4.1. Therapeutic indications

Indicated in the treatment of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

4.2. Posology and method of administration

Posology

The dose is one drop of Dorzolamide/ Timolol eye drops in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic agent is being used, Dorzolamide/ Timolol eye drops and the other agent should be administered at least ten minutes apart.

This medicinal product is a sterile solution that does not contain a preservative. The solution from one individual single-dose container is to be used immediately after opening for administration to the affected eye(s).

Since sterility cannot be maintained after the individual single-dose container is opened, any remaining contents must be discarded immediately after administration.

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

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.

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.

Instructions for use

Patients should be informed of the correct handling of the single-dose container. Please see section 6.6 for specific diagrams and instructions for use.

Paediatric population

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of 2 years has not been established. Currently available data regarding safety in paediatric patients ≥ 2 and < 6 years of age are described in section 5.1)

4.3. Contraindications

Dorzolamide/ Timolol eye drops are contraindicated in patients with:

• reactive airway disease, including bronchial asthma or a history of 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 pacemaker, overt cardiac failure, cardiogenic shock

• severe renal impairment (CrCl < 30 ml/min) or hyperchloraemic acidosis

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

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 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 ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Cardiac disorders:

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension therapy with beta- blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of 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 disorders:

Patients with severe peripheral circulatory disturbance/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.

Dorzolamide/ Timolol eye drops 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

This medicinal product 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 sulfonamido 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 ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with this medicinal product. If such reactions occur, discontinuation of Dorzolamide/ Timolol eye drops should be considered.

While taking beta-blockers, patients with a history of atopy or a history of 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 doses of adrenaline used to treat anaphylactic reactions.

Concomitant Therapy

The effect on intra-ocular pressure or the known effects of 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 closely 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

Hypoglycaemia/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.

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 systemic beta- agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

Therapy with beta-blockers may aggravate 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 Dorzolamide/ Timolol eye drops (preserved formulation), urolithiasis has been reported infrequently. Because Dorzolamide/ Timolol eye drops contains a topical carbonic anhydrase inhibitor that is absorbed systemically, 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 angle-closure 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 a history of intraocular surgery while using dorzolamide. There is an increased potential for developing corneal oedema in patients with low endothelial cell counts. Precautions should be used when prescribing Dorzolamide/ Timolol eye drops to these groups of patients.

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

As with the use of other antiglaucoma medicines, 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 three years, no significant difference in mean intraocular pressure has been observed after initial stabilisation.

Contact Lens Use

This medicinal product has not been studied in patients wearing 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 this medicine.

In a clinical study, Dorzolamide/ Timolol eye drops (preservative free) was used concomitantly 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., oestrogen, insulin, thyroxine).

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, catecholamine-depleting medicines or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, quanethidine, 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 dorzolamide/timolol (preserved formulation) alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic beta- blockers and adrenaline (epinephrine) has been reported occasionally.

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

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Dorzolamide/ Timolol eye drops should not be used during pregnancy.

Dorzolamide

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

Timolol

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

Epidemiological studies have not revealed malformative effects but show a risk for 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 the neonate 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 days of life.

Breast-feeding

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

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce systemic absorption, see section 4.2. If treatment with Dorzolamide/ Timolol eye drops 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 patients' ability to drive and/or operate machinery.

4.8. Undesirable effects

In a clinical study for Dorzolamide/ Timolol eye drops (preservative free) the observed adverse reactions have been consistent with those that were reported previously with Dorzolamide/ Timolol eye drops (preserved formulation), dorzolamide hydrochloride and/or timolol maleate.

During clinical studies, 1035 patients were treated with Dorzolamide/ Timolol eye drops (preserved formulation). Approximately 2.4% of all patients discontinued therapy with Dorzolamide/ Timolol eye drops (preserved formulation) because of local ocular adverse reactions; approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).

Dorzolamide/ Timolol eye drops (preservative free) has been shown to have a similar safety profile to Dorzolamide/ Timolol eye drops (preservative containing formulation) in a repeat dose double- masked, comparative study.

Like other topically applied ophthalmic medicines, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration.

The following adverse reactions have been reported with Dorzolamide/ Timolol eye drops (preservative free) or one of its components either during clinical trials or during post-marketing experience:

[Very Common: (≥ 1/10), Common: (≥ 1/100, <1/10), Uncommon: (≥ 1/1000, <1/100), and Rare: (≥ 1/10,000, <1/1000), Not known (cannot be estimated from the available data)]

System Organ Class (MedDRA)

Formulation

Very Common

Common

Uncommon

Rare

Not Known**

Immune system disorders

Dorzolamide/ Timolol eye drops (preservative free)

signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis

Timolol maleate eye drops, solution

signs and symptoms of allergic reactions including angioedema, urticaria, localised and generalised rash, anaphylaxis

pruritus

Metabolism and nutrition disorders

Timolol maleate eye drops, solution

hypoglycaemia

Psychiatric disorders

Timolol maleate eye drops, solution

depression*

insomnia*, nightmares*, memory loss

hallucination

Nervous system disorders

Dorzolamide hydrochloride eye drops, solution

headache*

dizziness*, paraesthesia*

Timolol maleate eye drops, solution

headache*

dizziness*, syncope*

paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*, cerebral ischaemia

Eye disorders

Dorzolamide/ Timolol eye drops (preservative free)

burning and stinging

conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing

Foreign body sensation in eye

Dorzolamide hydrochloride eye drops, solution

eyelid inflammation*, eyelid irritation*

iridocyclits*

irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)*

Foreign body sensation in eye, photophobia

Timolol maleate eye drops, solution

signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes*

visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases)*

ptosis, diplopia, choroidal detachment following filtration surgery* (see Special warning and precautions for use 4.4)

itching, tearing, redness, blurred vision, corneal erosion

Ear and labyrinth

Timolol maleate eye drops, solution

tinnitus*

Cardiac disorders

Timolol maleate eye drops, solution

bradycardia *

chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block

atrioventricular block, cardiac failure

Dorzolamide hydrochloride eye drops, solution

Palpitations, tachycardia

Vascular disorders

Timolol maleate eye drops, solution

hypotension*, claudication, Raynaud's phenomenon* , cold hands and feet*

Dorzolamide hydrochloride eye drops, solution

hypertension

Respiratory, thoracic, and mediastinal disorders

Dorzolamide/ Timolol eye drops (preservative free)

sinusitis

shortness of breath, respiratory failure, rhinitis, rarely bronchospasm

dyspnoea

Dorzolamide hydrochloride eye drops, solution

epistaxis*

dyspnoea

Timolol maleate eye drops, solution

dyspnoea*

bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory failure, cough*

Gastrointestinal disorders

Dorzolamide/ Timolol eye drops (preservative free)

dysgeusia

Dorzolamide hydrochloride eye drops, solution

nausea*

throat irritation, dry mouth*

Timolol maleate eye drops, solution

nausea*, dyspepsia*

diarrhoea, dry mouth*

dysgeusia, abdominal pain, vomiting

Skin and subcutaneous tissue disorders

Dorzolamide/ Timolol eye drops (preservative free)

contact dermatitis, Stevens- Johnson syndrome, toxic epidermal necrolysis

Dorzolamide hydrochloride eye drops, solution

rash*

Timolol maleate eye drops, solution

alopecia*, psoriasiform rash or exacerbation of psoriasis*

skin rash

Musculoskeletal and connective tissue disorders

Timolol maleate eye drops, solution

systemic lupus erythematosus

myalgia

Renal and urinary disorders

Dorzolamide/ Timolol eye drops (preservative free)

urolithiasis

Reproductive system and breast disorders

Timolol maleate eye drops, solution

Peyronie's disease*, decreased libido

sexual dysfunction

General disorders and administration site conditions

Dorzolamide hydrochloride eye drops, solution

asthenia/ fatigue*

Timolol maleate eye drops, solution

asthenia/ fatigue*

*These adverse reactions were also observed with dorzolamide/timolol (preserved formulation) during post-marketing experience.

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

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 deliberate ingestion of Dorzolamide/ Timolol eye drops (preserved formulation) or Dorzolamide/ Timolol eye drops (preservative free).

Symptoms

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

Only limited information is available with regard 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 dialyze readily.