Okobrinol (Drops) Instructions for Use

Marketing Authorization Holder

Stmfarm LLC (Russia)

Manufactured By

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Brinzolamide (Rec.INN registered by WHO)

Timolol (Rec.INN registered by WHO)

Dosage Form

Okobrinol

Eye drops 10 mg/ml+5 mg/ml

Dosage Form, Packaging, and Composition

Eye drops

5 ml – bottles – carton packs – By prescription

Clinical-Pharmacological Group

Antiglaucoma drug – carbonic anhydrase inhibitor + beta-adrenoblocker

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; beta-adrenergic blockers

Pharmacological Action

Combined antiglaucoma agent. Brinzolamide and timolol reduce elevated intraocular pressure, primarily by reducing the secretion of intraocular fluid, but through different pathways. The combined action of brinzolamide and timolol exceeds the effect of each substance individually for reducing intraocular pressure.

Brinzolamide is an inhibitor of carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary body of the eye reduces the production of intraocular fluid, presumably by slowing the formation of bicarbonate ions with a subsequent reduction in sodium and fluid transport.

Timolol is a non-selective beta-adrenergic receptor blocker without sympathomimetic activity, does not have a direct depressant effect on the myocardium, and does not possess membrane-stabilizing activity. A number of studies have shown that topical application of timolol reduces the formation of intraocular fluid and slightly enhances its outflow.

Pharmacokinetics

With topical application, Brinzolamide and timolol penetrate into the systemic circulation. The C_max of brinzolamide in erythrocytes is about 18.4 µM. At steady state, after application of this combination, the mean C_max of timolol in plasma and AUC_0-12h of timolol was 0.824±0.453 ng/ml and 4.71±4.29 ng×h/ml, respectively, and the mean C_max of timolol was reached at 0.79±0.45 h. Brinzolamide is moderately bound to plasma proteins (about 60%) and accumulates in erythrocytes due to selective binding to carbonic anhydrase II and, to a lesser extent, carbonic anhydrase I. Its active metabolite, N-desethylbrinzolamide, also accumulates in erythrocytes, where it binds primarily to carbonic anhydrase I. Due to the affinity of brinzolamide and its metabolite for erythrocytes and tissue carbonic anhydrase, their plasma concentrations are low. Metabolism of brinzolamide occurs via N-dealkylation, O-dealkylation, and oxidation of the N-propyl side chain. The main metabolite is N-desethylbrinzolamide, which, in the presence of brinzolamide, binds to carbonic anhydrase I and also accumulates in erythrocytes. In vitro studies have shown that the isoenzyme CYP3A4 is primarily responsible for the metabolism of brinzolamide, as well as the isoenzymes CYP2A6, CYP2B6, CYP2C8 and CYP2C9. Metabolism of timolol occurs via two pathways: formation of an ethanolamine side chain on the thiadiazole ring and formation of an ethanol side chain on the morpholine nitrogen and a similar side chain with a carbonyl group attached to the nitrogen. Metabolism of timolol is carried out mainly by CYP2D6. Brinzolamide is excreted mainly in urine and feces in comparable amounts, 32% and 29% respectively. About 20% is excreted as metabolites in the urine. Brinzolamide and N-desethylbrinzolamide are mainly detected in the urine, as well as residual amounts (<1%) of other metabolites (N-desmethoxypropyl and O-desmethyl). Timolol and its metabolites are excreted mainly by the kidneys. About 20% of timolol is excreted unchanged in the urine, the rest as metabolites. The T_1/2 of timolol is 4.8 h after topical application of this combination.

Indications

For the reduction of elevated intraocular pressure in open-angle glaucoma and ocular hypertension in patients for whom monotherapy has been insufficient to reduce intraocular pressure.

ICD codes

Dosage Regimen

Instill one drop into the conjunctival sac of the affected eye(s)twice daily, approximately every 12 hours.

Do not exceed the recommended dosage.

If using other topical ophthalmic medications, maintain an interval of at least 5 minutes between applications.

To prevent contamination, avoid contact between the dropper tip and the eye, eyelids, or any other surface.

Immediately after administration, close the bottle tightly.

This regimen is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension where monotherapy provides insufficient control.

Adverse Reactions

Infections and infestations frequency unknown – nasopharyngitis, pharyngitis, sinusitis, rhinitis.

Blood and lymphatic system disorders frequency unknown – decrease in red blood cell count, increased blood chloride content.

Immune system disorders frequency unknown – anaphylaxis, systemic lupus erythematosus, systemic allergic reactions, including angioedema, local and generalized rash, hypersensitivity, urticaria, pruritus.

Metabolism and nutrition disorders frequency unknown – hypoglycemia, decreased appetite.

Psychiatric disorders uncommon – insomnia; frequency unknown – depression, memory loss, apathy, depressed mood, decreased libido, nightmares, nervousness.

Nervous system disorders common – dysgeusia; frequency unknown – cerebral ischemia, cerebrovascular disorder, syncope, exacerbation of signs and symptoms of myasthenia gravis, somnolence, motor dysfunctions, amnesia, memory impairment, paresthesia, tremor, hypesthesia, ageusia, dizziness, headache.

Eye disorders common – blurred vision, eye pain, eye irritation; uncommon – corneal erosion, punctate keratitis, anterior chamber effusion, photophobia, dry eye syndrome, eye discharge, eye pruritus, foreign body sensation in eyes, eye hyperemia, scleral hyperemia, increased lacrimation, conjunctival hyperemia, eyelid erythema; frequency unknown – increased optic disc cupping, choroidal detachment after filtering surgery, keratitis, keratopathy, corneal epithelial defect, corneal epithelium disorder, increased intraocular pressure, eye deposits, corneal staining, corneal edema, decreased corneal sensitivity, conjunctivitis, inflammation of meibomian glands, diplopia, decreased contrast vision, photopsia, decreased visual acuity, visual impairment, pterygium, eye discomfort sensation, dry keratoconjunctivitis, eye hypesthesia, scleral pigmentation, subconjunctival cyst, vision disorder, eye swelling, eye allergic reactions, madarosis, eyelid disorders, eyelid edema, ptosis, blepharitis, asthenopia, crusting on eyelid margins, increased lacrimation.

Ear and labyrinth disorders frequency unknown – vertigo, tinnitus.

Cardiac disorders uncommon – decreased blood pressure; frequency unknown – cardiac arrest, heart failure, chronic heart failure, AV block, cardiorespiratory distress syndrome, angina pectoris, bradycardia, irregular heart rate, arrhythmia, palpitations, tachycardia, increased heart rate, chest pain, edema, hypotension, hypertension, increased blood pressure, Raynaud’s phenomenon, cold hands and feet.

Respiratory, thoracic and mediastinal disorders uncommon – cough; frequency unknown – bronchospasm (mainly in patients with a history of bronchospastic disease), dyspnea, bronchial asthma, epistaxis, bronchial hyperreactivity, laryngeal irritation, nasal congestion, upper respiratory tract congestion, postnasal drip syndrome, sneezing, dry nose sensation, pharyngeal and laryngeal pain, rhinorrhea.

Gastrointestinal disorders frequency unknown – vomiting, upper abdominal pain, abdominal pain, diarrhea, dry mouth, nausea, esophagitis, dyspepsia, abdominal discomfort sensation, stomach discomfort sensation, increased peristalsis, gastrointestinal disorder, oral hypesthesia and paresthesia, flatulence, impaired liver function tests.

Skin and subcutaneous tissue disorders frequency unknown – urticaria, maculopapular rash, generalized pruritus, skin induration, dermatitis, alopecia, psoriasiform rash or exacerbation of psoriasis, rash, erythema.

Musculoskeletal and connective tissue disorders frequency unknown – myalgia, muscle spasms, arthralgia, back pain, pain in extremity.

Renal and urinary disorders frequency unknown – renal pain, pollakiuria.

Reproductive system and breast disorders frequency unknown – erectile dysfunction, sexual dysfunction, decreased libido.

Investigations frequency unknown – increased blood potassium, increased blood LDH.

General disorders and administration site conditions: frequency unknown – chest pain, pain, fatigue, asthenia, malaise, chest discomfort sensation, abnormal sensations, feeling of anxiety, irritability, peripheral edema.

Contraindications

Reactive airway diseases, including bronchial asthma, history of bronchial asthma, severe chronic obstructive pulmonary disease; severe allergic rhinitis; sinus bradycardia; sick sinus syndrome; sinoatrial block; second- or third-degree AV block; severe heart failure; cardiogenic shock; hyperchloremic acidosis; severe renal failure; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Should be used with caution in patients with severe hepatic impairment.

Use in Renal Impairment

The drug is contraindicated in severe renal failure.

Pediatric Use

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

Geriatric Use

In elderly patients, orally administered carbonic anhydrase inhibitors may affect the ability to engage in activities requiring increased attention or coordination. This effect should be taken into account when prescribing Azarga, because with topical application the drug penetrates into the systemic circulation.

Special Precautions

Brinzolamide and timolol may undergo systemic absorption.

Topically applied timolol can cause the same adverse reactions from the cardiovascular and respiratory systems, as well as other undesirable reactions, as systemically used beta-blockers.

In patients with cardiovascular diseases (e.g., coronary artery disease, Prinzmetal’s angina, heart failure) and hypotension, therapy with beta-blockers should be critically evaluated and the possibility of treatment with other active substances considered. Close monitoring for signs of disease exacerbation and adverse reactions is necessary in patients suffering from cardiovascular diseases.

Beta-blockers may mask the symptoms of hyperthyroidism.

Beta-blockers have been reported to increase muscle weakness observed in some symptoms of myasthenia gravis (e.g., diplopia, ptosis, and generalized weakness).

Respiratory reactions, including death from bronchospasm in patients with asthma after taking topical beta-blockers, have been reported.

Beta-blockers should be prescribed with caution to patients prone to spontaneous hypoglycemia or patients with labile diabetes, as these drugs may mask the symptoms of acute hypoglycemia.

Development of acid-base balance disturbances has been described with the use of oral forms of carbonic anhydrase inhibitors. In patients at risk of renal failure, the drug should be used with caution due to the possible risk of metabolic acidosis.

Orally administered carbonic anhydrase inhibitors may affect the ability to engage in activities requiring increased attention and/or coordination in elderly patients. These phenomena may be observed with the use of the drug Azarga, because brinzolamide penetrates into the systemic circulation with topical application.

Patients with atopy or a history of severe anaphylactic reactions to various allergens, receiving beta-blockers, may react more strongly to exposure to these allergens and may also be resistant to usual doses of adrenaline when treating anaphylactic reactions.

Cases of choroidal detachment have been described with the use of drugs that inhibit the formation of intraocular fluid (e.g., timolol, acetazolamide) after filtering surgeries.

The action of beta-blockers in ophthalmic preparations may block the systemic effects of beta-agonists, such as epinephrine. The anesthesiologist should be informed about the patient’s use of timolol.

When using this combination in patients who are taking systemic beta-blockers, the possible mutual enhancement of the pharmacological action of the drugs, both in relation to the known systemic effects of beta-blockers and in relation to the reduction of intraocular pressure, must be taken into account. Such patients require careful monitoring.

Concomitant use of two topical beta-blockers is not recommended.

There is a possibility of enhanced systemic effects resulting from carbonic anhydrase inhibition in patients taking oral carbonic anhydrase inhibitors simultaneously with this combination. Concomitant administration of this combination and oral carbonic anhydrase inhibitors is not recommended.

The effect of brinzolamide on corneal endothelial function in patients with corneal disorders (especially patients with low endothelial cell counts) has not been studied. In patients using contact lenses, careful monitoring of the corneal condition is necessary when using brinzolamide, as carbonic anhydrase inhibitors may affect corneal hydration. Careful monitoring is recommended for patients with corneal disorders, such as patients with diabetes or corneal dystrophy.

Effect on ability to drive vehicles and operate machinery

This combination has a minor influence on the ability to drive and use machines. If the patient experiences temporary blurred vision after using the drug, it is not recommended to drive a car and engage in other activities requiring increased concentration and speed of psychomotor reactions until it is restored. Carbonic anhydrase inhibitors may impair the ability to perform tasks requiring increased concentration and/or coordination.

Drug Interactions

Brinzolamide, a carbonic anhydrase inhibitor, may be absorbed systemically with topical application. Cases of acid-base balance disturbances as a result of using oral carbonic anhydrase inhibitors have been described. The possibility of such disturbances should be considered in patients using this combination.

Concomitant use with oral carbonic anhydrase inhibitors is not recommended, as there is a possibility of enhanced systemic adverse reactions. The metabolism of brinzolamide is mediated by cytochrome P450 isoenzymes: CYP3A4 (mainly), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. Drugs that inhibit the CYP3A4 isoenzyme, such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin, should be prescribed with caution due to the possible inhibition of brinzolamide metabolism by the CYP3A4 isoenzyme. Caution should be exercised when co-administering with CYP3A4 isoenzyme inhibitors. However, accumulation of brinzolamide is unlikely because it is eliminated by the kidneys. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

Enhancement of the systemic effects of beta-blockers (decreased heart rate, depression) may develop with the simultaneous use of CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine) and timolol.

There is a possibility of enhanced hypotensive effect and/or the development of marked bradycardia with the simultaneous use of topical beta-blockers with oral calcium channel blockers, guanethidine, beta-blockers, antiarrhythmic drugs (including amiodarone), cardiac glycosides and parasympathomimetics.

Beta-blockers may reduce the response to epinephrine in the treatment of anaphylactic reactions. The drug should be prescribed with caution to patients with atopy or a history of anaphylaxis.

In some cases, mydriasis may develop as a result of simultaneous use of topical beta-blockers and adrenaline (epinephrine).

The effect on intraocular pressure, or the known effects of systemic beta-blockers, may be enhanced if timolol is prescribed to a patient already receiving a systemic beta-blocker. Such patients must be carefully monitored.

The use of two topical beta-blockers is not recommended.

In case of use with other topical ophthalmic drugs, the interval between their applications should be at least 5 minutes.

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.