Tapticom eye drops 0.0015%+0.5% 0.3ml, 30ml

Composition

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1 ml of eye drops contains 0.015 mg of tafluprost and 5 mg of timolol, which corresponds to 6.84 mg of timolol maleate;

excipients :

glycerin sodium phosphate,

dodecahydrate;

trilon B,

polysorbate 80,

sodium hydroxide and / or concentrated hydrochloric acid,

water for injection.

Pharmacological action

Pharmacodynamics .

mechanism of action

Tapticom ® is a combination drug containing two active ingredients-tafluprost and timolol. These two active substances reduce intraocular pressure (IOP) by additional mechanisms of action, and the combined action results in an additional reduction compared to the action of only one of the two substances.

Tafluprost is a fluorinated analog of prostaglandin F 2ɑ. Tafluprost acid, a biologically active metabolite of tafluprost, is a highly active selective human PROSTANOID FP receptor antagonist.

Pharmacodynamic studies in animals show that tafluprost reduces intraocular pressure, increasing the uveoscleral outflow of eye fluid.

Timolol maleate is a non-selective beta-adrenergic drug. The exact mechanism of action of timolol maleate to reduce intraocular pressure is not yet fully established, although studies on fluorescein and tonography studies suggest that the main effect may be associated with reduced fluid formation. However, some studies also showed a slight increase in outflow activation.

clinical efficacy

In a 6-month study (n = 400) of patients with open-angle glaucoma or ophthalmic hypertension and an average untreated OBE from 24 to 26 mm Hg, the effect of reducing IOP with Tapticom ® (once daily in the morning) was compared with the combined intake of 0.0015% tafluprost (once daily in the morning) and 0.5% timolol (twice daily). Tapticom ® in its effect was no less effective (not inferior) than 0.0015% tafluprost and 0.5% timolol, which were used together. The average daily decrease in OBE relative to the initial values was 8 mmHg in both groups with a primary endpoint of 6 months (the decrease

ranged from 7 to 9 mmHg in both groups at different time points during the day during study visits).

In another 6-month study (n = 564), Tapticom ® was compared with monotherapy-matched patients with open-angle glaucoma or ophthalmic hypertension and an average untreated WTO of 26 to 27 mm Hg. Patients insufficiently controlled with 0.0015% tafluprost (WTO 20 mm Hg or more with treatment) or 0.5% timolol (WTO 22 mm Hg or more with treatment) were randomized to Tapticom ® treatment or the same monotherapy. The average daily decrease in OBE when taking Tapticom ® was statistically higher than the average daily decrease in OBE when taking tafluprost, which patients received once a day in the morning, or when taking timolol, which they received twice a day, at visits at 6 weeks, for 3 months (the primary endpoint of evaluating effectiveness) and for 6 months. The average daily decrease in OBE relative to the initial values when taking Tapticom ® was 9 mm Hg compared to 7 mm Hg, which was observed with both monotherapies. The decrease in OBE when taking Tapticom ® at various points in time during the day ranged from 8 to 9 mm Hg in the comparison group, tafluprost was used as monotherapy, and from 7 to 9 mm Hg in the comparison group, timolol was used as monotherapy.

Summary data obtained from patients who took Tapticom ® and had a high initial OBE of 26 mm Hg (mean daily) or higher in two baseline studies (n = 168) showed that the average daily reduction in OBE was 10 mm Hg at the primary endpoint (3 or 6 months), ranging from 9 to 12 mm Hg at various time points throughout the day.

pharmacokinetic properties

absorption

Plasma concentrations of tafluprost acid and timolol were studied in healthy volunteers after single and repeated use of Tapticom ® for eight days (once a day),0.0015% tafluprost (once a day) and 0.5% timolol (twice a day). The concentration of tafluprost acid in blood plasma reached its maximum value 10 minutes after taking the dose and decreased below the lower limit of detection (10 pg / ml) 30 minutes after taking Tapticom ®. Accumulation of tafluprost acid was insignificant, and the mean urinary tafluprost acid concentration (mean AUC 0 – last ) (monotherapy: 4.45 + 2.57 pg • h / ml Tapticom ® : 3.60 + 3.70 pg • h / ml) and the mean maximum concentration ( max ) (monotherapy: 23.9 +11.8 pg / ml Tapticom ® : 18.7 + 11.9 pg / ml) were slightly lower when treated with Tapticom ® compared to monotherapy with tafluprost on day 8. The concentration of timolol in blood plasma reached its maximum value with a median T max (median time to reach the maximum concentration of the drug) of 15 and 37.5 minutes after taking Tapticom ® on days 1 and 8, respectively. On day 8, the mean urinary timolol concentration (mean AUC 0 – last) (5750 + 2440 pg • h / ml Tapticom ® monotherapy 4560 + 2980 pg • h / ml) and the mean maximum concentration (max) (1100 + 550 pg / ml Tapticom ® monotherapy 840 + 520 pg / ml) were slightly lower with Tapticom ® treatment compared to timolol monotherapy. Low plasma timolol levels during treatment with Tapticom ® are probably associated with the dose of Tapticom  once a day compared to taking a twice-daily dose of timolol as monotherapy.

Tafluprost and timolol are absorbed through the cornea. In animals, after a single instillation, the penetration of tafluprost through the cornea when using Tapticom ® was similar to that when using tafluprost as monotherapy, while the penetration of timolol was slightly less when using Tapticom ® compared to that when using timolol as monotherapy. As for tafluprost acid, the AUC of 4h was 7.5 ng * h / ml after taking Tapticom ® and 7.7 ng • h / ml after taking tafluprost as a monopreparation. According to timolol, the 4h AUC was 585 ng * h / ml and 737 ng • h / ml after taking Tapticom ® and timolol monopreparation, respectively. The T max for tafluprost acid was 60 minutes for both Tapticom ® treatment and tafluprost monopreparation, while the T max for timolol was 60 minutes for Tapticom ® treatment and 30 minutes for timolol monotherapy.

distribution

Tafluprost

In animals, there was no specific distribution of radiolabeled tafluprost in the iridium-ciliary zone or choroid, as well as in the retinal pigment epithelium, which indicated a low affinity of the melanin pigment. In the study with general actoradiography in animals, the highest concentration of radioactivity was observed in the cornea, and only then in the eyelids, sclera and iris. Outside the eye, radioactivity spread to the lacrimal organs, palate, esophagus and gastrointestinal tract, kidneys, liver, gallbladder, and bladder. The binding of tafluprost acid to human serum albumin in vitro was 99% at a tafluprost acid concentration of 500 ng / ml

. timolol

In animals, the maximum level of timolol-related radioactivity in the eye fluid was reached 30 minutes after a single instillation of timolol labeled with the radioactive isotope 3 H (0.5% solution: 20 µl / eye) in both eyes. Timolol is removed from the eye fluid much faster than from the tissues of the pigmented iris and ciliary body.

Metabolism

Tafluprost

The main metabolic pathway of tafluprost in humans, which has been studied in vitro, is hydrolysis to a pharmacologically active metabolite, tafluprost acid, which is further metabolized by glucuronidation or beta-oxidation. Beta-oxidation products of 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which are pharmacologically inactive, may be subject to glucuronidation or hydroxylation. The cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid. According to the results of studying animal corneal tissue with purified enzymes, the main esterase responsible for ester hydrolysis to tafluprost acid is carboxylesterase. Butylcholinesterase, but not acetylcholinesterase, can also promote hydrolysis.

timolol

Timolol is metabolized in the liver, mainly by the enzyme CYP2D6 to inactive metabolites, which are mainly eliminated from the body by the kidneys.

Deduction

Tafluprost

After instilling tafluprost labeled with the radioactive isotope 3 H (0.005% ophthalmic solution,5 µl / eye) once a day for 21 days in both eyes in animals, approximately 87% of the total radioactive dose was eliminated from the body. The total amount that was excreted in the urine was approximately 27-38% of the dose and approximately 44-58% of the dose was excreted in the faeces.

timolol

The established plasma half-life is approximately 4: 00. Timolol is extensively metabolized in the liver, and the metabolites are excreted in the urine along with 20% of the unchanged timolol after oral use.

Indications

Reduced intraocular pressure (IOP) in adult patients with open-angle glaucoma or ophthalmic hypertension who do not respond sufficiently to local monotherapy with beta-blockers or prostaglandin analogues and require combination therapy and who are indicated for the use of eye drops that do not contain preservatives.

Contraindications

Allergic reactions to the active ingredients or to any of the auxiliary components of the drug.

Respiratory tract irritation, as well as a history of bronchial asthma or severe chronic obstructive pulmonary disease.

Sinus bradycardia, sinus node weakness syndrome, as well as sinoatrial block, II-III degree block that is not controlled by a pacemaker, severe heart failure or cardiogenic shock.

Side effects

In clinical trials, more than 484 patients were treated with Tapticom ®. A common treatment-related adverse reaction reported was conjunctiva / hyperemia. It occurred in approximately 7% of patients who participated in clinical trials; in most cases, it was mild, and in 1.2% of patients it was associated with discontinuation of treatment.

Adverse reactions reported in clinical trials using Tapticom ® were limited to those previously reported with the use of one of the active substances – tafluprost or timolol. No new adverse reactions characteristic of Tapticom ® were observed in clinical studies. Most of the adverse reactions reported were ocular, mild to moderate in severity, and not serious.

Like other topical ophthalmic medications, tafluprost and timolol are absorbed systemically. This may cause similar side effects to those seen with systemic beta blockers. The incidence of systemic adverse reactions after topical application of ophthalmic drugs is lower than with systemic use. The following adverse reactions include those that have been observed within the ophthalmic beta-blocker class.

These adverse reactions have been reported when taking Tapticom ® in clinical trials (within each group listed below, the frequency of occurrence of adverse reactions is presented in order of decreasing frequency).

The frequency of possible adverse reactions listed below was determined using the following symbols: very common (≥1/10); common (≥ 1/100 to <1/10); infrequent (≥1/1,000 to <1/100); rare (≥1/10,000 to very rare ( unknown (frequency cannot be determined based on existing data).

Tapticom ® (tafluprost / timolol combination)

Nervous system disorders

Infrequently : headache

From the side of the visual organs

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

Infrequently: unusual sensation in the eyes, dry eyes, eye discomfort, conjunctivitis, erythema of the eyelids, eye allergy, edema of the eyelids, superficial punctate keratitis, increased lacrimation, inflammation of the anterior chamber of the eye, asthenopia (rapid eye fatigue), blepharitis (inflammation of the eyelids).

Additional adverse reactions that have been observed with the use of one of the active ingredients (tafluprost or timolol), and may also occur with the use of Tapticom®, are listed below.

Tafluprost

From the side of the visual organs: Reduced visual acuity, increased pigmentation of the iris, pigmentation of the eyelids, conjunctival edema, discharge from the eyes, cellular reaction of the anterior chamber moisture, cellular opalescence in the anterior chamber of the eye, allergic conjunctivitis, conjunctival pigmentation, conjunctival follicles, deepening of the eyelid furrow, iritis (inflammation of the iris) / uveitis (inflammation of the choroid of the eyeball).

From the skin and its derivatives: hypertrichosis of the eyelids.

From the respiratory system: exacerbation of bronchial asthma, shortness of breath (shortness of breath / difficulty breathing).

timolol

From the immune system: signs and symptoms of allergic reactions, including angioedema, urticaria, single and multiple rashes, anaphylactic reaction, pruritus.

From the side of metabolism and nutrition: hypoglycemia.

From the side of the psyche: depression, sleep disorders (insomnia), nightmares, memory loss, nervousness.

Nervous system disorders: dizziness, syncope, paresthesia, increased myasthenia gravis, hemorrhagic stroke, cerebral ischemia.

From the side of the visual organs: keratitis, reduced corneal sensitivity, visual disturbances and disorders, including changes in refraction (due to the withdrawal of myotic agents in some cases), ptosis (drooping of the eyelid), diplopia (double vision), choroidal detachment after filter surgery, lacrimation, corneal erosion.

From the side of the organs of hearing and balance: ringing / tinnitus.

From the heart : bradycardia, chest pain, rapid heartbeat, edema, arrhythmia, congestive heart failure, cardiac arrest, heart block, blockage, heart failure.

Vascular disorders: hypotension, lameness, Raynaud’s disease, cold limbs (hands and feet).

Respiratory, thoracic and mediastinal disorders: dyspnea (shortness of breath / difficulty breathing), bronchospasm (especially in patients with pre-existing bronchospastic disease), respiratory disorders, cough.

From the digestive system : nausea, dyspepsia (digestive disorders), diarrhea, dry mouth, dysgeusia( taste disorders), abdominal pain, vomiting.

From the skin and its derivatives : alopecia (baldness), psoriasis-like rashes or exacerbation of psoriasis, skin rash.

Musculoskeletal and connective tissue disorders: systemic lupus erythematosus, myalgia (muscle pain), arthropathy (joint disease).

From the genitals and mammary glands : Peyronie’s disease (fibroplastic penile induration), decreased sexual desire (libido), sexual dysfunction.

General disorders and reactions at the injection site: asthenia (general weakness) / fatigue, thirst.

Cases of corneal calcification have been reported very rarely due to the use of phosphate-containing eye drops in some patients with significant corneal damage.

Interaction

No specific interaction studies with other drugs have been conducted.

Possible additional effects resulting in hypotension and / or severe bradycardia when ophthalmic beta-blocker solution is used simultaneously with oral calcium channel blockers, beta-blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.

Oral beta-blockers may increase the “rebound” hypertension that occurs after clonidine withdrawal.

Increased effects of systemic beta blockers (e. g. decreased heart rate, depression)have been reported during combined treatment with CYP2D6 inhibitors (such as quinidine, fluoxetine, paroxetine) and timolol.

Mydriasis caused by concomitant use of ophthalmic beta-blockers and epinephrine (epinephrine) has rarely been reported.

How to take, course of use and dosage

The recommended therapy is to instill 1 drop of ocular fluid into the conjunctival sac of the affected eye (s) once a day.

If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye (s) once a day.

Tapticom ® is a sterile solution that does not contain preservatives. Designed for one-time use only, one dropper tube is enough to treat both eyes. Any unused solution or its residues must be disposed of immediately.

Elderly patients

There is no need to change the dosage in elderly patients.

Renal and hepatic insufficiency

The use of tafluprost and timolol eye drops in patients with renal / hepatic insufficiency has been studied, so Tapticom ® should be used with caution in such patients.

How to use

Ophthalmic use

To reduce the risk of darkening the skin of the eyelids, patients should wipe off excess fluid from the skin.

With lacrimal-nasal occlusion or closing of the eyelids for 2 minutes, systemic absorption decreases. This may result in a reduction in systemic side effects and an increase in local activity.

If more than one ophthalmic drug is prescribed, the interval between instillations of each of these drugs should be at least 5 minutes.

Contact lenses should be removed before instilling eye drops and wait at least 15 minutes, after which they can be put back on.

Patients should be advised to avoid direct eye contact with the vial, as this may result in eye injury.

Patients should also be informed that ophthalmic solutions, if handled improperly, may become contaminated with common bacteria that are known to cause eye infections. The use of contaminated solutions can result in serious eye damage and subsequent loss of vision.

Children.

Safety and efficacy of Tapticom ® for children (under 18 years of age) not installed. No data available. Tapticom ® should not be used in children.

Overdose

Overdose with topical application of tafluprost is unlikely to occur or be associated with toxicity.

Accidental overdose of timolol has been reported, resulting in symptoms of general poisoning similar to those observed with systemic beta-blockers, such as dizziness, headache, difficulty breathing (shortness of breath), bradycardia, bronchospasm, and cardiac arrest (see also section “Adverse reactions”).

If an overdose of Tapticom ® occurs, treatment should be symptomatic and supportive. Timolol is not actively removed by hemodialysis.

Active ingredient

Tafluprost, Timolol

Conditions of release from pharmacies

By prescription

Dosage form

eye drops