol and its metabolites are mainly excreted by the kidneys. Approximately 20% of the timolol dose is excreted unchanged in the urine, and the remaining part is also excreted in the urine in the form of metabolites.


Clinical characteristics.


Indications.


Duotrav® is prescribed to reduce intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular hypertension who do not respond sufficiently to topical beta-blockers or prostaglandin analogues.


Contraindications.


Hypersensitivity to active substances or other components of the drug.


Hypersensitivity to other beta-blockers.


Conditions that are accompanied by airway hyperreactivity, including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.


Sinus bradycardia, sinus node weakness syndrome, including sinoauricular block, Grade II - III atrioventricular block, not controlled by a pacemaker.


Severe heart failure, cardiogenic shock.


Severe allergic rhinitis and corneal dystrophy.


Tags: Duotrave