1. Name Of The Medicinal Product
LEVOBUNOLOL 0.5% eye drops, solution
2. Qualitative And Quantitative Composition
Levobunolol Hydrochloride : 5 mg per ml.
For excipients, see 6.1.
3. Pharmaceutical Form
Eye drops, solution.
4. Clinical Particulars
4.1 Therapeutic Indications
• Ocular hypertension.
• Chronic open-angle glaucoma.
4.2 Posology And Method Of Administration
Ophthalmic route
One drop of levobunolol 0.5% in the affected eye twice a day.
In some cases, only 1 drop of levobunolol 0.5% daily may be sufficient, particularly when the intraocular pressure is maintained at satisfactory levels.
Nasolacrimal occlusion or gently closing the eyelid for 3 minutes after instillation of the drops is recommended. This may reduce the systemic absorption of medications administered via the ocular route and result in a decrease in systemic side effects.
If deemed necessary, the ophthalmologist can associate levobunolol eye drops to one or more anti-glaucoma medications (by local and/or systemic routes).
However, it is not advisable to combine 2 of beta-adrenergic blocking agent eye drops (see precaution for use).
Other eye drops have to be instilled at least 15 minutes before or after levobunolol.
However, normalisation of the intraocular pressure with levobunolol eye drops may require several weeks; consequently, the treatment monitoring should include a measurement of intraocular pressure after approximately 4 weeks of therapy.
Substitution therapy
When levobunolol eye drops is substituted for another anti-glaucoma agents, this eye drops has to be discontinued at the end of a complete day and one drop of levobunolol eye drops should be applied in the affected eye twice a day on the following day.
When levobunolol eye drops is substituted for several anti-glaucoma agents administered simultaneously, only one medication should be discontinued at a time.
When levobunolol eye drops is substituted for miotic agents, a monitoring of the patient's refraction can be necessary when the effects of miotics have disappeared.
The medical prescription should be accompanied by the monitoring of the intraocular pressure, particularly at the onset of therapy.
Use in children:
No clinical studies have been performed in children with levobunolol eye drops. Consequently, its use is not recommended.
4.3 Contraindications
It is necessary to keep in mind the contraindications of the systemic administration of beta-adrenergic blocking agents. Systemic side effects may occur after topical administration:
-asthma or chronic obstructive pulmonary diseases
-heart failure when not adequately controlled,
-cardiogenic shock,
-second and third degree atrioventricular block (without cardiac pacemaker),
-Prinzmetal's angina,
-sick sinus syndrome (including sinoatrial block),
-bradycardia (< 45 to 50 beats per minute),
-Raynaud's disease and peripheral circulatory disorders,
-untreated phaeochromocytoma,
-hypotension,
-hypersensitivity to any component of the medication,
Combination with floctafenine (see 4.5 Interactions with other medicinal products and other forms of interactions).
Combination with sultopride (see 4.5 Interactions with other medicinal products and other forms of interactions).
4.4 Special Warnings And Precautions For Use
This medicinal product contains sodium metabisulphite and benzalkonium chloride.
Ocular
-The effect on intraocular pressure or the known effects of systemic beta
-The combination of two eye drops of beta-adrenergic blocking agents is not recommended (see 4-2 Posology and method of administration).
-When this eye drops is used to lower intraocular pressure in patients with angle-closure glaucoma, it should be given in combination with a miotic.
In these patients, the immediate treatment objective is to reopen the angle by constriction of the pupil with a miotic agent, since levobunolol has no or little effect on the pupil.
-With anti-glaucoma agents decreasing the aqueous humour secretion (described with timolol and acetazolamide), choroidal detachments and ocular hypotension were reported further to surgical treatment of glaucoma.
Wearing contact lenses:
There is a risk of contact lenses intolerance due to the decrease of lachrymal secretion linked in general to the use of beta-adrenergic blocking agents.
Patients should be instructed to wait at least15 minutes after instillation of Levobunolol Alcon before inserting contact lenses. Levobunolol Alcon should not be administered while wearing contact lenses. Benzalkonium chloride may cause eye irritation and is known to discolour soft contact lenses.
-A decrease of levobunolol sensitivity may appear with a prolonged treatment. The absence of tachyphylaxis should be checked every year in long term treatment.
General
It is necessary to keep in mind the special warnings and precautions of the systemic administration of beta-adrenergic blocking agents. Systemic side effects may occur after topical administration:
The concomitant use of a beta-blocker with certain calcium antagonists (bepridil, verapamil, diltiazem) or beta-blockers used to treat cardiac insufficiency is not recommended (see 4.5 Interactions with other medicinal products and other forms of interactions).
Athletes: athletes should be warned that this medicine contains an active component that may induce a positive analytical result in antidoping controls.
Discontinuation of treatment
Systemic treatment with beta-adrenergic blocking agents should not be directly discontinued particularly in patients with angina: a sudden discontinuation may induce serious rhythm disorders, myocardial infarction or sudden death.
The dosage should be lowered gradually, i.e. over 1-2 weeks.
Bradycardia
If the heart rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to bradycardia, the dosage should be reduced.
Heart failure
Special care should be taken in patients with controlled heart failure
First degree atrioventricular block
Due to the negative dromotropic effect of beta-adrenergic blocking agents, levobunolol should be administered with caution to patients having first degree atrioventricular block.
Phaeochromocytoma
When beta-adrenergic blocking agents are used in the treatment of hypertension due to a treated phaeochromocytoma, blood pressure should be closely monitored.
Patients with renal failure and/or hepatic failure
In these at risk patients, dosage adjustments are often needed when beta-adrenergic blocking agents are used systemically.
Diabetic patients
Patients should be advised to reinforce self-monitoring of their glycaemia at the beginning of treatment.
Signs and symptoms of hypoglycaemia, especially tachycardia, palpitations and sweating may be masked.
Psoriasis
As worsening of the disease have been reported with beta-adrenergic blocking agent, treatment should be weighed up in this indication.
Allergic reactions
In patients who may present a severe anaphylactic reaction of any origin, in particular those associated with iodine contrast products or floctafenine (see interactions), or during a desensitisation treatment, treatment with a beta-adrenergic blocking agent may exacerbate the reaction and a resistance to the usual dosages of epinephrine.
General anaesthesia
Beta-adrenergic blocking agents may reduce the sympathetic reflex mechanism. Continuation of treatment with beta-adrenergic blocking agents throughout surgery reduces the risk for cardiac arrhythmia, ischemia and acute blood pressure increases. The anaesthetist should be informed when the patient is receiving a beta-adrenergic blocking agent.
-If discontinuation of the treatment is necessary, 48 hours may be necessary to re-establish the sensitivity to catecholamines.
-In some cases, treatment with beta-adrenergic blocking agents cannot be discontinued :
.in patients with coronary heart failure, it is advisable to continue the treatment until surgery, due to the risk associated with sudden withdrawal of beta-adrenergic blocking agents.
.in emergency or when the treatment cannot be discontinued, the patient should be protected from vagal dominance by an adequate pre-administration of atropine, renewed if necessary. The anaesthetist should use the least cardioplegic products possible and should compensate for blood losses.
-The increase of anaphylactic risk linked to beta-adrenergic blocking agents should be taken into account.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask some signs, in particular cardiovascular signs.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
1 ) Eye drops
Ophthalmic monitoring is required in patients with concomitant use of eye drops containing epinephrine (risk of mydriasis).
2 ) Other drugs
Even if there is little systemic passage of beta-adrenergic blocking agents after topical administration, interactions with other medicinal products may occur.
Consideration should be given to the interactions observed with beta-adrenergic blocking agents administered systemically.
Contraindicated association
+ Floctafenine
Beta-adrenergic blocking agents may affect the cardiovascular regulating mechanisms which counterbalance shock or hypotension caused by floctafenine.
+ Sultopride
Increased risk of ventricular rhythm disorders, notably torsade de pointes (atypical rapid ventricular tachycardia).
Associations not recommended
+ Calcium antagonists (bepridil, diltiazem and verapamil)
Automatism disorders (excessive bradycardia, sinusal arrest), sinoatrial and atrioventricular conduction disorders, and heart failure (synergy of effects).
If necessary the combination may be made under strict clinical and ECG monitoring, in particular in elderly subjects or at the start of treatment.
+ Beta blockers used in cardiac insufficiency
Risk of increase of undesirable side effects of beta-blockers, notably with excessive risk of bradycardia.
Associations requiring precautions for use
+ Halogen volatile anaesthetic drugs
Beta-adrenergic blocking agents may affect the cardiovascular regulating mechanisms (the beta-adrenergic inhibition may be reversed during surgery with the use of beta-stimulating agents).
Treatment with beta-adrenergic blocking agents should not generally be discontinued and, in all cases, abrupt withdrawal should be avoided. The anaesthetist should be aware of such a treatment.
+ Anticholinesterases: donezepil, galantamine, rivastigmine, neostigmine, pyridostigmine, tacrine, ambenonium
Risk of excessive bradycardia (addition of bradycardiogenic effects).
Regular clinical monitoring.
+An increase of the systemic effects of topical beta-adrenergic blocking agent and an increase of the blood concentrations of beta-adrenergic blocking agent were reported with the combination of topical beta-adrenergic blocking agent and quinidine, probably due to the inhibition of the metabolism of the beta-adrenergic blocking agent by quinidine (described with timolol).
+ Baclofen
Increased antihypertensive effect.
Blood pressure should be monitored and the dosage of the antihypertensive drug should be adjusted, if required.
+ Clonidine and other central antihypertensives (alphamethyldopa, guanfacine, moxonidine, rilmenidine)
Significant increase in arterial pressure in the event of sudden discontinuation of the treatment by the central antihypertensive.
Avoid the sudden discontinuation of the central antihypertensive. Clinical monitoring.
+ -Insulin, hypoglycaemic sulphonic agents, and glinides
Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycaemia: palpitations, tachycardia.
The patient should be informed and instructed to monitor his glycaemia, in particular when the treatment is initiated.
+ Lidocaine :
With lidocaine intravenous route, increase of lidocaine blood levels and possibly increased risk of neurologic and cardiac undesirable effects (decrease of lidocaine hepatic metabolism).
The dosage of lidocaine should be adjusted accordingly.
Clinical, electrocardiographic and possibly lidocaine blood levels monitoring are advised during treatment with a beta-adrenergic blocking agent, and after its withdrawal.
+ Medicinal products causing torsade de pointes
Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide) and class III antiarrhythmics (amiodarone, dofetilide, ibutilide, sotalol), certain neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), and other medicinal products such as: bepridil, cisapride, diphenamil, erythromycin IV, vincamine IV, mizolastrine, halofantrine, sparfloxacine, petamidine, moxifloxacine…
Increased risk of ventricular rhythm disorders, notably torsade de pointes.
Clinical and electrocardiographic monitoring.
+Amiodarone
Abnormal contractility, automatism and conduction (inhibition of the sympathetic mechanisms regulating the cardiac function).
A clinical monitoring should be made when both drugs, amiodarone and the beta-bloquant are combined.
+ Propafenone
Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).
Clinical and ECG monitoring.
Associations to Consider :
+ NSAIDs (general route) including selective cox-2 inhibitors
Decrease of antihypertensive effect (inhibition of the vasodilating prostaglandins by NSAIDs and sodium retention with pyrazoled NSAIDs).
+ Alpha blockers for urological purposes: alfuzosine, doxazosine, prazosine, tamsulosine, terazosine
Increase in the hypotensive effect, risk of increased orthostatic hypotension.
+ Amifostine
Increase in the antihypertensive effect.
+ Calcium antagonists (dihydropyridines)
Hypotension, left ventricular failure in patients with latent or uncontrolled cardiac failure (in-vitro negative inotropic effects, of drug-related intensity, have been shown with dihydropyridines compounds, and may add up to the negative inotropic effects of beta-adrenergic blocking agents). Moreover, treatment with beta-adrenergic blocking agents could minimise the reflex sympathetic reaction in case of excessive haemodynamic changes.
+ Imipraminic antidepressants (tricyclic), neuroleptics
Hypotensive effect with increased risk of orthostatic hypotension (additive effect).
+ Mefloquine
Risk of excessive bradycardia (addition of bradycardiogenic effects).
+ Dipyridamole (IV)
Increase of the antihypertensive effect.
4.6 Pregnancy And Lactation
The systemic passage of topical beta-adrenergic blocking agents exists but it is smaller than with systemic agents.
Pregnancy
Studies in animals have not revealed any teratogenic effect.
In clinical practice, no teratogenic effect has been reported to date, and results of controlled prospective studies with some beta-adrenergic blocking agents have not revealed malformations at birth.
In neonate of treated mothers, the action of beta-adrenergic blocking agents persists during several days after birth and could result in bradycardia, respiratory distress, hypoglycaemia; generally, the persistence of effect is without clinical consequence. Nevertheless, a cardiac failure may occur by reduction of the cardiovascular compensation reaction, requiring hospitalisation and intensive-care treatment (see overdose) and avoiding filling solutes (risk of acute pulmonary oedema).
This drug may be prescribed during pregnancy if necessary.
In case of treatment until delivery, close monitoring of the neonate (heart rate and glycaemia for the first 3 to 5 day of life) is recommended.
Lactation
Beta-adrenergic blocking agents are excreted in human milk.
The risk of hypoglycaemia and bradycardia has been described for some beta-adrenergic blocking agents with little binding to plasmatic proteins. Therefore, breast-feeding is not recommended when treatment is needed.
4.7 Effects On Ability To Drive And Use Machines
There are undesirable effects associated with this eye drops (particularly visual disturbances) which may affect the ability to drive and use machines.
4.8 Undesirable Effects
The most frequently reported undesirable effects with levobunolol eye drops are local ocular reactions. Like other topically applied ophthalmic drugs, levobunolol eye drops may be absorbed systemically and adverse reactions seen with oral beta blockers may also occur.
Cardiac Disorders:
Bradycardia (occasionally severe), atrioventricular block (heart block; slowing of atrioventricular conduction or worsening or an existing atrioventricular block), syncope, palpitations, arrhythmia.
Vascular Disorders:
hypotension, peripheral coldness, intermittent claudication, Raynaud's phenomena.
Eye Disorders:
Conjunctivitis, eye irritation, blepharitis, conjunctival hyperaemia, keratoconjunctivitis sicca, ocular pruritus, keratitis, corneal disorder (decreased corneal sensitivity), vision blurred, visual disturbance (including refractive changes due to withdrawal of miotic therapy in some cases), diplopia, eyelid ptosis, choroidal detachment (following filtration surgery).
Gastrointestinal Disorders:
Abdominal pain upper, dyspepsia, dry mouth, nausea, vomiting, diarrhea,
General Disorders and Administration Site Disorders:
asthenia, fatigue, lethargy, chest pain.
Immune System Disorders:
allergic reactions including anaphylaxis, angioedema, urticaria, rash (localized and generalized; see also Skin and Subcutaneous Tissue Disorders).
Investigations:
antinuclear antibody positive (with extremely rare clinical relevance, such as symptoms of lupus erythematosus, which regress at treatment discontinuation).
Metabolism and Nutrition Disorders:
hypoglycaemia.
Nervous System Disorders:
headache, ataxia, dizziness, increase in signs and symptoms of myasthenia gravis.
Psychiatric Disorders:
hallucination, confusion, nightmare, depression, insomnia, sleep disorder, libido decreased.
Reproductive System and Breast Disorders:
erectile dysfunction.
Respiratory, Thoracic, and Mediastinal disorders:
dyspnea, cough, bronchospasm (predominantly in patients with pre-existing bronchospastic disease).
Skin and Subcutaneous Tissue Disorders:
Urticaria, angioneurotic oedema (angio-oedema), alopecia, rash, rash psoriasiform, psoriasis (exacerbation).
4.9 Overdose
Although systemic passage of beta-adrenergic blocking agents administered topically is low, overdoses are possible.
Should accidental ocular overdosage occur, flush the eye(s) with sterile water or sodium chloride solution 0.9%.
Symptoms and management of overdose are similar to that of systemically administered beta-adrenergic blocking agents.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code : S01ED03
ANTIGLAUCOMA
BETA-ADRENERGIC BLOCKING AGENT.
(S = Sensory organ)
The three pharmacological characteristics of the levobunolol are:
• non cardioselective beta-adrenergic blocking agent,
• absence of partial agonist potency [or absence of intrinsic sympathomimetic activity (ISA)],
• no significant membrane stabilising effect (local anaesthetic or quinidine-like).
Levobunolol hydrochloride eye drops lowers intraocular pressure, whether or not associated with glaucoma by decreasing aqueous humour secretion.
5.2 Pharmacokinetic Properties
As with other eye drops, levobunolol may pass in systemic circulation.
5.3 Preclinical Safety Data
There are no preclinical data of relevance to the prescriber additional to that already included in other sections of the SmPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Benzalkonium chloride, disodium edetate, polyvinyl alcohol, sodium metabisulphite (E223), disodium phosphate dodecahydrate (E339), potassium dihydrogen phosphate (E340), sodium chloride, hydrochloric acid and/or sodium hydroxide, purified water.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
2 years.
6.4 Special Precautions For Storage
Do not store above 25°C.
Keep the container in the outer carton in order to protect from light. Do not freeze. Discard the product 28 days after first opening.
6.5 Nature And Contents Of Container
Opaque polyethylene bottle and dropper tip with white polypropylene cap, containing 5 ml or 10 ml of eye drops.
6.6 Special Precautions For Disposal And Other Handling
No special precautions.
7. Marketing Authorisation Holder
Cusi (UK) Ltd.,
Pentagon Park,
Boundary Way,
Hemel Hempstead,
Herts.,
HP2 7UD, UK
8. Marketing Authorisation Number(S)
PL 16020/0010
9. Date Of First Authorisation/Renewal Of The Authorisation
July 1999/
2004
10. Date Of Revision Of The Text
November 2004
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