Combigan, eye drops 5 ml

Combigan is a combination drug that contains two active ingredients: the adrenomimetic brimonidine, which stimulates alpha2-adrenoreceptors, and the beta-adrenoreceptor blocker timolol. Both substances are able to reduce elevated intraocular pressure by mutual amplification of the effect, which makes the hypotensive effect more pronounced (compared to the effectiveness of each individual component).

The first component, brimonidine, being an alpha-adrenergic receptor antagonist, is thousands of times more selective for alpha2-adrenoreceptors compared to alpha1-adrenoreceptors. Its selectivity is expressed in the absence of vasoconstriction (vasoconstriction) and mydriasis (pupil dilation). Brimonidine provides a hypotensive effect by increasing the outflow of intraocular fluid through the uveoscleral pathway.

The second component, timolol, is a non-selective beta-adrenoreceptor blocker. It has no intrinsic membrane-stabilizing and sympathomimetic activity. The substance lowers intraocular pressure by reducing intraocular fluid formation. The mechanism of its action is not precisely defined; it may be related to inhibition of the synthesis of CAMP or caused by endogenous stimulation of beta-adrenergic receptors.

After instillation, the bulk of the drug is excreted by the kidneys as metabolites within 5 days.

Pharmacokinetics

Mean maximum plasma concentrations (Cmax) of brimonidine and timolol after administration of Combigan® prepatarator were 0.0327 and 0.406 ng/mL, respectively.

Brimonidine

Brimonidine plasma concentrations are very low when 0.2% solution is administered as eye drops. Brimonidine is slightly metabolized in the tissues of the eye, the binding to plasma proteins is about 29%. The half-life (T1/2) of the drug after topical application is on average about 3 hours.

Timolol

80% of timolol used in the form of eye drops enters the systemic bloodstream by absorption through the vessels of the conjunctiva, nasal mucosa and lacrimal tract. After instillation of the eye drops, the maximum concentration of timolol in the aqueous humor of the eye is reached after 1-2 hours. The half-life (T1/2) of timolol in blood plasma is about 7 hours. Timolol is insignificantly bound 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.

The drug is recommended if the effectiveness of local beta-adrenoreceptor blockers is insufficient.

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Active ingredient

Brimonidine, Timolol

Composition

In 1 ml of solution of eye drops contains:

Active substances

• Brimonidine tartrate – 2.0 mg/mL.
• Timolol maleate – 6.8 mg/ml.
  • Timolol converted to thymolol – 5.0 mg/ml.

Excipients .

Benzalkonium chloride,

sodium hydrophosphate heptahydrate, <

Sodium dihydrophosphate monohydrate,

Hydrochloric acid,

Sodium hydroxide,

water.

How to take, the dosage

In adult patients (including the elderly), one drop of Combigan is instilled into each eye twice daily, 12 hours apart, usually in the morning and evening.

If more than one drop of the drug is needed, the next instillation should be done 5 minutes apart.

To reduce the risk of possible systemic absorption, use a short-term (less than one minute) fingertip pressure at the inner corner of the eye in the projection of the lacrimal sac.

As with other eye drops, to reduce possible systemic absorption, short-term (1 minute) pressure on the lacrimal sac in the area of the lacrimal sac projection at the inner corner of the eye is recommended.

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Interaction

Special studies on the study of drug interaction of Combigan® have not been conducted. Nevertheless, the possibility of enhancing the effect of drugs depressing the central nervous system (alcohol, barbiturates, opium derivatives, sedatives, general anesthetics) in concomitant use with the Combigan® medicine should be considered.

Timolol may exacerbate compensatory tachycardia and increase the risk of marked reduction of blood pressure when used with general anesthetics. The anesthesiologist should be advised of the use of Combigan prior to the upcoming surgery.

The simultaneous use of timolol and epinephrine may cause mydriasis.

Beta-adrenoblockers may increase the hypoglycemic effect of hypoglycemic drugs. They may also mask hypoglycemia.

The hypertensive response to abrupt withdrawal of clonidine may increase with the use of a beta-adrenoblocker.

An increase in the hypotensive effect (e.g., decrease in HR) when using timolol with quinidine is possible due to the fact that quinidine slows down the metabolism of timolol via the cytochrome P450 isoenzyme, CYP2D6.

The co-administration of beta-adrenoblockers with general anesthesia drugs may mask compensatory tachycardia and increase the risk of markedly lower blood pressure, so the anesthesiologist should be warned about the patient’s use of Combigan.

Cimetidine, hydralazine, ethanol may increase the plasma concentration of timolol.

Precaution is required when using drugs that affect metabolism and absorption of circulating catecholamines, e.g., chlorpromazine, methylphenidate, reserpine. Concomitant administration of MAO inhibitors is contraindicated. In patients who received MAO inhibitors, treatment with Combigan may be prescribed 14 days after withdrawal of the MAO inhibitor.

There have been reports of potentiation of the effects of combined use of eye drops containing timolol and oral “slow” calcium channel blockers, guanethidine or beta-adrenoblockers, antiarrhythmic drugs, cardiac glycosides or parasympathomimetics, which manifested as a marked decrease in blood pressure and/or marked bradycardia. After the use of brimonidine in very rare cases (

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Special Instructions

Like all ophthalmic products for topical use, Combigan can be absorbed systemically.

Contact lenses should be removed before administering Combigan. They can be put back on no sooner than 15 minutes after the procedure.

The dispenser tip should never be allowed to touch any surface to avoid contaminating the contents of the bottle and your eyes.

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

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

In patients with a history of agonic manifestations and severe anaphylactic reactions to various allergens, administration of epinephrine in commonly used doses may decrease or not be effective against the background of the drug of beta-adrenoblocker group. Beta-adrenoblockers may also mask symptoms of hyperthyroidism and worsen the course of Prinzmetal angina, vascular disease, both peripheral and central, and arterial hypotension.

The signs suggestive of acute hypoglycemia, particularly tachycardia, palpitations and sweating, may be masked by therapy with beta-adrenoblockers.

If therapy with Combigan must be discontinued, as with treatment of cardiovascular disease with systemic beta-adrenal blockers, therapy should be discontinued gradually to avoid the development of cardiac arrhythmias, myocardial infarction and/or sudden death which are increased by abrupt withdrawal of this group of drugs.

The excipient benzalkonium chloride in Combigan® may be irritating to the eye mucosa.

The shelf life of the drug after the first opening of the dropper bottle is 28 days. After this time, it is recommended to throw away 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 the date the vial was opened on the carton.

Impact on the ability to drive vehicles and machinery

The drug may affect the ability to drive vehicles and machinery, causing short-term visual impairment, sometimes weakness and drowsiness. If the above symptoms occur, you should refrain from performing potentially hazardous activities.

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Contraindications

• High sensitivity to drug components.
• High respiratory reactivity, including:
  • Bronchial asthma.
  • Bronchoobstruction, including history, severe chronic obstructive pulmonary disease.
• Sinus bradycardia.
• Atrioventricular block of degree II-III without an implanted artificial pacemaker.
• Heart failure.
• Cardiogenic shock.
• Companion therapy with monoamine oxidase inhibitors (MAOIs), antidepressants – tricyclic and tetracyclic (including mianserine).
• Ages under 18 years.
• Breast-feeding period.

With caution:

• Hepatic/renal insufficiency (use of the drug has not been sufficiently studied in this group of patients).
• Depression
• Cerebral or coronary insufficiency.
• Raino syndrome.
• Ortostatic hypotension
• Obliterating thrombangiitis.
• Severe cardiovascular disease of unstable course.
• Diabetes mellitus.
• Hypoglycemic episodes (in the absence of therapy).
• Pheochromocytoma (no previous treatment).
• Metabolic acidosis.
• Simultaneous use of radiopaque contrast agents.
• Injection of lidocaine, “slow” calcium channel blockers (verapamil, diltiazem) due to the risk of atrioventricular conduction depression, bradycardia, heart failure and decreased blood pressure.
• Simultaneous prescribing or changing the dose of drugs from groups of adrenomimetic agents (isoprenaline) and adrenoblockers (prazosin), as well as other agents affecting adrenergic transmission – due to their possible interaction with active drug components or change of their therapeutic potential.
  

Side effects

The most frequent side effects were conjunctival hyperemia (about 15% of patients) and burning sensation of the mucous membrane of the eye (about 11% of patients). In most cases, the severity of these symptoms was mild, and only 3.4% and 0.5%, respectively, required discontinuation of therapy.

In clinical studies of Combigan® the following side effects have been reported, taking into account the frequency of occurrence: very common (>1/10); common (>1/100,1/1000,

Over vision:

very often: hyperemia of the conjunctiva of the eye, burning sensation.

often: acute burning or stabbing pain, allergic conjunctivitis, corneal erosion, superficial keratitis, itching of eyelid skin, conjunctival folliculosis, visual disturbances, blepharitis, epiphora, dry eye mucosa, eye discharge, pain, eye mucosa irritation, feeling of foreign body.

infrequent: decreased visual acuity, conjunctival edema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, floating precipitates in the vitreous body, asthenopia, photophobia, hypertrophy of papillary muscles of the eye, eyelid soreness, pale conjunctiva, corneal edema, corneal infiltrates, vitreous tear. Mental disorders: often depression.

Nervous system disorders:

often – drowsiness, headache;

infrequent – dizziness, syncope.

Cardiovascular system disorders:

often – increased blood pressure;

infrequent: congestive heart failure, palpitations.

Respiratory system disorders:

infrequent: rhinitis, dry nasal mucosa.

Digestive system disorders:

often: dryness of the oral mucosa;

infrequent: perversion of taste.

Skin and subcutaneous fatty tissue:

often – eyelid edema, itching of eyelid skin, reddening of eyelid skin;

infrequent – allergic contact dermatitis.

Other disorders:

often – asthenic conditions.

Laboratory findings: often – increased liver enzyme activity.

The following side effects have been reported additionally since Combigan was placed on the market:

Cardiovascular side effects:

Frequency unknown – arrhythmia, bradycardia, tachycardia, decreased blood pressure.

Side effects that have been observed with one of the active substances, the possibility of which is not excluded with the use of Combigan:

Brimonidine

An organ of vision: iridocyclitis, miosis.

Mental disorders: insomnia.

Respiratory system disorders: inflammatory diseases of the upper respiratory tract, shortness of breath.

Digestive system disorders: perversion of taste, dyspepsia. Other: systemic allergic reactions.

Timolol

Visual disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal rupture (after filtration surgical treatment), refractive changes (due to withdrawal of myotic therapy in some cases).

Mental disorders: insomnia, nightmares, decreased libido.

Nervous system disorders: memory loss, worsening of symptoms of myasthenia gravis, paresthesia, cerebral ischemia. Hearing organ: tinnitus.

Cardiovascular system: complete transverse heart block, cardiac arrest.

vascular disorders: cerebral circulatory disorders, intermittent claudication, Raynaud’s syndrome, cold extremities. Respiratory system disorders: bronchospasm (mainly in patients with bronchoobstructive disorders in anamnesis), dyspnea, cough, respiratory failure.

In the digestive system: nausea, diarrhea, dyspepsia.

Skin and subcutaneous fatty tissue disorders: alopecia, psoriasis-like rash or exacerbation of psoriasis.

Musculoskeletal, connective and bone tissue disorders: systemic lupus erythematosus.

Others: peripheral edema, Peyronie’s disease, pain in the chest.

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Overdose

When used topically: loss of consciousness, significant decrease in BP, bradycardia, increased body temperature, cyanosis and apnea.
Oral administration: transient confusion, CNS depression, loss of consciousness or coma, marked BP decrease, bradycardia, body temperature increase, cyanosis and apnea.
Treatment: Emergency hospitalization.

Timolol.
General overdose: bradycardia, marked BP decrease, bronchospasm, dizziness, headache, cardiac arrest.
Treatment: symptomatic therapy, hemodialysis is ineffective.

Pregnancy use

It is contraindicated in children under 18 years of age.

There have been no controlled studies to study the use of Combigan in pregnant women.

Brimonidine

There are no data on the use of brimonidine in pregnant women. Reproductive toxicity has been demonstrated in animal studies with high doses of the drug having toxic effects on the mother. The degree of risk to humans has not been established.

Timolol

In animal studies, reproductive toxicity has been demonstrated with doses of the drug significantly higher than those recommended for use in clinical practice. In epidemiological studies no congenital fetal malformations were revealed, but the risk of intrauterine fetal growth retardation is known with oral use of drugs of beta-adrenoblocker group. In addition, symptoms characteristic of the beta-adrenoblocker group (bradycardia, decreased blood pressure, respiratory dyspnea, and hypoglycemia) were observed in newborns when beta-adrenoblockers were used by the mother until delivery.

In this regard, if Combigan is prescribed during pregnancy until delivery, medical monitoring of the newborn during the first days of life is necessary.

Combigan should only be used during pregnancy if it is absolutely necessary.

In lactation

Brimonidine and timolol have been found to be excreted with breast milk in preclinical studies. Breastfeeding should be stopped for the period of treatment.

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