Antiglaucoma preparations and miotics, Beta-Blocking Agents, Timolol, Combinations. ATC code: S01E D51

dorzolamide hydrochloride, timolol maleate

Each ml contains 20 mg dorzolamide (as Dorzolamide hydrochloride) and 5 mg timolol (as timolol maleate). Excipients: each ml of eye drops solution contains 0.075 mg benzalkonium chloride.

Eye drops, solution. Clear, slightly viscous, colourless aqueous solution.

Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

The dose is one drop of Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic medicinal product is being used, the other agent should be administered at least ten minutes apart.

Patients should be instructed to wash their hands before use and avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

In order to secure correct dosage - the dropper tip should not be enlarged.

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 ophthalmic Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution.

Usage instructions:

1. The tamper-proof seal on the bottle neck must be unbroken before the product is being used for the first time. A gap between the bottle and the cap is normal for an unopened bottle.

2. The cap of the bottle should be taken off.

3. The patient's head must be tilted back and the lower eyelid must be pulled gently down to form a small pocket between the eyelid and the eye.

4. The bottle should be inverted and squeezed until a single drop is dispensed into the eye. THE EYE OR EYELID MUST NOT BE TOUCHED WITH THE DROPPER TIP.

5. Steps 3 & 4 should be repeated with the other eye if it is necessary.

6. The cap must be put back on and the bottle must be closed straight after it has been used.

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. 

Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution is contra-indicated in patients with:

• reactive airway disease, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease

• sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock

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

• hypersensitivity to one or both active substances or to any of the excipients.

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

Cardiovascular/respiratory reactions

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The timolol component is a beta-blocker. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration, including worsening of Prinzmetal's angina, worsening of severe peripheral and central circulatory disorders, and hypotension.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked.

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate.

Hepatic impairment

Dorzolamide/Timolol eye drops solution has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.

Immunology and hypersensitivity

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The dorzolamide component is a sulphonamide. Therefore the same types of adverse reactions found with systemic administration of sulphonamides may occur with topical administration. 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 Dorzolamide/Timolol eye drops solution. If such reactions occur, discontinuation of Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution should be considered.

While taking β-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Concomitant therapy

The following concomitant medication is not recommended:

− dorzolamide and oral carbonic anhydrase inhibitors

− topical beta-adrenergic blocking agents.

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

Therapy with beta-blockers may mask certain symptoms of hypoglycaemia in patients with diabetes mellitus or hypoglycaemia.

Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

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 solution, urolithiasis has been reported infrequently. Because Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution 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 Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide/Timolol eye drops solution 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 intra-ocular surgery while using dorzolamide. Topical dorzolamide should be used with caution in such patients.

Choroidal detachment concomitant with ocular hypotony have been reported after filtration procedures with administration of aqueous suppressant therapies.

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 three years, no significant difference in mean intra-ocular pressure has been observed after initial stabilisation.

Contact lens use

Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution contains the preservative benzalkonium chloride, which may cause eye irritation. Benzalkonium chloride is known to discolour soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion.

Specific drug interaction studies have not been performed with Dorzolamide/Timolol eye drops solution.

In clinical studies, Dorzolamide/Timolol eye drops solution was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).

However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, 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, SSRIs) and timolol.

The dorzolamide component of Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution.

Although Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and 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.

In clinical studies no adverse experiences specific to Dorzolamide/Timolol have been observed; adverse experiences have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation.

During clinical studies, 1,035 patients were treated with Dorzolamide/Timolol eye drops solution. Approximately 2.4% of all patients discontinued therapy with Dorzolamide/Timolol eye drops solution 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).

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

[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) and Not known (cannot be estimated from the available data)].

Nervous system and Psychiatric disorders:

Dorzolamide hydrochloride ophthalmic solution:

Common: headache*

Rare: dizziness*, paresthesia*

Timolol maleate ophthalmic solution:

Common: headache*

Uncommon: dizziness*, depression*

Rare: insomnia*, nightmares*, memory loss, paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*

Eye disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: burning and stinging

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

Dorzolamide hydrochloride ophthalmic solution:

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

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

Timolol maleate ophthalmic solution:

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

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

Rare: ptosis, diplopia, choroidal detachment (following filtration surgery)*

Ear and labyrinth disorders:

Timolol maleate ophthalmic solution:

Rare: tinnitus*

Cardiac and Vascular disorders:

Timolol maleate ophthalmic solution:

Uncommon: bradycardia*, syncope*

Rare: hypotension*, chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, heart block*, cardiac arrest*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic, and mediastinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Common: sinusitis

Rare: shortness of breath, respiratory failure, rhinitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: epistaxis*

Timolol maleate ophthalmic solution:

Uncommon: dyspnoea*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, cough*

Gastro-intestinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: taste perversion

Dorzolamide hydrochloride ophthalmic solution:

Common: nausea*

Rare: throat irritation, dry mouth*

Timolol maleate ophthalmic solution:

Uncommon: nausea*, dyspepsia*

Rare: diarrhoea, dry mouth*

Skin and subcutaneous tissue disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: contact dermatitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: rash*

Timolol maleate ophthalmic solution:

Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis*

Musculoskeletal and connective tissue disorders:

Timolol maleate ophthalmic solution:

Rare: systemic lupus erythematosus

Renal and Urinary disorders:

Dorzolamide/Timolol ophthalmic solution:

Uncommon: urolithiasis

Reproductive system and breast disorders:

Timolol maleate ophthalmic solution:

Rare: Peyronie's disease*

General disorders and administration site disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, rarely bronchospasm

Dorzolamide hydrochloride ophthalmic solution:

Common: asthenia/fatigue*

Timolol maleate ophthalmic solution:

Uncommon: asthenia/fatigue*

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

Laboratory findings

Dorzolamide/Timolol eye drops solution was not associated with clinically meaningful electrolyte disturbances in clinical studies.

Actavis UK Ltd

(POM)

27 March 2012