SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 22.26 mg of dorzolamide hydrochloride corresponding to 20 mg dorzolamide and 6.83 mg of Timolol maleate corresponding to 5 mg Timolol.

Excipients with known effect

Benzalkonium chloride 0.075 mg/ml.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Eye drops, solution.

Clear, colourless slightly viscous solution.

4    CLINICAL PARTICULARS

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 in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic agent is being used, Dorzolamide 20 mg/ml and Timolol 5 mg/ml and the other agent should be administered at least ten minutes apart.

The dosage of this eye drop should not exceed twice daily.

If one dose is missed, treatment should continue with the next dose as normal. The duration of the treatment should be as recommended by the doctor.

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.

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.

Paediatric population

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 > 2 and < 6 years of age, see section 5.1).

Method of administration

•    First wash your hands.

•    Avoid touching the eye (or any other surface) with the tip of the bottle.

•    If you wear soft contact lenses, they should be removed before using the eye drops and wait at least 15 minutes before reinserting.

•    These drops are supplied in a plastic bottle with an insert cap assembly, with a tamper proof dust cover. When using the bottle for the first time, snap of the dust cover by turning it clockwise to break the seal.

•    Unscrew the inner cap.

•    Tilt your head back and look at the ceiling.

•    Pull the lower eyelid gently downwards to form a pocket between your eyelid and eye.

•    Hold the bottle upside down above the eye and gently squeeze the bottle to release a drop into your eye. DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.

•    Keep the affected eye closed and press your fingertip against the inside corner of the closed eye, and hold for 2 minutes. This is important because it reduces the amount of drug that goes into the rest of your body.

•    Repeat for the other eye if instructed to do so by your doctor.

•    Recap the bottle after every use, tighten the inner cap on the nozzle.

4.3 Contraindications

Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops, Solution is 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 pace-maker, 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 the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. The 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 20 mg/ml and Timolol 5 mg/ml Eye Drops, Solution 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

Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops, Solution 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 sulphonamides. Therefore, the same types of adverse reactions found with systemic administration of sulphonamides 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution. If such reactions occur, discontinuation of Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops, Solution 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 dose 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 betablocking 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 this medicinal product, urolithiasis has been reported infrequently. Because Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops, Solution contains 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. Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 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 intraocular pressure, has been observed after initial stabilisation.

Contact Lens //.ve Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution contains the preservative benzalkonium chloride which may cause eye irritation. Remove contact lenses prior to application and 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

No specific drug interaction studies have been performed with Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.

In clinical studies, Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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).

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, 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 the systemic absorption, see section 4.2.

If treatment with Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 clinical studies for Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution the observed adverse reactions have been consistent with those that were reported previously with dorzolamide hydrochloride and/or timolol maleate.

In clinical studies, 1035 patients were treated with Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution. Approximately 2.4% of all patients discontinued therapy 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).

Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation; this may cause similar undesirable effects as seen with systemic betablocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration.

The following adverse reactions have been reported with Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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)

System Organ Class (MedDRA)	Formulation	Very Commo n	Common	Uncommon	Rare	Not Known**
Immune system	Dorzolamide 20 mg/ml and				signs and symptoms

disorders	Timolol 5 mg /ml Eye Drops Solution				of systemic allergic reactions, including angioedema , urticaria, pruritus, rash, anaphylaxis
	Timolol maleate eve drops, solution				signs and symptoms of allergic reactions including angioedema , urticaria, localized and generalized rash, anaphylaxis	Pruritus
Metabolism and nutrition disorders	Timolol maleate eye drops, solution					hypoglycae mia
Psychiatric disorders	Timolol maleate eye drops, solution			depression*	insomnia*, nightmares* , memory loss
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*, cerebrovasc ular accident*, cerebral ischaemia
Eye disorders	Dorzolamide 20 mg/ml and	burning and	conjunctiv al

	Timolol 5 mg/ml Eye Drops Solution	stinging	injection, blurred vision, corneal erosion, ocular itching, tearing
	Dorzolamide hydrochloride eye drops, solution		eyelid inflammati on*, eyelid irritation*	iridocyclitis *	irritation including redness*, pain,* eyelid crusting*, transient myopia (which resolved upon discontinuat ion of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)*
	Timolol maleate eye drops, solution		signs and symptoms of ocular irritation including blepharitis * 5 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 disorders	Timolol maleate eye drops, solution				tinnitus*
Cardiac	Timolol			bradycardia	chest pain*,	atrioventric

disorders	maleate eve drops, solution			*	palpitation*, oedema*, arrhythmia* , congestive heart failure*, heart block, cardiac arrest*	ular block, cardiac failure
Vascular disorders	Timolol maleate eve drops, solution				hypotension *, 5 claudication , Raynaud’s phenomeno n*, cold hands and feet*
Respiratory , thoracic, and mediastinal disorders	Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution		sinusitis		shortness of breath, respiratory failure, rhinitis, rarely bronchospas m
	Dorzolamide hydrochloride eye drops, solution				epistaxis*
	Timolol maleate eye drops, solution			dyspnoea*	bronchospas m (predomina ntly in patients with preexisting bronchospas tic disease)*, respiratory failure, cough*
Gastrointe stinal disorders	Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution	dysgeusi a

	Dorzolamide hydrochloride eve drops, solution		nausea*		throat irritation, dry mouth*
	Timolol maleate eve drops, solution			nausea*, dyspepsia*	diarrhoea, dry mouth*	dysgeusia, abdominal pain, vomiting
Skin and subcutaneo us tissue disorders	Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution				contact dermatitis, Stevens- Johnson syndrome, toxic epidermal necrolysis
	Dorzolamide hydrochloride eye drops, solution				rash*
	Timolol maleate eye drops, solution				alopecia*, psoriasifor m rash or exacerbatio n of psoriasis*	skin rash
Musculoske letal and connective tissue disorders	Timolol maleate eye drops, solution				systemic lupus erythematos us	myalgia
Renal and urinary disorders	Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution			urolithiasis
Reproducti ve system and breast disorders	Timolol maleate eye drops, solution				Peyronie’s disease*, decreased libido	sexual dysfunction
General disorders and administrati on site conditions	Dorzolamide hydrochloride eye drops, solution		asthenia/fa tigue*
	Timolol maleate eye drops,			asthenia/ fatigue*

*These adverse reactions were also observed with Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution during post-marketing experience.

**Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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 Yellow card scheme at www.mhra.gov .uk/yellowcard.

4.9 Overdose

No data are available in humans in regard to overdose by accidental or deliberate ingestion of Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.

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 dialyse readily.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta blocking agents, Timolol, combinations, ATC code: S01ED51

Mechanism of Action

Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular 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 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 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 (IOP) compared to either component administered alone.

Following topical administration, Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 loss. It also reduces intra-ocular pressure without the common side effects 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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

Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Paediatric 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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, topical administration 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 trials, 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 topical administration, 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 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 active substance 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, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated CrCl 30-60 ml/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.

Timolol maleate

In a study of plasma active substance concentration in six 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 morning dosing was 0.46 ng/ml and following afternoon dosing was 0.35 ng/ml.

5.3 Preclinical safety data

The ocular and systemic safety profile of the individual components 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 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Hydroxyethyl Cellulose,

Mannitol,

Sodium citrate,

Benzalkonium Chloride,

Sodium hydroxide (to adjust pH),

Water for Injections.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

The product should be used no longer than 28 days after first opening the container.

6.4    Special precautions for storage

For storage conditions before and after first opening (see Section 6.3).

Do not store above 25°C.

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

6.5    Nature and contents of container

5 ml solution filled in 5 ml LDPE bottle with insert-cap assembly comprising of a dark blue coloured screw cap over a LDPE nozzle with tamper-evident LDPE dustcover sealing the bottle cap. One such bottle is packed in a carton.

Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution is available in the following packaging configuration:

1 x 5 ml (single 5 ml bottle).

6.6    Special precautions for disposal and other handling No special requirements.

7    MARKETING AUTHORISATION HOLDER

FDC Pharma,

Unit 6 Fulcrum 1,

Solent Way, Whiteley,

Fareham, Hampshire,

PO15 7FE.

United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 35638/0005.

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/06/2011

10    DATE OF REVISION OF THE TEXT

30/11/2016