Instructions Brizal eye drops suspension 10 mg/ml bottle 5 ml
Composition
active ingredient: brinzolamide;
1 ml of the drug contains brinzolamide, calculated as 100% dry matter, 10 mg;
Excipients: tyloxapol, carbomer (carbopol 974P), disodium edetate, benzalkonium chloride, mannitol (E 421), sodium chloride, 1 M sodium hydroxide solution or 1 M hydrochloric acid solution, water for injections.
Dosage form
Eye drops, suspension.
Main physicochemical properties: white or almost white homogeneous suspension.
Pharmacotherapeutic group
Drugs used in ophthalmology. Antiglaucoma drugs and miotics. Carbonic anhydrase inhibitors. ATX code S01E C04.
Pharmacological properties
Pharmacodynamics.
Carbonic anhydrase (CA) is an enzyme found in many tissues of the human body, including the eye. Carbonic anhydrase catalyzes the reversible reaction of hydration of carbon dioxide and dehydration of carbonic acid.
Inhibition of carbonic anhydrase in the ciliary body of the eye reduces the secretion of intraocular fluid, mainly by slowing the formation of bicarbonate ions with a subsequent decrease in sodium and fluid transport. The result is a decrease in intraocular pressure (IOP), which is a major risk factor in the pathogenesis of optic nerve damage and visual field loss due to glaucoma. Brinzolamide is an inhibitor of carbonic anhydrase II (CA-II), the dominant isoenzyme of the eye, with in vitro IC50 = 3.2 nM and Ki = 0.13 nM relative to CA-II.
Brinzolamide revealed no special hazard for humans based on conventional non-clinical safety studies, repeated dose toxicity, genotoxicity and carcinogenic potential.
Pharmacokinetics.
After topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its high affinity for CA-II, brinzolamide actively penetrates red blood cells (erythrocytes) and exhibits a long half-life in the blood (average approximately 24 weeks). In clinical practice, the formation of the metabolite N-desethylbrinzolamide, which also binds to CA and accumulates in erythrocytes, has been observed. This metabolite binds primarily to CA-I in the presence of brinzolamide. In plasma, concentrations of both brinzolamide and N-desethylbrinzolamide are low, generally below the limit of quantification (< 7.5 ng/ml).
Plasma protein binding is not complete (approximately 60%). Brinzolamide is excreted primarily by the kidneys (approximately 60%). Approximately 20% of the dose is recovered in the urine as metabolites. Brinzolamide and N-desethylbrinzolamide are the dominant components excreted in the urine, with trace amounts (< 1%) of the N-desmethoxypropyl and O-desmethyl metabolites.
In a pharmacokinetic study, healthy volunteers received brinzolamide orally as 1 mg capsules twice daily for 32 weeks. To assess the level of systemic CA inhibition, CA activity in erythrocytes was measured.
Brinzolamide reached saturation of erythrocyte CA-II within 4 weeks (concentration was approximately 20 μM). N-desethylbrinzolamide accumulated in erythrocytes to reach steady-state concentrations ranging from 6 to 30 μM within 20 to 28 weeks. Inhibition of total erythrocyte CA-II activity under steady-state conditions was approximately 70 to 75%.
Patients with moderate renal impairment (creatinine clearance 30-60 mL/min) were administered 1 mg brinzolamide orally twice daily for 54 weeks. Brinzolamide concentrations in red blood cells after 4 weeks ranged from 20 to 40 μM. Under steady-state conditions, brinzolamide and its metabolite concentrations in red blood cells ranged from 22 to 46.1 and 17.1 to 88.6 μM, respectively.
As creatinine clearance decreased, erythrocyte N-desethylbrinzolamide concentrations increased and total erythrocyte CA activity decreased, but erythrocyte brinzolamide concentrations and CA-II activity remained unchanged. In patients with severe renal impairment, the inhibition of total CA activity was greater, although it was less than 90% under steady-state conditions.
In studies with topical ocular administration, steady-state brinzolamide concentrations in red blood cells were similar to those observed after oral administration, but N-desethylbrinzolamide concentrations were lower. Carbonic anhydrase activity was approximately 40-70% of baseline.
Clinical characteristics.
Indication
Brizal® is intended to reduce elevated intraocular pressure in:
ocular hypertension,
open-angle glaucoma,
as monotherapy in adult patients insensitive to beta-blockers, in adult patients for whom beta-blockers are contraindicated, or as adjunctive therapy to beta-blockers or prostaglandin analogues.
Contraindication
Hypersensitivity to the active substance or to any other component of the drug.
Known hypersensitivity to sulfonamides (see also section "Special warnings and precautions for use").
Severe renal failure.
Hyperchloremic acidosis.
Interaction with other medicinal products and other types of interactions
Specific drug interaction studies have not been conducted with brinzolamide. In clinical trials, brinzolamide was used in combination with prostaglandin analogues and timolol eye drops without evidence of adverse interactions. In combination therapy for glaucoma, the interaction between brinzolamide and miotics or adrenergic receptor agonists has not been evaluated.
Brinzolamide is a carbonic anhydrase inhibitor and although administered topically, it is absorbed systemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. This interaction should be considered in patients receiving Brizolamide.
The cytochrome P450 isoenzymes responsible for the metabolism of brinzolamide are CYP3A4 (major), CYP2A6, CYP2C8 and CYP2C9. CYP3A4 inhibitors, such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin, are expected to inhibit the metabolism of brinzolamide by the CYP3A4 enzyme. Caution should be exercised when concomitantly administering CYP3A4 inhibitors. Since brinzolamide is primarily excreted by the kidneys, accumulation is unlikely. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.
Application features
Systemic effect
Brizal® is a carbonic anhydrase inhibitor of the sulfonamide group and, although applied topically, is absorbed systemically. The same types of adverse reactions as those seen with sulfonamides may occur with topical administration. If signs of serious adverse reactions or hypersensitivity occur, the drug should be discontinued.
Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. Brinzolamide has not been studied in premature neonates (less than 36 weeks of gestation) or neonates less than 1 week of age. Brinzolamide should be used in patients with significant renal tubular immaturity or anomalies only after careful consideration of the benefit-risk ratio, as there is a potential risk of metabolic acidosis.
Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination in elderly patients. Brisal® is absorbed systemically, so such effects may also occur with topical administration.
Simultaneous use
In patients taking oral carbonic anhydrase inhibitors and Brizal®, there is a possibility of an increase in the known systemic adverse reactions of carbonic anhydrase inhibitors. The simultaneous use of Brizal® and oral carbonic anhydrase inhibitors has not been studied and is therefore not recommended (see also section "Interaction with other medicinal products and other forms of interaction").
Brinzolamide has been primarily evaluated in combination with timolol in the treatment of glaucoma. In addition, the intraocular pressure (IOP)-lowering effect of brinzolamide in combination with the prostaglandin analogue travoprost has been studied. Long-term studies of brinzolamide and travoprost as combination therapy are lacking.
There is limited experience with the use of brinzolamide in patients with pseudoexfoliative glaucoma and pigmentary glaucoma. It is recommended to treat such patients with caution and to closely monitor intraocular pressure. Brinzolamide has not been studied in patients with angle-closure glaucoma, therefore its use in such patients is not recommended.
The potential effect of brinzolamide on corneal endothelial function has not been studied in patients with corneal damage (particularly in patients with low endothelial cell counts). No direct studies have been conducted in patients wearing contact lenses, and close monitoring is recommended in such patients when using brinzolamide, as carbonic anhydrase inhibitors may affect corneal hydration and contact lens wear may increase the risk of corneal damage. Close monitoring is also recommended in patients with other corneal damage, such as those with diabetes.
Benzalkonium chloride, commonly used as a preservative in ophthalmic preparations, may cause punctate keratopathy and/or toxic ulcerative keratopathy. Since Brisal® contains benzalkonium chloride, careful monitoring is required with frequent or prolonged treatment with the drug in patients with dry eyes or patients with corneal injuries.
The use of brinzolamide in patients wearing contact lenses has not been studied. Brinzolamide contains benzalkonium chloride, which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove contact lenses before using Brinzolamide eye drops and to wait 15 minutes after instillation before reinserting contact lenses.
After discontinuation of Brisal® treatment, the reduction in intraocular pressure is expected to continue for 5-7 days and a potential withdrawal effect may occur.
Use during pregnancy or breastfeeding
There are no or limited amount of data from the use of brinzolamide in pregnant women. Animal studies have shown reproductive toxicity. Brizal® should not be administered during pregnancy or to women of childbearing potential not using contraception.
Breast-feeding
Brizal® should not be used during breastfeeding, as the drug may pass into breast milk.
Ability to influence reaction speed when driving vehicles or other mechanisms
Temporary blurred vision or other visual disturbances or adverse reactions from the nervous system (drowsiness, dizziness, impaired coordination of movements) may adversely affect the ability to drive or operate machinery (see also section "Adverse reactions"). If blurred vision occurs during instillation, the patient should wait until vision recovers.
Method of administration and doses
When using Brisal® as monotherapy or adjunctive therapy, the dose is 1 drop in the conjunctival sac of the affected eye(s) 2 times daily. Some patients may achieve better results with 1 drop 3 times daily.
If another ophthalmic antiglaucoma agent is replaced with Brizal®, the other agent should be discontinued and Brizal® should be started the next day.
If more than one ophthalmic agent is applied topically, the interval between their applications should be at least 5 minutes.
If a dose is missed, treatment should be continued with the next dose according to the treatment schedule. The dose should not exceed 1 drop in the affected eye(s) 3 times daily.
Method of application
For ophthalmic use.
It is recommended to press on the nasolacrimal orifice or gently close the eyelids after instillation. This reduces the systemic absorption of drugs administered into the eye, which reduces the likelihood of systemic side effects.
The bottle should be shaken well before use. To prevent contamination of the dropper tip and the contents of the bottle, care should be taken not to touch the eyelids, surrounding skin or other surfaces with the dropper tip. The bottle should be kept tightly closed during storage.
Use in the elderly
There is no need for dose adjustment in elderly patients.
Use in liver and kidney dysfunction
The use of brinzolamide in patients with hepatic impairment has not been studied and is therefore not recommended for the treatment of such patients.
Brinzolamide has not been studied in patients with severe renal impairment (creatinine clearance < 30 ml/min) or in patients with hyperchloremic acidosis. Since brinzolamide and its major metabolite are primarily excreted by the kidneys, Brinzolamide is contraindicated in these patients (see also section 4.3).
Children
The efficacy and safety of Brizam® in patients under 18 years of age have not been established and its use is not recommended in such patients. Experience in children is limited.
Overdose
No cases of overdose have been reported.
Treatment of overdose should be symptomatic and supportive. Electrolyte imbalance, acidosis and possible nervous system effects may occur. Serum electrolyte levels (especially potassium) and blood pH should be monitored.
Adverse reactions
Cardiac disorders: cardiorespiratory distress, angina pectoris, bradycardia, arrhythmia, tachycardia, hypertension, decreased blood pressure.
Blood and lymphatic system disorders: decreased red blood cell count, increased blood chloride levels.
Nervous system disorders: dysgeusia (bitter or unusual taste), headache, drowsiness, impaired coordination of movements, amnesia, memory impairment, dizziness, paresthesia, tremor, hypoesthesia, ageusia.
Ophthalmological disorders: blepharitis, blurred vision, eye irritation, eye pain, dry eyes, eye discharge, ocular itching, foreign body sensation in the eye, eye hyperemia, corneal erosion, keratitis, punctate keratitis, keratopathy, ocular precipitates, corneal discoloration, corneal epithelial defect, increased intraocular pressure, increased optic disc excavation, corneal edema, conjunctivitis, eye edema, meibomitis, diplopia, hypersensitivity to bright light, photophobia, photopsia, decreased visual acuity, allergic conjunctivitis, pterygium, scleral pigmentation, asthenopia, ocular discomfort, abnormal eye sensitivity, keratoconjunctivitis sicca, ocular hypoesthesia, subconjunctival cyst, conjunctival hyperemia, eyelid pruritus, eyelid margin scaling, increased lacrimation, corneal epithelium disorder, corneal disorder, visual impairment, eye allergic manifestations, madarosis, eyelid disorder, eyelid erythema.
Respiratory, thoracic and mediastinal disorders: dyspnea, bronchial hyperactivity, cough, epistaxis, pain in the pharynx and larynx, throat irritation, nasal congestion, upper respiratory tract congestion, excessive secretion of nasopharyngeal mucus, rhinitis, sneezing, dry nose, bronchial asthma.
Gastrointestinal disorders: dry mouth, esophagitis, diarrhea, nausea, vomiting, dyspepsia, upper abdominal pain, abdominal discomfort, stomach discomfort, flatulence, increased intestinal peristalsis, gastrointestinal disorders, oral hypoesthesia or paresthesia.
Renal and urinary disorders: renal pain, pollakiuria.
Skin and subcutaneous tissue disorders: urticaria, rash, maculopapular rash, generalized pruritus, alopecia, skin induration, dermatitis, erythema.
Musculoskeletal and connective tissue disorders: back pain, muscle spasms, myalgia, arthralgia, pain in extremities.
Infectious and parasitic diseases: nasopharyngitis, pharyngitis, sinusitis, rhinitis.
Injury, poisoning and procedural complications: foreign body sensation in the eye.
General disorders: pain, chest discomfort, asthenia, fatigue, discomfort, anxiety, irritability, chest pain, peripheral edema, malaise, drug residue.
Reproductive and breast disorders: erectile dysfunction.
Mental disorders: apathy, depression, depressed mood, decreased libido, nightmares, insomnia, nervousness.
Immune system disorders: hypersensitivity.
Liver and biliary tract disorders: abnormal liver function tests.
During short-term clinical trials of brinzolamide, approximately 12.5% of children experienced adverse events related to the use of this medicinal product, the majority of which were non-serious local ophthalmological effects such as conjunctival hyperaemia, eye irritation, ocular discharge, and lacrimation increased.
Dysgeusia (a bitter or unusual taste in the mouth after instillation) was a systemic adverse reaction associated with the use of brinzolamide eye drops and was commonly reported in clinical trials. It was probably caused by the eye drops entering the nasopharynx via the nasolacrimal duct. Nasolacrimal occlusion or tight eyelid closure after instillation may reduce the likelihood of this effect.
Brinzolamide is a systemically absorbed carbonic anhydrase inhibitor of the sulfonamide group.
Gastrointestinal, neurological, hematological, renal, and metabolic side effects are common with systemic carbonic anhydrase inhibitors. The same types of side effects that are common with oral carbonic anhydrase inhibitors can occur with topical use.
No unexpected side effects were observed with the combination therapy of brinzolamide eye drops and travoprost. The side effects observed with the combination treatment were also observed with the use of each drug separately.
Expiration date
2 years.
Do not use after the expiry date stated on the packaging.
The shelf life after opening the bottle is 28 days.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
5 ml per bottle.
1 bottle per pack.
Vacation category
According to the recipe.
Producer
PJSC "Farmak".
Location of the manufacturer and address of its place of business
Ukraine, 04080, Kyiv, Frunze St., 74.
