Dorzolamide / Timolol 20 / 5 mg / ml Eye Drops, Solution

1. Name Of The Medicinal Product

Dorzolamide/Timolol 20/5 mg/ml Eye Drops, Solution

2. Qualitative And Quantitative Composition

One millilitre of solution contains 20 mg of dorzolamide (as hydrochloride) and 5 mg of timolol (as maleate).

Excipient: benzalkonium chloride (0.075 mg/ml)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution

Dorzolamide/Timolol Eye Drops Solution is a colourless to slightly yellowish, viscous solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Dorzolamide/Timolol 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.

4.2 Posology And Method Of Administration

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

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

Please see section 6.6 Instructions for use/handling.

Paediatric use

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. (For information regarding safety in paediatric patients

4.3 Contraindications

Dorzolamide/Timolol Eye Drops Solution is contraindicated in patients with:

• hypersensitivity to the active substances or to any of the excipients

• 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 (CrCl < 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

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

Because of the active substance timolol, cardiac failure should be adequately controlled before beginning therapy with Dorzolamide/Timolol 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

The fixed combination of dorzolamide and timolol 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 medicinal product may be absorbed systemically. The active substance dorzolamide is a sulphonamide. Therefore the same types of adverse reactions found with systemic administration of sulphonamides may occur with ocular use. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

Local ocular adverse reactions, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with the fixed combination of dorzolamide and timolol. If such reactions occur, discontinuation of Dorzolamide/Timolol 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 the fixed combination of dorzolamide and timolol, urolithiasis has been reported infrequently. Because Dorzolamide/Timolol 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 Eye Drops Solution.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. The fixed combination of dorzolamide and timolol 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 substances for the treatment of glaucoma, 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 Eye Drops Solution contains the preservative benzalkonium chloride, which may cause eye irritation.

Contact lenses should be removed prior to application and at least 15 minutes should have passed before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses.

Paediatric use

See section 5.1.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Specific interaction studies have not been performed with the fixed combination of dorzolamide and timolol.

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6.

The active substance dorzolamide in Dorzolamide/Timolol 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 interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such interactions should be considered in patients receiving Dorzolamide/Timolol Eye Drops Solution.

Although Dorzolamide/Timolol 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, the fixed combination of dorzolamide and timolol was used concomitantly with the following systemic medicinal products without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory active substances including acetylsalicylic acid, 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 substances or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, narcotics, and monoamine oxidase (MAO) inhibitors.

4.6 Pregnancy And Lactation

Use during pregnancy

No studies were performed in pregnant women. In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed. Dorzolamide/Timolol Eye Drops Solution should not be used during pregnancy.

Use during lactation

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. Timolol does appear in human milk. Dorzolamide/Timolol Eye Drops Solution should not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

Dorzolamide/Timolol Eye Drops Solution has minor or moderate influence on the ability to drive and use machines. Possible adverse reactions such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable Effects

In clinical studies no adverse experiences specific to the fixed combination of dorzolamide and 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 the fixed combination of dorzolamide and timolol. Approximately 2.4% of all patients discontinued therapy with the fixed combination of dorzolamide and timolol 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 the fixed combination of dorzolamide and timolol or one of its components either during clinical studies or during post-marketing experience:

Very common (

Common (

Uncommon (

Rare (

Musculoskeletal and connective tissue disorders

Timolol maleate ophthalmic solution:

Rare: systemic lupus erythematosus

Nervous system disorders

Dorzolamide hydrochloride ophthalmic solution

Common: headache*

Rare: dizziness*, paresthesia*

Timolol maleate ophthalmic solution

Common: headache*

Uncommon: dizziness*

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

Psychiatric disorders

Timolol maleate ophthalmic solution

Uncommon: depression*

Rare: nightmares*, decreased libido*,

Eye disorders

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 disorders

Timolol maleate ophthalmic solution

Uncommon: bradycardia*, syncope*

Rare: palpitation*, oedema*, arrhythmia*, heart block*, cardiac arrest*

Vascular disorders

Rare: hypotension*, chest pain*, congestive heart failure*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic, and mediastinal disorders

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

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

Rare: contact dermatitis

Dorzolamide hydrochloride ophthalmic solution

Rare: rash*

Timolol maleate ophthalmic solution

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

Renal and urinary disorders

Uncommon: urolithiasis

Reproductive system and breast disorders

Timolol maleate ophthalmic solution

Rare: Peyronie's disease*

General disorders and administration site disorders

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 the fixed combination of dorzolamide and timolol during post-marketing experience.

Laboratory findings

The fixed combination of dorzolamide and timolol was not associated with clinically meaningful electrolyte disturbances in clinical studies.

4.9 Overdose

No data are available in humans in regard to overdose by accidental or deliberate ingestion of the fixed combination of dorzolamide and timolol

There have been reports of inadvertent overdose 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 overdose 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 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: Ophthalmologicals - Beta-Blocking Agents - Timolol, Combinations

ATC Code: S01E D51

Mechanism of action

Dorzolamide/Timolol Eye Drops Solution is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intra-ocular pressure by reducing aqueous humor 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 humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to 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 intra-ocular pressure reduction compared to either component administered alone.

Following ocular use, Dorzolamide/Timolol Eye Drops Solution reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Dorzolamide/Timolol Eye Drops Solution reduces intra-ocular pressure without the common adverse reactions of miotics such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical effects

Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of the fixed combination of dorzolamide and timolol 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 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 the fixed combination of dorzolamide and timolol b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of the fixed combination of dorzolamide and timolol b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of the fixed combination of dorzolamide and timolol b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Paediatric use

A three 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 six and greater than or equal to two years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received the fixed combination of dorzolamide and timolol in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of the fixed combination of dorzolamide and timolol was 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, ocular use of dorzolamide hydrochloride allows for the active substance to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical studies, this resulted in a reduction in IOP without the acid-base 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 ocular use, active substance and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free fraction of the active substance in plasma are maintained. The parent active substance forms a 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 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 non-linearly, resulting in a rapid decline of dorzolamide concentration initially, followed by a slower elimination phase with a half-life of about four months.

When dorzolamide was given orally to 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; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, ocular use of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated CrCl 30-60 millilitre/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic adverse reactions were directly attributable to this finding.

Timolol maleate

In a study of plasma concentration in six subjects, the systemic exposure to timolol was determined following twice daily ocular use of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/millilitre and following afternoon dosing was 0.35 ng/millilitre.

5.3 Preclinical Safety Data

The ocular and systemic safety profile of the individual components is well established. Furthermore, no adverse ocular reactions were seen in animals treated topically with dorzolamide hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of Dorzolamide/Timolol Eye Drops Solution.

6. Pharmaceutical Particulars

6.1 List Of Excipients

benzalkonium chloride

hydroxyethylcellulose mannitol (E421)

sodium citrate dihydrate

sodium hydroxide (for pH-adjustment)

hydrochloric acid (for pH-adjustment)

water for injection

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

Dorzolamide/Timolol Eye Drops Solution should be used no longer than 28 days after first opening the container.

6.4 Special Precautions For Storage

Keep the bottle in the outer carton in order to protect from light.

Do not store above 30°C.

6.5 Nature And Contents Of Container

Dorzolamide/Timolol Eye Drops Solution is available in the following packaging configurations:

1 x 5 ml, 3 x 5 ml and 6 x 5 ml eye drops

LDPE bottle with LDPE dropper and HDPE cap.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

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 Dorzolamide/Timolol Eye Drops Solution eye drops solution.

Instructions for use

Please follow these instructions carefully when using Dorzolamide/Timolol Eye Drops Solution eye drops solution. It is recommended that you wash your hands before putting in your eye drops.

1. You must not use the bottle if the tamper-proof seal on the bottle neck is broken before you first use it.

2. To open the bottle unscrew the cap by turning it until the tamper-proof seal breaks.

3. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and your eye.

4. Invert the bottle and press gently as shown (Fig. 2 and 3) until a single drop as instructed by your doctor is dispensed into your eye. DO NOT TOUCH YOUR EYE OR EYELID WITH THE TIP OF THE CONTAINER.

5. Repeat steps 3 and 4 with the other eye if instructed to do so by your doctor.

6. Reclose the bottle by turning the cap firmly immediately after use and return the bottle to the original outer carton.

7. The dispenser tip is designed to provide a pre-measured drop; therefore, do not enlarge the hole of the dispenser tip.

7. Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0705

9. Date Of First Authorisation/Renewal Of The Authorisation

14/07/2009

10. Date Of Revision Of The Text

11/2010