INSTRUCTIONS for medical use of the medicinal product COMBIGAN® (COMBIGAN®)

Composition:

Active substances: brimonidine tartrate, timolol maleate;

1 ml of solution contains brimonidine tartrate 2.0 mg; timolol maleate 6.8 mg (equivalent to 5.0 mg of timolol);

Excipients: benzalkonium chloride – 0.05 mg; sodium hydrogen phosphate, heptahydrate; sodium dihydrogen phosphate, monohydrate; hydrochloric acid or sodium hydroxide; purified water.

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear yellowish-green solution.

Pharmacotherapeutic group. Agents used in ophthalmology. Antiglaucoma agents. Timolol, combinations.

ATC code: S01ED51.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Combigan® contains two active substances: brimonidine tartrate and timolol maleate. Both of these substances reduce elevated intraocular pressure (IOP) through a combined effect, resulting in a significantly greater hypotensive effect compared to the efficacy of each component administered separately. Combigan® acts rapidly.

Brimonidine tartrate is an alpha2-adrenergic receptor agonist, with approximately 1000-fold greater selectivity for alpha2-adrenergic receptors compared to alpha1-adrenergic receptors. This selectivity is reflected in the absence of mydriasis and vasoconstriction in the microcirculatory vessels.

The hypotensive effect of brimonidine is believed to be due to increased outflow of aqueous humor through the uveoscleral pathway and reduced aqueous humor production.

Timolol is a non-selective beta1- and beta2-adrenergic blocker that lacks significant direct sympathomimetic activity, has no direct myocardial depressant effect, and does not exhibit membrane-stabilizing activity. Timolod reduces IOP by decreasing aqueous humor production. The exact mechanism of action is not fully established, but it may be related to inhibition of cyclic adenosine monophosphate (cAMP) synthesis induced by endogenous stimulation of beta-adrenergic receptors.

Clinical Efficacy

In three controlled, double-blind clinical studies, administration of Combigan® (twice daily) resulted in clinically significant additional reduction in mean diurnal IOP compared to treatment with timolol (twice daily) or brimonidine (twice or three times daily) alone.

In a study involving patients whose IOP was inadequately controlled after a 3-week run-in period with any medication, additional mean diurnal IOP reductions of 4.5, 3.3, and 3.5 mm Hg were observed over 3 months of treatment with Combigan® (twice daily), timolol (twice daily), and brimonidine (twice daily), respectively. In this study, statistically significant additional IOP reduction was demonstrated only when compared to brimonidine, but not to timolol, although a positive trend was evident at all time points. A pooled analysis of data from two other studies demonstrated a statistical advantage of Combigan® over timolol.

Additionally, the IOP-lowering effect of Combigan® was not inferior to that achieved with concomitant therapy using brimonidine and timolol (both administered twice daily).

Sustained IOP-lowering effect of Combigan® over 12 months has been demonstrated in double-blind studies.

Pharmacokinetics

Plasma concentrations of brimonidine and timolol in healthy volunteers were determined in a crossover study comparing the individual drugs and Combigan®. There were no statistically significant differences in area under the concentration–time curve (AUC) values between administration of Combigan® and treatment with the individual agents.

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

Brimonidine

After instillation of 0.2% ophthalmic solution, plasma concentrations of brimonidine are very low. Brimonidine undergoes minimal metabolism in ocular tissues. Plasma protein binding is approximately 29%. The elimination half-life (T1/2) after topical administration averages approximately 3 hours. Following oral administration, brimonidine is well absorbed and rapidly eliminated.

The majority of the drug (approximately 74% of the absorbed dose) is excreted by the kidneys as metabolites within 5 days; unchanged drug is not detected in urine. In vitro studies using liver cells from animals and humans indicate that aldehyde oxidase and cytochrome P450 are significantly involved in the metabolic process. Therefore, systemic elimination is primarily determined by hepatic metabolism. Brimonidine forms reversible binding with melanin in ocular tissues without causing adverse effects. Accumulation does not occur in the absence of melanin. Brimonidine is not significantly metabolized in ocular tissues.

Timolol

After topical administration of 0.5% ophthalmic solution to patients undergoing cataract surgery, peak timolol concentration in ocular fluid was 898 ng/mL one hour after administration. The elimination half-life (T1/2) of timolol in plasma is approximately 7 hours. Timolol exhibits minimal plasma protein binding. Timolol is partially metabolized in the liver, and both the active substance and its metabolites are excreted by the kidneys.

Preclinical Safety Data

The ocular and systemic safety profiles of the individual components are well established. Preclinical studies revealed no special hazard for humans in conventional pharmacological safety studies of the individual components, repeated-dose toxicity, genotoxicity, or carcinogenicity. Additional repeated-dose toxicity studies using Combigan® showed no hazard for humans.

Brimonidine

Brimonidine tartrate did not show teratogenic effects in animals. However, it caused abortions in rabbits and reduced postnatal growth in rats at systemic doses approximately 37 and 134 times higher, respectively, than those administered to humans during treatment.

Timolol

In animal studies, beta-adrenergic blockers demonstrated the ability to reduce umbilical blood flow, decrease fetal growth, delay ossification, and increase fetal and neonatal mortality, but without teratogenicity. Embryotoxicity (resorption) in rabbits and fetotoxicity (delayed ossification) in rats were observed with timolol at high maternal doses. Teratogenicity studies in mice, rats, and rabbits using oral doses of timolol up to 4200 times higher than the daily dose of Combigan® in humans showed no congenital anomalies.

Clinical characteristics.

Indications.

Reduction of intraocular pressure (IOP) in patients with chronic open-angle glaucoma and ocular hypertension when topical beta-adrenergic blockers are insufficiently effective.

Contraindications.

Hypersensitivity to any component of the drug.
Increased airway reactivity, including bronchial asthma and episodes of bronchospasm, even in medical history, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sinoatrial node dysfunction syndrome, atrioventricular block, second- or third-degree atrioventricular block without an implanted cardiac pacemaker, cardiac failure, cardiogenic shock.
Concomitant therapy with monoamine oxidase inhibitors (MAOIs), antidepressants affecting noradrenergic transmission (tricyclic antidepressants and mirtazapine).

Interaction with other medicinal products and other types of interactions.

Specific studies on drug interactions of Combigan® have not been conducted. However, the possibility of enhanced effects of medicinal products that depress the central nervous system (alcohol, barbiturates, opioid derivatives, sedatives, or general anesthetics) should be considered during concomitant use with Combigan®.

Potentiation of effects has been reported with concomitant use of ophthalmic solutions containing timolol and calcium channel blockers ("slow" calcium channel blockers), beta-adrenergic blockers, antiarrhythmic agents (including amiodarone), cardiac glycosides, parasympathomimetics, or guanethidine, manifesting as significant reduction in arterial pressure and/or pronounced bradycardia. Also, following brimonidine administration, very rare cases (< 1/10000) of reduced arterial pressure have been reported. Therefore, Combigan® should be used with caution when co-administered with systemically acting antihypertensive agents.

Concomitant use of ophthalmic beta-adrenergic blockers and adrenaline (epinephrine) may lead to the development of mydriasis.

Beta-adrenergic blockers may enhance the hypoglycemic effect of antidiabetic agents. They may also mask signs and symptoms of hypoglycemia (see section "Special precautions for use").

The hypertensive response to abrupt withdrawal of clonidine may be intensified during concomitant use of beta-adrenergic blockers.

Systemic effects of beta-adrenergic blockers (heart rate reduction, depression) may be enhanced when timolol is used concomitantly with CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine).

Concomitant use of beta-adrenergic blockers with general anesthetic agents may mask compensatory tachycardia and increase the risk of arterial hypotension (see section "Special precautions for use"). Therefore, the anesthesiologist must be informed about the patient's use of Combigan®.

Combigan® should be used with caution when administered concomitantly with iodine-containing radiographic contrast agents and during intravenous lidocaine administration.

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

Medicinal products affecting the metabolism and uptake of circulating catecholamines (e.g., chlorpromazine, methylphenidate, reserpine) should be used cautiously due to lack of data on circulating catecholamines after administration of Combigan®.

Concomitant systemic-acting medicinal products (regardless of pharmaceutical form) that may interact with alpha-adrenergic agonists or interfere with their activity, such as adrenergic receptor agonists or antagonists (isoprenaline, prazosin), should be prescribed cautiously (or their dosage adjusted).

Although specific drug interaction studies with Combigan® have not been conducted, there is a theoretical possibility of additive effects in reducing intraocular pressure when used concomitantly with prostamides, prostaglandins, carbonic anhydrase inhibitors, and pilocarpine.

Brimonidine is contraindicated during concomitant use of MAO inhibitors and when using antidepressants affecting noradrenergic neurotransmission (such as tricyclic antidepressants and mirtazapine). Patients who have received MAO inhibitors should not be prescribed Combigan® until 14 days after discontinuation of the MAO inhibitor.

Special precautions for use.

To prevent eye infection and contamination of the eye drops, avoid contact between the dropper tip and any surfaces.

Eye-related side effects.

During clinical trials, ocular allergic reactions (allergic conjunctivitis and allergic blepharitis) were observed in some patients. Allergic conjunctivitis was reported in 5.2% of patients, typically beginning between 3 and 9 months of treatment. Overall, 3.1% of patients discontinued the medication due to this reaction. Allergic blepharitis was reported rarely (<1%). If an allergic reaction occurs, treatment with Combigan® should be discontinued.

Delayed-type hypersensitivity reactions have been reported with the use of 0.2% brimonidine tartrate solution, some of which were associated with elevated intraocular pressure.

Systemic effects.

Like all topically administered ophthalmic drugs, Combigan® may be absorbed systemically. There is no observed increase in systemic absorption of the individual active ingredients. Due to the presence of the beta-adrenergic component, timolol, the same types of adverse reactions as with systemic beta-blockers may occur. The frequency of systemic adverse reactions with topical administration is lower than with systemic administration. For information on reducing systemic absorption, see the section "Dosage and administration".

Cardiac disorders.

Rare cases of cardiac disorders, including fatal outcomes associated with cardiac failure, have been reported following treatment with timolol. Patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal’s angina, and cardiac failure) and those undergoing antihypertensive therapy with beta-blockers should be carefully evaluated, and alternative therapies with different active ingredients should be considered. Patients with cardiovascular diseases should be monitored for signs of worsening conditions and adverse reactions.

Due to the negative effect on conduction time, beta-blockers should be used with caution in patients with first-degree heart block.

As with systemic beta-blockers, if discontinuation of Combigan® is necessary in patients with ischemic heart disease, therapy should be tapered gradually to avoid cardiac arrhythmias, myocardial infarction, or sudden death.

Vascular disorders.

Treatment should be administered with caution in patients with severe peripheral circulatory disorders (e.g., severe forms of Raynaud’s disease or Raynaud’s syndrome).

Respiratory disorders.

Respiratory disorders, including a fatal case due to bronchospasm, have been observed in patients with bronchial asthma after administration of certain ophthalmic beta-blockers.

Combigan® should be used with caution in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and only if the expected benefit outweighs the potential risk.

Hypoglycemia/diabetes mellitus.

Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia or those with labile diabetes mellitus, as beta-blockers may mask the signs and symptoms of acute hypoglycemia.

Hyperthyroidism.

Beta-blockers may mask the signs and symptoms of hyperthyroidism.

Combigan® should be used with caution in patients with metabolic acidosis and pheochromocytoma (without prior treatment).

Corneal disorders.

Ophthalmic beta-blockers may cause dry eyes. They should be used with caution in patients with corneal diseases.

Use with other beta-blockers.

The effect on intraocular pressure or known systemic effects of beta-blockers may be enhanced when timolol is used in patients already taking another systemic beta-blocker. The response to treatment should be closely monitored in such patients. The use of two topical beta-blockers is not recommended.

Anaphylactic reactions.

In patients with atopy or a history of severe anaphylactic reactions to various allergens, treatment with beta-blockers may increase the reaction upon re-exposure to allergens and may result in lack of response to usual doses of adrenaline.

Retinal detachment.

Cases of retinal detachment have been reported with drugs that reduce the production of intraocular fluid (e.g., timolol, acetazolamide) following filtration surgery for glaucoma.

Anesthesia.

Ophthalmic beta-blockers may block the effects of beta-agonists such as adrenaline. The anesthesiologist should be informed about timolol use prior to any planned surgery.

Benzalkonium chloride.

The excipient benzalkonium chloride contained in Combigan® may cause irritation of the ocular mucosa, symptoms of dry eye, and may affect the tear film and corneal surface with prolonged use. Contact lenses must be removed before instillation of Combigan® and may be reinserted 15 minutes after administration.

Benzalkonium chloride is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. Combigan should be used with caution in patients with dry eye and in patients with compromised corneal integrity. Patients should be monitored during prolonged treatment.

The use of Combigan® in patients with closed-angle glaucoma has not been studied.

Hepatic/renal impairment.

Use in these patient groups has not been sufficiently studied; therefore, Combigan should be used with caution in patients with hepatic or renal impairment.

In patients with severe renal dysfunction on hemodialysis, treatment with timolol has been associated with marked reduction in blood pressure.

Phosphate buffer.

Combigan contains phosphates, which in rare cases may lead to corneal deposits due to calcium accumulation during treatment.

Use during pregnancy or breastfeeding.

Controlled studies on the use of Combigan® in pregnant women have not been conducted; therefore, the use of this medication during pregnancy is contraindicated.

Timolol passes into breast milk; therefore, the use of Combigan® during breastfeeding is contraindicated.

Brimonidine tartrate.

There are no adequate data on the use of brimonidine tartrate in pregnant women. Animal studies have shown toxic effects on the reproductive system at high maternal doses. The potential risk to humans is unknown.

Timolol.

Animal studies have shown toxic effects on the reproductive system at doses significantly higher than those used in clinical practice.

Epidemiological studies have not shown an increased risk of congenital malformations, but a risk of intrauterine growth retardation has been demonstrated with oral beta-blockers. Additionally, signs and symptoms of beta-blockade (such as bradycardia, hypotension, respiratory complications, and hypoglycemia) have been observed in newborns whose mothers received beta-blockers before delivery. If Combigan® is used during pregnancy up to delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding

Brimonidine tartrate.

It is unknown whether brimonidine is excreted in human breast milk; however, it is excreted in the milk of lactating rats.

Timolol.

Beta-blockers are excreted in breast milk. However, it is unlikely that the doses of timolol in eye drops are sufficient to result in significant passage into breast milk or to cause clinical symptoms of beta-blockade in infants. For information on reducing systemic absorption, see the section "Dosage and administration".

Combigan® should not be used in women who are breastfeeding.

Ability to affect driving and operating machinery.

Combigan® has a minor influence on the ability to drive vehicles or operate machinery. Blurred vision, weakness, and drowsiness may occur transiently after administration of Combigan®, which may impair reaction speed. If such symptoms occur, patients should refrain from activities requiring high attention.

Method of Administration and Dosage

Recommended Dosages for Adults (including elderly patients)

Recommended dose: one drop of Combigan® in the affected eye twice daily, approximately 12 hours apart. When using two or more ophthalmic products, a 5-minute interval between instillations is required.

Method of Administration

As with other ophthalmic drops, to reduce potential systemic absorption, it is recommended to apply brief pressure on the lacrimal sac at its projection near the inner canthus of the eye or to close the eyelids for 2 minutes immediately after each instillation. This may reduce systemic adverse reactions and enhance local effect.

Children

The safety and efficacy of Combigan® in children have not been established; therefore, it should not be used in pediatric practice.

Overdose

Overdose with Combigan® in humans has rarely been reported and did not result in adverse reactions. Management of overdose includes supportive and symptomatic therapy. Maintenance of the patient's respiration should be ensured.

Brimonidine

Overdose with topical administration

Cases have been observed as already described in the section "Adverse Reactions".

Overdose following accidental oral ingestion (adults)

Very limited information is available regarding accidental brimonidine overdose in adults. Only one case has been documented, which resulted in arterial hypotension. Following this episode of arterial hypotension, a "rebound" hypertension was observed.

In overdose cases with alpha2-adrenergic agonists, the following symptoms have been reported: decreased blood pressure, asthenia, vomiting, somnolence, sedation, bradycardia, arrhythmia, miosis, apnea, hypotonia, hypothermia, respiratory depression, and seizures.

Timolol

Symptoms of systemic timolol overdose are similar to those observed with systemic beta-adrenergic blockers: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, and cardiac arrest.

Timolol is not completely eliminated by hemodialysis.

Adverse Reactions

According to data from a 12-month clinical study, the most commonly reported adverse effects were ocular conjunctival hyperemia (approximately 15% of patients) and ocular burning sensation (approximately 11% of patients). In most cases, these symptoms were mild in intensity; discontinuation of therapy was required in only 3.4% and 0.5% of cases, respectively.

The frequency of adverse reactions was defined as follows: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000).

Ocular disorders:

very common – ocular conjunctival hyperemia, burning sensation;
common – acute burning or stinging eye pain, allergic conjunctivitis, corneal erosion, superficial keratitis, eyelid skin pruritus, conjunctival folliculitis, visual disturbance, blepharitis, epiphora, dryness of ocular mucosa, eye discharge, eye pain, ocular mucosa irritation, foreign body sensation;
uncommon – decreased visual acuity, conjunctival edema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, floaters in the vitreous body, asthenopia, photophobia, ocular papillary muscle hypertrophy, eyelid tenderness, conjunctival pallor, corneal edema, corneal infiltrates, vitreous rupture.

Psychiatric disorders:

common – depression.

Nervous system disorders:

common – somnolence, headache;
uncommon – dizziness, syncope.

Cardiovascular disorders:

common – arterial hypertension;
uncommon – congestive heart failure, cardiac arrhythmia.

Respiratory system disorders:

uncommon – rhinitis, nasal mucosa dryness.

Gastrointestinal disorders:

common – dryness of oral mucosa;
uncommon – taste disturbance, nausea, diarrhea.

Skin and subcutaneous tissue disorders:

common – eyelid edema, eyelid skin pruritus, eyelid erythema;
uncommon – allergic contact dermatitis.

General disorders and administration site conditions:

common – asthenic conditions.

During the post-marketing period for Combigan® additional adverse reactions have been reported:

Ocular disorders:

frequency unknown – blurred vision.

Cardiovascular disorders:

frequency unknown – arrhythmia, bradycardia, tachycardia, arterial hypotension.

Skin disorders:

frequency unknown – facial skin redness.

Adverse reactions observed during use of one of the active substances, which may also occur during use of Combigan®:

Brimonidine

Ocular disorders: iritis, iridocyclitis (anterior uveitis), miosis.

Psychiatric disorders: insomnia.

Respiratory disorders: upper respiratory tract inflammatory diseases, dyspnea.

Gastrointestinal disorders: gastrointestinal symptoms.

General disorders and administration site conditions: systemic allergic reactions.

Skin and subcutaneous tissue disorders: skin reactions, including facial skin redness, facial skin edema, pruritus, rash, and vasodilation.

Immune system disorders: hypersensitivity.

When brimonidine was used in combination with other medications for the treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, arterial hypotension, hypotension, bradycardia, hypothermia, cyanosis, pallor, respiratory depression, and apnea were reported in newborns and children under 2 years of age.

High frequency and severe degrees of somnolence have been reported in children aged 2 years and older, particularly in children aged 2–7 years and in children with body weight ≤ 20 kg.

Timolol

Like other topical ophthalmic agents, Combigan® (brimonidine tartrate/timolol) can enter the systemic circulation. Absorption of timolol may cause adverse effects similar to those observed with systemic beta-adrenergic blockers. The frequency of systemic adverse effects after topical administration is lower than with systemic administration.

Additional adverse reactions have been observed with the use of ophthalmic beta-adrenergic blockers, and there is potential for these to occur with the use of Combigan®:

Immune system disorders: systemic allergic reactions, including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reactions, systemic lupus erythematosus.

Endocrine disorders: hypoglycemia, masking of hypoglycemic symptoms in patients with diabetes mellitus.

Psychiatric and nervous system disorders: loss of consciousness, dizziness, headache, insomnia, nightmares, memory loss, stroke, worsening of myasthenia gravis symptoms, paresthesia, cerebral ischemia, hallucinations, behavioral changes and psychiatric disorders including confusion, hallucinations, restlessness, disorientation, nervousness.

Ocular disorders: signs and symptoms of eye irritation (burning sensation, sharp pain, itching, lacrimation, redness), blepharitis, blurred vision, dry eye sensation, keratitis, decreased corneal sensitivity, diplopia, ptosis, uveal rupture (after filtration surgery), corneal erosion, cystoid macular edema, pseudopemphigoid, conjunctivitis.

Aural disorders: tinnitus.

Cardiovascular disorders: bradycardia, palpitations, congestive heart failure, chest pain, atrioventricular heart block, heart failure, heart block, cardiac arrest, arrhythmia, cerebral ischemia, stroke, intermittent claudication, edema, pulmonary edema, worsening of angina pectoris, arterial hypotension, Raynaud's syndrome, cold extremities, loss of consciousness.

Respiratory disorders: bronchospasm (predominantly in patients with a history of bronchospastic disorders), dyspnea, cough, respiratory insufficiency, nasal congestion, upper respiratory tract infection.

Gastrointestinal disorders: diarrhea, dysgeusia, nausea, dry mouth sensation, dyspepsia, vomiting, abdominal pain, anorexia.

Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis, skin rashes.

Musculoskeletal, connective tissue and bone disorders: myalgia.

Renal and urinary disorders: Peyronie's disease, peripheral edema.

Genital disorders: sexual dysfunction, decreased libido, retroperitoneal fibrosis.

General disorders and administration site conditions: asthenia/increased fatigue.

Adverse reactions to ophthalmic solutions containing phosphates.

Very rarely, corneal calcification associated with the use of ophthalmic solutions containing phosphates has been reported in patients with significantly damaged corneas.

Shelf life: 1 year 9 months.

The shelf life of the medicinal product after first opening the dropper bottle is 28 days.

Storage conditions:

Store in the original packaging, protected from light, at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging:

5 mL of the medicinal product in a low-density polyethylene dropper bottle with a capacity of 10 mL, closed with a cap made of impact-resistant polystyrene. One or three dropper bottles, together with the instruction for medical use, are packed in a cardboard box.

Prescription status:

Prescription only.

Manufacturer/Marketing Authorization Holder:

Allergan Pharmaceuticals Ireland.

Address of manufacturer and/or marketing authorization holder:

Castlebar Road, Westport, Co. Mayo, F28 AW83, Ireland.