Allergan Ltd

Section Number

Subject

Change

4.2

Posology and method of administration

Amended text:

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.

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

Amended text:

Reactive airway disease i        Bncluding bronchial asthma (or a history of bronchial asthma), severe  or chronic obstructive pulmonary disease.

Uncontrolled cardiac failure.

SHistory of sinus 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

Amended Text:

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 significant cardiac disease, pulse rates should be monitored.

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.

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; however, a causal relationship between levobunolol and alopecia has not been established.

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 ondialysis, 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

Amended Text:

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. 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

Amended Text:

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.

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

Amended Text:

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.

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

Amended Text:

Immune System Disorders

Not known: Hypersensitivity

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

General Disorders and Administration Site Conditions

Not known: Face oedema, AstheniaFatigue

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

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

Respiratory: 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

10

DATE OF REVISION OF THE TEXT

Amended Text:

            22^nd October 2008

29^th September 2009

Section Number

Subject

Change

1

Name of medicinal product

Revised Text:

Betagan 0.5% w/v Unit Dose Eye Drops, Solution

Replaces:

Betagan Unit Dose 0.5% w/v Eye Drops, Solution

2

Qualitative and quantitative composition

Revised Text:

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

For a full list of excipients, see section 6.1.

Replaces:

Levobunolol Hydrochloride 0.5% w/v

For excipients, see 6.1

3

Pharmaceutical form

Revised Text:

A clear, colourless to brown sterile eye drops solution supplied in single-use plastic ampoules.

4.2

Posology and method of administration

Revised Text:

Adults   Adults (including the elderly):  The recommended dosage is one drop of Betagan in        the affected eye(s) once or twice daily.  Discard product after use.

Betagan is not recommended for use in children due to lack of safety and efficacy data (see section 5.1).

Method of administration: topical into the conjunctival sac.

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.

Replaces:

Adults (including the elderly):  The usual dosage is one drop in the affected eye

 once  or twice daily.  Discard product after use.

Use in children is not currently recommended.

Concurrent therapy with pilocarpine and other miotics may be used where necessary.

4.3

Contraindications

Revised text:

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

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

Uncontrolled cardiac failure.

History of sinus bradycardia, second and third-degree atrioventricular block, overt cardiac failure or cardiogenic shock.

Replaces:

Use in patients hypersensitive to the active ingredient, excipients or -adrenoceptor

 blockers.

Use in patients with severe obstructive pulmonary disease.

Use in patients with uncontrolled cardiac failure, second and third-degree

 atrioventricular block, cardiogenic shock or sinus bradycardia.

4.4

Special warnings and precautions for use

Revised text:

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 significant cardiac disease, pulse rates should be monitored.

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.

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; however, a causal relationship between levobunolol and alopecia has not been established.

Replaces:

As with other topically applied ophthalmic drugs, Betagan may be absorbed

 systemically. Betagan can be used with caution in patients with obstructive

 pulmonary disease provided that adequate supervision is maintained. If increased

 airways resistance develops consideration must be given to its discontinuation.

4.5

Interaction with other medicaments medicinal products and other forms of interaction

Revised text:

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.

Replaces:

Additive effects may be noted if the product is used in patients with concomitant

 blockade therapy or other hypertensives.

4.6

Pregnancy and lactation

Revised Text:

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.

Replaces:

The product should not be used during pregnancy or lactation unless considered

 essential by the physician.  There is no experience of use during pregnancy and

 there have been no studies concerning excretion in breast milk.

4.7

Effects on ability to drive and use machines

Revised Text:

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.

Replaces:

None known.

4.8

Undesirable effects

Revised Text:

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

Eye Disorders

Very Common: Eye irritation, Conjunctival irritation

Common: Blepharitis, Conjunctivitis

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

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

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

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

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

Respiratory: respiratory failure.

Replaces:

Ocular: transient burning and stinging on instillation; iridocyclitis and

 blepharoconjunctivitis can occur occasionally; visual disturbances.

Cardiovascular: bradycardia; hypotension.

Respiratory: dyspnoea; asthma.

CNS: headache; transient ataxia and dizziness; lethargy.

Dermatological: urticaria and pruritis have been rarely reported

4.9

Overdosage

Text added:

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 sulphate 0.25 to 2 mg to

 induce vagal blockade. Conventional therapy for hypotension, bronchospasm, heart

 block and cardiac failure may be necessary.

5.1

Pharmacodynamic properties

Text added:

Safety and effectiveness of Betagan in paediatric patients have not been

 established.

5.2

Pharmacokinetic properties

Revised Text:

The onset of action with one drop of Betagan can be detected within one hour of

 treatment  after instillation, with maximum effect seen between two and six hours.

6.2

Incompatibilities

Revised Text:

Not applicable

Replaces:

None known

6.3

Shelf life

Text added:

The eye drop solution should be used immediately after opening. Any unused solution should be discarded.

6.4

Special precautions for storage

Revised text:

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

Replaces:

Keep the container in the outer carton.

6.6

Special precautions for disposal and handling

Revised Text:

Ensure that the single dose container is intact before use. Discard any unused solution (i.e. once opened do not re-use container for subsequent doses).

Replaces:

Discard after use.

10

Date of revision of text

Revised Text:

22^nd October 2008

Replaces:

15^th June 2005