Travalza^® Duo (Drops) Instructions for Use

Marketing Authorization Holder

Otisipharm, JSC (Russia)

Manufactured By

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Timolol (Rec.INN registered by WHO)

Travoprost (Rec.INN registered by WHO)

Dosage Form

Travalza® Duo

Eye drops 5 mg+0.04 mg/1 ml: dropper bottles 2.5 ml 1, 2, or 3 pcs; 5 ml 1 pc.

Dosage Form, Packaging, and Composition

Eye drops as a clear or slightly opalescent, colorless to light yellow liquid.

Excipients: propylene glycol – 7.5 mg, sodium chloride – 3.2 mg, boric acid – 3 mg, macrogolglycerol hydroxystearate (polyoxyl 40 hydrogenated castor oil) – 1 mg, benzalkonium chloride calculated as dry substance – 0.15 mg, sodium hydroxide solution 1M – to pH 6.00, water for injection – to 1 ml.

2.5 ml – dropper bottles (1) – cardboard boxes.
2.5 ml – dropper bottles (2) – cardboard boxes.
2.5 ml – dropper bottles (3) – cardboard boxes.
5 ml – dropper bottles (1) – cardboard boxes.
2.5 ml – dropper bottles (1) – foil film bags (1) – cardboard boxes.
2.5 ml – dropper bottles (1) – foil film bags (2) – cardboard boxes.
2.5 ml – dropper bottles (1) – foil film bags (3) – cardboard boxes.
5 ml – dropper bottles (1) – foil film bags (1) – cardboard boxes.

Clinical-Pharmacological Group

Antiglaucoma drug – synthetic prostaglandin F2α analogue + beta-adrenoblocker

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; beta-adrenergic blockers

Pharmacological Action

A combined agent for use in ophthalmology, the action of which is due to the properties of its constituent components.

Travoprost is a synthetic analogue of prostaglandin F_2α, is a highly selective agonist of prostaglandin FP receptors and reduces intraocular pressure by increasing the outflow of aqueous humor. The main mechanism of action of travoprost is associated with an increase in uveoscleral outflow. It does not have a significant effect on the production of aqueous humor.

Timolol is a non-selective β-adrenergic receptor blocker without sympathomimetic activity, does not have a direct depressant effect on the myocardium, and does not possess membrane-stabilizing activity. When applied topically, it reduces intraocular pressure by reducing the production of aqueous humor and slightly increasing its outflow.

Due to the complementary mechanisms of action of both components, the reduction in intraocular pressure under the influence of the combination is more significant than the action of each of these components separately.

Intraocular pressure decreases approximately 2 hours after application, and the maximum effect is achieved after 12 hours. A significant reduction in intraocular pressure can persist for 24 hours after a single application of the agent.

Pharmacokinetics

Travoprost and timolol are absorbed through the cornea of the eye. Hydrolysis of travoprost to its biologically active form, travoprost free acid, occurs in the cornea.

Travoprost free acid is rapidly eliminated from plasma within an hour – the plasma concentration decreases below the detection threshold – less than 0.01 ng/ml (can vary from 0.01 to 0.03 ng/ml). The C_max of timolol in plasma is 1.34 ng/ml and remains at the detection threshold for 12 hours, and the T_max of timolol is reached within 0.69 hours after topical application. The T_1/2 of timolol is 4 hours after topical application of the agent.

Metabolism is the main route of elimination for travoprost and travoprost free acid. The systemic metabolism pathways are parallel to the metabolism pathways of endogenous prostaglandin F2α, which are characterized by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl group, and β-oxidative cleavage of the upper side chain. Travoprost free acid and its metabolites are excreted by the kidneys. Less than 2% of travoprost is found in the urine as the free acid.

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

Indications

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

ICD codes

Dosage Regimen

Topically, 1 time/day, at the same time.

To reduce the risk of systemic side effects, it is recommended to compress the nasolacrimal duct by pressing in the area of its projection at the inner corner of the eye after applying the agent.

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

Adverse Reactions

Immune system disorders: uncommon – hypersensitivity reactions; possibly – systemic allergic reactions, including angioedema, urticaria, local and generalized rash, pruritus, anaphylactic shock.

Psychiatric disorders rare – nervousness; possibly – insomnia, nightmares, memory loss; frequency unknown – depression.

Nervous system disorders: uncommon – dizziness, headache; possibly – cerebral ischemia, worsening of signs and symptoms of myasthenia; frequency unknown – stroke, syncope, paresthesia.

Eye disorders: very common – conjunctival hyperemia; common – punctate keratitis, eye pain, visual disturbances, blurred vision, dry eye syndrome, eye itching, eye discomfort, eye irritation (burning sensation, stinging sensation, itching, lacrimation, conjunctival injection); uncommon – keratitis, iritis, conjunctivitis, anterior chamber inflammation, blepharitis, photophobia, decreased visual acuity, asthenopia, eye edema, eyelid erythema, increased eyelash growth, allergic eye phenomena, conjunctival edema, eyelid edema; rare – corneal erosion, meibomianitis, subconjunctival hemorrhage, crusting on eyelid margins, trichiasis, distichiasis; possibly – uveitis, conjunctival disorders, conjunctival folliculosis, iris hyperpigmentation, vitreous detachment in the postoperative period of fistulizing eye surgery, decreased corneal sensitivity, diplopia; frequency unknown – macular edema, ptosis, corneal pathology.

Cardiac and vascular disorders: uncommon – bradycardia, arterial hypertension, arterial hypotension; rare – arrhythmia, heart rhythm disorders; possibly – chest pain, congestive heart failure, AV block, cardiac arrest, Raynaud’s syndrome, cold extremities; frequency unknown – heart failure, tachycardia, chest pain, palpitations, peripheral edema.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, postnasal drip syndrome; rare – dysphonia, bronchospasm, cough, throat irritation, pharyngolaryngeal pain, nasal discomfort; possibly – bronchospasm (mainly in patients with existing bronchospastic diseases); frequency unknown – bronchial asthma.

Gastrointestinal disorders: possibly – dysgeusia, dyspepsia, diarrhea, dry mouth, abdominal pain, vomiting; frequency unknown – dysgeusia.

Hepatobiliary disorders rare – increased ALT and AST activity.

Skin and subcutaneous tissue disorders: uncommon – contact dermatitis, hypertrichosis; rare – skin discoloration, alopecia, periorbital skin hyperpigmentation; possibly – skin scaling, psoriasiform rash or exacerbation of psoriasis; frequency unknown – skin rash.

Musculoskeletal and connective tissue disorders: rare – limb pain.

Renal and urinary disorders: rare – chromaturia.

Metabolism and nutrition disorders possibly – hypoglycemia.

Reproductive system and breast disorders possibly – sexual dysfunction, decreased libido.

General disorders and administration site conditions rare – thirst, increased fatigue; possibly – asthenia.

Contraindications

Hypersensitivity to the components of the agent; hypersensitivity to the group of beta-blockers; reactive airway disease, including bronchial asthma (including history), as well as severe COPD; sinus bradycardia, sick sinus syndrome, including sinoatrial block, second- or third-degree AV block without a pacemaker; decompensated chronic heart failure, cardiogenic shock; severe allergic rhinitis; corneal dystrophy; pregnancy, breastfeeding period; age under 18 years.

With caution

Neovascular, closed-angle (narrow-angle) glaucoma, pigmentary and congenital glaucoma, open-angle glaucoma with pseudophakia, pseudoexfoliative glaucoma, acute inflammatory eye diseases, in patients with pseudophakia with rupture of the posterior lens capsule or in patients with anterior chamber intraocular lens, in patients at risk of developing cystoid macular edema, iritis, uveitis; in patients with atopy or with a history of severe anaphylactic reactions to various allergens; in patients with labile diabetes mellitus and a tendency to hypoglycemia; in patients with hyperthyroidism, Prinzmetal’s angina; in patients scheduled for surgical interventions.

Use in Pregnancy and Lactation

Pregnancy

Travoprost has a negative pharmacological effect on both the course of pregnancy and the fetus or newborn.

The agent has reproductive toxicity.

Data on the use of the agent or its components in pregnant women are absent or limited.

Epidemiological studies with oral use of beta-blockers did not reveal effects associated with malformations, but indicate a risk of intrauterine growth retardation. In addition, when systemic beta-blockers were used by the mother before delivery, signs and symptoms of beta-adrenergic blockade were noted in newborns (e.g., bradycardia, hypotension, respiratory depression, hypoglycemia).

The use of the agent is contraindicated during pregnancy. If the agent is used before delivery, careful monitoring of the newborn’s condition should be carried out in the first days of life.

Breastfeeding period

It is unknown whether Travoprost is excreted in human breast milk. Timolol is excreted in breast milk, which could potentially lead to the development of serious adverse reactions in the breastfed infant. However, when timolol is used at therapeutic doses, it is unlikely that sufficient amounts of the drug will be present in breast milk to cause symptoms of β-adrenergic blockade in the child. The use of the agent during breastfeeding is not recommended.

Women of childbearing potential

The use of the agent in women of childbearing potential is not recommended unless reliable contraception is used.

Use in Hepatic Impairment

The drug is approved for use in hepatic impairment

Use in Renal Impairment

The drug is approved for use in renal impairment

Pediatric Use

The safety and efficacy of the agent in children and adolescents under 18 years of age have not been established. Data are not available.

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Like other topical ophthalmic agents, Travoprost and timolol are absorbed into the systemic circulation. Due to the presence of timolol in the composition of the agent, which has a beta-adrenergic blocking effect, the same types of adverse reactions from the cardiovascular system, lungs and other organs may develop as with the use of systemic beta-blockers.

In patients with cardiovascular diseases (e.g., coronary artery disease, Prinzmetal’s angina, heart failure) and arterial hypotension, the advisability of using beta-blockers should be critically assessed and the possibility of using other active substances should be considered. In patients with cardiovascular diseases, the presence of signs of worsening of these diseases and the development of adverse reactions should be assessed. Since beta-blockers negatively affect conduction time, they should be used with caution in patients with first-degree AV block.

In patients with severe disorders or diseases of peripheral circulation (i.e., severe forms of Raynaud’s disease or syndrome), treatment should be carried out with caution.

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

In patients with mild to moderate COPD, the agent should be used with caution and only if the intended benefit outweighs the possible risk.

In patients prone to developing spontaneous hypoglycemia, as well as in patients with labile diabetes mellitus, beta-blockers should be used with caution, as they may mask the signs and symptoms of acute hypoglycemia.

Beta-blockers may mask the signs of hyperthyroidism.

Beta-blockers have been reported to potentiate muscle weakness, which is consistent with certain symptoms of myasthenia gravis (e.g., diplopia, ptosis, and generalized muscle weakness).

Ophthalmic beta-blockers can cause dry eyes. In patients with corneal diseases, the drug should be used with caution.

Cases of choroidal detachment have been reported in patients who used drugs that suppress the production of aqueous humor (e.g., timolol and acetazolamide) after undergoing fistulizing eye surgery.

When using timolol in patients who are already using systemic beta-blockers, an enhancement of the effect on intraocular pressure or other known effects of systemic beta-blockers is possible. The response to therapy in such patients should be carefully monitored. The use of two topical beta-blockers is not recommended.

Prostaglandins and prostaglandin analogues are biologically active substances that can be absorbed through the skin. Women during pregnancy, as well as women planning pregnancy, should take appropriate precautions to avoid direct contact of the agent with the skin. If a significant part of the agent does get on the skin (which is unlikely), the area of skin that came into contact with the agent should be washed immediately with water.

The use of timolol by patients with atopy or a history of severe pathological reactions to various allergens may provoke more severe reactions in response to the administration of various allergens. Such patients may respond poorly to the administration of usual doses of epinephrine to relieve anaphylactic reactions.

This agent may gradually change eye color by increasing the number of melanosomes (pigment granules) in melanocytes. Before starting treatment, patients should be informed about the possibility of permanent eye color change. Treatment of only one eye may lead to permanent heterochromia. The long-term effect on melanocytes and the consequences of this effect are currently unknown. The change in iris color occurs slowly and may not be noticeable for several months or years.

Eye color change is predominantly noted in patients with mixed iris color (blue-brown, gray-brown, yellow-brown or green-brown), a similar effect has been observed in patients with brown eyes. Typically, brown pigmentation around the pupil spreads concentrically towards the periphery of the iris; as a result, the entire iris or its parts become more brown. After the end of therapy, no further accumulation of brown pigment in the iris was noted.

Darkening of the skin of the periorbital area and/or eyelids has been reported with the use of this agent.

This agent may gradually change the condition of the eyelashes in the treated eye(s); these changes include changes in length, thickness, pigmentation and/or number of eyelashes.

The mechanism of these changes is currently not established.

Macular edema has been observed during treatment with prostaglandin F2α analogues. The agent should be used with caution in patients with neovascular, closed-angle (narrow-angle) glaucoma, pigmentary and congenital glaucoma, open-angle glaucoma with pseudophakia, pseudoexfoliative glaucoma, inflammatory eye diseases, aphakia, pseudophakia with rupture of the posterior lens capsule or anterior chamber intraocular lens, as well as in patients with risk factors for macular edema, iritis, uveitis.

Changes in the periorbital area and eyelids have been observed with the use of prostaglandin analogues.

Ophthalmic beta-blockers may suppress beta-agonist effects, e.g., of epinephrine. The anesthesiologist should be informed if the patient is receiving timolol.

Effect on ability to drive vehicles and operate machinery

Temporary blurred vision or other visual disturbances after application of this agent may affect the ability to drive a car or use machinery. If blurred vision occurs after application of the agent, the patient should wait for vision to clear before driving a vehicle or operating machinery.

Drug Interactions

During combined treatment with inhibitors of the CYP2D6 isoenzyme (for example, quinidine, fluoxetine, paroxetine) and timolol, cases of increased systemic effect of beta-blockers (for example, decreased heart rate, depression) have been noted.

When using an ophthalmic solution of a beta-blocker simultaneously with calcium channel blockers, other beta-blockers, antiarrhythmic drugs (including amiodarone), cardiac glycosides, and parasympathomimetics, the development of additive effects leading to arterial hypotension and/or pronounced bradycardia is possible.

Against the background of concomitant use of beta-blockers and clonidine, rebound arterial hypertension may develop after abrupt withdrawal of the latter. Beta-blockers may reduce the response to epinephrine used in the treatment of anaphylactic reactions. Particular caution should be exercised in patients with a history of atopy and anaphylaxis.

Simultaneous use of two topical beta-blockers or two topical prostaglandin analogs is not recommended.

The development of mydriasis has been reported with the simultaneous use of ophthalmic beta-blockers and epinephrine.

Beta-blockers may enhance the effect of hypoglycemic drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.