Simbrinza, eye drops 2 mg/ml+10 mg/ml 5 ml

Pharmacotherapeutic group: Antiglaucoma drugs and myotics. Carboangidrase inhibitors. Brinzolamide in combination with other drugs.

The ATC code: S01EC54

Pharmacological properties

Pharmacodynamics

The mechanism of action

The drug Simbrinza® contains two active ingredients: brinzolamide and brimonidine tartrate. These two components decrease intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and intraocular hypertension (IOP) by inhibiting the production of aqueous humor in the ciliary body. Although both brinzolamide and brimonidine reduce IOP by inhibiting aqueous humor formation, their mechanisms of action are different.

Brinzolamide acts by inhibiting the type 2 enzyme carboanhydrase (CA-II) in the ciliary epithelium, which reduces the formation of bicarbonate ions with a subsequent
reduction in the passage of sodium and fluid through the ciliary epithelium, resulting in a reduction in aqueous humor formation. Brimonidine, an alpha 2-adrenergic receptor agonist, inhibits the enzyme adenylate cyclase and inhibits the cAMP-dependent formation of aqueous humor. In addition, the use of brimonidine leads to an increase in uveoscleral outflow.

Pharmacokinetics

Absorption

After topical application, brinzolamide is absorbed through the cornea. The substance also penetrates into the systemic bloodstream, where it binds firmly to carboangidase in erythrocytes. Plasma concentrations of brinzolamide are very low. Blood elimination half-life in humans is long (>100 days) due to binding to erythrocyte carboangidase.
Brinzolamide is rapidly absorbed into ocular tissue after topical application. In rabbit studies the maximum concentration in ocular tissues was reached in less than an hour in most cases. Maximum human plasma concentrations are <1 ng/ml and are reached within <1 hour. The plasma elimination half-life is about 2-3 hours. No accumulation is observed with continued use.

The clinical study examined the pharmacokinetics of Simbrinza® when administered topically 2 and 3 times daily compared to brinzolamide and brimonidine monotherapy administered in the same dosing regimens.

The pharmacokinetics of brinzolamide and N-dezethylbrinzolamide in whole blood when reaching equilibrium concentrations were similar when using the combination drug Simbrinza and brinzolamide monotherapy. Similarly, the pharmacokinetics of brimonidine upon reaching equilibrium in plasma with the fixed combination was similar to that observed with brimonidine alone, with the exception of the twice-daily Simbrinza® use group, in which the average AUC0-12 hours was approximately 25% lower than with brimonidine twice-daily monotherapy.

Distribution

In rabbit studies, maximum concentrations of brinzolamide in ocular tissues after topical administration are achieved in the anterior segment of the eye: cornea, conjunctiva, aqueous humor, iris and ciliary body. Prolonged presence in ocular tissues is due to binding of the drug to carboangidase. Brinzolamide binds moderately (about 60%) to human plasma proteins.

Brimonidine exhibits affinity to pigmented tissues of the eye, particularly the iris and ciliary body, which is due to the known ability of the molecule to bind to melanin. However, clinical and preclinical safety data show that the drug is well tolerated and safe with continued use.

Metabolism

Brinzolamide is metabolized by cytochrome P450 isoenzymes in the liver, specifically CYP3A4, CYP2A6, CYP2B6, CYP2C8 and CYP2C9. The major metabolite is Ndezethylbrinzolamide, followed by N-desmethoxypropyl and O-desmethyl metabolites, as well as an N-propionic acid analog formed by oxidation of the N-propyl side chain of O-desmethylbrinzolamide. Brinzolamide and N-dezethylbrinzolamide do not inhibit cytochrome P450 isoenzymes at concentrations at least 100 times higher than the maximum systemic concentrations.

Brimonidine is extensively metabolized by hepatic aldehydoxidase to form 2-oxobrimonidine, 3-oxobrimonidine and 2,3-dioxobrimonidine, which are the major metabolites. Oxidative cleavage of the imidazoline ring to 5-bromo-6-guanidinoquinoxaline is also observed.

Brinzolamide is mainly excreted unchanged in the urine. In humans, the urine detects 60% brinzolamide and 6% N-desethylbrinzolamide of the administered dose. In rats, excretion of the drug with bile (about 30% of the administered dose) mainly in the form of metabolites was also shown.

Brimonidine is excreted mainly in the urine as metabolites. In preclinical in vivo experiments, urinary metabolites accounted for 60% to 75% of the administered dose
of the drug in both oral and intravenous routes of administration.

Linearity/nonlinearity

The pharmacokinetics of brinzolamide are inherently nonlinear due to saturable binding to carboanhydrase in whole blood and various tissues.

The exposure at equilibrium does not increase in proportion to the dose. In contrast, brimonidine exhibits linear pharmacokinetics across the clinical therapeutic dose range.

The relationship between pharmacokinetics and pharmacodynamics

The drug Simbrinza is intended to act locally within the tissues of the eye. Evaluation of intraocular exposure in humans of effective doses is not possible.

The effects of the drug’s pharmacokinetics and pharmacodynamics in humans on IOP reduction have not been established.

Other special patient populations

There have been no studies to determine the effect of age, race, renal or hepatic impairment with Simbrinza®.

A study of brinzolamide use in Japanese compared to patients of other ethnicities showed similar systemic pharmacokinetics in both groups.

A study of brinzolamide in patients with impaired renal function showed that systemic exposure to brinzolamide and N-dezethylbrinzolamide in patients with moderate
renal impairment was 1.6 to 2.8 times that of patients with normal renal function. This increase in equilibrium concentrations of the drug and its metabolites did not cause inhibition of erythrocyte carboanhydrase to levels associated with systemic side effects. However, the use of the combination drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min). Cmax, AUC and half-life of brimonidine are similar in elderly patients (>65 years) and adult patients of younger age. The effect of renal and hepatic dysfunction on the systemic pharmacokinetics of brimonidine has not been evaluated. Given the low systemic exposure of brimonidine after topical ophthalmic use, changes in plasma exposure are not expected to be clinically significant.

Children

The systemic pharmacokinetics of brinzolamide and brimonidine, in monotherapy or in combination, have not been studied in pediatric patients.

Indications

Active ingredient

Composition

How to take, the dosage

The drug is intended for topical use.

In adults, 1 drop of Simbrinz® is placed into the conjunctival sac twice daily.

The bottle must be shaken well before use.

After use to decrease the risk of systemic side effects, covering the eyelids and applying gentle finger pressure to the lacrimal sac projection at the inner corner of the eye for 2 minutes after instillation is recommended to minimize systemic absorption and potentiate local action. (see section “Special Precautions”).

Do not touch the eyelids or other surfaces with the pipette tip of the bottle to avoid contamination of the solution. Close the vial tightly after use. Simbrinza® may be used concomitantly with other ophthalmic topical medications to reduce intraocular pressure. If more than one ophthalmic topical medication is used, an interval of at least 5 minutes should be observed between applications.

If a dose is missed, treatment should be continued with the next dose according to the schedule. The dose should not exceed 1 drop in the affected eye(s) 2 times a day.

Patient special groups

Patients who are elderly (over 65 years of age)

Dose adjustment is not necessary in patients over 65 years of age.

The use of Simbrinz® in patients with impaired hepatic and/or renal function

The use of Simbrinz® in patients with impaired hepatic function has not been studied, so caution is recommended when using the drug in these patients
(see section “Caution”).

The use of Simbrinza® has not been studied in patients with severe renal impairment (creatinine clearance <30 ml/min) and patients with hyperchloremic acidosis.

Because the brynzolamide in Simbrinza® and its metabolites are eliminated primarily by the kidneys, Simbrinza® is contraindicated in these patients (see section “Contraindications”).

In children

The safety and effectiveness of Simbrinza® in children and adolescents 2-18 years of age have not been studied, therefore it is not recommended for this category of patients (see section “Contraindications”). Simbrinza® is contraindicated in infants and children less than 2 years of age for safety reasons (see section “Contraindications”).

Interaction

Simbrinza® is contraindicated in patients receiving monoamine oxidase inhibitors and antidepressants affecting noradrenergic transmission (such as tricyclic antidepressants and mianserine) (see section “Contraindications”). Tricyclic antidepressants may impair the ability of Simbrinz® to reduce IOP.

We recommend caution when using concomitantly with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) due to the possibility of additive or potentiating effects.

There are no data on circulating catecholamine concentrations after administration of Simbrinza® . However, caution is recommended when treating patients receiving drugs that may affect metabolism and uptake of circulating amines (e.g., chlorpromazine, methylphenidate, reserpine, serotonin-norepinephrine reuptake inhibitors).
Drugs of class of alpha-adrenoreceptor agonists (such as brimonidine tartrate) may decrease pulse rate and decrease blood pressure. After using Simbrinza® , a slight decrease in blood pressure was observed in some patients. Caution is recommended when Simbrinza® is used concomitantly with antihypertensive drugs and/or cardiac glycosides.

We advise caution when starting simultaneous treatment (or changing the dose) with drugs with systemic effects (regardless of dosage
form) that may interact with alpha-adrenoreceptor agonists or prevent their activity, i.e. adrenergic receptor agonists or antagonists (e.g. isoprenaline, prazosin).

Brinzolamide is a carboanhydrase inhibitor that, although used topically, penetrates into the systemic bloodstream. Disturbance of acid-base
balance has been reported with the use of oral carboanhydrase inhibitors. In patients receiving Simbrinza® , possible interactions should be considered.
There is a possibility of enhancing the known systemic effects of carboanhydrase inhibitors in patients receiving oral carboanhydrase inhibitor and
brinzolamide for topical use. Simultaneous use of Simbrinza® and oral carboangiidrase inhibitors is not recommended.

The cytochrome P-450 isoenzymes responsible for the metabolism of brinzolamide include CYP3A4 (major), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. CYP3A4 inhibitors
such as ketoconazole, itraconazole, clotrimazole, ritonavir, and troleandomycin are expected to inhibit the metabolism of brinzolamide involving CYP3A4. Caution is recommended with concomitant use of CYP3A4 inhibitors. However, accumulation of brinzolamide is unlikely because the main route of excretion is the kidneys. Brinzolamide is not an inhibitor of cytochrome P-450 isoenzymes.

Special Instructions

The drug should not be injected. Patients should be instructed not to take Simbrinza® orally.

The effect on the visual organ

The use of Simbrinz® has not been studied in patients with closed-angle glaucoma and its use in these patients is not recommended. The possible effect of Brinzolamide on corneal endothelial function in patients with corneal disorders has not been studied (especially in patients with low endothelial cell counts). The use of the drug has also not been studied in patients who wear contact lenses, and therefore close monitoring of these patients is recommended when using brinzolamide, since carboenhydrase inhibitors may affect corneal hydration, and wearing contact lenses may increase the risk of corneal damage. Close monitoring of patients with corneal disorders, including patients with diabetes mellitus or corneal dystrophy, is recommended. Simbrinza® may be used when contact lenses are worn with close monitoring (see below under Benzalkonium Chloride).

Brimonidine tartrate may cause allergic eye reactions. If allergic reactions occur, treatment with the drug should be discontinued. There have been reports of delayed-type hypersensitivity reactions on the eye side when using brimonidine tartrate, with IOP increase in some cases.

Potential effects after discontinuation of Simbrinza® treatment have not been studied, in particular the duration of IOP effect of the drug has not been evaluated.
After discontinuation of brinzolamide administration the preservation of IOP lowering effect is expected within 5-7 days. IOP reduction with brimonidine may last longer.

Systemic effects

The drug Simbrinza® contains brinzolamide, a sulfonamide carboanhydrase inhibitor that, despite topical use, penetrates into the systemic bloodstream. Local administration of sulfonamides may cause the same adverse reactions as systemic administration. If signs of a serious hypersensitivity reaction occur, the drug should be discontinued immediately.

Cardiac disorders

A slight decrease in blood pressure has been observed in some patients after use of Simbrinza®. Caution is recommended with concomitant use of antihypertensive drugs and/or cardiac glycosides, as well as in patients with severe or unstable and uncontrolled cardiovascular disease (see section “Interaction with other medicinal products”).

The drug Simbrinza® should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s syndrome, orthostatic hypotension or obliterative thrombangiitis.

Disorders of acid-base balance

Disorders of acid-base balance have been reported with the use of oral carboanhydrase inhibitors. Simbrinza® contains brinzolamide, a carboanhydrase inhibitor, which, despite local use, penetrates into the systemic bloodstream. Local administration of Simbrinza® may cause the same adverse reactions as with oral carboanhydrase inhibitors (i.e., acid-base imbalances) (see section “Interaction with other medicinal products”).

The drug should be used with caution in patients at risk of renal dysfunction because of the possible risk of metabolic acidosis. Simbrinza® is contraindicated in patients with severe renal dysfunction (see section “Contraindications”).

Hepatic impairment

The use of Simbrinza® has not been studied in patients with hepatic impairment; caution should be exercised when treating these patients (see section “Doses and administration”).

Attention span

Orderal carboenhydrase inhibitors may impair the ability to perform tasks requiring concentration and/or physical coordination in elderly patients.
Simbrinza® penetrates into the systemic blood flow; therefore, these phenomena may be observed when the drug is used topically (see section “Effect on ability to drive or operate machinery”).

Benzalkonium chloride

Simbrinza® contains benzalkonium chloride which may irritate the eyes and discolor soft contact lenses. Avoid contact with soft contact lenses. Patients should be instructed to remove contact lenses before putting Cymbrinz® in and wait at least 15 minutes before putting them back in.

Benzalkonium chloride has been reported to cause pitting keratopathy and/or toxic ulcerative keratopathy. Close monitoring is required with frequent or prolonged use.

Periatric use

The safety and efficacy of Simbrinza® in children and adolescents from 2 to 18 years of age has not been established. In cases where brimonidine in the form of eye drops was used
as part of treatment of congenital glaucoma in newborns and infants, symptoms of brimonidine overdose (such as loss of consciousness, decreased blood pressure, hypotension, bradycardia, hypothermia, cyanosis and apnea) have been reported. Therefore, Simbrinza® is contraindicated in children under 2 years of age (see section “Contraindications”).

The treatment of children aged 2 years and older (especially those aged 2-7 years and/or weighing less than 20 kg) is not recommended due to possible central nervous system side effects
(see section “Overdose”).

Impact on ability to drive, operate machinery

The drug Simbrinza® has a moderate effect on the ability to drive vehicles and operate mechanisms.

The Simbrinza® drug may cause dizziness, fatigue and/or drowsiness, which may have an adverse effect on the ability to drive or operate machinery.

Temporary blurred vision or other visual disturbances may occur, which may affect the ability to drive or operate machinery.

Synopsis

Contraindications

Hypersensitivity to the active or excipients, or to sulfonamides:

– In therapy with monoamine oxidase inhibitors (MAOIs);
– In the use of antidepressants that affect noradrenergic transmission (such as tricyclic antidepressants and mianserine);
– Severe renal dysfunction;
– Hyperchloremic acidosis;
– Infants and children under 2 years of age;

With caution:

– A history of closed-angle glaucoma;
– Disorders of liver function;
– Corneal disorders;
– Severe, unstable and/or uncontrolled cardiovascular disease;
– Depression;
– Cerebral or coronary insufficiency, Raynaud’s syndrome, orthostatic hypotension or obliterating thrombangiitis;
– Pregnancy and breastfeeding period (see section “Use during pregnancy and breastfeeding”).
– Children at the age of 2 – 18 years old due to the lack of efficacy and safety data;
– Concomitant use with CNS-depressing agents;
– Concomitant use with agents that may affect metabolism and uptake of circulating amines;
– When concurrent use with antihypertensive agents and/or cardiac glycosides;
– When concurrent treatment (or change of dose) with systemic drugs (regardless of dosage form) that may interact with alpha-adrenoceptor agonists or prevent their activity;
– Wearing contact lenses;
– Patients with risk of renal dysfunction.

Side effects

In clinical trials using Simbrinz® twice daily, the most common adverse reactions were eye hyperemia and allergic eye reactions, occurring in approximately 6-7% of patients, and dysgeusia (bitter or unusual taste in the mouth after dosing), occurring in approximately 3% of patients. The safety profile of Simbrinza® was similar to that of its individual components (brinzolamide 10 mg/mL and brimonidine 2 mg/mL).

The following adverse reactions have been reported during clinical studies with Simbrinz® twice daily and during clinical trials and post-registration follow-up with the individual components, brinzolamide and brimonidine.

Unwanted reactions are classified according to the following classification: Very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare
(≥1/10000, <1/1000), very rare (<1/10000), unknown (cannot be estimated from available data). Within each frequency group, adverse reactions are presented in descending order of severity.

Infectious and parasitic diseases: infrequent – nasopharyngitis2, pharyngitis2, sinusitis2; frequency unknown – rhinitis2.

Blood and lymphatic system disorders: infrequent – decreased number of red blood cells2, increased level of chloride2.

Immune system disorders: infrequent – hypersensitivity reactions3.

Mental disorders: infrequent – apathy2, depression2,3, depressed mood2, insomnia1, decreased libido2, nightmares2, nervousness2.

Nervous system disorders: frequent – somnolence1, dizziness3, dysgeusia1; infrequent – headache1, motor dysfunction2, amnesia2, memory impairment2, paresthesia2;
very rare – syncope3; frequency unknown – tremor2, hypoesthesia2, aguesia2.

Visual organ disorders: frequent – allergic reaction from the eyes1, keratitis1, eye pain1, eye discomfort1, blurred vision1, visual disturbance3, eye hyperemia1, pale conjunctiva3; infrequent – corneal erosion1, corneal edema2, blepharitis1, corneal deposits (precipitates)1, conjunctival disorders (papillae)1, photophobia1, photopsia2, ocular edema2, eyelid edema1, conjunctival edema1, dry eye1, eye discharge1, decrease in visual acuity2, increased lacrimation1, pterygium2, eyelid erythema1, meibomyitis2, diplopia2, eye pain in bright light2, ocular hypoesthesia2, sclera pigmentation2, subconjunctival cyst2, eye discomfort1, asthenopia1; Very rare – uveitis3, miosis3; frequency unknown – visual disturbances2, madarosis2.

Hearing and labyrinth disorders: infrequent – dizziness1, tinnitus2.

Cardiac disorders:infrequent – cardiorespiratory distress2, angina2, arrhythmia3, palpitations2,3, irregular heart rhythm2, bradycardia2,3, tachycardia3.

Vascular disorders: infrequent – decreased blood pressure1; very rare – increased blood pressure3.

Respiratory system, thorax and mediastinum disorders: infrequent – shortness of breath2, bronchial hyperresponsiveness2, pharyngeal laryngeal pain2, dry throat1, cough2, nasal bleeding2, upper airway congestion2, nasal congestion1, rhinorrhea2, irritation of pharynx2, dry nasal cavity1, postnasal syndrome1, sneezing2;
frequency unknown – asthma2.

Gastrointestinal disorders: frequent – dry mouth1; infrequent – dyspepsia1, esophagitis2, abdominal discomfort1, diarrhea2, vomiting2, nausea2, rapid defecation2, flatulence2, oral hypoesthesia2, oral paresthesia.1

Liver and biliary tract disorders: frequency unknown – abnormal liver function2.

Skin and subcutaneous tissue disorders: infrequent – contact dermatitis1, urticaria2, rash2, maculopapular rash2, generalized itching2, alopecia2, skin thickening2; common unknown – facial edema3, dermatitis2,3, erythema2,3.

Muscular and connective tissue disorders: infrequent – back pain2, muscle cramps2, myalgia2; frequency unknown – arthralgia2, pain in extremities2.

Renal and urinary tract disorders: infrequent – renal pain2

Genital and mammary disorders: infrequent – erectile dysfunction2;

General disorders and disorders of the injection site: infrequent – pain2, chest discomfort2, feeling worse2, feeling anxious2, irritability2, drug residues1; infrequent unknown – chest pain2, peripheral edema2,3.

Note

1 adverse reactions observed with Simbrinza®.
2 additional adverse reactions observed with brinzolamide monotherapy.
3 additional adverse reactions observed with brimonidine monotherapy.

Description of Individual Adverse Reactions

Dysgeusia was the most common systemic adverse reaction associated with the use of Simbrinza® (3.4%). This is probably due to nasopharyngeal contact of the eye drops through the nasolacrimal duct and is mainly due to the presence of brynzolamide in Simbrinz®. Nasolacrimal duct occlusion or mild occlusion of the eyelids after injection may reduce the incidence of this effect (see section “Dosage and administration”).

The drug Simbrinza® contains brinzolamide, a sulfonamide carboanhydrase inhibitor that penetrates into the systemic bloodstream. Gastrointestinal, nervous system, blood, renal and metabolic effects are mainly related to the systemic action of carboanhydrase inhibitors. Local administration of carboangiidrase inhibitors may produce the same adverse reactions as those produced by oral administration.

The undesired reactions associated with brimonidine in Simbrinza® include allergic reactions in the eyes, increased fatigue and/or somnolence, and dry mouth. Brimonidine use is associated with a minimal decrease in blood pressure. Some patients who received Simbrinza® had a decrease in blood pressure similar to that observed with brimonidine monotherapy.

Overdose

In case of overdose of Simbrinza® , symptomatic and supportive therapy should be administered. The patient’s airway should be monitored.

Due to the presence of brynzolamide in Simbrinz® preparation electrolyte imbalance, acidosis and nervous system disorders may occur.

Serum electrolytes (particularly potassium) and blood pH should be monitored.

There is very limited information regarding accidental swallowing of brimonidine in Simbrinza® in adult patients. To date, the only reported adverse event has been decreased blood pressure. An episode of hypotension has been reported to be accompanied by a ricochetaneous increase in blood pressure.

There have been reports that overdose with other oral alpha-2-agonists causes symptoms such as decreased blood pressure, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea, hypotension, hypothermia, respiratory depression and seizures.

In children

There have been reports of serious adverse events in children after accidental ingestion of Brimonidine in Simbrinza®. Patients experienced symptoms of CNS depression: temporary development of coma or decreased level of consciousness, lethargy, somnolence, hypotension, bradycardia, hypothermia, pallor, respiratory depression and apnea, which required admission to an intensive care unit and intubation if indicated. All phenomena were reported to be reversible within 6-24 hours.

Pregnancy use

Pregnancy

There are no or limited data on the use of Simbrinza® in pregnant women. Brinzolamide had no teratogenic effect in rats and rabbits after systemic administration.

In studies of oral administration of brinzolamide in animals, no direct adverse effects on reproductive function were found. In animal studies brinzolamide penetrated through the placenta and entered the bloodstream of the embryo in limited amounts. It is not recommended to use Simbrinza® during pregnancy and in women of reproductive age who do not use reliable contraceptive measures.

Breastfeeding

It is not known whether Simbrinza® is excreted with breast milk in women. Available pharmacodynamic/toxicological data from animal studies have shown that minimal amounts of brinzolamide are excreted into breast milk after oral administration. Brinzolamide is excreted in breast milk after oral administration.

The drug Simbrinza® should not be used during breastfeeding.

Fertility

Preclinical data showed no effect of brinzolamide or brimonidine on fertility.

There are no data on the effect of Simbrinza® on fertility with topical ophthalmic use in humans.