BRYZOTON

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRIZOTON® (BRIZOTON)

Composition:

Active substances: brinzolamide, timolol maleate;

1 ml of suspension contains brinzolamide 10 mg, timolol maleate (calculated as 100 % substance) 6.84 mg, equivalent to timolol 5 mg;

Excipients: tyloxapol, carbomer, disodium edetate, benzalkonium chloride, mannitol (E 421), sodium chloride, 1 M sodium hydroxide solution, 1 M hydrochloric acid solution, water for injections.

Pharmaceutical form. Eye drops.

Main physicochemical properties: white or almost white homogeneous suspension.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma preparations and miotics. β-blockers. ATC code S01ED51.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Brisolton® eye drops contain two active substances: brinzolamide and timolol maleate. These two components reduce elevated intraocular pressure (IOP) by decreasing the secretion of aqueous humor, but they do so through different mechanisms of action. The combined effect of these two active substances results in an additional reduction of IOP compared to the effect achieved with either component used alone.

Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA II), the predominant isoenzyme in the eye. Inhibition of carbonic anhydrase in the ciliary processes of the eye reduces the secretion of aqueous humor, primarily by slowing the formation of bicarbonate ions, followed by a reduction in the transport of sodium and fluid.

Timolol is a non-selective β-adrenergic receptor blocker that lacks intrinsic sympathomimetic and membrane-stabilizing activity and does not directly depress myocardial function. Tonography and fluorophotometric studies in humans have confirmed that its primary action is related to a reduction in aqueous humor formation and a slight increase in its outflow.

Pharmacodynamic Effects

Clinical Effects

In a twelve-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension, who in the opinion of the investigators could benefit from combination therapy and who had a mean IOP of 25 to 27 mm Hg, the mean reduction in IOP with brinzolamide/timolol eye drops administered twice daily was 7 to 9 mm Hg. At all time points during all patient visits, the mean IOP reduction with the combination of brinzolamide/timolol was not inferior to that achieved with dorzolamide 20 mg/mL + timolol 5 mg/mL.

In a six-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension with a mean IOP of 25 to 27 mm Hg, the mean reduction in IOP with brinzolamide/timolol eye drops administered twice daily was 8 to 9 mm Hg, which was 3 mm Hg greater than with brinzolamide 10 mg/mL twice daily and 2 mm Hg greater than with timolol 5 mg/mL twice daily. A statistically significant reduction in mean IOP was observed compared to brinzolamide and timolol monotherapy at all visits throughout the study.

In three controlled clinical studies, ocular discomfort after instillation of brinzolamide/timolol eye drops was significantly lower than with dorzolamide 20 mg/mL + timolol 5 mg/mL combination.

Pharmacokinetics.

Absorption

After topical ocular administration, brinzolamide and timolol are absorbed through the cornea into the systemic circulation. In a pharmacokinetic study, healthy volunteers received oral brinzolamide 1 mg twice daily for 2 weeks to shorten the time to reach steady-state concentration before starting brinzolamide/timolol eye drops. After administration of brinzolamide/timolol eye drops twice daily for 13 weeks, the concentration of brinzolamide in red blood cells (RBCs) averaged 18.8 ± 3.29 µM, 18.1 ± 2.68 µM, and 18.4 ± 3.01 µM at weeks 4, 10, and 15, respectively, indicating that a stable concentration of brinzolamide is maintained in RBCs.

At steady-state after administration of brinzolamide/timolol eye drops, the mean maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC0-12h) of timolol were 27% and 28% lower, respectively (Cmax: 0.824 ± 0.453 ng/mL; AUC0-12h: 4.71 ± 4.29 ng•h/mL) compared to timolol 5 mg/mL (Cmax: 1.13 ± 0.494 ng/mL; AUC0-12h: 6.58 ± 3.18 ng•h/mL). The low systemic impact of timolol after administration of brinzolamide/timolol eye drops is not clinically significant. After administration of brinzolamide/timolol eye drops, the mean Cmax of timolol in plasma was reached at 0.79 ± 0.45 hours.

Distribution

Plasma protein binding of brinzolamide is moderate (approximately 60%). Due to its high affinity for CA-II and to a lesser extent for CA-I, brinzolamide penetrates into RBCs. Its active metabolite, N-desethylbrinzolamide, also accumulates in RBCs, where it primarily binds to CA-I. The affinity of brinzolamide and its metabolite for RBCs and tissue CA results in low plasma concentrations.

Tissue distribution data in rabbits demonstrated that timolol can be quantitatively detected in aqueous humor for up to 48 hours after administration of brinzolamide/timolol eye drops. At steady-state, timolol can be detected in human plasma for up to 12 hours after administration of brinzolamide/timolol eye drops.

Metabolism

Brinzolamide metabolism involves N-dealkylation, O-dealkylation, and oxidation of its N-propyl side chain. N-desethylbrinzolamide is the main metabolite of brinzolamide formed in humans, which also binds to CA-I in the presence of brinzolamide and accumulates in RBCs. In vitro studies have shown that brinzolamide metabolism is primarily associated with CYP3A4, as well as at least four other isoenzymes (CYP2A6, CYP2B6, CYP2C8, and CYP2C9).

Timolol is metabolized via two pathways. One involves the formation of an ethanolamine side chain in the thiadiazole ring, and the other involves the formation of an ethanolic side chain at the morpholine nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. Timolol metabolism is primarily associated with CYP2D6.

Excretion

Brinzolamide is primarily excreted by the kidneys (approximately 60%). Nearly 20% of the dose is found in urine as metabolite. Brinzolamide and N-desethylbrinzolamide are the main components detected in urine, along with traces of N-desmethoxypropyl and O-desmethyl metabolites (<1%).

Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of the timolol dose is excreted unchanged in urine, with the remainder excreted in urine as metabolites. The elimination half-life (t1/2) of timolol in plasma is 4.8 hours after administration of brinzolamide/timolol eye drops.

Preclinical Safety Data

Brinzolamide

Preclinical data indicate no risk to humans with brinzolamide use, as demonstrated by pharmacological studies of single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenic potential, and ocular local irritation studies.

In rabbit studies of developmental toxicity following oral doses of brinzolamide up to 6 mg/kg/day (214 times the recommended daily clinical dose of 28 µg/kg/day), no effect on fetal development was observed despite significant maternal toxicity. Similar studies in rats revealed a slight reduction in fetal skull and sternum ossification in dams receiving brinzolamide at 18 mg/kg/day (642 times the recommended daily clinical dose). However, this effect was not observed in dams receiving 6 mg/kg/day. These results were obtained at doses causing metabolic acidosis, reduced maternal body weight gain, and reduced fetal weight. A dose-dependent reduction in fetal weight was observed in dams receiving oral brinzolamide: from a slight reduction (approximately 5–6%) at 2 mg/kg/day to about 14% at 18 mg/kg/day. During lactation, no adverse effects on offspring were observed at 5 mg/kg/day.

Timolol

Preclinical data indicate no risk to humans with timolol use, as demonstrated by studies of single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenic potential, and ocular local irritation.

Toxicological studies on the reproductive effects of timolol showed delayed fetal ossification in rats in the absence of postnatal adverse reactions (at a dose of 50 mg/kg/day, 3,500 times the daily clinical dose of 14 µg/kg/day) and increased fetal resorption in rabbits (at a dose of 90 mg/kg/day, 6,400 times the daily clinical dose).

Clinical characteristics.

Indications.

Reduction of intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension in whom monotherapy has not provided sufficient reduction of intraocular pressure.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
• Hypersensitivity to other β-blockers.
• Hypersensitivity to sulfonamides (see section "Special precautions for use").
• Conditions associated with hyperreactivity of the airways, including bronchial asthma or history of bronchial asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker. Severe heart failure, cardiogenic shock.
• Severe allergic rhinitis.
• Hyperchloremic acidosis (see section "Method of administration and dosage").
• Severe renal impairment.

Interaction with other medicinal products and other forms of interaction.

No studies on the interaction of Brinzolamide eye drops with other medicinal products have been conducted.

Although Brinzolamide eye drops, containing brinzolamide, a carbonic anhydrase inhibitor, are intended for local administration, the drug is systemically absorbed. With oral administration of carbonic anhydrase inhibitors, disturbances in acid-base balance have been reported. This interaction should be considered in patients using Brinzolamide eye drops.

There is a possibility of additive effects on the known systemic effects of carbonic anhydrase inhibitors in patients taking oral carbonic anhydrase inhibitors and brinzolamide eye drops. Concomitant use of eye drops containing brinzolamide and oral carbonic anhydrase inhibitors is not recommended.

Cytochrome P450 isoenzymes responsible for brinzolamide metabolism include CYP3A4 (major), CYP2A6, CYP2B6, CYP2C8, and CYP2C9. Inhibitors of CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir, and troleandomycin are expected to inhibit CYP3A4-mediated metabolism of brinzolamide. Caution is advised when co-administering CYP3A4 inhibitors. However, accumulation of brinzolamide is unlikely since it is primarily eliminated by the kidneys. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

There is a possibility of additive effects leading to arterial hypotension and/or marked bradycardia when ophthalmic β-blocker eye drops are used concomitantly with oral or intravenous calcium channel blockers (diltiazem), β-blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, and reserpine.

β-blockers may reduce sensitivity to adrenaline in the treatment of anaphylactic reactions. Particular caution is required in patients with a history of atopy or anaphylaxis (see section "Special precautions for use").

Hypertensive reaction may be enhanced when β-blockers are used during abrupt withdrawal of clonidine. Caution is recommended when Brinzolamide eye drops and clonidine are used concomitantly.

Enhanced systemic effects of β-blockers (e.g., reduced heart rate, depression) have been reported during combined therapy with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol. Combination therapy should be used with caution.

β-blockers may enhance the hypoglycemic effect of antidiabetic agents. Also, β-blockers may mask signs and symptoms of hypoglycemia (see section "Special precautions for use").

Occasionally, mydriasis has been reported during concomitant use of ophthalmic β-blockers and adrenaline (epinephrine).

Special precautions for use

Systemic effects

Brinzolamide and timolol are systemically absorbed. Due to the presence of the β-adrenergic active component timolol, when using the medicinal product, the same adverse reactions affecting the cardiovascular system, lungs, and other adverse reactions may occur as with systemic administration of β-adrenergic receptor blockers. The frequency of systemic adverse reactions with local ophthalmic administration is lower than with systemic administration. To reduce systemic absorption, see section "Dosage and administration".

Since the medicinal product is systemically absorbed, hypersensitivity reactions typical of all sulfonamide derivatives, including Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur in patients using Brinzoptik® eye drops. During treatment with Brinzoptik® eye drops, patients should be informed about the signs and symptoms of hypersensitivity reactions and the need for careful monitoring of skin reactions.

Cardiac disorders

β-blockers should be used with caution in patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal's angina, and heart failure), arterial hypotension, and consideration should be given to alternative treatments. Patients with cardiovascular diseases should be closely monitored to avoid missing symptoms of worsening conditions or adverse reactions.

Due to the negative effect on impulse conduction time, β-blockers should be prescribed with caution only to patients with first-degree heart block.

Vascular disorders

Patients with severe peripheral circulatory disorders (e.g., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Hyperthyroidism

β-blockers may mask symptoms of hyperthyroidism.

Muscle weakness

Exacerbation of muscle weakness associated with myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness) has been reported during treatment with β-adrenergic receptor blockers.

Respiratory disorders

Adverse reactions affecting the respiratory system, including fatal outcomes due to bronchospasm in patients with asthma, have been reported after administration of certain locally applied ophthalmic β-adrenergic receptor blockers.

Brinzoptik® eye drops should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and only when the expected benefit outweighs the potential risk.

Hypoglycemia/diabetes

β-adrenergic receptor blockers should be used with caution in patients prone to spontaneous hypoglycemia or with decompensated diabetes, as β-blockers may mask symptoms and signs of acute hypoglycemia.

Acid-base balance disturbances

Brinzoptik® eye drops contain brinzolamide, which is a sulfonamide. When applied locally, the same adverse reactions as with sulfonamides may occur. Acid-base balance disturbances have been reported with oral administration of carbonic anhydrase inhibitors. Since there is a risk of metabolic acidosis, the medicinal product should be used with caution in patients at risk of kidney damage. If symptoms of serious reactions or hypersensitivity occur, the use of the medicinal product should be discontinued.

Mental performance

Oral carbonic anhydrase inhibitors may impair the ability to perform activities requiring mental alertness and/or physical coordination. Brinzoptik® eye drops are systemically absorbed; therefore, these effects may also occur with local administration of the drops.

Anaphylactic reactions

During treatment with β-adrenergic blockers, patients with a history of atopy or severe anaphylactic reactions to various allergens may exhibit heightened reactivity upon re-exposure to these allergens and may not respond to usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported during treatment aimed at reducing intraocular fluid secretion (e.g., timolol, acetazolamide) following trabeculotomy.

Surgical anesthesia

Local ophthalmic administration of β-adrenergic receptor blockers may block systemic beta-agonist effects, such as those of adrenaline. If a patient is receiving timolol, the anesthesiologist should be informed.

Concomitant use

The effect on IOP or known systemic effects of β-blockers may be enhanced when timolol is administered to patients already receiving systemic β-blockers. Such patients should be carefully monitored. Concomitant use of two topical β-blockers or two topical carbonic anhydrase inhibitors is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). There is a possibility of additive effects to the known systemic effects of carbonic anhydrase inhibitors in patients who are taking oral carbonic anhydrase inhibitors and Brinzoptik® eye drops. Concomitant use of Brinzoptik® eye drops and oral carbonic anhydrase inhibitors has not been studied and is therefore not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Ophthalmic effects

Experience with the use of brinzolamide/timolol combination in eye drops for the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma is limited. Caution should be exercised when treating such patients, and continuous monitoring of IOP is recommended.

After discontinuation of the medicinal product, a reduction in IOP is expected to persist for 5–7 days, and a withdrawal effect may potentially occur.

Brinzoptik® eye drops have not been studied in patients with closed-angle glaucoma and therefore their use in this patient group is not recommended.

Ophthalmic beta-blockers may cause dry eye. Patients with corneal disorders should be treated with caution.

The potential effect of brinzolamide on corneal endothelial function in patients with compromised cornea (particularly in patients with low endothelial cell count) has not been studied.

Particular attention should be paid to patients who wear contact lenses, as studies in this patient group have not been conducted. Therefore, careful monitoring is recommended when using brinzolamide, as carbonic anhydrase inhibitors may affect corneal hydration. This may lead to corneal edema and decompensation; therefore, the use of contact lenses may increase the risk of corneal damage. Careful monitoring is also recommended in other corneal disorders, such as in patients with diabetes mellitus or corneal dystrophy.

Brinzoptik® eye drops may be used during contact lens wear under careful monitoring (see section "Benzalkonium chloride" below).

Benzalkonium chloride

Brinzoptik® eye drops contain benzalkonium chloride, which may cause eye irritation and discoloration of soft contact lenses. Contact between the medicinal product and soft contact lenses should be avoided. Patients should be advised to remove contact lenses before instilling Brinzoptik® eye drops and to wait 15 minutes after instillation before reinserting contact lenses.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Careful monitoring of patients is required during frequent or prolonged use of the drops.

Hepatic impairment

Brinzoptik® should be used with caution in patients with severe hepatic impairment.

Use during pregnancy or breastfeeding

Pregnancy

There are no adequate data on the use of brinzolamide and timolol in pregnant women. Animal studies with brinzolamide have demonstrated toxic effects on reproductive function (see section "Preclinical safety data"). Brinzoptik® eye drops should not be used during pregnancy. To reduce systemic absorption, see section "Dosage and administration".

Epidemiological studies have not shown negative effects on fetal development; however, oral administration of β-blockers has been associated with risks to intrauterine development. In addition, signs and symptoms of β-blockade (e.g., bradycardia, arterial hypotension, respiratory distress, and hypoglycemia) have been observed in newborns whose mothers received β-blockers before delivery. Newborns should be closely monitored during the first days of life if the mother used Brinzoptik® eye drops before delivery.

Given the lack of or limited data on the use of brinzolamide in pregnant women and animal studies demonstrating toxic effects on reproductive function, this medicinal product should not be prescribed during pregnancy or to women of childbearing potential who are not using contraceptive methods.

Breastfeeding

It is unknown whether brinzolamide is excreted in human breast milk. Animal studies have demonstrated excretion of brinzolamide in breast milk after oral administration (see section "Dosage and administration").

β-blockers are excreted in human breast milk. However, with therapeutic doses of timolol administered ophthalmically, it is unlikely that its presence in breast milk would be sufficient to cause clinical symptoms of β-blockade in infants. To reduce systemic absorption, see section "Preclinical safety data". Nevertheless, a risk to the breastfed infant cannot be excluded. The decision to discontinue breastfeeding or to refrain from using Brinzoptik® eye drops should be made by the physician, taking into account the benefit to the woman and the risk to the infant.

Reproductive function

No studies have been conducted to evaluate the effect on human reproductive function following topical ophthalmic administration of Brinzoptik® eye drops.

Preclinical data did not demonstrate any effect of brinzolamide or timolol on reproductive function in males or females after oral administration.

No effect on reproductive function in males or females is expected with the use of Brinzoptik® eye drops.

Ability to affect reaction speed when driving or operating machinery

Brinzoptik® eye drops have minimal impact on the ability to drive or operate machinery.

Transient blurred vision or visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs upon instillation, patients should wait until vision clears before driving or operating machinery.

Carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination (see section "Special precautions for use").

Method of Administration and Dosage

Use in adults, including elderly patients

The dose is 1 drop of Brizoton® ophthalmic solution instilled into the conjunctival sac of the affected eye(s) twice daily.

Systemic absorption can be reduced by applying pressure to the lacrimal sac area (punctal occlusion) or by closing the eyelids. This reduces the risk of systemic adverse reactions and increases local efficacy (see section "Special Warnings and Precautions for Use").

If a dose is missed, treatment should be continued by administering the next dose according to the prescribed schedule. The dose should not exceed 1 drop in the affected eye(s) twice daily.

When switching from another ophthalmic anti-glaucoma agent to Brizoton® ophthalmic solution, the previous medication should be discontinued and Brizoton® treatment initiated the following day.

Patients with hepatic or renal impairment

No studies with Brizoton® or 5 mg/mL timolol ophthalmic solution have been conducted in patients with hepatic or renal impairment. Dose adjustment is not required in patients with hepatic impairment or in those with mild to moderate renal impairment.

Brizoton® has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with hyperchloremic acidosis (see section "Contraindications"). Since brinzolamide and its main metabolite are primarily excreted by the kidneys, Brizoton® is contraindicated in these patient groups (see section "Contraindications").

Brizoton® should be used with caution in patients with severe hepatic impairment (see section "Special Warnings and Precautions for Use").

Method of Administration

For ophthalmic use only.

Patients should be advised to shake the bottle well before use.

After first opening, the tamper-evident ring should be removed.

To prevent contamination of the dropper tip and the solution, care must be taken not to touch the eyelids, surrounding areas, or any other surfaces with the tip of the dropper bottle. Patients should be advised to close the bottle tightly after each use.

If more than one ophthalmic agent is being used, at least 5 minutes should elapse between the instillation of each product. Ophthalmic ointments should be administered last.

Children

The safety and efficacy of Brizoton® ophthalmic solution in children under 18 years of age have not been established. Data on use in this patient group are lacking.

Overdose

In case of accidental ingestion of the solution, symptoms of β-blocker overdose may include bradycardia, hypotension, heart failure, and bronchospasm.

In the event of Brizoton® ophthalmic solution overdose, treatment should be symptomatic and supportive. Due to the presence of brinzolamide, electrolyte imbalance and metabolic acidosis may occur, as well as possible effects on the central nervous system. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that timolol is difficult to eliminate from the body by dialysis.

Adverse reactions

Summary of safety data

In clinical studies, the most common adverse reactions were blurred vision, eye irritation, and eye pain, occurring in approximately 2–7% of patients.

Summary of adverse reactions presented in tabular form

During clinical studies of the brinzolamide/timolol combination in ophthalmic drops and of the individual components brinzolamide and timolol, as well as in the post-marketing period, the adverse reactions listed below have been reported. These reactions are classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

1Adverse reactions observed with the use of brinzolamide/timolol combination in ophthalmic drops.

2Additional adverse reactions observed with the use of timolol as monotherapy.

3Additional adverse reactions observed with the use of brinzolamide as monotherapy.

Description of some adverse reactions

Dysgeusia (bitter or unusual taste in the mouth after instillation) was a systemic adverse reaction frequently reported in clinical studies associated with the use of brinzolamide/timolol combination in ophthalmic drops. This reaction was likely related to brinzolamide and caused by the entry of eye drops into the nasopharynx via the nasolacrimal duct. Pressing on the area of the nasolacrimal duct or careful closure of the eyelids after instillation may reduce the likelihood of this effect (see section "Dosage and administration").

Brisolton® eye drops contain brinzolamide, a sulfonamide-class carbonic anhydrase inhibitor that is systemically absorbed. Systemic carbonic anhydrase inhibitors typically cause gastrointestinal, neurological, hematological, renal, and metabolic disturbances. Similar types of adverse reactions characteristic of oral carbonic anhydrase inhibitors may also occur with their topical use.

Timolol is absorbed into the systemic circulation. This may cause systemic adverse reactions typical of systemic β-blockers. The adverse reactions listed above include those common to the class of ophthalmic β-blockers.

The additional adverse reactions listed above are related to the use of individual components and may potentially occur with the use of Brisolton® eye drops. The frequency of systemic adverse reactions after topical ophthalmic administration is lower than with systemic administration. For reducing systemic absorption, see section "Dosage and administration".

The following adverse reactions have been reported during systemic therapy with timolol: pulmonary edema, reduced exercise tolerance, increased sweating, exfoliative dermatitis, difficulty concentrating, urinary retention, hyperglycemia, wheezing, and nonspecific thrombocytopenic purpura.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Shelf life after first opening of the container – 28 days.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging.

5 ml in a bottle. 1 bottle in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business activities.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.