Combigan eye drops 2mg + 5mg / ml, 5 ml

• Open-angle glaucoma;

• ophthalmic hypertension (with insufficient effectiveness of local therapy with beta-blockers).

In adults, including elderly patients:

Locally, it is instilled into the conjunctival sac of the affected eye 1 drop 2 times / day with an interval of 12 hours. CombiganЃ can be used with other ophthalmic preparations to reduce intraocular pressure. If more than 2 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, short-term (within 1 minute) pressure on the lacrimal sac in the area of ??the projection of the lacrimal sac of the eye at the inner corner of the eye is recommended.

Eye drops in the form of a clear solution of greenish-yellow color.

1 ml

brimonidine tartrate 2 mg

timolol maleate 6.8 mg,

which corresponds to the content of timolol 5 mg

Excipients: benzalkonium chloride, sodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, hydrochloric acid, sodium hydroxide, water.

• Hypersensitivity to the components of the drug;

• increased airway reactivity, including bronchial asthma and episodes of bronchial obstruction, incl. history of severe chronic obstructive pulmonary disease;

• sinus bradycardia, atrioventricular block II-III degree without an implanted artificial pacemaker, heart failure, cardiogenic shock;

• concomitant therapy with monoamine oxidase (MAO) inhibitors, antidepressants - tricyclic and tetracyclic (including mianserin);

• age under 18;

• lactation period.

Carefully:

• renal / hepatic impairment (the use of the drug has not been sufficiently studied in this group of patients);

• depression, cerebral or coronary insufficiency, Raynaud's syndrome, orthostatic hypotension, thromboangiitis obliterans;

• severe cardiovascular diseases of an unstable course;

• diabetes mellitus, episodes of hypoglycemia (in the absence of therapy);

• pheochromocytoma (without prior treatment);

• metabolic acidosis;

• simultaneous use of X-ray contrast agents;

• intravenous administration of lidocaine, blockers of 'slow' calcium channels (verapamil, diltiazem) due to the risk of inhibition of atrioventricular conduction, the development of bradycardia, heart failure and a decrease in blood pressure;

• simultaneous prescribing or changing the dose of drugs taken from the groups of adrenergic agonists (isoprenaline) and adrenergic blockers (prazosin), as well as other drugs that affect adrenergic transmission - due to their possible interaction with the active components of the drug or changes in their therapeutic potential.

pharmachologic effect

KombiganЃ is a combined drug that contains 2 active substances: brimonidine, an adrenergic agonist that stimulates alpha2-adrenergic receptors, and timolol, a beta-adrenergic receptor blocker. Both active substances reduce intraocular pressure (IOP) due to combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each of the components separately.

Brimonidine is an alpha-adrenergic receptor agonist, and it has 1000 times greater selectivity for alpha2-adrenergic receptors than alpha1-adrenergic receptors. 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 beta-blocker that does not have internal sympathomimetic and membrane-stabilizing activity. 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 the synthesis of cyclic adenosine monophosphate (cAMP) and is caused by endogenous stimulation of beta-adrenergic receptors.

Pharmacokinetics

The average values ??of the maximum concentration of the drug in the blood plasma (Cmax) of brimonidine and timolol after administration of the CombiganЃ preparation were 0.0327 and 0.406 ng / ml, respectively.

Brimonidine

When installing a 0.2% solution in the form of eye drops, the concentration of brimonidine in the blood plasma is very low. Brimonidine is slightly metabolized in the tissues of the eye, the connection with blood plasma proteins is about 29%. The half-life (T1 / 2) of the drug after topical application is on average about 3 hours.

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

Timolol

80% of timolol, used in the form of eye drops, enters the systemic circulation by absorption through the vessels of the conjunctiva, nasal mucosa and lacrimal tract. After the installation of eye drops, the maximum concentration of timolol in the aqueous humor of the eye is reached in 1-2 hours. The half-life (T1 / 2) of timolol in blood plasma is about 7 hours. Timolol binds slightly to blood plasma proteins. Timolol is partially metabolized in the liver; the active substance and its metabolites are excreted by the kidneys.

Side effect

The most common side effects were conjunctival hyperemia (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 mild, the cancellation of therapy was required only in 3.4% and 0.5% of cases, respectively.

In the course of clinical studies of the drug CombiganЃ, the following side effects were reported, taking into account the frequency of occurrence: very often (> 1/10); often (> 1/100, <1/10); rarely (> 1/1000, <1/100); very rare (<1/10000).

On the part of the organ of vision:

very often: conjunctival hyperemia, burning sensation.

often: acute burning or stabbing pain, allergic conjunctivitis, corneal erosion, superficial keratitis, itching of the eyelid skin, conjunctival follicle, blurred vision, blepharitis, epiphora, dry eye mucosa, eye discharge, pain, irritation of the eye mucosa, foreign body sensation ...

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, soreness of the eyelids, pallor of the conjunctiva, corneal edema. Mental disorders: often - depression.

From the nervous system:

often - drowsiness, headache;

infrequently - dizziness, syncope.

On the part of the cardiovascular system:

often - increased blood pressure;

infrequently: congestive heart failure, palpitations.

From the respiratory system:

infrequently: rhinitis, dryness of the nasal mucosa.

From the digestive system:

often - dryness of the oral mucosa;

infrequently - a perversion of taste.

On the part of the skin and subcutaneous fat:

often - swelling of the eyelids, itching of the eyelid skin, redness of the eyelid skin;

infrequently - allergic contact dermatitis.

Other violations:

often asthenic conditions.

Laboratory indicators: often - an increase in the activity of liver enzymes.

The following side effects have been reported additionally since the introduction of CombiganЃ on the market:

On the part of the cardiovascular system:

The frequency is unknown - arrhythmia, bradycardia, tachycardia, decreased blood pressure.

Side effects that were observed when using one of the active substances, the possibility of which is not excluded when using the drug CombiganЃ:

Brimonidine

From the side of the organ of vision: iridocyclitis, miosis.

Mental disorders: insomnia.

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

From the digestive system: taste perversion, dyspepsia. Others: systemic allergic reactions.

Timolol

From the side of the organ of vision: decreased sensitivity of the cornea, diplopia, ptosis, rupture of the choroid (after filtration surgery), changes in refraction (due to the cancellation of miotic therapy in some cases).

Mental disorders: insomnia, nightmares, decreased libido.

From the nervous system: memory loss, worsening of symptoms of myasthenia gravis, paresthesia, cerebral ischemia. On the part of the organ of hearing: tinnitus.

From the side of the cardiovascular system: complete transverse heart block, cardiac arrest.

Vascular disorders: cerebrovascular accident, intermittent claudication, Raynaud's syndrome, cold extremities. From the respiratory system: bronchospasm (mainly in patients with a history of broncho-obstructive diseases), shortness of breath, cough, respiratory failure.

From the digestive system: nausea, diarrhea, dyspepsia.

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

On the part of the musculoskeletal system, connective and bone tissue: systemic lupus erythematosus

Others: peripheral edema, Peyronie's disease, chest pain.

Application during pregnancy and lactation

No controlled studies have been conducted to study the use of CombiganЃ in pregnant women.

Brimonidine

There is no data on the use of brimonidine in pregnant women. In animal studies, reproductive toxicity has been demonstrated at high doses of the drug, which have toxic effects on the mother. The degree of risk to humans has not been established.

Timolol

In animal studies, reproductive toxicity was established when using doses of the drug that significantly exceed those recommended for use in clinical practice. In epidemiological studies, no congenital malformations of the fetus have been identified, but the risk of delayed intrauterine development of the fetus with oral administration of drugs of the group of beta-blockers is known. In addition, symptoms characteristic of the group of beta-blockers (bradycardia, decreased blood pressure, respiratory dyspnea and hypoglycemia) were observed in newborns when beta-blockers were used by the mother until delivery.

In this regard, if CombiganЃ is prescribed during pregnancy up to the moment of delivery, medical monitoring of the condition of the newborn during the first days of life is necessary.

KombiganЃ can be used during pregnancy only in case of special need.

During lactation

In preclinical studies, it was found that brimonidine and timolol are excreted in breast milk. Breastfeeding should be discontinued for the duration of treatment.

Application for violations of liver function

Use with caution in liver failure.

Application for impaired renal function

Use with caution in renal failure.

Application in children

Contraindicated in children under 18 years of age.

Use in elderly patients

Assign to adults, including elderly patients:

special instructions

It is unacceptable to touch the tip of the vial to any surfaces in order to avoid infection of the eye and the contents of the vial. Like all topical ophthalmic preparations, CombiganЃ can be absorbed systemically.

If allergic reactions occur, treatment with CombiganЃ should be discontinued.

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

While taking the drug of the group of beta-blockers in patients with agonic manifestations and severe anaphylactic reactions to various allergens in history, a decrease or lack of effectiveness from the administration of epinephrine in usually used doses is possible. Beta-blockers can also hide the symptoms of hyperthyroidism and worsen the course of Prinzmetal angina pectoris, vascular diseases, both peripheral and central, as well as arterial hypotension.

Signs indicating acute hypoglycemia, in particular, tachycardia, palpitations and sweating, can be masked during therapy with beta-blockers.

If it is necessary to stop therapy with CombiganЃ, as well as in the treatment of cardiovascular diseases with beta-blockers of systemic action, therapy is gradually canceled in order to avoid the development of cardiac arrhythmias, myocardial infarction and / or sudden death, the risk of which increases with abrupt withdrawal of drugs of this group.

The excipient benzalkonium chloride contained in CombiganЃ can irritate the mucous membrane of the eyes. Before installing CombiganЃ, contact lenses must be removed; they can be put back on after 15 minutes. The shelf life of the drug after the first opening of the dropper bottle is 28 days. After the specified time has elapsed, it is recommended to discard the dropper bottle, even if it still contains a residual amount of the drug. This is to avoid the risk of infection. Patients are advised to write down the date when the bottle was opened on the cardboard packaging.

Influence on the ability to drive vehicles and mechanisms

KombiganЃ has an insignificant effect on the ability to drive vehicles and mechanisms. During treatment with CombiganЃ, transient visual impairment (blurred), episodes of weakness and drowsiness may develop, which can have an adverse effect if the patient's work is associated with potentially hazardous activities. If these symptoms occur, you should refrain from performing hazardous activities.

Overdose

Brimonidine

Overdose when applied topically: loss of consciousness, decreased blood pressure, bradycardia, hypothermia, cyanosis and apnea.

Accidental Oral Overdose: With accidental ingestion of brimonidine, clinical manifestations included: CNS depression, transient confusion, loss of consciousness or coma, decreased blood pressure, bradycardia, hypothermia, and apnea; which led to the need for urgent hospitalization in the emergency department, in some cases, tracheal intubation was performed. Full functional recovery was reported in all reported cases within 6 to 24 hours. In case of an overdose caused by drugs of the alpha2-adrenergic agonist group, the following symptoms were reported: decreased blood pressure, asthenia, vomiting, drowsiness, sedation, bradycardia, arrhythmias, miosis, apnea, hypothermia, respiratory depression, convulsions.

Timolol

—имптомы общей передозировки тимолола: брадикарди¤, снижение артериального давлени¤, бронхоспазм, головна¤ боль, головокружение, остановка сердца. ¬ клиническом исследовании показано, что тимолол не выводитс¤ при гемодиализе полностью.

?сли передозировка диагностирована, проводитс¤ симптоматическа¤ терапи¤.

Ћекарственное взаимодействие

—пециальных исследований по изучению лекарственного взаимодействи¤ препарата  омбиганЃ не проводилось. “ем не менее, следует учитывать возможность усилени¤ эффекта лекарственных средств, угнетающих центральную нервную систему (алкоголь, барбитураты, производные опи¤, седативные препараты, общие анестетики) при одновременном применении с препаратом  омбиганЃ.

“имолол может усугубл¤ть компенсаторную тахикардию и повышать риск выраженного снижени¤ артериального давлени¤ при применении с общими анестетиками. Ќеобходимо предупредить врача-анестезиолога о применении препарата  омбиганЃ перед предсто¤щей операцией.

ѕри одновременном применении тимолола и эпинефрина возможно развитие мидриаза.

Ѕета-адреноблокаторы могут усиливать гипогликемический эффект гипогликемических препаратов. ќни также могут маскировать гипогликемию.

vипертензивна¤ реакци¤ на внезапную отмену клонидина может усилитьс¤ на фоне применени¤ бета-адреноблокатора.

”силение гипотензивного эффекта (например, снижение „——) при применении тимолола совместно с хинидином возможно, вследствие того, что хинидин замедл¤ет метаболизм тимолола посредством изофермента цитохрома –450, CYP2D6.

—овместное применение бета-адреноблокаторов с лекарственными препаратами дл¤ общей анестезии может скрывать компенсаторную тахикардию и повышать риск выраженного снижени¤ артериального давлени¤, поэтому врача-анестезиолога необходимо предупредить о применении пациентом препарата  омбиганЃ.

?иметидин, гидралазин, этанол могут повышать концентрацию тимолола в плазме крови.

Ќеобходимо с осторожностью примен¤ть лекарственные препараты, которые оказывают вли¤ние на метаболизм и усвоение циркулирующих катехоламинов, например, хлопромазин, метилфенидат, резерпин. —опутствующий прием ингибиторов ћјќ противопоказан. Ѕольным, получавшим ингибиторы ћјќ, лечение препаратом  омбиганЃ может быть назначено через 14 дней после отмены ингибитора ћјќ.

It was reported about the potentiation of the effects of the combined use of eye drops containing timolol, and taken orally blockers of 'slow' calcium channels, guanethidine or beta-blockers, antiarrhythmic drugs, cardiac glycosides or parasympathomimetics, which was manifested by a pronounced decrease in blood pressure and / or severe bradycardia. After the use of brimonidine, in very rare cases (<1/10000), a decrease in blood pressure has been reported. In this regard, it is necessary to use CombiganЃ with caution with drugs that have systemic antihypertensive effects.