Bimoptic Plus (Drops) Instructions for Use

Marketing Authorization Holder

S.C. Rompharm Company S.R.L. (Romania)

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

Bimoptic Plus

Eye drops 0.3 mg+5 mg/1 ml: 3 ml bottle with dropper cap

Dosage Form, Packaging, and Composition

Eye drops in the form of a clear solution from colorless to light yellow.

Excipients : citric acid monohydrate – 0.14 mg, sodium hydrogen phosphate heptahydrate – 2.68 mg, sodium chloride – 6.8 mg, benzalkonium chloride – 0.05 mg, 1M sodium hydroxide solution or 1M hydrochloric acid solution – to adjust pH to 7.3±0.1, purified water – to 1 ml.

3 ml – polyethylene bottles with a capacity of 5 ml (1) with a dropper cap – cardboard boxes.
3 ml – polyethylene bottles with a capacity of 5 ml (3) with a dropper cap – cardboard boxes.

Clinical-Pharmacological Group

Antiglaucoma drug – synthetic prostaglandin F2α analogue + beta-adrenoblocker

Pharmacotherapeutic Group

Combined antiglaucoma agent (synthetic prostaglandin F_2α analogue + beta-adrenergic blocker)

Pharmacological Action

Combined medicinal product for use in ophthalmology. Bimatoprost and timolol reduce intraocular pressure through combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each component separately.

Bimatoprost belongs to synthetic prostamides, and is structurally similar to prostaglandin F2-alpha (PGF2α). Bimatoprost does not affect 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 the uveoscleral pathway of the eye.

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

Pharmacokinetics

Systemic absorption of the Bimatoprost+timolol combination is minimal and does not differ between combined therapy and instillation of each component separately.

In vitro studies have shown that Bimatoprost penetrates the iris and sclera of the eye. After instillation of 0.03% bimatoprost solution, 1 drop into both eyes once daily for 2 weeks, the C_max of bimatoprost in blood plasma is reached within 10 minutes after application, and within 1.5 hours the concentration in blood plasma decreases to the lower limit of quantification (0.025 ng/ml). The mean values of C_max and AUC_0-24h of bimatoprost were similar on day 7 and day 14 of use 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 use. Bimatoprost is moderately distributed in tissues, the systemic V_d at C_ss of the drug is 0.67 L/kg. Bimatoprost is predominantly in the 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 excreted primarily by the kidneys. About 67% of the drug administered intravenously to healthy volunteers was excreted by the kidneys, and 25% through the intestine. 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.

In patients who underwent cataract surgery, after instillation of eye drops in the form of a 0.5% solution, the C_max of timolol in the intraocular fluid after 1 hour was 898 ng/ml. Some amount of timolol enters the systemic circulation. Timolol is slightly bound to plasma proteins. Timolol that enters the systemic circulation is metabolized in the liver. The T_1/2 of timolol is about 4-6 hours. Part of timolol metabolized in the liver is excreted through the intestine, and another part and metabolites are excreted by the kidneys.

Indications

For the reduction of intraocular pressure in patients with open-angle glaucoma and ocular hypertension when topical application of drugs from the beta-blocker and prostaglandin analogue groups is insufficiently effective.

ICD codes

Dosage Regimen

The recommended dose for adults (including elderly patients) is 1 drop into the conjunctival sac of the affected eye once daily, in the morning or evening.

Apply daily at the same time. It is believed that the use of this combination in the evening is more effective for reducing intraocular pressure than use in the morning. Nevertheless, the possibility of adhering to the chosen application regimen should be taken into account.

Adverse Reactions

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

Psychiatric disorders frequency unknown – insomnia, nightmares.

Nervous system disorders common – headache, dizziness; frequency unknown – dysgeusia.

Eye disorders very common – conjunctival hyperemia; common – punctate keratitis, corneal erosion, burning sensation, eye itching, eye tingling sensation, foreign body sensation, dry eye, eyelid redness, eye pain, photophobia, eye discharge, visual impairment, eyelid skin itching, decreased visual acuity, blepharitis, eyelid edema, eye mucosal irritation, increased lacrimation, eyelash growth; uncommon – iridocyclitis, conjunctival edema, eyelid tenderness, asthenopia, trichiasis, iris hyperpigmentation, deepening of the eyelid fold, eyelid retraction; frequency unknown – cystoid macular edema, eye edema, blurred vision.

Cardiac disorders frequency unknown – bradycardia.

Respiratory, thoracic and mediastinal disorders common – rhinitis; uncommon – dyspnea; frequency unknown – bronchospasm (mainly in patients with pre-existing bronchospastic disease), asthma.

Skin and subcutaneous tissue disorders common – eyelid skin pigmentation, hirsutism, skin hyperpigmentation (periocular); frequency unknown – alopecia.

General disorders and administration site conditions frequency unknown – fatigue.

Like other topical ophthalmic drugs, drugs containing this combination are absorbed into the systemic circulation.

Absorption of timolol may cause adverse effects characteristic of systemic beta-blockers. 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 component (bimatoprost or timolol) and are potentially possible during treatment with this combination are presented below.

Immune system disorders systemic allergic reactions, including anaphylaxis.

Metabolism and nutrition disorders hypoglycemia.

Psychiatric disorders depression, memory loss.

Nervous system disorders syncope, acute cerebrovascular accident, exacerbation of signs and symptoms of myasthenia gravis, paresthesia, cerebral ischemia.

Eye disorders decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (after glaucoma surgery), keratitis, blepharospasm, retinal hemorrhage, uveitis.

Cardiac disorders AV block, cardiac arrest, cardiac arrhythmias, heart failure, congestive heart failure, chest pain, palpitations, edema, decreased blood pressure, increased blood pressure, Raynaud’s syndrome, cold extremities.

Respiratory, thoracic and mediastinal disorders exacerbation of bronchial asthma, exacerbation of COPD, cough.

Gastrointestinal disorders nausea, diarrhea, dyspepsia, dry mouth, abdominal pain, vomiting, increased liver enzyme activity.

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

Musculoskeletal and connective tissue disorders muscle pain.

Reproductive system and breast disorders sexual dysfunction, decreased libido.

General disorders and administration site conditions: asthenia.

Contraindications

Syndrome of increased airway reactivity, including bronchial asthma in the acute stage and previous episodes in history; severe COPD; sinus bradycardia, sick sinus syndrome, sinoatrial block, second and third degree AV block without an implanted artificial pacemaker; clinically significant heart failure; cardiogenic shock; age under 18 years; hypersensitivity to the components of the combination.

With caution

Impaired liver and kidney function (the drug has not been sufficiently studied in this category of patients); presence of risk factors for macular edema (e.g., aphakia, pseudophakia, rupture of the posterior lens capsule, as well as intraocular surgery, retinal vein occlusion, inflammatory eye diseases and diabetic retinopathy); active intraocular inflammation (e.g., uveitis), as it may be exacerbated; mild to moderate COPD, and only in cases where the expected benefit outweighs the possible risk; first degree AV block due to negative impact on intracardiac conduction time; corneal diseases, as the drug may induce dry eye syndrome; diabetes mellitus (unstable) and impaired glucose tolerance, since the beta-blocker timolol included in the drug may mask the signs of hypoglycemia; inflammatory eye changes, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma (no data on efficacy and safety studies).

Use in Pregnancy and Lactation

In case of using drugs containing this combination 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 used in doses significantly exceeding those prescribed in clinical practice. Therefore, drugs containing this combination should not be used, except in cases of special necessity.

Beta-blockers are excreted in 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 lack of a sufficient amount of active substance in breast milk.

It is not known whether Bimatoprost passes into human breast milk, but it has been established that it is contained in the milk of lactating rats. Should not be used in women during breastfeeding.

Special Precautions

In patients with cardiovascular diseases (such as coronary artery disease, Prinzmetal’s angina and heart failure) and when undergoing antihypertensive therapy with beta-blockers, the advisability of therapy with the Bimatoprost+timolol combination should be assessed, and the use of other drugs should be considered. Monitoring of the condition of patients with cardiovascular diseases is necessary to observe for signs of worsening of these diseases and adverse reactions.

Respiratory reactions, including fatal outcomes due to bronchospasm in patients with bronchial asthma, have been reported after the use of some ophthalmic beta-blockers.

Beta-blockers may mask the symptoms of hypoglycemia, hyperthyroidism.

Timolol may affect intraocular pressure or enhance the effect of systemic beta-blockers in patients already receiving a beta-blocker for systemic use. Careful monitoring of such patients is recommended. Simultaneous administration of two topical beta-blockers is not recommended.

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

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

Ophthalmic drugs with beta-adrenergic blocking action may suppress the systemic effects of beta-agonists, for example, epinephrine (adrenaline). The anesthesiologist must be informed about the patient’s use of timolol.

Before starting treatment, patients should be informed about the possible growth of eyelashes, increased pigmentation of the eyelid skin and pigmentation of the iris of the eyes, since these side effects have been established during studies of bimatoprost and the fixed combination Bimatoprost+timolol. Some changes may be permanent, may be accompanied by the occurrence of differences between the eyes if the drug was instilled only in one eye.

Increased pigmentation of the iris is due to increased production of melanocytes, not just an increase in their number.

The duration of the 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.

It has been reported that pigmentation of the periorbital area in some patients is reversible.

Refractive changes are possible (due to withdrawal of miotic therapy in some cases).

Influence on the ability to drive vehicles and mechanisms

Transient blurred vision may occur after instillation, so the patient should wait until vision is fully restored before driving vehicles and operating machinery.

Drug Interactions

Potentiation of the effects of the combined use of ophthalmic beta-blocker solutions and orally taken 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 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 periodically reported with the simultaneous use of ophthalmic beta-blockers and adrenaline (epinephrine).

Patients using a drug containing this combination with other prostaglandin analogues should be monitored to control changes in intraocular pressure.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.