Taptik eye drops 0.0015% + 0.5% dropper bottle 0,3 ml №30

Dosage Form

Transparent colorless solution.

Composition

1 ml of the preparation contains:

Active ingredients:

tafluprost - 15.0 mcg and Timolol maleate - 6.84 mg (based on timolol - 5.0 mg).

Excipients:

glycerol - 22.5 mg, disodium hydrogen phosphate - 4.9 mg, disodium edetate - 0.5 mg, polysorbate 80 - 0.75 mg, sodium hydroxide - 0.04-0.06 mg or hydrochloric acid - 0.0-0, 2 mg to bring the pH, water for injection to 1 ml.

pharmachologic effect

Taptikom® is a medicinal product containing a fixed combination of two active ingredients - tafluprost and timolol. Both active ingredients reduce intraocular pressure (IOP), mutually reinforcing the effects of each other, resulting in the effect of lowering IOP when using the combined drug is more pronounced than the effect of each of the active ingredients separately.

Tafluprost is a fluorinated prostaglandin F2a analog. Tafluprost acid, being a biologically active metabolite of tafluprost, has a high activity and selectivity for human FP receptors (prostaglandin F2a receptors). Data from pharmacodynamic studies (preclinical studies) indicate that tafluprost reduces IOP, enhancing uveoscleral outflow of aqueous humor. Timolola maleate is a non-selective beta-blocker.The exact mechanism of reducing IOP in the application of timolol maleate is currently not fully established, however, the methods of fluorescence and tonography indicate that the main effect may be due to a decrease in the formation of intraocular fluid. At the same time, some studies noted a slight increase in its outflow. It has been shown that in patients with open-angle glaucoma or ocular hypertension and an average IOP before treatment, 24-26 mm Hg. st. the effect of IOP reduction on the background of using Taptic® was not lower than the effect observed with the combined use of 0.0015% tafluprost and 0.5% timolol, and the decrease in the average daily IOP after 6 months was 8 mm Hg. st. from the original values.

In addition, a comparison was made of the activity of the drug Taptikom® and the corresponding monotherapy drugs in patients with open-angle glaucoma or ophthalmic hypertension and the mean IOP before treatment, which was 26-27 mm Hg. st. The decrease in the average daily IOP against the background of the use of the drug Taptic® was statistically more significant than that on the background of tafluprost monotherapy applied once a day, in the morning, or with timolol used twice a day. After 3 months of treatment, the decrease in mean daily IOP compared with its baseline level in the group of the drug Taptikom® was 9 mm Hg. st. compared to 7 mmHg. Art., observed in both groups of monotherapy. The decrease in IOP in those who used TAPTIC® during the day fluctuated between 7 and 9 mm Hg. st.

The combined data from these two clinical studies in patients (n = 168) with initially high IOP of 26 mm Hg. st.or higher showed that after 3 or 6 months of those who received TAPTIC®, the average daily decrease in IOP was Hummer. Art., with a range of 9 to 12 mm Hg. st. during the day.

Pharmacokinetics

Absorption.

In healthy volunteers' blood plasma, tafluprost and timolol acid concentrations were determined after a single and repeated use of 8 days of the drug Taptikom® in the form of eye drops (once a day), as well as 0.0015% tafluprost (1 time per day) and 0, 5% timolol (2 times a day). It was found that the maximum concentration of tafluprost acid in the blood plasma is reached by 10 minutes after using the drug Taptikom® (time to reach the maximum concentration, Tmax), followed by its decrease below the sensitivity threshold of the method (10 pg / ml) for about 30 minutes. The accumulation of tafluprost acid was negligible and on the 8th day of treatment the mean values ​​of AUCoiast (area under the concentration-time curve) (monotherapy: 4.45 ± 2.57 pg * h / ml; Taptik®: 3.60 ± 3, 70 pg * h / ml) and Stach (monotherapy: 23.9 ± 11.8 pg / ml; Taptik®: 18.7 ± 11.9 pg / ml) were slightly lower when using the drug Taptik® compared to tafluprost monotherapy. The concentration of timolol in the blood plasma after the instillation of the drug Taptikom® on the first and eighth day reached a maximum after 15 minutes and 37.5 minutes (median Ttah), respectively. On the eighth day, the AUCo-iast value of timolol (monotherapy: 5750 ± 2440 pg * h / ml; Taptik®: 4560 ± 2980 pg * h / ml) and the average value of Stax (monotherapy: 1100 ± 550 pg / ml; Taptik®: 840 ± 520 pg / ml) were slightly lower with the use of the drug Taptikom® than with timolol monotherapy.A lower concentration of timolol in the blood plasma when using the drug Taptikom® is explained by its single use per day, while timolol monotherapy is used 2 times a day.

Absorption of tafluprost and timolol through the cornea. Based on the results of preclinical studies, it was found that the penetration of tafluprost from Taptikom® through the cornea was comparable to its penetration when using tafluprost in monotherapy once a day, while the penetration of timolol from Taptikom® was slightly lower than that of timolol monotherapy. The concentration of AUC4-4aca tafluprost acid after instillation of the drug Taptikom® was 7.5 ng * h / ml and 7.7 ng * h / ml - after instillation of the mono-drug tafluprost. The concentration of A and C4 hours of timolol after using the drug Taptikom® and the monotherapy drug was 585 ng "h / ml and 737 ng * h / ml, respectively. Ttahluprost acid is 60 minutes - both when using the drug Taptikom®, and in monotherapy with tafluprost, and Ttah timolol is 60 minutes when using the drug Taptikom® and 30 minutes in the treatment with timolol monotherapy.

Distribution

Tafluprost.

According to preclinical studies, the distribution of tafluprost labeled with a radioisotope in the tissues of the eye suggests that tafluprost has a low affinity for melanin pigment.

An autoradiographic study showed that the highest concentration of radioactivity was observed in the cornea, followed by the eyelids, sclera, and iris.The distribution of radioactively-labeled tafluprost in other organs was as follows: lacrimal apparatus, palate, esophagus, gastrointestinal tract, kidneys, liver, gall bladder. The binding of tafluprost acid to human serum albumin in vitro was 99% at a concentration of 500 ng / ml of tafluprost acid.

Timolol.

According to preclinical studies, the maximum concentration of timolol with a radioactive label in aqueous humor is reached 30 minutes after a single application of timolol containing the radioactive 'H isotope (0.5% solution: 20 μl / eye). Timolol is removed from aqueous humor much faster than from pigment-containing tissues of the iris and ciliary body.

Metabolism

Tafluprost

The main metabolic pathway for tafluprost in the human body, confirmed by in vitro studies, is hydrolysis to form a pharmacologically active metabolite, tafluprost acid, which is then metabolized by glucuronidation or beta-oxidation. Beta oxidation products are

pharmacologically inactive 1,2-dinor and 1,2,3,4-tetranor of tafluprost acid, which can be glucuronidated or hydroxylated. The cytochrome P450 enzyme system does not participate in the metabolism of tafluprost acid. In a study conducted on rabbit cornea with refined enzymes, it was found that the main esterase responsible for the ester hydrolysis of tafluprost to tafluprost acid is carboxylesterase. Butyrylcholinesterase can also promote hydrolysis.

Timolol.

Timolol is metabolized in the liver with the participation of the cytochrome P450 CYP2D6 isoenzyme with the formation of inactive metabolites, which are excreted mainly by the kidneys.

Removal

Tadrivnpocm.

In a study on rats, it was found that after instillation of 3H-tafluprost in the form of a 0.005% ophthalmic solution in both eyes once a day for 21 days, about 87% of the total radioactive dose is excreted through the excretory organs. Approximately 27-38% of the total dose was excreted by the kidneys, and about 44-58% through the gastrointestinal tract.

TliM 0: 10.1

The expected half-life of plasma is about 4 hours. After ingestion, timolol is gradually metabolized in the liver, and metabolites are excreted in the urine along with 20% of unchanged gimolol.

Data on the removal of timolol obtained by its oral administration.

Side effects

In clinical trials, more than 484 patients received treatment with Taptikcom®. The most commonly reported side effect associated with the treatment, which occurred in approximately 7% of patients, was conjunctival / eye hyperemia, in most cases mild. The undesirable reactions observed in clinical studies of the drug Taptikom® were limited to the same reactions that were previously observed with the separate use of tafluprost and timolol. No new adverse reactions, characteristic only for the drug Taptikom®, have been identified in clinical studies.The majority of undesirable reactions were observed on the part of the organ of vision, had a mild or moderate degree; no serious reactions were noted.

To assess the frequency of undesirable reactions, according to the MEDDRA terminology, the following classification was used: very often (> 1/10 of cases); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000) and unknown (the frequency cannot be determined from the available data).

Taptikom® (combination of tafluprost and timolol).

Violations of the nervous system.

Infrequently: a headache.

Violations by the organ of vision.

Often: conjunctival hyperemia / eyes, itchy eyes, eye pain, eyelash changes (increase in length, thickness and number of eyelashes), change in color of eyelashes, eye irritation, foreign body sensation in eyes, blurred vision, photophobia.

Infrequently ", discomfort in the eyes, dry eye mucosa, discomfort in the eyes, conjunctivitis, erythema of the eyelids, symptoms of allergic eye damage, eyelid edema, superficial punctate keratitis, watering eyes, an inflammatory reaction in the anterior chamber moisture, asthenopia, blepharitis.

Adverse reactions that were observed during the period of treatment with tafluprost or tgsholol, and which can potentially develop with the use of the drug Taptikom®:

Taflunrost.

Violations on the part of the organ of vision: reduction of visual acuity, increased pigmentation of the iris, pigmentation of the eyelids, swelling of the conjunctiva, the appearance of discharge from the eyes, cellular opalescence in the anterior chamber of the eye, allergic conjunctivitis,conjunctival pigmentation, conjunctival follicles, deepening of the eyelid fold, iritis / uveitis.

Disturbances of the skin and subcutaneous tissues: eyelid hypertrichosis.

Respiratory disorders: Unknown: exacerbation of asthma, shortness of breath.

Timolol.

Immune system disorders: allergic reactions, including

angioedema, urticaria, local or generalized skin rash, anaphylaxis, pruritus.

Metabolic and nutritional disorders: hypoglycemia.

Mental disorders: depression, insomnia, nightmares, memory loss,

nervousness.

Nervous system disorders: dizziness, fainting, paresthesia, increased symptoms of myasthenia, acute cerebrovascular accident, cerebral ischemia.

Violations on the part of the organ of vision: keratitis, decreased corneal sensitivity, impaired visual acuity, including refractive changes (in some cases as a result of withdrawal of miotic therapy), ptosis, diplopia, vascular detachment after a fistulizing operation (see section "Specific instructions"), tearing cornea erosion.

Violations of the organ of hearing and balance: ringing in the ears.

Cardiac disorders: bradycardia, chest pain, palpitations, edema, arrhythmia, congestive \ 0009 cardiac \ 0009 failure, cardiac arrest, heart block, atrioventricular block, heart failure.

Vascular disorders: decrease in blood pressure, intermittent claudication, Raynaud's phenomenon, cold hands and feet.

Disturbances of the respiratory system, organs of the chest and mediastinum: shortness of breath, bronchospasm (mainly in patients with an indication of a bronchospastic disease), respiratory failure, cough.

Disorders of the gastrointestinal tract: nausea, dyspepsia , diarrhea, dryness of the oral mucosa, dysgeusia, abdominal pain, vomiting.

Disorders of the skin and subcutaneous tissues: alopecia, psoriasis-like rash or exacerbation of the course of psoriasis, skin rash.

Disorders of the musculoskeletal and connective tissues: systemic lupus erythematosus, myalgia, arthropathy.

Reproductive system and breast disorders: Peyronie's disease, decreased libido, sexual dysfunction.

Sales featuresprescription.

Special conditions.

System effects:

Like other ophthalmic drugs, tafluprost and timolol are absorbed systemically. Due to the presence of a beta-adrenergic component of timolol in the preparation, the same undesirable reactions from the cardiovascular system and respiratory organs can develop as with the use of systemic beta-blockers. The incidence of systemic adverse reactions after topical application of eye drops is lower than after systemic administration. Information on measures to reduce systemic absorption is presented in the section "Route of administration and dosage".

Heart disorders:

In patients with cardiovascular diseases (for example, coronary heart disease, Prinzmetal angina, heart failure) and arterial hypotension, the need for beta-blocker therapy should be carefully assessed and the possibility of using other groups should be considered. It is necessary to monitor the condition of patients with cardiovascular diseases in order to timely identify the symptoms of worsening diseases and adverse reactions. Due to their negative effect on the speed of the impulse, beta-blockers should be used with caution in patients with atrioventricular block I degree.

Vascular disorders:

It is necessary to use the drug with caution in patients with severe impairment of the peripheral circulation (for example, severe forms of Raynaud's disease or Raynaud's syndrome).

Respiratory disorders:

After using some ophthalmic beta-blockers, the risk of unwanted reactions from the respiratory organs, including deaths due to bronchospasm in patients with bronchial asthma, may increase. In patients with mild / moderate chronic obstructive pulmonary disease (COPD), TAPTIC® should be used with caution and only if the expected benefit of its use outweighs the possible risk.

Hypoglycemic I / Sugar Diabetes:

Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia, or in patients with a labile course of diabetes, as beta-blockers can mask the signs and symptoms of acute hypoglycemia.

Beta-blockers can also mask signs of hyperthyroidism. Abrupt withdrawal of therapy with a beta-blocker can lead to worsening symptoms of the disease.

Corneal diseases:

Ophthalmic beta-blockers may contribute to the development of dry eye syndrome. Caution must be exercised when using the drug in patients with corneal diseases.

Other beta blockers:

The effect on intraocular pressure or the known effects of systemic blockade of beta-adrenergic receptors can be enhanced with the use of timolol (one of the active ingredients of the drug Taptikom®) in patients already receiving systemic beta-blocker. The condition of such patients should be carefully monitored. It is not recommended to use two local beta-blockers simultaneously.

Angle-closure glaucoma:

In patients with angle-closure glaucoma, the primary goal of therapy is to open the anterior chamber angle of the eye. This requires the constriction of the pupil with a miotic preparation. Timolol has a minimal effect on the pupil, or does not have at all. When timolol is used to reduce elevated intraocular pressure with angle-closure glaucoma, it should be used in combination with miotics, and not as monotherapy.

Anaphylactic reactions:

When beta-blockers are used, patients with atopic history or severe Anaphylactic reactions to a number of allergens in the history may react more strongly to the repeated administration of such allergens and not respond to the usual doses of epinephrine used to treat anaphylactic reactions.

Choroid detachment:

Reported cases of detachment of the choroid when using drugs that suppress the production of aqueous humor (for example, timolol, acetazolamide) after fistulizing operations.

General anesthesia:

Ophthalmic beta-blockers can block the effects of systemic agonists of beta-adrenergic receptors, such as adrenaline. The anesthetist should be informed about the patient's use of timolol.

Prior to treatment, patients should be informed about the possible excessive growth of eyelashes, darkening of the eyelid skin and increased iris pigmentation, which are associated with tafluprost therapy. Some of these changes may be permanent, and this can lead to differences in the appearance of the eye, if only one eye has been treated.

The change in pigmentation of the iris occurs slowly and may remain imperceptible for several months. The change in eye color is observed mainly in patients with iris of mixed colors, for example, if the eyes are brown-blue, gray-brown, yellow-brown or green-brown.Treatment of only one eye can lead to persistent heterochromia.

Influence on ability to drive vehicles and mechanisms.

The effect of the drug Taptik on the ability to drive and work with mechanisms has not been studied. As with the use of any other ophthalmologic agents, after using the drug, short-term misting of rhenium may occur, therefore, it is necessary to refrain from driving and performing activities that require an increased concentration of attention and psychomotor speed before restoring vision.

Indications

Reduction of intraocular pressure (IOP) in adult patients with open-angle glaucoma or intraocular hypertension with insufficient response to local monotherapy with beta-adrenergic blockers or prostaglandin analogs in cases where combination therapy is indicated, as well as in patients who are expected to improve treatment tolerance through the use of preservative-free eye drops.

Contraindications

Hypersensitivity to tafluprost, timolol or any of the components of the drug;

• Syndrome of increased reactivity of the respiratory tract, including bronchial asthma or history of bronchial asthma, severe chronic obstructive pulmonary disease;
• Sinus bradycardia, sick sinus syndrome, including sinoatrial heart block, atrioventricular block II and III degree without a pacemaker;
• Decompensated heart failure, cardiogenic shock;
• Age up to 18 years (no data of clinical use);
• Pregnancy;
• Breast-feeding.

Carefully

Taptikom® should be used with caution due to limited experience with patients with hepatic and renal failure, patients with aphakia, pseudophakia with rupture of the posterior lens capsule or lens implantation in the anterior chamber of the eye, pseudoexfoliative glaucoma and pigment glaucoma, as well as with risk factors for cystic macular edema or iritis / uveitis. There is no experience of using tafluprost with neovascular, angle-closure, narrow-angle and congenital glaucoma.

The drug should also be used with caution in patients with corneal diseases (can cause dry eye syndrome), cardiovascular diseases (ischemic heart disease, Prinzmetal angina, heart failure, atrioventricular block I degree), peripheral circulatory disorders (in severe forms of the disease Raynaud or Raynaud's syndrome), chronic obstructive pulmonary disease (COPD) of mild and moderate severity (use of the drug is possible only if the expected benefit exceeds the potential risk), labile diabetes or spontaneous hypoglycemia (because beta-blockers can hide the clinical signs and symptoms of acute hypoglycemia), with concomitant beta-blockers (when ingested and as an ophthalmic).

Pregnancy, lactation and fertility

There are no adequate data on the use of the drug Taptikom® in pregnant women.

Women of childbearing age need to use effective methods of contraception during the period of treatment with Taptikom®.

Do not use the drug Taptikcom during pregnancy, except for special cases (if there are no other methods of treatment).

Tafluprost.

There are no adequate data on the use of tafluprost in pregnant women. Tafluprost may have an adverse pharmacological effect on the course of pregnancy and / or on the development of the fetus or newborn child. Animal studies show evidence of reproductive toxicity of tafluprost. At the same time, the potential risk of its use in humans is not known.

Adequate data on the use of timolol in pregnant women are not available. Taptikom® should not be used in pregnant women, except in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Information on measures to reduce systemic absorption is presented in the section "Route of administration and dosage".

In epidemiological studies, no systemic abnormalities in the development of the fetus were detected, but there was a risk of intrauterine growth retardation in case of taking beta-blockers orally. In addition, the clinical manifestations and symptoms of blockade of beta-adrenergic receptors (for example, bradycardia, hypotension, respiratory disorders and hypoglycemia) were observed in newborns if beta-blockers were used before delivery.In the case of the use of the drug Taptik® before delivery, it is necessary to carefully monitor the condition of the newborn during the first days of life.

Breast-feeding

It is known that beta-blockers penetrate into breast milk. However, it is unlikely that when using timolol in the composition of the eye drops at the recommended therapeutic doses, sufficient quantities of the substance can penetrate into breast milk to cause symptoms of beta-adrenoreceptor blockade in an infant. Information on measures to reduce systemic absorption is presented in the section "Route of administration and dosage".

There is no data on the excretion of tafluprost or its metabolites in human breast milk. Available toxicological data in animals indicate a possible excretion of tafluprost and its metabolites into breast milk. However, it is unlikely that when using tafluprost as part of eye drops at the recommended therapeutic doses, sufficient amounts of the substance will be absorbed into breast milk to cause clinical symptoms in an infant.

As a precautionary measure, breastfeeding is not recommended if the mother requires therapy with Taptik®.

Fertility

There are no data on the effect of Taptik® on fertility (fertility) in humans.

Drug interaction

Clinical studies on the interaction of the drug were not conducted.

Possible reduction in blood pressure and / or the appearance of clinically pronounced bradycardia in the case of simultaneous use of ophthalmologic drugs containing beta-blockers, and systemic use of blockers of “slow” Calcium channels, other beta-blockers, antiarrhythmic drugs (including amiodarone), cardiac glycosides, parasympathomimetics, guanethidine.

Acceptance of beta-blockers inside can lead to increased "ricochet" arterial hypertension, observed with the withdrawal of clonidine.

With simultaneous use of inhibitors of the isoenzyme CYP2D6 (for example, quinidine, Fluoxetine , paroxetine) and timolol, an increase in the systemic effect of a beta-blocker (decrease in heart rate, depression) was reported. With the simultaneous use of ophthalmic drugs containing beta-blockers and adrenaline (epinephrine), in some cases, pupil dilation was noted.