Travapress Duo, eye drops (5 mg+0.04 mg)/ml 2.5ml

Pharmacotherapeutic group: Antiglaucoma combined agent (synthetic prostaglandin F2-alpha analogue + beta-adrenoblocker).

ATX code: S01ED51.

Pharmacological properties

Pharmacodynamics

The drug Travapress Duo contains two active ingredients: Timolol and Travoprost. Both reduce intraocular pressure. Because of their complementary mechanisms of action, the decrease in intraocular pressure is greater with the combination than with each of the components alone.

Timolol

. Timolol is a non-selective blocker of beta-adrenoreceptors without sympathomimetic activity, has no direct depressant effect on the myocardium, has no membrane-stabilizing activity.

When used topically, it reduces intraocular pressure by reducing aqueous humor formation and slightly increasing its outflow.

Travoprost

Travoprost, an analogue of prostaglandin F2-alpha, is a highly selective agonist of prostaglandin FP receptors and reduces intraocular pressure by increasing aqueous outflow. The main mechanism of action of travoprost is associated with an increase in uveoscleral outflow. It has no significant effect on the production of aqueous humor.

The intraocular pressure decreases approximately 2 hours after drug administration, and the maximum effect is achieved after 12 hours. Significant decrease in intraocular pressure may persist for up to 24 hours after a single application of the drug.

Pharmacokinetics

Absorption and pDistribution

Travoprost and timolol are absorbed through the cornea of the eye. In the cornea there is hydrolysis of travoprost to its biologically active form, free acid travoprost. Free hervoprost acid is rapidly eliminated from plasma within one hour – plasma concentrations fall below the detection threshold of less than 0.01 ng/ml (can vary from 0.01 to 0.03 ng/ml). The maximum plasma concentration (Cmax) of timolol is 1.34 ng/ml and persists to the detection threshold for 12 h, and the time to reach the maximum concentration (Tmax) of timolol is reached within 0.69 h after topical administration. The half-life (T1/2) of timolol is 4 h after topical administration of timolol+travoprost.

Metabolism and excretion

Metabolism is the major route of elimination of travoprost and free acid travoprost. The systemic metabolic pathways parallel those of endogenous prostaglandin F2a, which are characterized by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl group, and P-oxidative cleavage of the upper side chain link. Free hervoprost acid and its metabolites are mostly excreted by the kidneys. Less than 2% of hervoprost is found as free acid in the urine.

Timolol and the resulting metabolites are excreted mainly by the kidneys. About 20% of timolol is excreted unchanged, the rest is excreted as metabolites.

Indications

Reduction of elevated intraocular pressure in open-angle glaucoma and intraocular hypertension in patients resistant to monotherapy with beta-adrenoblockers or prostaglandin analogues.

Active ingredient

Timolol, Travoprost

Composition

Composition per 1 ml of the drug:

acting ingredients: travoprost 0.040 mg, timolol 5.000 mg (in the form of timolol maleate 6.800 mg);

complementary substances: boric acid 3,000 mg, sodium chloride 2,500 mg, mannitol 3,000 mg, macrogoal glyceryl hydroxystearate (Collifor RH40) 1,000 mg, propylene glycol 7,500 mg, 1 M hydrochloric acid solution or 1 M sodium hydroxide solution to pH 6.8 ± 0.1, purified water to 1.0 ml.

How to take, the dosage

For topical use.

Travapress Duo is instilled into the conjunctival sac of the eye once daily, evening or morning at the same time.

In order to decrease the risk of systemic HP, it is recommended that the nasolacrimal duct be compressed after instillation by applying pressure to the nasolacrimal canal projection at the inner corner of the eye.

If a dose of the drug is missed, treatment should be continued with the next dose. The daily dose of the drug should not exceed 1 drop in the conjunctival sac of the eye once a day.

The drug Travapress Duo may be used in combination with other topical ophthalmic drugs to reduce intraocular pressure. In this case, the interval between applications should be at least 5 minutes.

The tip of the dropper bottle should not touch any surface in order to avoid contamination of the dropper bottle and its contents. The bottle should be closed after each use.

Patient Special Groups

Application in hepatic and renal failure

. There have been no studies of the use of timolol+travoprost eye drops or timololol 5 mg/mL eye drops in patients with hepatic or renal impairment.

The use of travoprost has been investigated in patients with mild to severe hepatic impairment and mild to severe renal impairment (with a creatinine clearance of 14 mL/min or less). No dose adjustment is required in these groups of patients.

Dose adjustment of timolol+travoprost eye drops in patients with hepatic or renal impairment is probably not required.

Application in children

The safety and effectiveness of timolol+travoprost eye drops in children and adolescents under 18 years of age have not been established. No data are available.

Interaction

There have been no studies on interaction with other medicinal products.

When using CYP2D6 cytochrome inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol, there have been cases of increased systemic effects of beta-adrenoblockers (e.g., decreased heart rate, depression).

In co-administration of eye drops containing timolol with “slow” calcium channel blockers, guanethidine, beta-adrenoblockers, antiarrhythmic agents (including amiodarone), parasympathomimetics and cardiac glycosides, adverse effects may develop, leading to development of arterial hypotension and/or marked bradycardia.

The co-administration of beta-adrenoblockers and clonidine may lead to “ricochet” arterial hypertension after abrupt withdrawal of the latter.

Beta-adrenoblockers may decrease the response to epinephrine (adrenaline) used in the treatment of anaphylactic reactions. Particular caution should be exercised in patients with a history of atopy and anaphylaxis (see section “Special Precautions”).

The simultaneous use of two local beta-adrenoblockers or two local prostaglandin analogues is not recommended!

The development of mydriasis (dilation of the pupils) has been reported when using ophthalmic beta-adrenoblockers and epinephrine (adrenaline) together.

Beta-adrenoblockers may increase the effect of hypoglycemic drugs.

Special Instructions

Systemic effects

In common with other ophthalmic drugs for topical use, timolol and travoprost are absorbed into the systemic bloodstream.

Due to the beta-adrenergic action of the active ingredient, timolol, the same cardiovascular and respiratory HRs may be observed as with systemic beta-adrenoblockers.

Cardiac disorders

. In patients with cardiovascular disease (e.g., coronary heart disease, Prinzmetal angina, heart failure) and arterial hypotension, treatment with beta-adrenoblockers should be critically evaluated and other medications should be considered. In patients with cardiovascular disease, signs of worsening of the course of these diseases and the development of HF should be evaluated. Because beta-adrenoblockers adversely affect conduction time, they should be used with caution in patients with grade I atrioventricular block.

vascular disorders

In patients with severe peripheral circulatory disorders (including severe forms of Raynaud’s disease or syndrome), treatment should be used with caution.

Respiratory disorders

The patient’s condition should be monitored before and during timolol therapy. Respiratory reactions, including death from bronchospasm in patients with bronchial asthma, have been described after use of some ophthalmic drugs from the beta-adrenoblocker group.

In patients with mild to moderate COPD, the combination timolol+travoprost should be used with caution and only if the anticipated benefit exceeds the possible risk.

Hypoglycemia/sugar diabetes

Beta-adrenoblockers should be used with caution in patients prone to developing spontaneous hypoglycemia and in patients with a labile course of diabetes, as beta-adrenoblockers may mask the signs and symptoms of hypoglycemia.

Hyperthyroidism

Beta-adrenoblockers may mask symptoms of hyperthyroidism.

Muscular weakness

. Beta-adrenoblockers may potentiate muscle weakness, which is consistent with certain symptoms of myasthenia gravis (e.g., diplopia, ptosis, and generalized muscle weakness).

Corneal disease

Beta-adrenoblockers for ophthalmic use may cause dry eyes. The drug should be used with caution in patients with corneal diseases.

Ocular choroidal detachment

. Choroidal detachment has been reported in patients who have used drugs that inhibit aqueous humor production (e.g., timolol and acetazolamide) following fistulizing eye surgery.

Other beta-adrenoblockers

. When timolol is used in patients who are already using systemic beta-adrenoblockers, there may be increased effects on intraocular pressure or other known effects of systemic beta-adrenoblockers. Response to therapy in such patients should be closely monitored. The use of two beta-adrenoblockers for topical use is not recommended (see section “Interaction with other medicinal products”).

Skin absorption

Prostaglandins and prostaglandin analogues are biologically active substances that can be absorbed through the skin. Women who are pregnant or who are planning to become pregnant should take appropriate precautions to ensure that the contents of the vial do not come into direct contact with the skin. If a significant portion of the contents of the vial does come in contact with the skin (which is unlikely), the area of skin on which the product has come in contact should be washed immediately with water.

Anaphylactic reactions

The use of timolol in patients with a history of atopy or severe anaphylactic reactions to various allergens may provoke more severe reactions in response to allergen management. Such patients may respond poorly to the administration of normal doses of epinephrine (adrenaline) to control anaphylactic reactions.

Ophthalmic effects

A gradual change in eye color may be noted with the use of travoprost due to an increase in the number of melanosomes (pigment granules) in melanocytes. Patients should be advised of the possibility of permanent discoloration of the eye before starting treatment. Treatment of only one eye can lead to irreversible heterochromia. The long-term effects on melanocytes and the consequences are currently unknown. Iris color change is slow and may not be noticeable for months or years. Color change is more often seen in patients with mixed iris color (blue-iris, gray-iris, yellow-iris and green-iris), and a similar effect has been seen in patients with brown eyes. In typical cases, brown pigmentation around the pupil spreads concentrically to the periphery of the iris, causing the entire iris or its parts to become more brown. There is no further accumulation of brown pigment in the iris at the end of therapy.

Darkening of the periorbital skin and/or eyelids has been reported with the use of travoprost.

Travoprost may gradually change the condition of the lashes in the treated eye(s); these changes include changes in lash length, thickness, pigmentation, and/or number of lashes. The mechanism for these changes is currently unknown.

The development of macular edema has been noted during treatment with prostaglandin F_2α analogues.

Travoprost should be used with caution in patients with neovascular, closed-angle, narrow-angle, pigmentary and congenital glaucoma; Open angle glaucoma with pseudophakia, pseudoexfoliative glaucoma, inflammatory diseases of the visual organ, aphakia, pseudophakia with rupture of the posterior lens capsule or anterior chamber intraocular lens, and in patients with risk factors for macular edema, iritis, uveitis.

In the use of prostaglandin analogues, changes in the periorbital area and eyelids were noted. A deepening of the eyelid sulcus was observed only in studies in monkeys, whereas no data on this effect were obtained in clinical studies in humans, allowing it to be considered species-specific.

Anesthesia in surgical procedures

Ophthalmic drugs from the beta-adrenoblocker group may inhibit the beta-agonist effects of, for example, adrenaline. The anesthesiologist should be informed if the patient uses timolol. Auxiliary Agents

The Travapress Duo Eye Drops contain propylene glycol, which may cause skin irritation.

The Travapress Duo Eye Drops contain macrogoal glyceryl hydroxystearate which may cause skin reactions.

Contact lenses

The patient should be warned to remove contact lenses before putting in Travapress Duo and not wear them for 15 minutes afterwards.

Influence on ability to drive or operate machinery

Transient blurring of vision or other visual disturbances after use may affect the ability to operate vehicles or machinery. If blurred vision is noted after injection, the patient must wait until clarity of vision is restored before driving or operating machinery.

Synopsis

Transparent colorless solution.

Contraindications

• High sensitivity to the active ingredients or any of the excipients.
• High sensitivity to other beta-adrenoblockers.
• Reactive airway disease, including bronchial asthma (including history) and severe chronic obstructive pulmonary disease (COPD).
• Sinus bradycardia, sinus node weakness syndrome including sinoatrial block, grade II or III atrioventricular block without a pacemaker.
• Decompensated chronic heart failure.
• Cardiogenic shock.
• Allergic rhinitis of severe course.
• Corneal dystrophy.
• Pregnancy and breastfeeding.
• Children under 18 years of age (safety and efficacy not established).

With caution

Neovascular, closed-angle, narrow-angle glaucoma; pigmented and congenital glaucoma; open-angle glaucoma with pseudoaphakia; pseudoexfoliative glaucoma; acute inflammatory diseases of the visual organ; in patients with pseudoaphakia in case of a ruptured posterior capsule of the lens or in patients with an anterior chamber intraocular lens; In patients at risk of cystoid macular edema, iritis, uveitis; in patients with atopy or a history of severe anaphylactic reactions to various allergens; in patients with labile diabetes mellitus and propensity for hypoglycemia; in patients with hyperthyroidism, Prinzmetal angina; in patients scheduled for surgical intervention.

Side effects

General safety profile of timolol+travoprost

In clinical studies involving 2170 patients who received therapy with the fixed combination of timolol+travoprost, the most frequent adverse event was conjunctival injection (12.0%).

Data on adverse events

The following adverse events were observed during clinical trials and post-registration use of the fixed combination timolol+travoprost and are classified according to the following frequency of adverse events: very common (≥1/10), common (≥1/100 to <1/10), infrequent (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency unknown (assessment based on available data is not possible). In each group, adverse events are listed in descending order of severity.

Immune system disorders infrequent hypersensitivity

Mental disorders rarely nervousness: frequency unknown depression

Nervous system disorders: infrequent dizziness, headache, frequency unknown stroke, fainting, paresthesia

Visual system disorders very common conjunctival hyperemia:

• often pitting keratitis, ocular pain, visual disturbances, blurred vision, dry eye syndrome, itchy eyes, eye discomfort, eye irritation
• infrequent keratitis, iritis, conjunctivitis, inflammation of anterior chamber, blepharitis, photophobia (photophobia), decreased visual acuity, asthenopia, ocular edema, lacrimation, erythema of eyelids, increased eyelash growth, allergic eye symptoms, conjunctival edema, oedema of eyelids
• in rare/li>
• commonly corneal erosion, meibomitis, subconjunctival hemorrhage, crusting of eyelid margins, trichiasis, distichiasis
• frequency unknown macular edema, ptosis, corneal pathology

Heart disorders infrequent bradycardia:

• often arrhythmia, heart rhythm disturbances
• frequency unknown heart failure, tachycardia, chest pain, palpitations

vascular disorders infrequent arterial hypertension, arterial hypotension: frequency unknown peripheral edema

Respiratory system, thoracic and mediastinal disorders:

• infrequent dyspnea, postnasal syndrome
• often dysphonia, bronchospasm, cough, throat irritation, pharyngeal laryngeal pain, nasal discomfort
• frequency unknown bronchial asthma

Gastrointestinal disorders: frequency unknown dysgeusia

Hepatobiliary system disorders: rarely increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) activity

Skin and subcutaneous tissue disorders:

• frequent contact dermatitis, hypertrichosis
• frequent urticaria, skin discoloration, alopecia, periocular skin hyperpigmentation
• frequently unknown skin rash

Skeletal and connective tissue disorders: rarely pain in the extremities

Rarely, kidney and urinary tract disorders: Rarely chromaturia

General disorders and disorders at the site of administration: rarely thirst, increased fatigue

Additional adverse events that were noted during therapy with monocomponents alone may be noted during therapy with a fixed combination of timolol+travoprost.

Travoprost

Visual disorders, uveitis, conjunctival disorders, conjunctival folliculosis, iris hyperpigmentation

Skin and subcutaneous tissue disorders Skin peeling

Timolol

Like other topical ophthalmic drugs, timololol is absorbed into the systemic bloodstream. This can cause the same range of adverse events as with oral forms of beta-adrenoblockers.

Overdose

In case of overdose in local ophthalmic use, toxic effects on the visual organ are not expected. Immediate flushing of the eyes with water is recommended.

Symptoms

In accidental oral administration, overdose symptoms due to systemic exposure to beta-adrenoblockers may include bradycardia, hypotension, heart failure and bronchospasm, and cardiac arrest.

Treatment

Treatment in cases of accidental ingestion of timolol+travoprost eye drops should include symptomatic and supportive therapy. Hemodialysis is ineffective with respect to excretion of timolol.

Pregnancy use

Pregnancy

Travoprost has adverse pharmacological effects both on pregnancy and on the fetus or newborn. There are no or limited data on the use of the combination of travoprost + timolol or its individual components in pregnant women.

The results of animal studies of travoprost have shown reproductive toxicity. Epidemiological studies of oral use of beta-adrenoblockers have not shown effects associated with malformations, but suggest a risk of delayed intrauterine development. In addition, signs and symptoms of beta-adrenoceptor blockade (e.g., bradycardia, arterial hypotension, respiratory depression, and hypoglycemia) have been reported in newborns when mothers use systemic beta-adrenoblockers before delivery.

The use of the drug Travapress Duo is contraindicated during pregnancy. If Travapress Duo is used before delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding period

It is not known whether Travoprost in the dosage form of eye drops penetrates into human breast milk. Based on animal studies, travoprost and its metabolites have been shown to penetrate into breast milk. Timolol penetrates into breast milk, potentially causing serious adverse reactions (AR) in a breastfed infant. However, when timolol is used in therapeutic doses, it is unlikely that enough is present in breast milk to develop symptoms of beta-adrenoceptor blockade in the infant.

The use of the drug Travapress Duo is contraindicated during breastfeeding.

Fertility

There are no data on the effect of timolol+travoprost eye drops on fertility in humans. Animal studies have shown no effect of travoprost or timolol on fertility at doses greater than 250 times the maximum recommended dose for topical ophthalmic use in humans.

Women of preserved reproductive potential/contraception

Travapress Duo is not recommended for women of preserved reproductive potential unless reliable contraception is used.