GLAUCOPT 20 MG / ML + 5 MG / ML EYE DROPS SOLUTION - summary of medicine characteristics

Glaucopt 20 mg/ml + 5 mg/ml eye drops, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 20 mg dorzolamide (equivalent to 22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (equivalent to 6.83 mg of timolol maleate).

Multi-dose-container

Excipients with known effect:

Each ml of eye drops solution contains 0.075 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Eye drops, solution.

Colourless to slightly yellow, viscous solution.

4.1 Therapeutic indications

Treatment of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or pseudoexfoliation glaucoma, when monotherapy with betablockers for topical use is not sufficient.

4.2 Posology and method of administration

Posology

The dose is one drop of VisuCOPT in the conjunctival sac of each affected eye twice a day.

Paediatric population

The efficacy in paediatric patients has not been established. Safety in paediatric patients below 2 years of age has not been established. Current available data on the safety profile in paediatric patients > 2 and < 6 years of age, are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

If another topical ophthalmic agent is being used, VisuCOPT and the other agent should be administered at least 10 minutes apart.

Patients should wash their hands before use and prevent the tip of the dropper from coming into contact with the eye or surrounding areas.

Patients should also be informed that ophthalmic solutions, if handled improperly, can become contaminated by common bacteria that are known to cause eye infections.

The use of infected solutions can cause serious damage to the eye and may result in subsequent loss of vision.

Pressing a finger into the corner of the eye or eyelid closure for 2 minutes reduces systemic absorption resulting in lower occurrence of systemic adverse reactions and increased local activity.

4.3 Contraindications

VisuCOPT is contraindicated in patients with:

Hypersensitivity to one or both of the active substances or any of the excipients listed in section 6.1.

Reactive diseases of the airways, including bronchial asthma or a history of a bronchial asthma, or severe chronic obstructive pulmonary disease.

Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree non-controlled atrioventricular block not controlled with a pacemaker, overt cardiac failure, cariogenic shock.

Severe renal impairment (creatinine clearance <30 ml/min) or hyperchloraemic acidosis.

The contraindications listed above are based on the active substances and are not unique to the combination.

4.4 Special warnings and precautions for use

Cardiovascular / respiratory reactions

Timolol maleate is absorbed systemically. The active substance timolol maleate is a beta-blocker, therefore, with topical administration the same types of cardiovascular, pulmonary and other adverse reactions may occur with systemic administration of beta-blockers.

The incidence of systemic adverse drug reactions after topical ophthalmic administration is lower than for systemic administration. To reduce systemic absorption, see section 4.2.

Cardiac disorders

In patients with cardiovascular disease (e.g., coronary heart disease, Prinzmetal angina and heart failure) and hypotension, beta-blocker therapy should be critically evaluated and therapy with other active substances should be considered. Patients with cardiovascular disease should be monitored for signs of deterioration of these diseases and adverse reactions.

Due to the adverse effect on conduction time, beta-blockers should always be administered with caution to patients with first-degree heart block.

Vascular diseases

Patients with severe peripheral circulation disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Respiratory disorders

Respiratory reactions, including death due to bronchospasm in asthmatic patients, have been reported following administration of some ophthalmic beta-blockers.

VisuCOPT should be used with caution in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

Hepatic impairment

VisuCOPT has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

Immunology and Hypersensitivity

VisuCOPT may be absorbed systemically. Dorzolamide contains a sulfonamide group, which is also found in sulfonamides. Therefore, the same types of adverse reactions found with systemic administration of sulfonamides may occur with topical administration, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue use of this preparation if signs of severe or hypersensitive reactions occur.

Adverse ocular reactions similar to those observed with dorzolamide hydrochloride eye drops were observed with the use of eye drops based on dorzolamide and timolol. If such reactions occur, discontinuation of therapy with this medicinal product should be considered.

Patients with a history of atopy or severe anaphylactic reaction to a variety of allergens, while taking beta-blockers, may be more reactive to an accidental, diagnostic or therapeutic repeated challenge to such allergens and may not respond to the usual doses of adrenaline used to treat anaphylactic reactions.

Concurrent therapy

The effect on IOP or known effects of a systemic beta-blockade may be enhanced when timolol maleate is administered to patients already taking a systemic beta-blocking agent. The response of these patients should be monitored carefully. The use of two beta-adrenergic blocking agents for topical use is not recommended (see section 4.5).

The use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Withdrawal of therapy

As with systemic beta-blockers, if discontinuation of ophthalmic timolol is required in patients with coronary heart disease, therapy should be discontinued gradually.

Additional effects of beta-blockade

Hypoglycemia/Di­abetes

Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with unstable diabetes as betablockers may mask the signs and symptoms of acute hypoglycaemia.

Hyperthyroidism

Therapy with beta-blockers can mask the signs of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may accelerate a worsening of symptoms.

Corneal diseases

Ophthalmic beta-blockers may induce dry eyes. Patients with diseases of the cornea should be treated with caution.

Surgical anaesthesia

Ophthalmologic preparations containing beta-blockers may block the systemic effects of beta-agonists e.g. adrenaline. The anaesthetist should be informed when the patient is receiving timolol maleate.

Beta-blocker therapy may exacerbate the symptoms of myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

In patients with a previous history of kidney stones, oral carbonic anhydrase inhibitor therapy has been associated with urolithiasis as a result of the alteration of acid-base balance. Although no changes in acid-base balance were observed with VisuCOPT, urolithiasis was infrequently reported.

VisuCOPT contains a topical carbonic anhydrase inhibitor that is systemically absorbed, therefore, patients with a previous history of kidney stones may be at greater risk for urolithiasis while using VisuCOPT.

Other

Management of patients with closed-angle glaucoma in the acute phase requires therapeutic interventions in addition to ocular hypotensive agents. VisuCOPT has not been studied in patients with acute angle-closure glaucoma.

In patients with pre-existing chronic corneal changes and/or history of intraocular surgery, corneal oedema and irreversible corneal decompensation with dorzolamide has been reported. There is an increased potential for

developing corneal oedema in patients with a low endothelial cell count.

Topical dorzolamide should be used with caution in this group of patients.

With the administration of aqueous suppressant therapy (e.g. timolol, acetazolamide), concomitant choroidal detachment to ocular hypotonia has been reported after filtering procedures.

As with the use of other antiglaucoma drugs, reduced responsiveness to ophthalmic timolol maleate after prolonged therapy has been reported in some patients. However, in clinical trials in which 164 patients were followed for at least 3 years, no significant differences in mean IOP were observed after initial stabilisation.

Use of contact lenses

VisuCOPT eye drops, contains the preservative benzalkonium chloride 0.075 mg/ml, equivalent to 0.375 mg / 5 ml. Benzalkonium chloride is known to discolour soft contact lenses. Contact lenses should be removed prior to application and the patient should wait at least 15 minutes before reinsertion.

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where the cornea may be compromised.

Patients should be monitored in case of prolonged use.

Paediatric population

See section 5.1.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed.

In clinical studies, eye drops based on dorzolamide and timolol were used concurrently with the following systemic therapies without evidence of undesired interactions: ACE inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (such as oestrogen, insulin, thyroxine).

There is potential for additive effects that may result in marked hypotension and/or bradycardia when thymol-malolactic ophthalmic solution is coadministered with oral calcium antagonists, drugs that cause catecholamine or beta blocker depletion, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomi­metics, guanethidine, narcotics and monoamine oxidase inhibitors (MAOIs).

During concomitant treatment with CYP2D6 inhibitors (e.g. quinidine, SSRI) and timolol, systemic beta-blockade (e.g. , decreased heart rate, depression) has been reported.

Although eye drops solution based on dorzolamide and timolol alone has little or no effect on the pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and epinephrine (adrenaline) has been reported occasionally.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic drugs.

Oral beta-blockers may exacerbate rebound hypertension which may result from the withdrawal of clonidine.

4.6 Fertility, pregnancy and lactation

Pregnancy

VisuCOPT should not be used during pregnancy.

Dorzolamide

No data on exposure to treatment during pregnancy are available. In rabbits, dorzolamide produced teratogenic effects at toxic maternal doses (see section 5.3).

Timolol

No data from the use of timolol maleate in pregnant women are available. Timolol maleate should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section 4.2.

Epidemiological studies have not shown malformative effects but show a risk of intra-uterine growth retardation when beta-blockers are administered orally. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in neonates when beta-blockers have been administered until delivery.

If VisuCOPT is administered until delivery, the neonate should be monitored closely during the first few days of life.

Breast-feeding

Dorzolamide

It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide, a reduction in body weight gain of offspring was observed.

Timolol

Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol maleate in eye drops it is not likely that sufficient amounts are present in breastmilk to produce beta-blocking symptoms in the infant. To reduce systemic absorption, see section 4.2.

Breast-feeding is not recommended if treatment with VisuCOPT is necessary.

4.7 Effects on ability to drive and use machines

VisuCOPT has minor influence on the ability to drive and use machines.

Possible adverse reactions, such as transient blurred vision, may interfere with the ability of some patients to drive and/or use machines.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials with VisuCOPT eye drops, the adverse reactions observed were consistent with those previously reported with dorzolamide hydrochloride and/or timolol maleate.

During clinical trials, 1035 patients were treated with eye drops based on dorzolamide and timolol. Approximately 2.4% of all patients discontinued therapy with this medicinal product due to local ocular adverse reactions, approximately 1.2% of all patients discontinued therapy due to local adverse reactions indicative of allergy or hypersensitivity (such as inflammation of the eyelid and conjunctivitis).

Timolol maleate is absorbed into the systemic circulation. This can cause adverse reactions similar to those seen with systemic beta-blocking agents. The incidence of systemic adverse drug reactions after topical ophthalmic administration is lower than for systemic administration.

Tabulated summary of adverse reactions

The following adverse reactions have been reported with VisuCOPT or one of its active substances during clinical trials or in the post-marketing setting.

Very common: (>1/10), Common: (>1/100 to <1/10), Uncommon: (>1/1,000 to <1/100), Rare: (>1/10,000 to <1/1,000), Very rare: (<1/10,000), Not known (cannot be estimated from the available data):

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No data are available in humans in regard to overdose by accidental or intentional ingestion of VisuCOPT eye drops, solution.

Symptoms

Cases of involuntary overdose with the ophthalmic solution of timolol maleate have been reported, resulting in systemic effects similar to those observed with systemically administered beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm and cardiac arrest. The most common signs and symptoms to be expected with dorzolamide overdose are alteration of the electrolyte balance, development of a state of acidosis and possible effects on the central nervous system.

Only limited information is available on the overdose of accidental or voluntary ingestion of dorzolamide hydrochloride in humans. Drowsiness with oral ingestion has been reported. With topical application, the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreaming and dysphagia.

Treatment

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol is not readily dialysed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiglaucoma and miotic preparations, Betablocking agents, Timolol, Combinations, ATC code S01E D51.

Mechanism of action

VisuCOPT is comprised of two active substances: dorzolamide hydrochloride and timolol maleate. Each of these active substances reduces the high IOP by decreasing the secretion of aqueous humour but does so by a different mechanism of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. The inhibition of carbonic anhydrase in the ciliary processes of the eye reduces aqueous humour secretion presumably by slowing the formation of bicarbonate ions, with a subsequent reduction in the transport of sodium and fluids. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering IOP has not been clearly established, although a study with fluorescein and tonography studies indicate that the predominant action may be related to the reduced formation of aqueous humour. However, in some studies a slight increase in the ease of outflow was also observed. The combined effect of these two active substances results in additional reduction in IOP when compared with either of the active substances administered alone.

Following topical administration, VisuCOPT reduces elevated IOP, whether or not associated with glaucoma. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and loss of the visual field of glaucomatous. VisuCOPT reduces IOP without the common adverse reactions of miotic agents such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical efficacy and safety

Clinical studies of up to 15 months have been performed to compare the effect on the IOP reduction of VisuCOPT eye drops, solution b.i.d. (administered in the morning and before going to bed) against timolol 0.5% and dorzolamide 2.0% administered individually and concomitantly in patients with glaucoma or ocular hypertension, for whom the concomitant therapy was considered appropriate in the studies. This included both untreated patients and patients not adequately controlled by timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy before enrolling into the study. In an analysis of the combined studies the effect of VisuCOPT eye drops, solution b.i.d. in the reduction of IOP was greater than that of monotherapy with Dorzolamide 2.0% t.i.d. or Timolol 0.5% b.i.d. The effect of VisuCOPT eye drops, solution b.i.d. in the reduction of IOP was equivalent to that of the concomitant therapy with Dorzolamide b.i.d. and Timolol b.i.d. The effect of VisuCOPT eye drops, solution b.i.d. in IOP reduction was demonstrated when measured at various predefined time points throughout the day and this effect was maintained during long-term administration.

Peadiatric population

A 3-month controlled study was conducted, the primary objective of which was to document the safety of 2.0% dorzolamide hydrochloride ophthalmic solution in children under 6 years of age. In this study, 30 patients younger than 6 years and above or equal to 2 years, whose IOP was not adequately controlled with dorzolamide or timolol monotherapy, received

VisuCOPT eye drops, in an open-label study. The efficacy in these patients has not been established. In this small group of patients, the administration of VisuCOPT twice a day was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, change in therapy or other reasons.

5.2 Pharmacokinetic properties

Dorzolamide hydrochloride

Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows the active substance to exert its effects directly in the eye at substantially lower doses and therefore with lower systemic exposure. In clinical studies, this resulted in a reduction in IOP without altering the acid-base balance or alterations in the electrolytes characteristic of oral carbonic anhydrase inhibitors.

When applied topically, dorzolamide reaches the systemic circulation. To evaluate the potential for inhibition of systemic carbonic anhydrase after topical administration, the concentrations of the active substance and metabolites in red blood cells and plasma were measured, as well as the inhibition of carbonic anhydrase in red blood cells. Dorzolamide accumulates in the red blood cells during chronic administration as a result of selective binding to type II (CA-II) carbonic anhydrase, while extremely low free active substance concentrations are maintained. From the active parent substance, a single N-desethyl metabolite is formed that inhibits CA-II in a less potent manner than the active parent substance, but also inhibits a less active CA-I isoenzyme. The metabolite also accumulates in the red blood cells where it is mainly bound to CA-I. Dorzolamide is moderately bound to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. At the end of the therapy, dorzolamide is eliminated from the red cells in a non-linear way, with a rapid initial decline in the concentration of the active substance followed by a slower elimination phase, with a half-life of about 4 months.

When dorzolamide was administered orally in order to simulate the maximum systemic exposure after long-term topical ocular administration, steady state was reached within 13 weeks. In the plasma, at steady state, there was virtually no free active substance or metabolite present; the inhibition of CA in the red blood cells was less than was thought necessary to obtain a pharmacological effect on renal or respiratory function. Similar pharmacokinetic results were observed after chronic topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (creatinine clearance estimated to be 30 to 60 ml/min) had higher concentrations of the metabolite in red blood cells, but no significant differences in carbonic anhydrase inhibition, and clinically significant systemic adverse reactions were not directly attributable to this finding.

Timolol maleate

In a study looking at plasma concentrations of the active substance in 6 subjects, the systemic exposure to Timolol was determined after twice daily topical administration of 0.5% timolol maleate ophthalmic solution. The mean peak plasma concentration following the morning dose was 0.46 ng/ml and following the evening dose was 0.35 ng/ml.

5.3 Preclinical safety data

The ocular and systemic safety profile of the individual active substances is well established.

Dorzolamide

In rabbits treated with maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the bodies of the vertebrae were observed.

Timolol

Animal studies have not shown teratogenic effect.

Furthermore, no adverse eye effects were observed in animals treated topically with ophthalmic solutions of dorzolamide hydrochloride and timolol maleate or with dorzolamide hydrochloride and timolol maleate administered concomitantly. In vitro and in vivo studies with each of the active substances did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of VisuCOPT eye drops solution.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

5.0 ml multidose bottle:

Mannitol (E421)

sodium citrate (E331) hydroxyethyl cellulose benzalkonium chloride sodium hydroxide (E524, for pH adjustment) water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After opening the bottle use within 28 days; after this period the remaining medicinal product must be discarded. Report the opening date in the space provided on the box.

6.4 Special precautions for storage

Store in the original package in order to protect from light.

Do not store above 25°C

6.5 Nature and contents of containerVisuCOPT 20 mg/ml + 5 mg/ml eye drops, solution - 5.0 ml bottle

Pack of one polyethylene bottle containing 5.0 ml.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

TurnKey PharmaConsulting Ireland Limited

Ellerman House,

Cratloe Wood, Cratloe,

County Clare, V95 X925

Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 52033/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/08/2021