SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

Betagan 0.5% w/v Eye Drops, Solution

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml solution contains 5.0 mg levobunolol hydrochloride, equivalent to 4.4 mg levobunolol.

Excipient(s): Contains benzalkonium chloride 0.04 mg/ml.

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Eye Drops, Solution

A clear, colourless to light yellow solution.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Reduction of intraocular pressure in chronic open-angle glaucoma and ocular hypertension.

4.2    Posology and method of administration

Posology

Adults (including the elderly)

The usual dose is one drop instilled in the affected eye(s) once or twice daily. Because of diurnal variations in intraocular pressure, satisfactory response is best determined by measuring the intraocular pressure at different times of the day.

Paediatric Population:

Betagan is not recommended for use in children due to lack of safety and efficacy data.

Intraocular pressure should be measured approximately four weeks after starting treatment with Betagan as a return to normal ocular pressure can take a few weeks.

Method of administration: topical into the conjunctival sac.

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 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 and third degree atrioventricular block not controlled with a pace maker; overt cardiac failure or cardiogenic shock.

4.4 Special warnings and precautions for use

Like other topically applied ophthalmic agents, levobunolol is absorbed systemically. Due to the beta-adrenergic component of Betagan (levobunolol), the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-blockers may occur. Incidence of systemic ADRs after topical ophthalmic administration are lower than for systemic administration. To reduce the systemic absorption, see 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 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 their negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree atrioventricular 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 levobunolol.

Betagan 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.

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.

Corneal diseases: Ophthalmic P-blockers may induce dryness of eyes. Patients with comeal diseases should be treated with caution.

Other beta-blocking agents: The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when levobunolol is given to 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).

Anaphylactic Reactions: 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 unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

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

Surgical anaesthesia: P-blocking ophthalmological preparations may block systemic P-agonist effects e.g. of adrenaline. The anaesthetist must be informed when the patient is receiving levobunolol.

The preservative in Betagan, benzalkonium chloride, 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. Avoid contact with soft contact lenses.

Betagan contains sodium metabisulfite which may rarely cause severe hypersensitivity reactions and bronchospasm.

4.5 Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been performed with levobunolol.

There is a potential for additive effects resulting in hypotension, and/or marked bradycardia when ophthalmic beta-blocker solutions are administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.

Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data for the use of levobunolol in pregnant women. Levobunolol should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see 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 Betagan is administered until delivery, the neonate should be carefully monitored during the first days of life. Animal studies with levobunolol have shown reproductive toxicity at doses significantly higher than would be used in clinical practice.

Breast-feeding

Beta-blockers are excreted in breast milk. However, at therapeutic doses of levobunolol 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 4.2.

If treatment with levobunolol during lactation is considered necessary for the benefit of the mother, consideration should be given to the cessation of breast feeding.

4.7 Effects on ability to drive and use machines

Betagan has minor influence on the ability to drive and use machines. Betagan may cause transient blurring of vision, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery.

4.8 Undesirable effects

Like other topically applied ophthalmic drugs, levobunolol 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 of beta-blocking agents is lower than for systemic administration.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following terminologies have been used in order to classify the occurrence of undesirable effects: 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).

The following adverse reactions have been reported with levobunolol:

Psychiatric Disorders

Not known: Depression

Nervous System Disorders

Not known: Confusion, Dizziness, Somnolence Lethargy, Headache, Insomnia Eye Disorders

Very Common: Eye irritation, , Eye pain Common: Blepharitis, Conjunctivitis

Not known: Conjunctival/Ocular hyperemia, Conjuctivitis allergic, Comeal reflex decreased, Iridocyclitis, Keratitis, Vision blurred, Punctate keratitis, Eye/Eyelids pruritus, Eye/Eyelid oedema, Eye discharge, Lacrimation increased, Dry eye

Cardiac Disorders

Not known: Syncope, Bradycardia, Atrioventricular block, Palpitations Vascular Disorders

Not known: Hypotension, Raynaud’s phenomenon

Respiratory, Thoracic, and Mediastinal Disorders

Not known: Asthma, Dyspnoea, Throat irritation, Nasal discomfort

Gastrointestinal Disorders

Not known: Nausea,

Skin and Subcutaneous Tissue Disorders

Not known: Urticaria, Dermatitis contact (including allergic contact dermatitis), Rash, Erythema of eyelid, Eyelid eczema, Skin exfoliation, Lichenoid keratosis, Pruritus

General Disorders and Administration Site Conditions

Not known: Face oedema, Fatigue/asthenia

Additional adverse reactions have been seen with other ophthalmic beta-blockers and may potentially occur with Betagan:

Eye Disorders: Choroidal detachment following filtration surgery, Corneal erosion, Diplopia, Ptosis

Immune System Disorders: Anaphylactic reaction, Systemic allergic reactions including angioedema

Metabolism and Nutrition Disorders: Hypoglycaemia Psychiatric disorders: Memory loss, Nightmares

Nervous System Disorders: Cerebral ischemia, Cerebrovascular accident, Increases in signs and symptoms of myasthenia gravis, Paraesthesia

Cardiac Disorders: Arrhythmia, Cardiac arrest, Cardiac failure, Chest pain, Congestive heart failure, Oedema

Vascular disorders: Cold hands and feet

Respiratory, Thoracic, and Mediastinal Disorders: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), Cough

Gastrointestinal Disorders: Abdominal pain, Diarrhoea, Dysgeusia, Dry mouth, Dyspepsia, vomiting

Skin and Subcutaneous Tissue Disorders: Alopecia, Psoriasiform rash or exacerbation of psoriasis

Reproductive System and Breast Disorders: Decreased libido, Sexual dysfunction

Adverse reactions reported in eye drops containing phosphates:

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

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, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There are no data available on human overdosage with Betagan, which is unlikely to occur via the ocular route. Should accidental ocular overdosage occur, flush the eye(s) with water or normal saline. If accidentally ingested, systemic symptoms may result and efforts to decrease further absorption may be appropriate. The symptoms associated with systemic overdosage are most likely to be bradycardia, hypotension, bronchospasm and cardiac failure. Therapy for overdosage of a beta-adrenergic agent should be instituted, such as intravenous administration of atropine sulfate 0.25 to 2 mg to induce vagal blockade. Conventional therapy for hypotension, bronchospasm, heart block and cardiac failure may be necessary.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Beta blocking agents ATC code: S01ED 03

5.1 Pharmacodynamic properties

Safety and effectiveness of Betagan in paediatric patients have not been established.

Levobunolol is a non-cardioselective beta-adrenoceptor blocking agent, equipotent at both beta-1 and beta-2 receptors. Levobunolol does not have significant local anaesthetic (membrane-stabilizing)    or intrinsic

sympathomimetic activity. Betagan has shown to be as effective as Timolol in lowering intraocular pressure.

Because of levobunolol’s affinity for beta-1 receptors there exists the theoretical possibility of a negative inotropic effect.

Betagan when instilled in the eye will lower elevated intraocular pressure as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure presents a major risk factor in the pathogenesis of glaucomatous field loss. The higher the level of intraocular pressure, the likelihood of optic nerve damage and visual field loss.

The primary mechanism of the ocular hypotensive activity of levobunolol hydrochloride is likely to be a decrease in aqueous humour production. There is little effect on pupil size or accommodation.

The blurred vision and night blindness often associated with miotics would not be expected with the use of Betagan. Patients with cataracts avoid the inability to see around lenticular opacities caused by pupil constriction.

5.2    Pharmacokinetic properties

The onset of action of one drop of Betagan can be detected one hour after instillation with the maximum effect seen between 2 and 6 hours. A significant decrease can be maintained for up to 24 hours following a single dose. The half lives of orally ingested levobunolol and of its active metabolite dihydrolevobunolol are between 6 and 7 hours.

5.3    Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzalkonium chloride Disodium edetate Poly(vinyl alcohol)

Sodium chloride

Sodium phosphate, dibasic, heptahydrate Potassium dihydrogen phosphate Sodium metabisulfite (E223)

Sodium hydroxide or hydrochloric acid to adjust pH Purified water

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months unopened.

Discard 28 days after first opening.

6.4    Special precautions for storage

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

Bottle and dropper tip made of low density polyethylene. The cap is either a "traditional", high impact, polystyrene cap or a high impact polystyrene compliance cap (C-Cap®) with an external rotating sleeve indicating daily dosage status. Both have a safety seal to ensure integrity. 10 ml bottles. Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

No special instructions.

7.    MARKETING AUTHORISATION HOLDER

Allergan Ltd

Marlow International

The Parkway

Marlow

Bucks

SL71YL

UK

8.    MARKETING AUTHORISATION NUMBER

PL 00426/0060

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23^rd March 1989 / 11^th February 2000

10 DATE OF REVISION OF THE TEXT

30/09/2014