Section Number

Subject

Change

10

DATE OF REVISION OF THE TEXT

Text Removed/Added

09/2009 08/2010

Section Number

Subject

Change

4.2

Posology and method of administration

Text deleted

Concurrent therapy may be used where necessary.

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.

4.3

Contraindications

Revised Text

Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.    

Sinus bradycardia, second and third-degree atrioventricular block not controlled with a pace maker, overt cardiac failure or cardiogenic shock.

Replaces

Bronchial asthma (or a history of bronchial asthma) or chronic obstructive pulmonary disease.        

Uncontrolled cardiac failure.

4.4

Special warnings and precautions for use

Revised Text

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.

4.5

Interactions with other medicinal products and other forms of interaction 

Revised text

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.

Replaces

Additive effects may be noted if the product is used 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.

4.6

Pregnancy and Lactation

Revised Text

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.

Replaces

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.

4.7

Effects on Ability to Drive and use Machines

Revised Text

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.

Replaces

Betagan may cause 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.

4.8

Undesirable Effects

Deleted Text:

Immune System Disorders

Not known: Hypersensitivity

Revised text

Eye Disorders

Very Common: Eye irritation, Conjunctival irritation

Common: Blepharitis, Conjunctivitis

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

Revised Text

General Disorders and Administration Site Conditions

Not known: Face oedema, Fatigue

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 symptom

Replaces

General Disorders and Administration Site Conditions

Not known: Face oedema, Asthenia

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

10

Date of (partial) revision of text

Updated text

29 September 2009

Replaces

22^nd October 2008