Bimokko-SZ (Drops) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Timolol (Rec.INN registered by WHO)

Bimatoprost (Rec.INN registered by WHO)

Dosage Form

Bimokko-SZ

Eye drops 0.3 mg+5 mg/1 ml: dropper bottles 2.5 ml or 5 ml

Dosage Form, Packaging, and Composition

Eye drops as a clear, colorless or light yellow solution.

Excipients: benzalkonium chloride, disodium phosphate anhydrous, citric acid monohydrate, sodium chloride, 1M hydrochloric acid solution, 1M sodium hydroxide solution, water for injections.

2.5 ml – dropper bottles (1) – cardboard packs.
5 ml – dropper bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiglaucoma drug – synthetic prostaglandin F2α analogue + beta-adrenoblocker

Pharmacotherapeutic Group

Drugs used in ophthalmology. Antiglaucoma drugs and miotic agents. Beta-blockers. Timolol in combination with agents

Pharmacological Action

A combined medicinal product, its constituent components Bimatoprost and Timolol reduce intraocular pressure (IOP) through combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each component separately.

Bimatoprost belongs to synthetic prostatamides, its chemical structure is similar to prostaglandin F2α (PGF2α). Bimatoprost does not affect any of the known types of prostaglandin receptors. The hypotensive action of bimatoprost is achieved by enhancing the outflow of intraocular fluid through the trabecula and the uveoscleral pathway of the eye.

Timolol is a non-selective beta-adrenoblocker, it does not possess intrinsic sympathomimetic and membrane-stabilizing activity. Timolol reduces IOP by decreasing the production of intraocular fluid. The exact mechanism of action is not established, it may be associated with the inhibition of cAMP synthesis and is caused by endogenous stimulation of β-adrenergic receptors.

Pharmacokinetics

Fixed combination Bimatoprost/Timolol

Systemic absorption of the drug is minimal and does not differ either with combined therapy or with separate instillation of each of the drug components.

In two 12-month studies, no systemic accumulation of either active substance was noted.

Bimatoprost

Absorption

In vitro studies have shown that Bimatoprost is absorbed through the cornea and sclera of the eye. When instilling a 0.3% solution of bimatoprost, 1 drop in both eyes once a day for 2 weeks, the C_max 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 quantification (0.025 ng/ml). The mean values of C_max and AUC_0-24 of bimatoprost were similar on day 7 and day 14 of application, and were 0.08 ng/ml and 0.09 ng×h/ml, respectively, indicating that the C_ss of bimatoprost is reached within the first week of application.

Distribution

Bimatoprost is moderately distributed in tissues, the systemic V_d at C_ss of the drug is 0.67 L/kg. Bimatoprost is predominantly found in blood plasma. The binding of bimatoprost to plasma proteins is approximately 88%.

Metabolism

Bimatoprost undergoes oxidation, N-deethylation and glucuronidation to form various metabolites.

Excretion

Bimatoprost is excreted primarily by the kidneys. About 67% of the drug administered intravenously to healthy volunteers was excreted in the urine, and 25% through the gastrointestinal tract. The T_1/2 of bimatoprost, determined after its intravenous administration, was approximately 45 minutes, and the total clearance was 1.5 L/h/kg.

Pharmacokinetics in the elderly

When bimatoprost is applied twice a day, the mean AUC_0-24 value in elderly patients is 0.0634 ng×h/ml, which significantly exceeds the value of this indicator in healthy young individuals – 0.0218 ng×h/ml.

However, this difference has no clinical significance, since the systemic exposure of bimatoprost during its topical application in elderly patients and healthy young individuals remains very low. No accumulation of bimatoprost in the systemic circulation is observed, the safety profile does not differ between elderly patients and young individuals.

Timolol

Absorption and distribution

In patients undergoing cataract surgery, after instillation of eye drops as a 0.5% solution, the C_max of timolol in the intraocular fluid after 1 hour was 898 ng/ml. A certain amount of the drug enters the systemic circulation. Timolol binds to plasma proteins to a small extent.

Metabolism

Timolol that enters the systemic circulation undergoes metabolism in the liver.

Excretion

The T_1/2 of timolol is about 4-6 hours. Part of the timolol metabolized in the liver is excreted through the gastrointestinal tract, and another part of it and metabolites are excreted by the kidneys.

Indications

Adults over 18 years of age for the reduction of elevated intraocular pressure (IOP) in

• Open-angle glaucoma
• Ocular hypertension with insufficient effectiveness of topical application of drugs from the group of beta-adrenoblockers or prostaglandin analogues.

ICD codes

Dosage Regimen

1 drop once a day in the morning or evening. The drug should be applied daily at the same time.

Available literature data for the fixed combination Bimatoprost/Timolol suggest that evening dose application may be more effective for IOP reduction than morning dose application. However, the possibility of adherence to the chosen regimen should be considered.

If the drug administration is missed once, the drug is administered the next day. It is not recommended to exceed the dose – 1 administration once a day.

The duration of treatment is determined by the doctor.

Special patient groups

Elderly patients: dose adjustment is not required.

Patients with impaired renal function: dose adjustment is not required.

Patients with impaired hepatic function: dose adjustment is not required.

Children

The drug BIMOKKO-SZ is contraindicated in children aged 0 to 18 years.

Method of administration

Topically, as instillations into the conjunctival sac.

When using several drugs for topical therapy in ophthalmology, it is necessary to observe an interval between instillations of at least 5 minutes.

Pressing on the nasolacrimal duct area or closing the eyelids for 2 minutes reduces systemic absorption, which may lead to a reduction in side effects and an increase in local action.

Adverse Reactions

Adverse reactions observed during clinical studies of the fixed combination Bimatoprost/Timolol with preservative were limited to those previously noted with separate use of the active substances bimatoprost and timolol. Adverse reactions observed during clinical studies of the fixed combination Bimatoprost/Timolol without preservative were limited to those previously noted with the use of the drug with preservative or separate use of the active substances bimatoprost and timolol.

Most of the adverse reactions observed during clinical studies were mild reactions related to the organ of vision and none of them were serious. According to a 12-month clinical study, with the use of the drug with preservative, the most frequent adverse reaction was conjunctival hyperemia (in most cases mild and non-inflammatory in nature), which was observed in approximately 26% of patients, and was also the reason for treatment discontinuation in 1.5% of patients.

With the use of the drug without preservative, hyperemia occurred in 21% of patients, and was the reason for treatment discontinuation in 1.4% of patients.

Tabulated summary of adverse reactions

Adverse reactions are listed below according to the involvement of organs, organ systems and frequency of occurrence. The frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1 000), very rare (<1/10000), frequency not known (frequency cannot be estimated from the available data).

The following adverse reactions were observed during a clinical study or based on post-registration experience with the drug with preservative and without preservative

¹Adverse reactions of the fixed combination Bimatoprost/Timolol, noted only for the drug without preservative.

²Adverse reactions of the fixed combination Bimatoprost/Timolol, noted only for the drug with preservative.

Like other topically applied ophthalmic drugs, the drug Bimokko-SZ is absorbed into the systemic circulation. The absorption of timolol may cause adverse effects similar to those of systemic beta-adrenergic blocking agents. The number of systemic adverse reactions after topical application is lower than after systemic application.

Other adverse reactions that have been observed with the use of each of the drug components (bimatoprost or timolol) and are potentially possible during treatment with the drug Bimokko-SZ:

^{1 Adverse reactions noted during therapy with timolol.}

^{2 Adverse reactions noted during therapy with bimatoprost.}

Adverse reactions to phosphate-containing eye drops

Very rare cases of corneal calcification have been reported with concomitant use with phosphate-containing eye drops in some patients with significant corneal damage.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to bimatoprost, timolol or to any of the excipients included in the drug;
• Hyperreactivity of the respiratory tract syndrome, including bronchial asthma in the acute stage and previous episodes in the medical history, severe chronic obstructive pulmonary disease (COPD);
• Sinus bradycardia, sick sinus syndrome, sinoauricular block, atrioventricular block II and III degree without an implanted artificial pacemaker, clinically significant heart failure, cardiogenic shock.

Use in Pregnancy and Lactation

Pregnancy

Adequate data on the use of the fixed combination Bimatoprost/Timolol in pregnant women are not available. The drug Bimokko-SZ should be used during pregnancy only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Bimatoprost

Adequate and well-controlled studies of the fixed combination Bimatoprost/Timolol in pregnant women have not been conducted. In animal studies, data on reproductive toxicity were obtained at high doses of bimatoprost.

Timolol

Epidemiological studies have not revealed congenital malformations of the fetus, but have established a risk of intrauterine growth retardation with oral administration of drugs from the beta-adrenoblocker group. In cases where patients took a beta-adrenoblocker until delivery, newborns showed clinical symptoms characteristic of this group of drugs (e.g., bradycardia, hypotension, respiratory distress syndrome and hypoglycemia). If the drug Bimokko-SZ is used until delivery, monitoring of the newborn’s condition during the first days of life is necessary. Animal studies have shown reproductive toxicity of timolol when using doses significantly exceeding those prescribed in clinical practice.

Breastfeeding period

Bimatoprost

It is not known whether Bimatoprost passes into human breast milk, but it has been found to be present in the milk of lactating rats. The drug Bimokko-SZ should not be used in women during breastfeeding.

Timolol

Beta-blockers pass into breast milk. However, when using timolol in the form of eye drops in therapeutic doses, the development of clinical symptoms in children is unlikely due to the insufficient amount of the drug in breast milk.

Use in Hepatic Impairment

Caution should be exercised in patients with impaired liver function (the drug has not been sufficiently studied in this category of patients). Dose adjustment is not required.

Use in Renal Impairment

Caution should be exercised in patients with impaired renal function (the drug has not been sufficiently studied in this category of patients). Dose adjustment is not required.

Pediatric Use

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

Geriatric Use

Dose adjustment is not required.

Special Precautions

Like other ophthalmic medicinal products, Bimokko-SZ can penetrate into the systemic circulation. Due to the presence of timolol, a β-adrenergic component, various types of adverse reactions (from the cardiovascular, respiratory and other systems) may occur, as with the use of systemic beta-blockers. The frequency of adverse reactions with topical administration of the drug is lower than with systemic use.

Cardiovascular System

Patients with cardiovascular diseases (such as coronary artery disease, Prinzmetal’s angina, heart failure) and those on antihypertensive therapy with beta-blockers should be critically evaluated and the use of other drugs should be considered. Monitoring of patients with cardiovascular diseases is necessary to observe for signs of worsening of these diseases and adverse reactions.

In patients with first-degree AV block, the drug should be used with caution due to its negative effect on intracardiac conduction time.

The drug should be used with caution in patients with severe peripheral circulatory disorders (for example, severe forms of Raynaud’s disease or Raynaud’s syndrome).

Respiratory System

Respiratory reactions, including fatal outcomes due to bronchospasm in patients with bronchial asthma, have been reported after the use of some ophthalmic beta-blockers. Bimokko-SZ should be used with caution in patients with mild/moderate COPD and should be used only when the potential benefit outweighs the possible risk.

Endocrine System

Caution should be exercised when using the drug in patients with (unstable) diabetes mellitus and impaired glucose tolerance, since the beta-blocker Timolol, which is part of Bimokko-SZ, can mask the signs of hypoglycemia.

Other Beta-Blockers

Timolol may affect IOP or enhance the effect of systemic beta-blockers in patients already receiving a systemic beta-blocker. Close monitoring of such patients is recommended. Also, the use of two topical beta-blockers is not recommended.

Anaphylactic Reactions

In patients with a history of atopic manifestations and severe anaphylactic reactions to various allergens, the doses of epinephrine (adrenaline) usually used to stop anaphylactic reactions may be ineffective while using beta-blockers.

Choroidal Detachment

There have been reports of cases of choroidal detachment with the use of drugs that reduce the production of intraocular fluid (for example, timolol, acetazolamide) after surgeries to improve the outflow of intraocular fluid.

Surgical Anesthesia

Ophthalmic drugs with beta-blocking action can suppress the systemic effects of beta-agonists, for example, adrenaline. The anesthesiologist should be warned that the patient is using timolol.

Liver Function

In patients with mild liver disease or initially elevated activity of liver enzymes – ALT, AST and/or total bilirubin, Bimatoprost did not affect liver function during a study period of more than 24 months. There are no data on adverse reactions due to the effect of timolol on liver function.

Caution should be exercised in patients with impaired liver and kidney function (the drug has not been sufficiently studied in this category of patients).

Organ of Vision

Bimokko-SZ should be used with caution

• In patients with acute intraocular inflammation (for example, uveitis), as inflammation may worsen;
• In patients with corneal diseases, as it may induce dry eye syndrome;
• In patients with inflammatory eye changes, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma (no data on efficacy and safety);
• In patients with risk factors for macular edema (for example, aphakia, pseudophakia, rupture of the posterior lens capsule, as well as intraocular surgery, retinal vein occlusion, inflammatory eye diseases and diabetic retinopathy).

The occurrence of macular edema, including cystoid macular edema, has been observed with the use of the fixed combination Bimatoprost/Timolol. Bimokko-SZ should be used with caution in patients with aphakia, pseudophakia, damage to the posterior lens capsule, as well as in patients at high risk of developing macular edema (for example, in the postoperative period of eye surgeries, with retinal vein occlusion, inflammatory eye diseases and diabetic retinopathy).

Skin

Hair growth is possible on those areas of the skin where the drug was accidentally applied. It is important to use Bimokko-SZ strictly in accordance with the method of application and to avoid getting Bimokko-SZ on the skin.

Before starting treatment, patients should be informed about the possible eyelash growth, increased pigmentation of the eyelid skin and pigmentation of the iris, since these side effects have been established in studies of bimatoprost and the fixed combination Bimatoprost/Timolol. Some changes may be permanent and may be accompanied by the occurrence of differences between the eyes if instillations were performed in only one eye. After discontinuation of the drug, iris pigmentation may remain permanent. After 12 months of treatment with the fixed combination Bimatoprost/Timolol, iris pigmentation was noted in 0.2% of patients. And after 12 months of treatment with bimatoprost eye drops alone – in 1.5%, no further increase in the frequency of this effect was observed during therapy lasting 3 years. Increased iris pigmentation is due to increased melanin production by melanocytes, and not simply an increase in the number of melanocytes. The duration of development of the effect of increased iris pigmentation is unknown. The change in iris color observed with the use of bimatoprost may be subtle over a period of several months to several years. The use of the drug does not affect nevi or pigment deposits on the iris. It has been reported that periorbital pigmentation in some patients is reversible.

Excipients

The excipient benzalkonium chloride, which is part of Bimokko-SZ, can cause irritation of the eye mucosa and discoloration of soft contact lenses. Contact lenses must be removed before administering the drug and can be put on 15 minutes after instillation. Benzalkonium chloride can cause punctate/ulcerative toxic keratopathy. In this regard, it is necessary to monitor the patient’s condition during frequent or prolonged treatment with Bimokko-SZ in persons with dry eye syndrome and corneal changes.

After opening the bottle, the possibility of microbial contamination of its contents cannot be ruled out, which can lead to inflammatory eye lesions. The shelf life of the drug after first opening the bottle is 60 days. After the specified time has elapsed, the bottle should be discarded, even if the solution has not been completely used.

It is recommended to write the date of opening the bottle on the cardboard package of the medicinal product.

Effect on Ability to Drive Vehicles and Operate Machinery

Transient blurred vision may occur after administration of the drug, so the patient should wait until vision is fully restored before driving a car or operating machinery.

Overdose

Overdose with Bimokko-SZ is unlikely or may be associated with toxic effects.

Symptoms

Bimatoprost

In case of unintentional oral ingestion of the fixed combination Bimatoprost/Timolol with preservative, the following information may be useful: no symptoms of toxic effects of bimatoprost were observed at doses up to 100 mg/kg/day during a 2-week oral administration 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 oral ingestion of the entire contents of one bottle (3 ml) of the fixed combination Bimatoprost/Timolol with preservative by a child weighing 10 kg.

In case of unintentional oral ingestion of the fixed combination Bimatoprost/Timolol without preservative, the following information may be useful: no symptoms of toxic effects of bimatoprost were observed at doses up to 100 mg/kg/day during a 2-week oral administration in an experiment on rats and mice; this is equivalent to human doses of 8.1 and 16.2 mg/kg, respectively. These doses are at least 7.5 times higher than the possible dose of bimatoprost in case of accidental oral ingestion of the contents of a cardboard package of the fixed combination Bimatoprost/Timolol without preservative (36 ml) by a child weighing 10 kg [(36 ml*0.3 mg/ml bimatoprost)/10 kg; 1.08 mg/kg].

Timolol

In case of timolol overdose, the following symptoms may be observed: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, shortness of breath, cardiac arrest. Studies have shown that Timolol is not completely removed by hemodialysis.

Treatment

In case of overdose, symptomatic and supportive therapy is required.

Drug Interactions

No specific studies on the drug interactions of the fixed combination Bimatoprost/Timolol have been conducted.

Potentiation of the effects of the combined use of ophthalmic beta-blocker solutions and orally administered slow calcium channel blockers, guanethidine, beta-blockers, parasympathomimetics, antiarrhythmic drugs (including amiodarone) and cardiac glycosides is possible, manifested by a decrease in blood pressure and/or marked bradycardia.

Potentiation of the systemic effects of beta-blockers (e.g., decreased heart rate, depression) has been reported with the concomitant use of timolol with CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine).

Cases of mydriasis have been occasionally reported with the simultaneous use of ophthalmic beta-blockers and adrenaline (epinephrine).

In studies of bimatoprost 0.3 mg/ml in patients with glaucoma or ocular hypertension, it was shown that exposure of the eye to bimatoprost more than once a day may reduce the IOP-lowering effect.

Patients using Bimokko-SZ with other prostaglandin analogues should be monitored to control changes in IOP.

Very rare cases of corneal calcification have been reported with concomitant use with phosphate-containing eye drops in some patients with significant corneal damage.

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Shelf life after opening the dropper bottle – 60 days.

Dispensing Status

The drug is dispensed by prescription.

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.