BETOPTIC SUSPENSION SINGLE DOSE 0.25% w/v, Eye Drops

Betaxolol 0.25% w/v (as hydrochloride)

For excipients, see 6.1.

Eye Drop Suspension

BETOPTIC SUSPENSION SINGLE DOSE is a sterile, preservative-free suspension for topical ocular administration which has been developed for patients with hypersensitivity to preservatives.

BETOPTIC SUSPENSION SINGLE DOSE lowers the intraocular pressure and is indicated in patients with chronic open-angle glaucoma and ocular hypertension.

Adults (including Elderly)

The recommended dose is one drop in the affected eye(s) twice daily. In some patients the intraocular pressure lowering responses to BETOPTIC SUSPENSION SINGLE DOSE may require a few weeks to stabilise. Careful monitoring of glaucoma patients is advised.

If the intraocular pressure of the patient is not adequately controlled on this regimen, concomitant therapy with pilocarpine and other miotics and/or adrenaline (epinephrine) and/or carbonic anhydrase inhibitors can be instituted.

Children

Safety and effectiveness in children have not been established.

The volume of each drop dispensed is 36μl.

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.

• Hypersensitivity to the active substance or to any of the excipients.

• Reactive airway disease including severe bronchial asthma or a history of severe bronchial asthma, 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.

Like other topically applied ophthalmic agents, betaxolol is absorbed systemically. Due to the beta-adrenergic component, betaxolol, 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: Ophthalmic betaxolol has been shown to have a minor effect on heart rate and blood pressure in clinical studies. 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. Treatment with BETOPTIC SUSPENSION SINGLE DOSE should be discontinued at the first signs of cardiac failure.

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: In controlled clinical studies, ophthalmic betaxolol has shown little effect on respiratory and cardiovascular function. Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.

Patients with mild/moderate bronchial asthma, a history of mild/moderate bronchial asthma or, mild/moderate chronic obstructive pulmonary disease (COPD) should be treated with caution.

Although cardioselective beta-blockers have less effect on lung function than non-selective beta-blockers, caution should be exercised in the treatment of glaucoma patients with obstructive airway disease. There have been reports of asthmatic attacks and pulmonary distress during Betoptic treatment in such patients. In individual cases, the risk to benefit ratio for each patient should be considered. An increase in airway resistance can be relieved by inhaled beta2-mimetics.

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.

Thyrotoxicosis: Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents, which might precipitate a thyroid storm.

Ocular/Corneal diseases: In patients with angle-closure glaucoma, the immediate treatment objective is to reopen the angle by constriction of the pupil with a miotic agent. Betaxolol has little or no effect on the pupil. When BETOPTIC SUSPENSION SINGLE DOSE is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used with a miotic and not alone.

Ophthalmic beta-blockers may induce dryness of eyes. Caution should be exercised in the use of beta-blocking agents in patients with corneal diseases, Sicca Syndrome or similar tear film abnormalities.

Other beta-blocking agents: The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when betaxolol 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)

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: Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving betaxolol. Consideration should be given to the gradual withdrawal of beta-adrenergic blocking agents prior to general anaesthesia because of the reduced ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli.

Contact lens wearers must remove their lenses prior to instillation of BETOPTIC SUSPENSION SINGLE DOSE and wait for 15 minutes after dosing before reinserting the contact lenses.

No specific drug interaction studies have been performed with betaxolol.

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, beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine and catecholamine-depleting drugs such as reserpine. Close observation of the patient is recommended.

Betaxolol is an adrenergic blocking agent; therefore, caution should be exercised in patients using concomitant adrenergic psychotropic drugs.

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

Pregnancy

Reproduction studies have been conducted with orally administered betaxolol HCl in rats and rabbits. There was evidence of drug related postimplantation loss in rabbits and rats at dose levels above 12 mg/kg and 128 mg/kg (1500 and 16,000 times the maximum recommended human ocular dose), respectively. Betaxolol HCl was not shown to be teratogenic, however, and there were no other adverse effects on reproduction at subtoxic dose levels.

There are no adequate data for the use of betaxolol in pregnant women. Betaxolol 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 BETOPTIC SUSPESION SINGLE DOSE is administered until delivery, the neonate should be carefully monitored during the first days of life.

Lactation

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

The ability to drive and use machines is unlikely to be affected, other than any problems associated with transient blurred vision following the use of BETOPTIC SUSPENSION SINGLE DOSE.

Like other topically applied ophthalmic drugs, betaxolol 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. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers

Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with BETOPTIC SUSPENSION SINGLE DOSE:

Immune system disorders:

Frequency unknown: Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders:

Frequency unknown: Hypoglycaemia.

Psychiatric disorders:

Rare: insomnia, depression

Frequency unknown: nightmares, memory loss, hallucinations, psychoses, confusion.

Nervous system disorders:

Rare: headache

Frequency unknown: Syncope, cerebrovascular accident, cerebral ischemia, increases in signs and symptoms of myasthenia gravis, dizziness, paraesthesia.

Eye disorders:

Common: discomfort (stinging and burning)

Uncommon: tearing

Rare: blurred vision, corneal disease, such as corneal punctate staining, superficial punctate keratitis, decreased corneal sensitivity, allergic reactions, dry eye, foreign body sensation, erythema, itching and photophobia.

Frequency unknown: Signs and symptoms of ocular irritation (e.g. redness), blepharitis, and choroidal detachment following filtration surgery (see 4.4 Special warnings and special precautions for use), corneal erosion, ptosis, diplopia.

Cardiac disorders:

Rare: bradycardia

Frequency unknown: Chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, cardiac failure. A slowed AV-conduction or increase of an existing AV-block

Vascular disorders:

Frequency unknown: Hypotension, Raynaud's phenomenon, cold and cyanotic hands and feet, Increase of an existing intermittent claudication,

Respiratory, thoracic, and mediastinal disorders:

Rare: dyspnoea, asthma

Frequency unknown: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), cough.

Gastrointestinal disorders:

Frequency unknown: Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders:

Rare: alopecia

Frequency unknown: Psoriasiform rash or exacerbation of psoriasis, skin rash.

Musculoskeletal and connective tissue disorders:

Frequency unknown: Myalgia.

Reproductive system and breast disorders:

Frequency unknown: Sexual dysfunction, decreased libido, impotence.

General disorders and administration site conditions:

Frequency unknown: Asthenia/fatigue.

An increase in Anti Nuclear Antibodies (ANA) has been seen; its clinical relevance is unclear.

No information is available on overdosage of humans after ocular application. The oral LD50 of the drug ranged from 350-920 mg/kg in mice and 860-1050 mg/kg in rats. The symptoms which might be expected with an overdose of systemically administered beta1- adrenergic receptor blocking agent are hypotension, bradycardia and acute cardiac failure.

No information is available on overdosage after ocular administration. A topical overdose of BETOPTIC SUSPENSION SINGLE DOSE may be flushed from the eye(s) with warm tap water.

Therapeutic Group: Ophthalmologicals – Antiglaucoma Preparations & Miotics.

ATC Code: S01E D02

Betaxolol, a cardioselective (beta1-adrenergic) receptor blocking agent, does not have significant membrane-stabilising (local anaesthetic) activity and is devoid of intrinsic sympathomimetic action. Orally administered beta-adrenergic blocking agents may reduce cardiac output in healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the sympathetic stimulatory effect necessary to maintain adequate cardiac function.

Betaxolol has no significant effect on pulmonary function as measured by FEV1, Forced Vital Capacity (FVC), FEV1/FVC and no evidence of cardiovascular beta-adrenergicblockade during exercise was observed.

When instilled in the eye, betaxolol has the action of reducing elevated as well as normal intraocular pressure (IOP), whether or not accompanied by glaucoma. It is thought to produce this effect by reducing the rate of production of aqueous humour as demonstrated by tonography and aqueous fluorophotometry. BETOPTIC SUSPENSION SINGLE DOSE provides IOP lowering activity equivalent to that demonstrated by BETOPTIC Ophthalmic Solution 0.5%. Ophthalmic betaxolol has little or no effect on the constriction of the pupil and little effect on respiratory and cardiovascular function.

Several studies have indicated that Betaxolol may have a beneficial effect on visual function for up to 48 months in patients with chronic open angle glaucoma and up to 60 months in patients with ocular hypertension. Moreover there is evidence that betaxolol maintains or increases ocular blood flow/perfusion.

Betaxolol is highly lipophilic which results in good permeation of the cornea, allowing high intraocular levels of the drug. Betaxolol is characterised by its good oral absorption, low first pass loss and a relatively long half-life of approximately 16-22 hours. The elimination of betaxolol is primarily by the renal rather than faecal route. The major metabolic pathways yield two carboxylic acid forms plus unchanged betaxolol in the urine (approximately 16% of the administered dose).

The onset of action of betaxolol can generally be noted within 30 minutes and the maximal effect can usually be detected 2 hours after topical administration. A single dose provides a 12-hour reduction in intraocular pressure.

The polar nature of betaxolol can produce apparent ocular discomfort. In this formulation, betaxolol molecules are ionically bound to the amberlite resin. Upon instillation the betaxolol molecules are displaced by ions in the tear film. This displacement process occurs over several minutes and enhances the ocular comfort observed for BETOPTIC SUSPENSION SINGLE DOSE.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Amberlite poly (styrene-divinyl benzene) sulphonic acid

Carbomer

Mannitol

Hydrochloric acid and/or Sodium Hydroxide

Purified Water

Not applicable

24 months

Do not store above 25°C.

BETOPTIC SUSPENSION SINGLE DOSE is packaged in a plastic single dose dispenser containing 0.25 ml and enclosed in a foil overwrap.

Shake before each use.

BETOPTIC SUSPENSION SINGLE DOSE is preservative-free, therefore do not reuse.

Discard single dose dispenser after use.

Alcon Laboratories (UK) Ltd,

Pentagon Park,

Boundary Way,

Hemel Hempstead,

Herts., HP2 7UD.

PL 0649/0124

9 December 1998

26^th March 2012