Glaucopt 20 mg/ml + 5 mg/ml eye drops, solution in single-dose-container – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Glaucopt 20 mg/ml + 5 mg/ml eye drops, solution in single-dose-container

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).

Single dose container

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Eye drops, solution.

Colourless or slightly yellow, viscous solution, with a pH between 5.4 and 5.8, and a Osmolality of 270-325 mOsmol/kg.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Indicated in the treatment of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or pseudoexfoliation glaucoma, when topical beta- blockers for monotherapy use is not sufficient.

4.2 Posology and method of administration

Posology

The dose is one drop of Glaucopt in the conjunctival sac of each affected eye two times daily.

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

This medicinal product is a sterile solution that does not contain preservatives.

Patients should be instructed to wash their hands before use and avoid allowing the tip of the container to come into contact with the eye or surrounding structures as this could cause injury to the eye.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients should be informed of the correct handling of the containers.

Method of administration

1. 1. Wash your hands
2. 2. Open the container. Take special care that the tip of the dropper container does not touch your eye, the skin around your eye or your fingers.
3. 3. Tilt your head backwards and hold the container upside down over the eye.
4. 4. Pull the lower eyelid downwards and look up. Hold and gently squeeze the container on the flattened sides of the container and let one drop fall into the space between the lower eyelid and the eye.
5. 5. Close your eye and press the inner corner of the eye with your finger for about two minutes. When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.
6. 6. Repeat steps 3 to 5 with the other eye if instructed to do so by your doctor.

Single-dose-container

This medicine is a sterile solution with no preservatives. The solution in each single-dose container must be used immediately after opening on the affected eye(s). Since sterility cannot be guaranteed after opening the single-dose container, any residues of the contents must be discarded immediately after use.

Paediatric population

The efficacy in paediatric patients has not been established. Safety in paediatric patients below 2 years of age has not been established. (For information regarding safety in paediatric patients ≥2 and <6 years of age, see section 5.1).

4.3 Contraindications

Glaucopt 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 airway diseases, 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 atrioventricular block not controlled with a pacemaker, overt cardiac failure, cariogenic shock.
• Severe renal impairment (creatinine clearance <30 ml/min) or hyperchloraemic acidosis.

The above are based on the components and are not unique to the combination.

4.4 Special warnings and precautions for use

Cardiovascular / respiratory reactions

Like other topically applied ophthalmic agents timolol maleate is absorbed systemically.

Due to beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur.

Incidence of systemic ADRs after topical 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 cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and therapy with other active substances should be considered. Patients with cardiovascular disease should be watched for signs of deterioration of these diseases and adverse reactions.

Due to its negative effect on conduction time, beta-blockers should only be given 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 patients with asthma, have been reported following administration of some ophthalmic beta-blockers.

Glaucopt 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

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

Immunology and Hypersensitivity

As with other topically applied ophthalmic agents, this medicinal product may be absorbed systemically. Dorzolamide contains a sulfonamide group, which also occurs 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.

If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

Local Occular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops have been seen with this medicinal product. If such reactions occur, discontinuation of this medicinal product should be considered.

While taking beta-blockers patients with a history of atopy or severe anaphylactic reaction to a variety of allergens, may be more reactive to repeated challenge with such allergens and may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

Concurrent therapy

The effect on intra-ocular pressure or the known effects of a systemic beta-blockade may be potentiated when timolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be clearly observed. The use of two topical beta-adrenergic blocking agents 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 needed in patients with coronary heart disease, therapy should be withdrawn 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 labile diabetes as beta- blockers may mask the signs and symptoms of acute hypoglycaemia.

Hyperthyroidism

Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block the systemic effects of beta-agonists e.g. adrenaline. The anesthesiologist should be informed when the patient is receiving timolol.

Therapy with beta-blockers may aggravate the symptoms of myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base disturbances have been observed with this medicinal product, urolithiasis has been reported infrequently.

Because Gluacopt contains a topical carbonic anhydrase inhibitor that is absorbed systemetically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while using this medicinal product.

Other

The management of patients with acute closed-angle glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. This medicinal product has not been studied in patients with acute angle-closure glaucoma.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal defects and/or history of intraocular surgery, while using dorzolamide. There is an increased potential for developing corneal oedema in patients with a low endothelial cell count. Precautions should be used when prescribing Glaucopt to these group of patients.

Choroidal detachment has been reported with administration of aqueous suppressant therapies (e.g. timolol, acetazolamide), after filtering procedures.

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

Benzalkonium chloride

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.

Use of contact lenses

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

Paediatric population

See section 5.1.

4.5 Interaction with other medicinal products and other forms of interaction

Specific medicine interaction studies have not been performed with Glaucopt.

In clinical studies, eye drops based on dorzolamide and timolol were used concurrently with the following systemic medications without evidence of adverse interactions: ACE inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory medicines including aspirin, and hormones (e.g estrogen, insulin, thyroxine).

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic betablocker solution is administered concomitantly with oral calcium blocker, catecholamine depleting medicines or beta adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics and monoamine oxidase (MAO) inhibitors

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

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

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

Oral beta-adrenergic blocking agents may exacerbate rebound hypertension which may follow the withdrawal of clonidine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Glaucopt should not be used during pregnancy.

Dorzolamide

No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effects at maternotoxic doses (see section 5.3).

Timolol

There are no adequate data for the use of timolol in pregnantwomen. Timolol should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects but show a risk of intra-uterine growth retardation when beta-blockers are administered by the oral route. 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 this medicinal product is administered until delivery, the neonate should be carefully monitored during the first few days of life.

Breast-feeding

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

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

If treatment with Glaucopt is required then lactation is not recommended.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Possible side effects, such as blurred vision, may affect some paitients ability to drive and/or operate machines.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials with Glaucopt 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 Glaucopt 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):

Not Known **

itch

hypoglycae mia

sensation of a foreign body in the eye

photophobia

itching,

tearing,

redness,

blurred

vision,

erosion of the cornea

atrioventricu lar block, heart failure

Palpitations, tachycardia

hypertension

dyspnoea

dyspnoea*

dysgeusia, abdominal pain,

vomiting

skin rash

myalgia

sexual dysfunction

* These adverse reactions were also observed with Dorzolamide Timolol eye drops solution during post-marketing experience.

** Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with DORZOLAMIDE/TIMOLOL eye drops solution.

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 Glaucopt.

Symptoms

There have been reports of inadvertent overdoses with timolol maleate ophthalmic solution, resulting in systemic effects similar to those observed with systemic 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 overdose of dorzolamide are electrolyte imbalance, development of an acidosis state and possibly central nervous system effects.

Only limited information is available with regards to human overdose by accidental or deliberate ingestion of dorzolamide hydrochloride. With oral ingestion somnolence has been reported. With topical application, the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams 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 does not dialyse readily.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Glaucopt is comprised of two active substances: dorzolamide hydrochloride and timolol maleate. Each of these active substances decreases the elevated intraocular pressure by reducing aqueous humour secretion but does so by a different mechanism of action.

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

Following topical administration, this medicinal product reduces elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field of glaucomatous visual field loss. this medicinal product reduces intraocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical studies of up to 15 months duration were conducted to compare the IOP lowering effect of Glaucopt b.i.d. (dosed morning and bedtime) to individually- and concomitantly administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension, for whom the concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy.

The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies the IOP lowering effect of Glaucopt, b.i.d. was greater than that of monotherapy with 2.0% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP lowering effect of Glaucopt, b.i.d. was equivalent to that of the concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of Glaucopt, solution b.i.d. in IOP reduction was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Peadiatric population

A 3-month controlled study with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under 6 and greater than or equal to 2 years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received Glaucopt in an open label phase.

Efficacy in these patients has not been established. In this small group of patients, twice daily administrations of Glaucopt were generally well tolerated, with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication 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 less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base balance disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, the active substance and metabolites concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in the RBCs during chronic dosing as a result of selective binding to CA-II, while extremely low concentrations of free active substance in plasma are maintained. The parent active substance formsa single N-desethyl metabolite that inhibits CA-II less potently than the parent active substance, but also inhibits a less active isoenzyme (CA-I ). The metabolite also accumulates in the RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of active substance concentration initially, followed by a slower elimination phase, with a half-life of about 4 months.

When dorzolamide was given orally simulate the maximum systemic exposure after long-term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; the CA inhibition in RBCs was less than that anticipated to be necessary for a 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 meaningful differences in carbonic anhydrase inhibition, and clinically significant systemic side effects were directly attributable to this finding.

Timolol maleate

In a study of plasma active substance concentrations in 6 subjects, the systemic exposure to Timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. 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 given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed.

Timolol

Animal studies have not shown teratogenic effect.

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Single-dose containers:

Mannitol (E421)

sodium citrate (E331)

hydroxyethyl cellulose

sodium hydroxide (E524, for pH adjustment)

water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

Glaucopt 20 mg/ml + 5 mg/ml eye drops, solution - single-dose containers

After opening the aluminum bag, use the containers within 7 days. Any unused containers must be discarded. The single-dose container must be used immediately after opening; the remaining medicinal product must be discarded.

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 container

Glaucopt 20 mg/ml + 5 mg/ml eye drops, solution - single dose containers Pack of 30, 60, 90 or 120 single-dose polyethylene containers, each containing 0.166 ml of solution. Pack contains 6, 12, 18 or 24 pouches, each pouch containing one strip of 5 single-dose containers.

Not all pack sizes may be marketed.

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

VISUfarma UK Ltd

4230 Park Approach,

Thorpe Park

Leeds

LS15 8GB

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 52223/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

11/08/2021

10 DATE OF REVISION OF THE TEXT

24/09/2026