Combigan® [Brimonidine, Timolol]

Pharmacological properties

Combigan - a combined drug, which consists of 2 active substances: brimonidine - an adrenergic agonist that stimulates α2-adrenergic receptors, and timolol - a blocker of β-adrenergic receptors. both active substances reduce high intraocular pressure (IOP) due to the combined interaction, leading to a significantly more pronounced hypotensive effect compared with the effectiveness of each of the components separately.

Brimonidine - α agonist₂-adrenergic receptors, moreover, it is characterized by 1000 times greater selectivity with respect to α₂-adrenoreceptors compared with α₁-adrenoreceptors. Selectivity is expressed in the absence of mydriasis and vasoconstriction of the vessels of the microvasculature. The hypotensive effect of brimonidine is provided by reducing the formation of intraocular fluid and increasing its outflow along the uveoscleral pathway.

Timolol is a non-selective β-adrenergic receptor blocker, does not have internal sympathomimetic and membrane-stabilizing activity, and is not a direct myocardial depressant. Timolol reduces IOP by reducing the formation of intraocular fluid. The exact mechanism of action has not been established, perhaps it is associated with inhibition of cAMP synthesis and is caused by endogenous stimulation of β-adrenergic receptors.

Pharmacokinetics The average values ​​of C_max in the blood plasma of brimonidine and timolol after the appointment of the drug, Combigan was 0.0327 and 0.406 ng / ml, respectively.

Brimonidine. At instillation of 0.2% solution in the form of eye drops, the concentration of brimonidine in blood plasma is very low. Brimonidine is slightly metabolized in the tissues of the eye, communication with plasma proteins is about 29%. T_½ the drug after topical administration averaged about 3 hours

The main part of the drug (about 74% of the dose that was absorbed into the systemic circulation) is excreted by the kidneys in the form of metabolites for 5 days, the drug was not detected unchanged in the urine. In vitro studies on animal and human liver cells have shown that aldehyde oxidase and cytochrome P450 are largely included in the metabolism process. Thus, systemic excretion is determined primarily by the metabolism of the drug in the liver.

Brimonidine forms feedback with melanin in the tissues of the eye without the development of adverse effects. Accumulation does not occur in the absence of melanin.

Brimonidine is not metabolized significantly in the tissues of the eye.

Timolol After topical application of 0.5% eye drops to patients undergoing cataract surgery, C_max timolol in the eye fluid was at the level of 898 ng / ml one hour after application. T_½ timolol in blood plasma is about 7 hours. Timolol to a small extent binds to plasma proteins. Timolol is partially metabolized in the liver, the active substance and its metabolites are excreted by the kidneys.

Indications

Open angle glaucoma. intraocular hypertension (with insufficient efficacy of topical β-adrenoreceptor blockers).

Application

Used in adults, including elderly patients. locally, 1 drop of the drug combigan is instilled into the conjunctival sac of the affected eye 2 times a day with an interval of 12 hours

Combigan can be used with other ophthalmic drugs to reduce IOP. If 2 or more drugs are used, then it is necessary to take a 5-minute break between instillations.

As with other eye drops, to reduce possible systemic absorption, a short press on the lacrimal sac at the site of its projection at the inner corner of the eye or closure of the eyelids for 2 minutes is recommended.

This should be done immediately after the instillation of each drop in order to reduce the severity of systemic side effects and enhance local action.

Children. The safety and effectiveness of the drug for children have not been established, so it is not used in pediatric practice.

Contraindications

Hypersensitivity to the components of the drug.

Increased reactivity of the respiratory tract, including AD and cases of bronchial obstruction, including a history of severe COPD.

Sinus bradycardia, sinus node dysfunction syndrome, AV block II – III degree without an implanted artificial pacemaker, heart failure, cardiogenic shock.

Concomitant therapy with MAO inhibitors, antidepressants that affect noradrenergic transmission (tricyclic antidepressants and mianserin).

Side effects

The most common side effects were conjunctival hyperemia of the eye (about 15% of patients) and a burning sensation of the mucous membrane of the eye (about 11% of patients). in most cases, the severity of these symptoms was weak, discontinuation of therapy was necessary only in 3.4 and 0.5% of cases, respectively.

The following side effects have been reported, taking into account the frequency of occurrence: very often (1/10); often (1/100, 1/10); infrequently (1/1000, 1/100); rarely (1/10 000, 1/1000); very rarely (1/10 000).

From the side of the organ of vision: very often - hyperemia of the conjunctiva of the eye, burning sensation; often - acute burning or stitching pain, allergic conjunctivitis, corneal erosion, superficial keratitis, itching of the eyelids, conjunctival folliculitis, impaired vision, blepharitis, epiphora, dry mucous membrane of the eye, discharge from the eye, pain, irritation of the mucous membrane of the eye, foreign body sensation redness of the skin of the eyelids; infrequently - decreased visual acuity, conjunctival edema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, floating precipitates in the vitreous body, asthenopia, photophobia, hypertrophy of the papillary muscles of the eye, sore eyelids, pallor of the conjunctiva, rupture of the body, rupture.

From the psyche: often - depression.

From the nervous system: often - drowsiness, headache; infrequently - dizziness, syncope.

From the cardiovascular system: often - hypertension; infrequently - congestive heart failure, palpitations, bradycardia, arterial hypotension.

On the part of the respiratory system: infrequently - rhinitis, dryness of the nasal mucosa.

From the digestive system: often - dryness of the oral mucosa; infrequently - taste disturbance, nausea, diarrhea.

On the part of the skin and subcutaneous fat: often - swelling of the eyelids, itching of the eyelids, redness of the skin of the eyelids, redness of the skin of the face.

From the immune system: infrequently - allergic contact dermatitis.

Other disorders: often - asthenic conditions.

Since the use of the drug Combigan additionally reported the following side effects.

From the side of the organ of vision: the frequency is unknown - blurred vision, impaired visual acuity.

From the cardiovascular system: the frequency is unknown - arrhythmia, bradycardia, tachycardia, arterial hypotension.

From the skin: the frequency is unknown - redness of the skin.

Side effects that were noted when using one of the active substances, the occurrence of which is not excluded with the use of the drug Combigan.

Brimonidine

On the part of the immune system: hypersensitivity, skin reactions (including redness of the skin, facial swelling, itching, rash), vasodilation.

From the side of the organ of vision: iritis, iridocyclitis (anterior uveitis), blanching of the conjunctiva of the eye, swelling of the conjunctiva of the eye, photophobia, conjunctivitis, miosis.

From the side of the psyche: insomnia.

From the cardiovascular system: palpitations / arrhythmia, tachycardia, loss of consciousness.

On the part of the respiratory system: inflammatory diseases of the upper respiratory tract, shortness of breath, dry nose.

From the digestive system: gastrointestinal symptoms, taste change.

On the part of the skin and subcutaneous fat: skin reactions, including redness of the skin, swelling of the face, itching, rash and vasodilation.

Others: systemic allergic reactions.

Timolol Like other local ophthalmic drugs, the Combigan drug (brimonidine tartrate / timolol) enters the systemic circulation. Timolol absorption can cause side effects similar to those observed with other systemic β-adrenergic blockers. The frequency of systemic side effects after topical application is lower than with systemic use.

When using ophthalmic β-adrenoreceptor blockers, the following additional adverse reactions were identified; there is a potential for their occurrence when using the Combigan drug.

On the part of the immune system: systemic allergic reactions, including Quinckes edema, urticaria, localized and generalized rash, pruritus, anaphylactic reactions, systemic lupus erythematosus.

From the endocrine system: hypoglycemia, masking the symptoms of hypoglycemia in patients with diabetes mellitus.

From the side of the organ of vision: signs and symptoms of eye irritation (burning sensation, acute pain, itching, lacrimation, redness), blepharitis, blurred vision, feeling of dry eyes, keratitis, decreased sensitivity of the cornea, diplopia, ptosis, rupture of the choroid (after filtering surgery treatment), corneal erosion, cystoid macular edema, pseudopemphigoid, conjunctivitis.

From the psyche / nervous system: loss of consciousness, dizziness, headache, insomnia, nightmares, memory loss, cerebrovascular accidents, increased symptoms of myasthenia gravis, paresthesia, cerebral ischemia, behavior changes and mental disorders, including confusion, hallucinations, anxiety, disorientation, nervousness.

On the part of the organ of hearing: ringing in the ears.

From the cardiovascular system: bradycardia, palpitations, congestive heart failure, chest pain, AV heart block, heart failure, heart block, cardiac arrest, arrhythmia, cerebral ischemia, stroke, intermittent claudication, edema, pulmonary edema, worsening angina pectoris, arterial hypotension, Raynauds syndrome, feeling of coldness in the limbs, loss of consciousness.

On the part of the respiratory system: bronchospasm (mainly in patients with a history of bronchospastic diseases), shortness of breath, cough, respiratory failure, nasal congestion, upper respiratory tract infection.

From the digestive system: diarrhea, dysgeusia, nausea, dry mouth, dyspepsia, vomiting, abdominal pain, anorexia.

On the part of the skin and subcutaneous fat: alopecia, psoriasis-like rashes or exacerbation of psoriasis, skin rashes.

From the musculoskeletal system, connective and bone tissue: myalgia.

From the kidneys and urinary tract: Peyronies disease, peripheral edema.

From the genital organs: sexual dysfunction, decreased libido, retroperitoneal fibrosis.

Others: asthenia / fatigue.

In the post-marketing period, the following adverse reactions were reported: dizziness, nausea.

special instructions

During clinical trials, some patients reported ocular allergic reactions (allergic conjunctivitis and allergic blepharitis). allergic conjunctivitis was detected in 5.2% of patients with a typical onset between the 3rd and 9th month. only 3.1% of patients stopped taking the drug. allergic blepharitis was rarely reported - 1%.if an allergic reaction is detected, treatment with the drug should be discontinued.

Like all topical ophthalmic preparations, Combigan can be absorbed systemically. There was no increase in systemic absorption of individual active substances. Due to the presence of the β-adrenergic component, timolol, the same types of adverse reactions are detected as with the use of systemic β-adrenergic receptor blockers. The incidence of systemic adverse reactions with topical application is lower than with systemic use.

Use with caution in patients with the following types of disorders.

Heart disorders. Patients with cardiovascular diseases (e.g., coronary heart disease, Prinzmetal angina and heart failure) and during antihypertensive therapy using β-adrenergic receptor blockers should be carefully examined and consider the possibility of drug therapy with other active substances. Patients with cardiovascular diseases should be examined for signs of worsening of these diseases and adverse reactions.

Due to the negative effect on the duration of excitation, β-adrenergic receptor blockers should be used with caution in patients with first-degree heart block.

As with the use of systemic β-adrenergic receptor blockers, if it is necessary to stop therapy with Combigan in patients with coronary artery disease, the treatment is canceled gradually, in order to avoid the development of cardiac arrhythmias, myocardial infarction and sudden death.

Vascular Disorders Patients with severely impaired / circulatory circulatory disorders (e.g., severe forms of Raynauds disease or Raynauds syndrome) should be treated with caution.

Respiratory distress. Use with caution Combigan in patients with moderate to moderate COPD (chronic bronchitis, emphysema). It should only be used if the expected benefit exceeds the potential risk.

Respiratory disorders, including death due to bronchospasm, were noted in patients with AD after the appointment of some ophthalmic β-adrenergic receptor blockers.

Hypoglycemia / diabetes. Β-adrenergic receptor blockers are used with caution in patients prone to spontaneous hypoglycemia, or with labile diabetes, since β-adrenergic receptor blockers can mask the signs and symptoms of acute hypoglycemia.

Hyperthyroidism Β-adrenergic blockers can mask the signs and symptoms of hyperthyroidism. With caution, Combigan should be used in patients with metabolic acidosis and pheochromocytoma (without prior treatment).

Ophthalmic diseases. Ophthalmic β-adrenergic blockers can cause dry eyes. It should be used with caution in patients with diseases of the cornea of ​​the eye.

Retinal detachment. Retinal detachment has been reported with drugs that reduce the accumulation of intraocular fluid (e.g. timolol) after filtration surgical treatment of glaucoma.

Combigan was not studied in patients with angle-closure glaucoma.

Delayed type hypersensitivity has been reported with 0.2% brimonidine tartrate solution, and some of the cases have been associated with increased IOP.

Use with other β-adrenergic blockers. The effect on IOP or the known effects of systemic β-adrenergic receptor blockers can be enhanced by the use of timolol in patients already taking another systemic β-adrenergic receptor blocker. Carefully monitor the response to treatment in these patients. The use of two local β-adrenergic blockers is not recommended.

Anaphylactic reactions.Against the background of treatment with a group of β-adrenergic receptor blockers in patients with atopy or with complex anaphylactic reactions to various allergens, an increase in the severity of the reaction with repeated administration of such allergens and the absence of the effect of epinephrine at normal doses are possible.

Anesthesia. Ophthalmic β-adrenergic receptor blockers can block the effect of beta-agonists, such as epinephrine. It is necessary to warn the anesthetist about the use of the drug Combigan before future surgery.

Hepatic / renal failure. Use with caution in patients with hepatic / renal failure. The use of the drug in patients of this group is not well understood.

In patients with severe renal impairment on hemodialysis, treatment with timolol was accompanied by a marked decrease in blood pressure.

With caution, the drug Combigan is prescribed with simultaneous use:

• radiopaque preparations containing iodine, and with the on / in the introduction of lidocaine;
• slow calcium channel blockers, guanethidine, β-adrenergic blockers, antiarrhythmic drugs (including amiodarone), cardiac glycosides or parasympathomimetics, due to the risk of the additive effect of lowering blood pressure and / or developing bradycardia;
• drugs that affect the metabolism and absorption of circulating catecholamines.

The excipient benzalkonium chloride contained in the drug Combigan can cause irritation of the mucous membrane of the eyes. Before installing Combigan, it is necessary to remove contact lenses, again they can be worn after 15 minutes.

Benzalkonium chloride is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. To prevent eye infection and contamination of eye drops, contact should be made to the tip of the dropper on any surface.

After the expiration date after opening the bottle (28 days), the dropper bottle is recommended to be discarded, even if it contains a residual amount of the drug. This is necessary in order to prevent the danger of infection. On cardboard packaging, it is recommended to record the date the bottle was opened.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Combigan has little effect on the ability to drive vehicles and mechanisms. Against the background of the use of the drug Combigan, short-term visual impairment (fuzziness), the development of weakness and drowsiness are possible. In the event of the indicated symptoms, one should refrain from activities that require special attention.

Use during pregnancy or lactation. Controlled studies to study the use of the drug Combigan in pregnant women have not been conducted. Therefore, the use of the drug during pregnancy is contraindicated.

Timolol passes into breast milk. The use of the drug during lactation is contraindicated.

Interactions

Special studies to study the drug interaction of the drug Combigan have not been conducted. however, one should take into account the possibility of enhancing the effect of drugs that depress the central nervous system (barbiturates, opium derivatives, sedatives, general anesthetics) and alcohol while using the combination drug.

With the simultaneous use of ophthalmic blockers of β-adrenergic receptors and epinephrine, the development of mydriasis is possible.

Β-adrenergic blockers can enhance the hypoglycemic effect of antidiabetic drugs. They can also mask the signs and symptoms of hypoglycemia.

The hypertensive reaction to the sudden withdrawal of clonidine may be enhanced by the use of β-adrenergic receptor blockers.

It is possible to enhance the systemic effect of β-adrenoreceptor blockers (decreased heart rate, depression) while using CYP 2D6 (quinidine, fluoxetine, paroxetine).

The combined use of β-adrenergic receptor blockers with drugs for general anesthesia can obscure compensatory tachycardia and increase the risk of arterial hypotension, therefore, an anesthetist needs to be warned about the use of Combigan by the patient.

With caution, use the drug Combigan simultaneously with radiopaque preparations containing iodine, and with the on / in the introduction of lidocaine.

Cimetidine, hydralazine, ethyl alcohol can increase the concentration of timolol in blood plasma.

Tricyclic antidepressants may reduce the hypotensive effect of systemic clonidine. It is not known whether the simultaneous use of these agents with Combigan will lead to a decrease in intraocular pressure.

It is necessary to use drugs with caution that affect the metabolism and absorption of circulating catecholamines, clompromazine, methylphenidate, reserpine.

With caution, prescribe (or change the dose) concomitant systemic drugs (regardless of the pharmaceutical form), which can interact with α-adrenergic agonists or disrupt their activity. For example, agonists or antagonists of adrenergic receptors (isoprenaline, prazosin).

Although no special studies have been conducted on the drug interaction of Combigan, there is a theoretical possibility of enhancing the additive effect of reducing IOP when used with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine.

Concomitant use of MAO inhibitors is contraindicated. Patients who received MAO inhibitors, Combigan treatment can be prescribed 14 days after the withdrawal of the MAO inhibitor.

Potentiation effects of the combined use of eye drops containing timolol and slow calcium channel blockers, guanethidine or β-adrenergic blockers, antiarrhythmic drugs (including amiodarone), cardiac glycosides or parasympathomimetics taken by mouth have been reported, which is manifested by a significant decrease in blood pressure and / or severe bradycardia . After the use of brimonidine, a decrease in blood pressure was very rarely reported (1/10 000). In this regard, it is necessary to use with caution Combigan with drugs that have a systemic hypotensive effect.

Overdose

An overdose of combigan in humans has been rarely reported. this did not lead to adverse reactions. overdose treatment includes supportive and symptomatic therapy. patient breathing should be maintained.

There were reports of an accidental overdose of the ophthalmic solution of timolol, leading to systemic effects similar to those observed with the use of systemic β-adrenergic receptor blockers, such as dizziness, headache, shortness of breath, bradycardia, arterial hypotension, bronchospasm and cardiac arrest.

Brimonidine

Overdose with topical application. Cases have already been identified that are indicated in the SIDE EFFECTS section.

Overdose with accidental ingestion. A limited amount of information has been obtained about an accidental overdose of brimonidine in adults. Only one case of overdose was recorded, as a result of which arterial hypotension developed. It was reported that after the end of the episode of arterial hypotension recorded "rebound" hypertension.

In case of an overdose caused by drugs of group α₂-adrenomimetics, the following symptoms were reported: decreased blood pressure, asthenia, vomiting, drowsiness, sedation, bradycardia, arrhythmia, miosis, apnea, hypothermia, respiratory depression, convulsions.

TimololSymptoms of a general overdose of timolol are similar to those observed with the use of systemic β-adrenoreceptor blockers: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, cardiac arrest.

Timolol is not completely excreted during hemodialysis.

Storage conditions

In the original packaging in a dark place at a temperature of no higher than 25 ° c. the shelf life of the drug after the first opening of the dropper bottle is 28 days.