Allergan Ltd

Section Number

Subject

Change

4.2

Posology and method of administration

Adults (including the elderly)

The recommended adult dose is one drop of Betagan once or twice daily in the affected eye(s). Discard product after use.

Children

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

Method of administration: topical into the conjunctival sac.

Concurrent therapy may be used where necessary.

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If required, Betagan may be used with other agents to lower intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended (see section 4.4).

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.

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) for one minute. This should be performed immediately following the instillation of each drop.

Transfer from other beta-blocking treatment

When another beta blocking agent is being used treatment must be discontinued after a full day of therapy. Start treatment with Betagan the next day with one drop of Betagan topically applied into the conjunctival sac in the affected eye(s) once or twice a day.

If Betagan is to replace a combination of anti-glaucoma products, only a single product should be removed at a time.  

Use in renal and hepatic impairment

Levobunolol hydrochloride has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients (see section 4.4).

4.3

Contraindications

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

Reactive airway disease including Bbronchial asthma (or a history of bronchial asthma) or chronic obstructive pulmonary disease

Uncontrolled cardiac failure.

History of sSinus bradycardia, 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

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As with other topically applied ophthalmic drugs, Betagan may be absorbed systemically and adverse reactions typical of oral beta-adrenoceptor agents may occur.

Respiratory and cardiac reactions have been reported including, rarely, death due to bronchospasm or associated with cardiac failure.

Congestive heart failure should be adequately controlled before beginning therapy with Betagan. In patients with a history of cardiac disease, pulse rates should be monitored.

Beta-blockers may mask the symptoms of thyrotoxicosis. Because these agents may block the systemic effects of hypoglycaemia they should be used with caution in diabetic patients who use insulin or oral hypoglycaemic drugs. Diabetic control should be monitored during Betagan therapy in patients with labile diabetes.

Stevens-Johnson syndrome has been reported following the use of levobunolol; however a causal relationship has not been established.

Beta-blockers have been associated with alopecia. Alopecia has been shown to be reversible upon levobunolol withdrawal.

Betagan has little or no effect on pupil size and if administered in angle-closure glaucoma, for reduction of intraocular pressure, must only be given in combination with a miotic.

Diminished response after prolonged therapy has been reported in some patients. If necessary, concomitant therapy can be instituted. In patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta-blockers should be used with great caution as aggravation of these disorders may occur.

Beta-blockers may induce bradycardia. If the pulse rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to the bradycardia, review of intraocular pressure lowering therapy may be required.

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.

Beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.

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Like other topically applied ophthalmic agents, Betagan may be absorbed systemically so the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur.

Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease including first degree atrioventricular block. Cardiac failure should be adequately controlled before beginning therapy. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked.

Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failures have been reported following administration of levobunolol.

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when Betagan 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.

In patients with angle closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Betagan has little or no effect on the pupil. When Betagan is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.

In patients with severe renal impairment on dialysis, treatment with levobunolol has been associated with pronounced hypotension.

Levobunolol may impair compensatory tachycardia and increase risk of hypotension when used in conjunction with anaesthetics. The anaesthetist must be informed if the patient is using Betagan.

Beta-blockers may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension. Betagan must be used with caution in patients with metabolic acidosis and untreated phaeochromocytoma.

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycaemia or to uncontrolled diabetic patients (especially those with labile diabetes) as beta-blockers may mask the signs and symptoms of acute hypoglycaemia. The indicatory signs of acute hypoglycaemia may be masked, in particular tachycardia, palpitations and sweating.

Betagan should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, or thromboangiitis obliterans.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

As with systemic beta-blockers, if discontinuation of treatment is needed in patients with coronary heart disease, therapy should be withdrawn gradually to avoid rhythm disorders, myocardial infarction or sudden death.

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

In patients with chronic eye inflammation and corneal dystrophy Betagan should only be applied in the event of stringent diagnosis & under continuous monitoring at short intervals.

Skin rashes and/or dry eyes associated with the use of beta-blockers have been reported. The incidence is small and symptoms have stopped on withdrawal of the beta-blockers. Discontinuation of the use of beta blockers should be considered if these symptoms are reported but cessation of treatment should be gradual.

Athletes should be aware that Betagan contains levobunolol that may induce a positive result in anti-doping controls.

4.5

Interaction with other medicinal products and other forms of interaction

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Betagan may have additive effects in patients taking systemic antihypertensive drugs. These possible additive effects may include hypotension, including orthostatic hypotension, bradycardia, dizziness, and/ or syncope. Conversely, systemic beta-adrenoceptor blocking agents may potentiate the ocular hypotensive effect of Betagan.

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No interaction studies have been performed

Although specific drug interactions studies have not been conducted with Betagan, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered. 

There is potential for additive effects resulting in hypotension, and/or marked bradycardia when eye drops with levobunolol are administered concomitantly with oral calcium channel blockers, Rauwolfia alkaloids, guanethidine, beta-blocking agents, anti‑arrhythmics, digitalis glycosides or parasympathomimetics.

Caution should be exercised and patients must be monitored when Betagan is used concomitantly with oral beta-adrenergic blocking agents, because of the potential for additive effects on systemic blockade. 

Enhanced hypotensive effect is seen when baclofen is given with beta‑blockers. Since some systemic absorption may follow topical application of beta-blockers, regular blood pressure monitoring is advised.

Although levobunolol has little effect on the size of the pupil, mydriasis has occasionally been reported when levobunolol has been used with mydriatic agents such as adrenaline.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4)

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and levobunolol, possibly because quinidine inhibits the metabolism of levobunolol via the P450 enzyme, CYP2D6.

Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Betagan.

Caution must be exercised if Betagan is used concomitantly with iodine contrast products or intravenously administered lidocaine.

Cimetidine may increase the plasma concentrations of levobunolol.

No data on the level of circulating catecholamines after Betagan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope or postural hypotension.

Although specific drug interactions studies have not been conducted with Betagan, known additive IOP lowering effect with prostamides, prostaglandins, alpha-agonists, carbonic anhydrase inhibitors and pilocarpine should be considered.

4.6

Pregnancy and Lactation

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For levobunolol hydrochloride no clinical data on exposed pregnancies are available.

Betagan should not be used during pregnancy unless clearly necessary.

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

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Pregnancy

There are no adequate data for the use of Betagan in pregnant women. Betagan should not be used during pregnancy unless clearly necessary.

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.

Lactation

Levobunolol is excreted in breast milk. Betagan should not be used by breast-feeding women.

4.7

Effects on Ability to Drive and Use Machines

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Betagan may cause dizziness, fatigue and/or drowsiness, which may impair the ability to drive or operate machinery.

Betagan may cause blurred and/or abnormal vision, which may also impair the ability to drive or to use machinery, especially at night or in reduced lighting. The patient should wait until these symptoms have cleared before driving or using machinery.

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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

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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).

Immune System Disorders

Not known: Hypersensitivity

Psychiatric Disorders

Not known: Depression

Nervous System Disorders

Not known: Ataxia, Confusion, Dizziness, Somnolence, Lethargy, Headache, Hallucinations, Impotence, Sleep disorder, Paraesthesia

Eye Disorders

Very Common: Eye irritation, Conjunctival irritation

Common: Blepharitis, Conjunctivitis

Not known: Dry eye, Corneal reflex decreased, Iridocyclitis, Keratitis, Visual disturbance, Eye/Eyelids pruritus, Eye/Eyelid oedema, Eye discharge, Lacrimation increased,

Cardiac Disorders

Not known: Syncope, Bradycardia, Atrioventricular block, Palpitations

Vascular Disorders

Not known: Hypotension

Respiratory, Thoracic, and Mediastinal Disorders

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

Gastrointestinal Disorders

Not known: Nausea, Vomiting, Diarrhoea, Eructation

Hepato-biliary Disorders

Not known: Elevated liver enzymes

Skin and Subcutaneous Tissue Disorders

Not known: Urticaria, Dermatitis, Rash, Erythema, Skin exfoliation, Lichenoid keratosis, Pruritus

General Disorders and Administration Site Conditions

Not known: Face oedema, Asthenia Fatigue

The following additional adverse reactions have been reported with ophthalmic use of beta₁ and beta₂ (non selective) blocking agents:

Eye disorders: including refractory changes, diplopia and ptosis

Cardiovascular: cerebrovascular accident, cerebral ischaemia, congestive heart failure, cardiac arrest

Respiratory: bronchospasm, respiratory failure

The following events have been reported with systemic beta‑blocker formulations and may occur with the topical formulation:

Nervous System Disorders: Sleep disturbance

Psychiatric disorders: Impotence, hallucinations, nightmares

Cardiac Disorders: Cardiac failure,

Vascular disorders: Cold extremities, Raynaud’s phenomenon, worsening intermittent claudication

Gastrointestinal Disorders: Abdominal pain upper, vomiting, diarrhea

Respiratory, Thoracic, and Mediastinal Disorders: Bronchospasm,

Endocrine disorders: Hypoglycaemia

Skin and Subcutaneous Tissue Disorders: Angioedema (Quincke’s oedema), cutaneous (see section 4.4) and psoriasis-like symptoms