Tizoptan eye drops 0.3mg/ml+5mg/ml vials, 3ml

Composition

>1 ml of the drug contains: active ingredients:  

• bimatoprost 0.3 mg,
• timolol maleate 6.83 mg (equivalent to timolol 5 mg);

excipients:  

• benzalkonium chloride 0.05 mg,
• citric acid monohydrate 0.14 mg,
• sodium hydrophosphate heptahydrate 2.68 mg,
• sodium chloride 6.8 mg,
• sodium hydroxide up to pH 7.3,
• hydrochloric acid up to pH 7.3,
• water for injection up to 1 ml

Pharmacological action

Tizoptan® is a combined drug, its components bimatoprost and timolol reduce intraocular pressure (IOP) due to the combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each of the components separately.

Bimatoprost belongs to synthetic prostamides, similar in chemical structure to prostaglandin F2a (PGF2a). Bimatoprost has no effect on any of the known types of prostaglandin receptors. The hypotensive effect of bimatoprost is achieved by increasing the outflow of intraocular fluid through the trabecula and along the uveoscleral pathway of the eye.

Timolol is a non-selective beta-blocker, does not have internal sympathomimetic and membrane-stabilizing activity.

Timolol reduces IOP by reducing the formation of intraocular fluid. The exact mechanism of action has not been established; it may be associated with inhibition of cyclic adenosine monophosphate (c-AMP) synthesis and is caused by endogenous stimulation of beta-adrenergic receptors.

Pharmacokinetics

Tizoptan®

Systemic absorption of the drug is minimal, does not differ both with combined treatment and with instillation of each of the components of the drug separately.

No systemic accumulation of any of the active substances was observed in two 12-month studies.

Bimatoprost

In vitro studies have shown that bimatoprost penetrates the iris and sclera.

When instilling a 0.03% solution of bimatoprost 1 drop in both eyes once a day for 2 weeks, the maximum concentration (Cmax) of bimatoprost in blood plasma is reached within 10 minutes after application, and within 1.5 hours its concentration in blood plasma decreases to the lower limit of determination (0.025 ng/ml). The average values of Cmax and the area under the concentration-time curve (AUC0-24 hours) of bimatoprost were close on days 7 and 14 of application, and were 0.08 ng/ml and 0.09 ng*h/ml, respectively, indicating that the equilibrium concentration of bimatoprost is reached during the first week of use.

Bimatoprost is moderately distributed in tissues, and the systemic volume of distribution when the equilibrium concentration of the drug is reached is 0.67 l / kg. Bimatoprost is mainly found in blood plasma.

The binding of bimatoprost to plasma proteins is approximately 88%. Bimatoprost undergoes oxidation, N-deethylation, and glucuronidation to form various metabolites.

Bimatoprost is mainly excreted by the kidneys. About 67% of the drug administered intravenously to healthy volunteers was excreted in the urine, and 25% – through the gastrointestinal tract (GIT). The half-life (T1/2) of bimatoprost determined after its intravenous use was approximately 45 minutes; and the total clearance was 1.5 l / h/kg.

In elderly patients:

When using bimatoprost 2 times a day, the average value (AUC0-24 hours) in elderly patients is 0.0634 ng * h/ml, which significantly exceeds the value of this indicator in healthy young people-0.0218 ng * h/ml.

However, this difference is not clinically significant, since the systemic exposure of bimatoprost when applied topically in elderly patients and healthy young people remains very low. Accumulation of bimatoprost in the systemic circulation is not observed, the safety profile does not differ in elderly patients and young people.

Timolol

In patients who underwent cataract surgery, after instillation of eye drops in the form of a 0.5% solution, the cmax of timolol in intraocular fluid after 1 h was 898 ng / ml. A certain amount of the drug enters the systemic circulation and undergoes metabolism in the liver. T1 / 2 of timolol is about 4-6 hours

. Part of timolol that has been metabolized in the liver is excreted through the gastrointestinal tract, and the other part and its metabolites are excreted by the kidneys. Timolol is slightly bound to plasma proteins.

Indications

Reduction of intraocular pressure (IOP)in patients with open-angle glaucoma and intraocular hypertension with insufficient effectiveness of topical use of beta-blockers and prostaglandin analogues.

Use during pregnancy and lactation

There are no adequate data on the use of a fixed bimatoprost/timolol combination in pregnant women. Tizoptan® during pregnancy should be used only in cases where the expected benefit to the mother exceeds the potential risk to the fetus. Adequate and strictly controlled studies of the combination of bimatoprost+timolol in pregnant women have not been conducted. In animal studies, data on reproductive toxicity at high doses of bimatoprost were obtained. Epidemiological studies did not reveal any congenital malformations of the fetus, but established the risk of delayed fetal development when taking drugs of the beta-blockers group inside. In cases where patients took a beta-blocker prior to delivery, newborns showed clinical symptoms characteristic of this group of drugs (for example, bradycardia, hypotension, respiratory distress syndrome and hypoglycemia). If the drug Tizoptan® is used up to delivery, it is necessary to monitor the condition of the newborn during the first days of life. Animal studies have shown the reproductive toxicity of timolol when using doses significantly higher than those prescribed in clinical practice. Thus, Tizoptan® it is not recommended to use during pregnancy, except in cases of special need. Beta-blockers pass into breast milk. However, when using timolol in the form of eye drops in therapeutic doses, it is unlikely that clinical symptoms will develop in children, due to the lack of sufficient amounts of the drug in breast milk. It is not known whether bimatoprost penetrates into human breast milk, but it has been established that it is found in the milk of lactating rats. Tizoptan® it should not be used in women during breastfeeding.

Contraindications

• Hypersensitivity to the components of the drug;
• Airway hyperresponsiveness syndrome, including acute bronchial asthma and a history of previous episodes, severe chronic obstructive pulmonary disease (COPD);
• Sinus bradycardia, sinus node weakness syndrome, sinoauricular block, grade II and III atrioventricular block without implanted artificial pacemaker, clinically pronounced heart failure, cardiogenic shock;
• Under 18 years of age.

With caution

Impaired liver and kidney function (the drug has not been sufficiently studied in this category of patients). In patients with risk factors for macular edema (for example, with aphakia, pseudophakia, rupture of the posterior lens capsule, as well as with intraocular surgery, retinal vein occlusion, inflammatory eye diseases and diabetic retinopathy).

In patients with active intraocular inflammation (for example, uveitis), as the inflammation may increase. In patients with mild to moderate chronic obstructive pulmonary disease (COPD), and only in cases where the expected benefit outweighs the possible risk.

In patients with grade I atrioventricular block due to the negative impact on the time of intracardiac conduction.

In patients with corneal diseases, as it may induce dry eye syndrome. In patients with diabetes mellitus (unstable course) and impaired glucose tolerance, since the beta-blocker timolol included in the preparation Tizoptan® can mask the signs of hypoglycemia.

In patients with inflammatory eye changes, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma (no data on efficacy and safety studies).

Side effects

Adverse reactions observed in clinical trials of the combination of bimatoprost+timolol were limited to those previously noted with the separate use of the active substances bimatoprost and timolol.

Most of the adverse reactions observed in clinical trials were mild visual organ reactions, and none of them were serious.

According to a 12-month clinical study, the most common adverse reaction was conjunctival hyperemia (in most cases of a mild non-inflammatory nature), which was observed in approximately 26% of patients and was the reason for discontinuation of treatment in 1.5% of patients.

Adverse reactions are listed below according to the involvement of organs and organ systems and frequency of occurrence. The frequency of occurrence of adverse reactions is determined as follows: very often (>1/10), often (>>1/100, >><1/10); infrequently (>1/1000, <1/10); infrequently (><1/100), rarely (>1/10000, <1/100), rarely (><1/1000), very rarely (

The following adverse reactions were observed during a 12-month clinical trial of the bimatoprost+timolol combination.

Immune system disorders:Frequency unknown: hypersensitivity reactions, including signs or symptoms of allergic dermatitis, angioedema, allergic eye reactions.

Mental disorders:frequency unknown: insomnia, nightmares.

Nervous system disorders:often: headache, dizziness; frequency unknown: dysgeusia.

Visual disturbances:very often: conjunctival hyperemia; often: spot keratitis, corneal erosion, burning sensation, itchy eyes, tingling sensation in the eyes, foreign body sensation, dry eyes, redness of the eyelids, eye pain, photophobia, eye discharge; infrequently: iridocyclitis, conjunctival edema, eyelid soreness, asthenopia, trichiasis, iris hyperpigmentation, eyelid crease deepening, eyelid retraction; frequency unknown – cystic macular edema, eye edema, blurred vision.

Disorders of the heart rate unknown: bradycardia.

Respiratory system disorders:often: rhinitis;infrequently: dyspnoea; frequency unknown: bronchospasm (mainly in patients with existing bronchospastic disease), asthma.

Skin and subcutaneous tissue disorders:often: pigmentation of the skin of the eyelids, hirsutism, periocular hyperpigmentation of the skin.

General disorders and disorders at the injection site:frequency unknown: fatigue.

Like other topically applied ophthalmic medications, Tizoptan® (bimatoprost+timolol) is absorbed into the systemic circulation. Absorption of timolol may cause undesirable effects similar to those of systemic beta-blocking agents. The number of systemic adverse reactions after topical application is lower than after systemic application.

Other adverse reactions that were observed with the use of each of the components of the drug and potentially possible during treatment with Tizoptan®:

Bimatoprost

Visual disturbances: allergic conjunctivitis, darkening of the eyelashes, blepharospasm, retinal hemorrhage, uveitis, periorbital erythema, blurred vision.

Cardiac disorders: increased blood pressure, Raynaud’s syndrome, cold extremities. General disorders and disorders at the injection site: asthenia.

Disorders of the gastrointestinal tract: nausea.

Laboratory and instrumental data: changes in the activity of liver enzymes.

Timolol

Visual disturbances: blepharospasm, retinal hemorrhage, uveitis.

Vascular disorders: reducing blood pressure.

Respiratory, thoracic and mediastinal disorders: exacerbation of asthma.

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

Immune system disorders: systemic allergic reactions, including angioedema, urticaria, focal and multiple rashes, rash, anaphylaxis.

Metabolic and nutritional disorders: hypoglycemia.

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

Nervous system disorders: syncope, acute cerebrovascular accident, increased symptoms of myasthenia gravis, paresthesia, brain ischemia.

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

Respiratory, thoracic and mediastinal disorders: cough.

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

Skin and subcutaneous tissue disorders: alopecia, psoriasis-like rashes or exacerbation of psoriasis, skin rash.

Musculoskeletal and connective tissue disorders: muscle pain.

Genital and breast disorders: sexual dysfunction, decreased libido. General disorders and disorders at the injection site: asthenia/fatigue.

Adverse reactions to phosphate-containing eye drops.

Very rarely, cases of corneal calcification have been reported when co-administered with phosphate-containing eye drops in some patients.

Interaction

No special studies have been conducted to study the drug interaction of a fixed combination of bimatoprost+timolol. It is possible to potentiate the effects of combined use of ophthalmic solutions of beta-blockers and oral slow calcium channel blockers, guanethidine, beta-blockers, parasympathomimetics, antiarrhythmic drugs (including amiodarone). and cardiac glycosides, which was manifested by a decrease in blood pressure and / or severe bradycardia. Potentiation of the systemic effects of beta-blockers (e. g. heart rate reduction, depression) has been reported when timolol is co-administered with CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine). Cases of mydriasis have been reported periodically with concomitant use of ophthalmic beta-blockers and epinephrine (epinephrine). Patients using Tizoptan® with other prostaglandin analogues should be monitored for changes in intraocular pressure. Very rarely, cases of corneal calcification have been reported when co-administered with phosphate-containing eye drops in some patients with significant corneal damage.

How to take, course of use and dosage

Recommended doses in adults (including elderly patients). One drop is instilled into the conjunctival sac of the affected eye 1 time a day in the morning or evening. The drug should be used daily at the same time. In the available literature data for the drug bimatoprost+timolol, it is assumed that the use of an evening dose may be more effective for reducing IOP than the use of a morning dose. However, you should consider following the selected mode. If the drug is missed once, the drug is administered the next day. It is not recommended to exceed the dose – 1 injection 1 time per day. If more than 2 medications are used, it is necessary to take a 5-minute break between each instillation. When pressing the nasolacrimal canal area or closing the eyelids for 2 minutes, systemic absorption decreases, which can lead to fewer side effects and increased local exposure.

Overdose

When Tizoptan® is administered, overdose is unlikely or may be associated with toxic effects. Bimatoprostin case of unintentional oral use of Tizoptan® with a preservative, the following information may be useful: there were no symptoms of toxic effects of bimatoprost in doses up to 100 mcg / kg / day during a 2-week oral use in an experiment on rats and mice. The dose used in the study, expressed in mg / m2, exceeds by 70 times the possible dose of bimatoprost in case of accidental ingestion of the contents of a bottle of Tizoptan® by a child with a body weight of 10 kg. Timolol If an overdose of timolol occurs, the following symptoms may occur: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, shortness of breath, and cardiac arrest. Studies have shown that timolol is not completely eliminated by hemodialysis. Treatment In case of overdose, it is necessary to conduct symptomatic and supportive therapy.

Special instructions

Just like other ophthalmic medications, Tizoptan® can enter the systemic circulation. Due to the presence of timolol, a beta-adrenergic component, various types of adverse reactions (from the cardiovascular, respiratory and other systems) can occur, as with the use of systemic beta-blockers. The incidence of adverse reactions with topical use of the drug is lower than with systemic use.

Cardiovascular system

Symptoms of heart failure should be compensated before starting the use of Tizoptan®. It is necessary to regularly monitor the condition of patients with severe heart failure, determine the heart rate.

Beta-blockers can mask the symptoms of hypoglycemia, hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central vascular disorders, as well as arterial hypotension.

Patients with severe peripheral circulatory disorders (for example, severe forms of Raynaud’s disease or Raynaud’s syndrome)should be treated with caution.

Respiratory system

When using timolol, there have been reports of respiratory side effects, including deaths due to bronchospasm in patients with bronchial asthma, and less often from heart failure.

Other beta-blockers

Timolol may affect intraocular pressure or increase the effect of systemic beta-blockers in patients already receiving a systemic beta-blocker. Careful monitoring of such patients is recommended. Also, the use of two local beta-blockers is not recommended.

Anaphylactic reactions

In patients with a history of atopic manifestations and severe anaphylactic reactions to various allergens, doses of epinephrine (epinephrine), which are usually used to stop anaphylactic reactions, may not be effective against the background of beta-blockers.

Choroidal detachment

Cases of choroidal detachment have been reported when using therapy that reduces the flow of intraocular fluid (for example, timolol, acetazolamide) after filtration surgery.

Surgical anesthesia

Ophthalmic drugs with beta-blocking effects may inhibit the systemic effects of beta-agonists, such as epinephrine.

It is necessary to warn the anesthesiologist about the use of timolol by the patient.

The liver

In patients with mild liver disease or initially elevated liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (ACT), and/or total bilirubin, bimatoprost had no effect on liver function during the study period of more than 24 months. There are no data on adverse reactions due to the effect of timolol on liver function.

Visual organ

Before starting treatment, patients should be informed about the possible growth of eyelashes, increased pigmentation of the skin of the eyelids and pigmentation of the iris of the eyes, since these side effects were established during studies of bimatoprost and the combination of bimatoprost+timolol.

Some changes may be permanent and may be accompanied by differences between the eyes if instillation of the drug was performed in only one eye. After drug withdrawal

Tizoptan® the pigmentation of the iris may remain constant. After 12 months of treatment with Tizoptan, the incidence of iris pigmentation was observed in 0.2% of patients. And after 12 months of treatment with only bimatoprost in the form of eye drops of 1.5%, a further increase in the frequency of this effect was not observed during therapy lasting 3 years.

Increased pigmentation of the iris is due to increased production of melanocytes, and not just an increase in their number. The duration of development of the effect of increased pigmentation of the iris is unknown. The change in the color of the iris of the eye observed with the use of bimatoprost may not be pronounced in the period from several months to several years.

The use of the drug does not affect nevi or pigment deposits on the iris of the eye. Periorbital pigmentation has been reported to be reversible in some patients. There may be a change in refraction (due to the withdrawal of therapy with myotic agents in some cases).

Leather

It is possible to grow hair on those areas of the skin on which the drug was accidentally applied. It is important to use Tizoptan ® strictly in accordance with the instructions for medical use and avoid ingestion of Tizoptan® on the skin.

Auxiliary substances

The excipient benzalkonium chloride, which is part of the preparation Tizoptan®, can cause irritation of the eye mucosa and discoloration of soft contact lenses. Contact lenses must be removed before the drug is administered, and they can be put on 15 minutes after instillation.

Benzalkonium chloride can cause acute keratitis and / or toxic corneal ulcers. In this regard, it is necessary to monitor the patient’s condition during frequent or prolonged treatment with Tizoptan® in people with dry eye syndrome and corneal changes.

After opening the bottle, it is impossible to exclude the possibility of microbial contamination of its contents, which can lead to inflammatory lesions of the eyes. The shelf life of the drug after the first opening of the bottle is 28 days. After the specified time has elapsed, the bottle should be discarded, even if the solution is not fully used.

It is recommended to write down the date of opening the bottle on the cardboard pack of the drug.

Influence on the ability to drive a car and other mechanisms

There may be a temporary deterioration in vision after use of the drug, so the patient should wait until full vision is restored before starting to drive a car or operate mechanisms.

Storage conditions

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf

life is 2 years.

Active ingredient

Bimatoprost, Timolol

Conditions of release from pharmacies

By prescription

Dosage form

eye drops