Bimoptik Plus, eye drops 0.3 mg+5 mg/ml 3 ml

Pharmacotherapeutic group: Antiglaucoma combined agent (prostaglandin F2-alpha analog synthetic + beta-adrenoblocker).

ATX code: S01ED51

Pharmacological properties

.Pharmacodynamics

The drug BIMOPTIC PLUS is a combination medicine. Its constituents bimatoprost and timolol lower intraocular pressure (IOP) through a synergistic interaction, resulting in a significantly more pronounced hypotensive effect compared to the effect of each component alone.

Bimatoprost is a synthetic prostamide with a chemical structure similar to prostaglandin F2-alpha (PGF2α). Bimatoprost has no effect on any of the known types of prostaglandin receptors. The hypotensive effect of bimatoprost is achieved by enhancing the outflow of intraocular fluid through the trabecula and through the uveoscleral pathway of the eye.

Timolol is a non-selective beta-adrenoblocker and has no intrinsic sympathomimetic and membrane-stabilizing activity.

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

pharmacokinetics

.Fixed combinationbimatoprost+timolol

Systemic absorption bimatoprost+timolol is minimal, not different with either combination treatment or instillation of each component of the drug alone.

Two 12-month studies showed no systemic cumulation of either active ingredient.

Bimatoprost
Absorption

Bimatoprost has been shown in in vitro studies to penetrate the iris and sclera. When instillation of 0.03% bimatoprost solution 1 drop in both eyes once a day for 2 weeks the maximum concentration (Cmax) of bimatoprost in plasma is reached within 10 minutes after application, and within 1.5 hours its concentration in plasma decreases to the lower limit of determination (0.025 ng/ml). The mean Cmax and area under the concentration-time curve (AUC_0-24 h) of bimatoprost were close on days 7 and 14 of administration, and were 0.08 ng/mL and
0.09 ng*h/mL respectively, indicating that the equilibrium concentration of bimatoprost is reached within the first week of use.

Distribution

Bimatoprost is moderately distributed in the tissues, and the systemic volume of distribution when the equilibrium concentration of the drug is reached is 0.67 L/kg. Bimatoprost is predominantly found in blood plasma. Bimatoprost binding to plasma proteins is approximately 88%.

Metabolism

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

Elimation

Bimatoprost is excreted primarily by the kidneys. About 67% of the drug administered intravenously to healthy volunteers was excreted by the kidneys and 25% was excreted through the intestine. The half-life (T1/2) of bimatoprost, determined after intravenous administration, was approximately 45 minutes; and total clearance was 1.5 L/h/kg.

In elderly patients

When bimatoprost is administered twice daily, the mean AUC_0-24 h in elderly patients is 0.0634 ng*h/ml, which is significantly higher than 0.0218 ng*h/ml in healthy young adults.

However, this difference has no clinical significance because the systemic exposure of bimatoprost to topical administration in elderly patients and healthy young adults is very low. There is no cumulation of bimatoprost in the systemic circulation and the safety profile does not differ between elderly patients and young adults.

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 intraocular fluid after
1 h was 898 ng/mL. Some timolol enters the systemic bloodstream. Timolol is slightly bound to plasma proteins.

Metabolism

Timololol that enters the systemic bloodstream is metabolized in the liver.

Evolution

The T_1/2 thymolol is about 4 to 6 h. Part of timolol metabolized in the liver is excreted through the intestine, and the other part and metabolites are excreted by the kidneys.

Indications

Active ingredient

Composition

Composition per 1 ml of the drug:

Active ingredients: bimatoprost – 0.30 mg, timolol maleate (6.80 mg) in terms of timolol – 5.00 mg;

Excipients: citric acid monohydrate – 0.14 mg, sodium hydrophosphate heptahydrate – 2.68 mg, sodium chloride – 6.80 mg, benzalkonium chloride – 0.05 mg, 1 M sodium hydroxide solution or 1 M hydrochloric acid solution to pH 7.3 + 0.1, purified water – to 1.00 ml.

How to take, the dosage

Recommended doses in adults (including elderly patients)

The recommended dose is 1 drop in the conjunctival sac of the affected eye once daily, morning or evening. The drug should be used at the same time every day.

The available literature on the use of the fixed combination of bimatoprost+timolol suggests that evening administration is more effective in lowering IOP than morning administration. However, consideration should be given to following the chosen regimen.

If the drug is missed once, it is administered the next day. It is not recommended to exceed the dose of 1 administration once a day. If more than 2 preparations are used, a 5-minute break between each instillation is necessary.

Pressing the nasolacrimal duct area or closing the eyelids for 2 minutes reduces systemic absorption, which may result in fewer side effects and increased local exposure.

Interaction

There have been no specific studies on drug interactions of the fixed combination of bimatoprost+timolol.

Potential potentiation of the effects of co-administration of ophthalmic solutions of beta-adrenoblockers and orally administered “slow” calcium channel blockers, guanethidine, beta-adrenoblockers, parasympathomimetics, antiarrhythmic drugs (including amiodarone) and cardiac glycosides, which manifested as decreased blood pressure and/or marked bradycardia is possible.

There have been reports of potentiation of the systemic effects of beta-adrenoblockers (e.g., decreased heart rate, depression) when using timolol together with CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine).

Cases of mydriasis have occasionally been reported with concomitant use of ophthalmic beta-adrenoblockers and adrenaline (epinephrine).

Patients using BIMOPTIC PLUS with other prostaglandin analogues should be monitored for IOP changes.

Very few cases of corneal calcification have been reported when combined with phosphate-containing eye drops in some patients with significant corneal damage.

Special Instructions

In the same way as other ophthalmic drugs, BIMOPTIC PLUS can penetrate into the systemic bloodstream. Due to the presence of timolol, a beta-adrenergic component, various types of adverse reactions (cardiovascular, respiratory and other systems) may occur, as with systemic beta-adrenoblockers. The incidence of adverse reactions is lower with local administration of the drug than with systemic use.

Cardiovascular

Patients with cardiovascular disease (such as coronary heart disease, Prinzmetal angina and heart failure) and on hypotensive therapy with beta-adrenoblockers should be critically evaluated and other drugs should be considered. Patients with cardiovascular disease should be monitored for signs of worsening of these diseases and adverse reactions.

Patients with severe peripheral circulatory disorders (e.g., severe Raynaud’s disease or Raynaud’s syndrome) should use the drug with caution.

Respiratory system

Relatory reactions, including deaths due to bronchospasm in patients with bronchial asthma, have been reported following use of some ophthalmic beta-adrenoblockers.

Endocrine system

Beta-adrenoblockers may mask symptoms of hypoglycemia, hyperthyroidism.

Other beta-adrenoblockers

Timolol may affect IOP or potentiate the effects of systemic beta-adrenoblockers in patients already receiving a systemic beta-adrenoblocker. Close monitoring of such patients is recommended. Also, the use of two topical beta-adrenoblockers is not recommended.

Anaphylactic reactions

In patients with a history of atopy and severe anaphylactic reactions to various allergens, doses of epinephrine (adrenaline), which are usually used to control anaphylactic reactions, may be ineffective with beta-adrenoblockers.

Chorioidal detachment

Cases of chorioidal detachment have been reported with the use of therapy that reduces intraocular fluid flow (e.g., timolol, acetazolamide) after filtration surgery.

Surgical anesthesia

Ophthalmic drugs with β-adrenoblocking effects may inhibit the systemic effects of β-agonists such as epinephrine (adrenaline). The anesthesiologist should be alerted to the patient’s use of timolol.

Liver function

In patients with mild liver disease or baseline elevated liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and/or total bilirubin, bimatoprost had no effect on liver function during a study period longer than 24 months.

There are no data on adverse reactions due to the effect of timolol on liver function.

Eye organ

Patients should be advised of possible eyelash growth, increased eyelid pigmentation, and iris pigmentation before starting treatment, as these side effects have been established in studies of bimatoprost and the fixed bimatoprost+timololol combination. Some changes may be permanent and may be accompanied by differences between eyes if instillations of the drug were only given in one eye. Iris pigmentation may remain permanent after withdrawal of BIMOPTIC PLUS. After 12 months of treatment with a fixed combination of bimatoprost+timolol, the incidence of iris pigmentation was noted in 0.2% of patients. And after 12 months of treatment with bimatoprost alone in the form of eye drops 1.5%, no further increase in the incidence of this effect was observed during the therapy duration of 3 years.

The increase in iris pigmentation is due to increased production of melanocytes, not simply an increase in their number.

The duration of the development of the effect of increased iris pigmentation is unknown. Changes in iris color seen with bimatoprost may be subtle for periods of several months to several years. Use of the drug has no effect on nevi or iris pigment deposits. Periorbital pigmentation has been reported to be reversible in some patients.

Possible changes in refraction (due to discontinuation of myotic therapy in some cases).

The skin

Possible hair growth on areas of the skin where the drug was accidentally applied. It is important to use BIMOPTIC PLUS strictly according to the directions for medical use and to avoid contact with the skin.

Associates

The excipient benzalkonium chloride, contained in the product BIMOTIC PLUS, may irritate the eye mucosa and change the color of the soft contact lenses. Contact lenses should be removed before insertion, and can be put on 15 minutes after instillation. Benzalkonium chloride may cause acute keratitis and/or toxic corneal ulceration. Therefore the patient should be monitored in case of frequent or prolonged treatment with BIMOPTIC PLUS in persons with dry eye syndrome and corneal changes.

After opening the vial one cannot rule out the possibility of microbial contamination of its contents which may lead to inflammatory eye lesions. The shelf life of the drug after the first opening of the bottle is 28 days. After this time the vial should be thrown away, even if the solution has not been completely used.

It is recommended that the date of opening of the bottle be written on the carton of the drug.

Influence on ability to drive vehicles and machinery

Transient visual impairment may occur after administration of the drug, so the patient should wait until full recovery of vision before starting to drive vehicles and machinery.

Synopsis

Contraindications

Cautions

Hepatic and renal disorders (the drug has not been adequately studied in this category of patients).

In patients with risk factors for macular edema (e.g., aphakia, pseudophakia, posterior lens capsule rupture, and intraocular surgery, retinal vein occlusion, inflammatory eye disease, and diabetic retinopathy).

In patients with active intraocular inflammation (e.g., uveitis) because the inflammation may worsen.

In patients with mild to moderate COPD, and only when the expected benefit exceeds the possible risk.

In patients with grade I atrioventricular block due to adverse effects on intracardiac conduction time.

In patients with corneal diseases, because it can induce dry eye syndrome.

In patients with diabetes mellitus (unstable course) and impaired glucose tolerance, because the beta adrenoblocker timolol contained in BIMOPTIC PLUS may mask the signs of hypoglycemia.

In patients with ocular inflammatory changes; neovascular, inflammatory, closed-angle glaucoma, congenital glaucoma (no data available to study efficacy and safety).

Side effects

Safety Profile Summary

The adverse reactions observed in clinical trials of bimatoprost + timolol with preservative were limited to those previously observed with the separate use of bimatoprost and timolol. Most of the adverse reactions observed in the clinical trials were mild visual reactions, none of which were serious. In a 12-month clinical trial of bimatoprost+timolol with a preservative, the most common adverse reaction was conjunctival hyperemia (mostly mild and noninflammatory) in approximately 26% of patients and resulted in discontinuation in 1.5%.

The adverse reactions are presented below according to organ involvement, organ system involvement, and frequency of occurrence.

The incidence of adverse reactions is defined as follows:

very common (> 1/10),frequent (>1/100 and < 1/10), infrequently (> 1/1000 and < 1/100), rarely
(≥ 1/10000 and < 1/1000),very rarely(<1/10000), frequency unknown (frequency cannot be determined from available data).

Immune system disorders:

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

Mental disorders:

Frequency unknown: insomnia, nightmares.

Nervous system disorders:

Frequently:headache, dizziness.

Frequency unknown: dysgeusia.

Visual disorders:

very common:conjunctival hyperemia.

Frequently: pitting keratitis, corneal erosion, burning sensation, itchy eyes, tingling sensation in eyes, foreign body sensation, dry eyes, reddened eyelids, eye pain, photophobia, eye discharge, visual disturbance, itchy eyelid skin, reduced visual acuity, blepharitis, edema of eyelids, eye mucosa irritation, increased tear production, lash growth.

Infrequent:iridocyclitis, conjunctival edema, painful eyelids, asthenopia, trichiasis, iris hyperpigmentation, deepening of the eyelid crease, eyelid retraction.

Frequency unknown: cystoid macular edema, ocular edema, blurred vision.

Cardiac disorders:

Frequency unknown: bradycardia.

Respiratory system disorders:

Frequent: rhinitis.

Infrequent: dyspnea.

Frequent unknown: bronchospasm (mainly in patients with existing bronchospastic disease), asthma.

Skin and subcutaneous tissue disorders

Frequently: eyelid skin pigmentation, hirsutism, skin hyperpigmentation (periocular).

Prevalence unknown: alopecia.

General disorders and disorders at the site of administration:

Frequency unknown: fatigue.

Like other topically administered ophthalmic drugs, BIMOPTIC PLUS (bimatoprost/thymololol) is absorbed into the systemic bloodstream.

The absorption of timolol may cause adverse effects similar to those of systemic beta-blocking agents. The number of systemic adverse reactions after topical administration is lower than after systemic administration.

Other adverse reactions that have been observed with each component of the drug (bimatoprost or timolol) and are potentially possible during treatment with BIMOPTIC PLUS:

Immune system disorders:

Systemic allergic reactions, including anaphylaxis1.

Disorders of metabolism and nutrition: hypoglycemia1.

Mental disorders: depression1, memory loss1.

Nervous system disorders: fainting1 , acute impairment of cerebral circulation1, increased signs and symptoms of myasthenia gravis1, paresthesia1, cerebral ischemia1.

Visual disturbances: decreased corneal sensitivity1, diplopia1, ptosis1, choroidal detachment (after surgical treatment of glaucoma)1, keratitis1, blepharospasm2, retinal hemorrhage2, uveitis2.

Cardiac abnormalities: atrioventricular block1, cardiac arrest1, heart rhythm disorders1, heart failure1, congestive heart failure1, chest pain1, palpitations1, edema1.

Vascular disorders: decreased blood pressure1, increased blood pressure2, Raynaud’s syndrome1, coldness of extremities1.

Disorders of the respiratory system, chest and mediastinum organs: aggravation of asthma2, exacerbation of COPD2, cough1.

Gastrointestinal tract disorders: nausea1,2, diarrhea1, dyspepsia1, dry oral mucosa1, abdominal pain1, vomiting1.

Skin and subcutaneous tissue disorders: psoriasis-like rashes1 or exacerbation of psoriasis1, skin rash1.

Muscular and connective tissue disorders: muscle pain1.

Gender and mammary gland disorders: sexual dysfunction1, decreased libido1.

General disorders and disorders at the site of administration: asthenia1,2.

Laboratory and instrumental findings:

Changes in liver enzyme activity2.

1 adverse reactions noted with timolol therapy

2adverse reactions noted with bimatoprost therapy

adverse reactions to phosphate-containing eye drops

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

Overdose

Ingestion of BIMOPTIC PLUS is unlikely to cause overdose or may be associated with toxic effects.

Bimatoprost

The following information may be helpful if bimatoprost+timolol is ingested unintentionally: No symptoms of toxic effects of bimatoprost at doses up to 100 mg/kg/day were observed during a 2-week oral administration experiment in rats and mice. The dose used in the study, expressed in mg/m2, was 70 times the possible dose of bimatoprost when the contents of a vial containing bimatoprost+timolol were accidentally ingested by a 10 kg child.

Timolol

The following symptoms may occur with timolol overdose: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, shortness of breath, cardiac arrest. Studies have shown that timolol is not completely excreted by hemodialysis. If an overdose occurs, symptomatic therapy is necessary.

Pregnancy use

Pregnancy

There are no adequate data on the use of the fixed combination of bimatoprost + timolol in pregnant women. BIMOPTIC PLUS in pregnancy should be used only when the expected benefit to the mother exceeds the potential risk to the fetus. Adequate and strictly controlled studies of a fixed combination of bimatoprost+timolol in pregnant women have not been conducted.

In animal studies, reproductive toxicity has been reported at high doses of bimatoprost.

Epidemiological studies have found no congenital fetal malformations, but have found a risk of intrauterine fetal delay when taking oral medications from the beta-adrenoblocker group. In cases where patients took a beta-adrenoblocker before delivery, newborns showed clinical symptoms characteristic of this group of drugs (e.g., bradycardia, hypotension, respiratory distress syndrome, and hypoglycemia).

If BIMOPTIC PLUS is used until delivery, the newborn’s condition must be monitored during the first days of life.

The reproductive toxicity of timolol has been demonstrated in animal studies when doses significantly higher than those prescribed in clinical practice are used. Therefore, BIMOPTIC PLUS should not be used in pregnancy unless absolutely necessary.

Breastfeeding period

Beta-adrenoblockers penetrate into breast milk. However, when timolol in the form of eye drops at therapeutic doses is unlikely to develop clinical symptoms in children, due to the lack of sufficient amount of the drug in the breast milk.

It is not known whether bimoprost penetrates into human breast milk, but it has been found to be present in the milk of lactating rats. BIMOPTIC PLUS should not be used in women during breastfeeding.

Similarities