Combigan^® (Drops) Instructions for Use

Marketing Authorization Holder

Allergan Pharmaceuticals Ireland (Ireland)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Timolol (Rec.INN registered by WHO)

Brimonidine (Rec.INN registered by WHO)

Dosage Form

Combigan®

Eye drops 2 mg+5 mg/1 ml: 5 ml dropper bottle 1 or 3 pcs.

Dosage Form, Packaging, and Composition

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

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

5 ml – plastic dropper bottles (1) – cardboard packs.
5 ml – plastic dropper bottles (3) – cardboard packs.

Clinical-Pharmacological Group

Antiglaucoma drug

Pharmacotherapeutic Group

Combined antiglaucoma agent (alpha2-adrenergic agonist + non-selective beta-adrenergic blocker)

Pharmacological Action

Combigan^® is a combined medicinal product containing 2 active substances: brimonidine – an adrenomimetic that has a stimulating effect on alpha₂-adrenergic receptors, and timolol – a beta-adrenergic receptor blocker. Both active substances reduce intraocular pressure (IOP) through combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each component separately.

Brimonidine is an agonist of alpha-adrenergic receptors, and it has 1000 times greater selectivity for alpha2-adrenergic receptors compared to alpha₁-adrenergic receptors. This selectivity is expressed in the absence of mydriasis and vasoconstriction of the microcirculatory bed vessels. The hypotensive action of brimonidine is provided by reducing the production of intraocular fluid and increasing its outflow through the uveoscleral pathway.

Timolol is a non-selective beta-adrenergic blocker, it does not possess intrinsic sympathomimetic and membrane-stabilizing activity. Timolol reduces IOP by decreasing the production of intraocular fluid. The exact mechanism of action is not established; it may be associated with the inhibition of cyclic adenosine monophosphate (cAMP) synthesis and is caused by endogenous stimulation of beta-adrenergic receptors.

Pharmacokinetics

The mean maximum plasma concentration values (C_max) of brimonidine and timolol after administration of Combigan^® were 0.0327 and 0.406 ng/ml, respectively.

Brimonidine

When instilled as a 0.2% ophthalmic solution, the plasma concentration of brimonidine is very low. Brimonidine is minimally metabolized in the eye tissues, plasma protein binding is about 29%. The half-life (T_1/2) of the drug after topical application averages about 3 hours.

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

Timolol

80% of timolol applied as eye drops enters the systemic circulation through absorption via the conjunctival vessels, nasal mucosa, and lacrimal tract. After instillation of eye drops, the maximum concentration of timolol in the aqueous humor of the eye is reached after 1-2 hours. The half-life (T_1/2) of timolol in plasma is about 7 hours. Timolol minimally 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;
• Ocular hypertension (with insufficient effectiveness of local therapy with beta-blockers).

ICD codes

Dosage Regimen

In adults, including elderly patients

Topically, instill 1 drop into the conjunctival sac of the affected eye 2 times/day with a 12-hour interval.

Combigan^® can be used with other ophthalmic drugs to reduce intraocular pressure. If more than 2 drugs are used, a 5-minute break between instillations is necessary.

As with the use of other eye drops, to reduce possible systemic absorption, it is recommended to apply brief (for 1 minute) pressure on the lacrimal sac in the projection area of the lacrimal sac of the eye at the inner corner of the eye.

Adverse Reactions

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

During clinical studies of Combigan^®, the following adverse effects were reported, taking into account the frequency of occurrence: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (< 1/10000).

Eye disorders

Very common: conjunctival hyperemia, burning sensation.

Common: acute burning or stinging pain, allergic conjunctivitis, corneal erosion, superficial keratitis, eyelid skin itching, conjunctival folliculosis, visual impairment, blepharitis, epiphora, eye mucosa dryness, eye discharge, pain, eye mucosa irritation, foreign body sensation.

Uncommon: decreased visual acuity, conjunctival edema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floaters, asthenopia, photophobia, hypertrophy of the eye’s papillary muscles, eyelid tenderness, conjunctival pallor, corneal edema, corneal infiltrates, vitreous rupture. Mental disorders: common – depression.

Nervous system disorders

Common – drowsiness, headache;

Uncommon – dizziness, syncope.

Cardiovascular system disorders

Common — increased blood pressure;

Uncommon: congestive heart failure, palpitations.

Respiratory system disorders

Uncommon: rhinitis, nasal mucosa dryness.

Gastrointestinal system disorders

Common — dry mouth;

Uncommon – taste perversion.

Skin and subcutaneous tissue disorders:

Common – eyelid edema, eyelid skin itching, eyelid skin redness;

Uncommon – allergic contact dermatitis.

Other disorders:

Common – asthenic conditions.

Laboratory parameters common – increased liver enzyme activity.

The following adverse effects have been additionally reported since the marketing of Combigan^®:

Cardiovascular system disorders

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

Adverse effects observed with the use of one of the active substances, the possibility of which cannot be excluded with the use of Combigan^®:

Brimonidine

Eye disorders iridocyclitis, miosis.

Mental disorders insomnia.

Respiratory disorders upper respiratory tract inflammatory diseases, dyspnea.

Gastrointestinal system disorders taste perversion, dyspepsia. Others: systemic allergic reactions.

Timolol

Eye disorders decreased corneal sensitivity, diplopia, ptosis, choroidal rupture (after filtering surgery), refraction changes (due to withdrawal of miotic therapy in some cases).

Mental disorders insomnia, nightmares, decreased libido.

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

Cardiovascular system disorders complete heart block, cardiac arrest.

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

Gastrointestinal system disorders nausea, diarrhea, dyspepsia.

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

Musculoskeletal, connective tissue and bone disorders systemic lupus erythematosus

Others peripheral edema, Peyronie’s disease, chest pain.

Contraindications

• Hypersensitivity to the components of the drug;
• Increased respiratory tract reactivity, including bronchial asthma and episodes of broncho-obstruction, incl. in history, severe chronic obstructive pulmonary disease;
• Sinus bradycardia, atrioventricular block II-III degree without an implanted artificial pacemaker, heart failure, cardiogenic shock;
• Concomitant therapy with MAO inhibitors (MAO), tricyclic and tetracyclic antidepressants (incl. mianserin);
• Age under 18 years;
• Breastfeeding period.

With caution

• Renal/hepatic insufficiency (use of the drug is insufficiently studied in this group of patients);
• Depression, cerebral or coronary insufficiency, Raynaud’s syndrome, orthostatic hypotension, obliterative thromboangiitis;
• Severe unstable cardiovascular diseases;
• Diabetes mellitus, episodes of hypoglycemia (in the absence of therapy);
• Pheochromocytoma (without prior treatment);
• Metabolic acidosis;
• Simultaneous use of radiopaque agents;
• Intravenous administration of lidocaine, “slow” calcium channel blockers (verapamil, diltiazem) due to the risk of inhibition of atrioventricular conduction, development of bradycardia, heart failure and decreased blood pressure;
• Simultaneous prescription or change in the dose of drugs from the groups of adrenomimetics (isoprenaline) and adrenoblockers (prazosin), as well as other agents affecting adrenergic transmission – due to their possible interaction with the active components of the drug or changes in their therapeutic potential.

Use in Pregnancy and Lactation

No controlled studies on the use of Combigan^® in pregnant women have been conducted.

Brimonidine

There are no data on the use of brimonidine in pregnant women. Animal studies have demonstrated reproductive toxicity at high doses of the drug that have toxic effects on the mother. The degree of risk to humans is not established.

Timolol

Animal studies have established reproductive toxicity when using doses of the drug significantly exceeding those recommended for clinical use. Epidemiological studies have not revealed congenital malformations of the fetus, but there is a known risk of intrauterine growth retardation with oral administration of beta-blocker drugs. In addition, symptoms characteristic of the beta-blocker group (bradycardia, decreased blood pressure, respiratory distress, and hypoglycemia) were observed in newborns in cases where beta-blockers were used by the mother until delivery.

In this regard, if Combigan^® is prescribed during pregnancy until the moment of delivery, medical monitoring of the newborn’s condition during the first days of life is necessary.

Combigan^® can be used during pregnancy only in case of special necessity.

During lactation

Preclinical studies have established that brimonidine and timolol are excreted in breast milk. Breastfeeding should be discontinued during treatment.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Use with caution in renal insufficiency.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Prescribed for adults, including elderly patients.

Special Precautions

It is unacceptable to touch the tip of the bottle to any surfaces to avoid infection of the eye and the contents of the bottle. Like all topical ophthalmic drugs, Combigan^® can be absorbed systemically.

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

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

Against the background of taking beta-blocker drugs, in patients with agonistic manifestations and severe anaphylactic reactions to various allergens in history, the effectiveness of epinephrine administration in usually used doses may be reduced or absent. Beta-blockers can also mask the symptoms of hyperthyroidism and worsen the course of Prinzmetal’s angina, vascular diseases, both peripheral and central, as well as arterial hypotension.

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

If it is necessary to discontinue therapy with Combigan^®, as well as in the treatment of cardiovascular diseases with systemic beta-blockers, therapy is withdrawn gradually 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 Combigan^® may have an irritating effect on the eye mucosa. Before instillation of Combigan^®, contact lenses must be removed; they can be put back on after 15 minutes. The shelf life of the drug after first opening the dropper bottle is 28 days. After the specified time has elapsed, the dropper bottle is recommended to be discarded, even if it still contains a residual amount of the drug. This is necessary to avoid the risk of infection. Patients are advised to write the date of opening the bottle on the cardboard package.

Effect on ability to drive vehicles and mechanisms

Combigan^® has a slight effect on the ability to drive vehicles and mechanisms. Against the background of treatment with Combigan^®, transient visual impairment (blurring), episodes of weakness and drowsiness may occur, which may adversely affect if the patient’s work is associated with potentially hazardous activities. If these symptoms occur, one should refrain from performing hazardous activities.

Overdose

Brimonidine

Overdose with topical application: loss of consciousness, decreased blood pressure, bradycardia, hypothermia, cyanosis and apnea.

Overdose with accidental oral ingestion: with accidental oral ingestion of brimonidine, clinical manifestations included: CNS depression, short-term confusion, loss of consciousness or coma, decreased blood pressure, bradycardia, hypothermia and apnea; which necessitated urgent hospitalization to the intensive care unit, in some cases – tracheal intubation was performed. Full functional recovery was reported in all reported cases within 6 to 24 hours. In overdose caused by drugs of the alpha2-adrenomimetic group, the following symptoms were reported: decreased blood pressure, asthenia, vomiting, drowsiness, sedative effect, bradycardia, arrhythmias, miosis, apnea, hypothermia, respiratory depression, convulsions.

Timolol

Symptoms of general timolol overdose bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, cardiac arrest. A clinical study has shown that timolol is not completely eliminated by hemodialysis.

If an overdose is diagnosed, symptomatic therapy is carried out.

Drug Interactions

No specific studies on the drug interactions of Combigan^® have been conducted. Nevertheless, the possibility of enhancing the effect of drugs that depress the central nervous system (alcohol, barbiturates, opiate derivatives, sedatives, general anesthetics) with simultaneous use with Combigan^® should be considered.

Timolol may exacerbate compensatory tachycardia and increase the risk of a pronounced decrease in blood pressure when used with general anesthetics. The anesthesiologist should be warned about the use of Combigan^® before the upcoming surgery.

With simultaneous use of timolol and epinephrine, mydriasis may develop.

Beta-blockers may enhance the hypoglycemic effect of hypoglycemic drugs. They may also mask hypoglycemia.

The hypertensive reaction to the sudden withdrawal of clonidine may be enhanced against the background of the use of a beta-blocker.

Enhancement of the hypotensive effect (e.g., decreased heart rate) when using timolol together with quinidine is possible, due to the fact that quinidine slows down the metabolism of timolol via the cytochrome P450 isoenzyme, CYP2D6.

Concomitant use of beta-blockers with drugs for general anesthesia may mask compensatory tachycardia and increase the risk of a pronounced decrease in blood pressure, so the anesthesiologist must be warned about the patient’s use of Combigan^®.

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

Medicinal products that affect the metabolism and uptake of circulating catecholamines, such as chlorpromazine, methylphenidate, and reserpine, should be used with caution. Concomitant use with MAO inhibitors is contraindicated. For patients who have been taking MAO inhibitors, treatment with Combigan^® may be initiated 14 days after discontinuation of the MAO inhibitor.

Potentiation of effects has been reported with the concomitant use of eye drops containing timolol and orally administered calcium channel blockers, guanethidine, beta-blockers, antiarrhythmic agents, cardiac glycosides, or parasympathomimetics, which manifested as a marked decrease in blood pressure and/or marked bradycardia. Following the use of brimonidine, a decrease in blood pressure has been reported in very rare cases (<1/10000). In this regard, Combigan^® should be used with caution in combination with drugs that have a systemic hypotensive effect.

Storage Conditions

Store in a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of the reach of children.

Shelf Life

Shelf life – 1 year and 9 months.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.