Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Laboratoires THEA, 12 Rue Louis Blériot, 63017 Clermont-Ferrand Cedex 2, FRANCE
As with all products containing beta-receptor blocking agents, Timolol is contraindicated in patients with:
Like other topically applied ophthalmic agents timolol maleate is absorbed systemically. Due to beta-adrenergic component, timolol maleate, 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 4.2.
As with any glaucoma treatment, regular examination of the intraocular pressure and cornea is recommended.
If TOPEX 1 mg/g is administered to reduce intraocular pressure in patients with closed-angle glaucoma, a miotic should be used in combination.
In such patients, the immediate objective of the treatment is to reopen the angle, which requires the use of a miotic agent in order to obtain pupil constriction, since timolol maleate has little or no effect on the pupil.
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.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
The dosage should be reduced if the rate falls below 50-55 beats per minute at rest, and if the patient presents bradycardia-related symptoms.
Beta-blockers may increase the risk of rebound hypertension.
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.
These patients should not receive β-blocking agents without concomitant α-adrenoceptor blocking therapy.
Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic betablockers.
TIOPEX 1 mg/g should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
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.
Beta-blockers may also mask the signs of hyperthyroidism.
It should be used with caution in patients with metabolic acidosis.
Ophthalmic β-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
There is a risk of intolerance to contact lenses due to a beta-blocker induced reduction in lacrimal secretion.
Timolol eye gel has not been studied in patients using contact lenses, and therefore the wearing of contact lenses should be avoided while using TIOPEX 1 mg/g.
The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol maleate 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).
While taking beta-blockers, patients with 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 has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Beta-blockers have been reported to aggravate psoriasis and its use in this condition therefore deserves careful consideration.
As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with coronary heart disease, therapy should be withdrawn gradually.
When such agents are administered orally in such high-risk subjects, a dosage adjustment is often necessary.
β-blocking ophthalmological preparations may block systemic β-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol maleate.
Sportsmen should be warned that this drug contains an active substance, which may induce a positive analytical result in anti-doping controls.
No specific drug interaction studies have been performed with timolol maleate.
Although the quantity of beta-blockers, which passes into the systemic circulation is low after ocular instillation, the risk of drug interactions is still present.
It is therefore advisable to keep in mind the interactions observed with beta-blockers given by general route.
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, betaadrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.
Potentiated systemic betablockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
Automatism disorders (excessive bradycardia, sinus arrest), sinoatrial and atrioventricular conduction disorders and increased risk of ventricular rhythm disorders (torsades de pointes) as well as cardiac failure.
This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or in those beginning treatment.
Automatism disorders (excessive bradycardia, sinus arrest) sinoatrial and atrioventricular conduction disorders and cardiac failure.
This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or those starting treatment.
Automatism disorders (excessive bradycardia, sinus arrest) sinoatrial and atrioventricular conduction disorders and cardiac failure.
This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or those starting treatment.
Potentiation of bradycardic effects can have fatal consequences. Beta-blockers are more at risk that they prevent adrenergic compensation mechanism.
Continuous clinical and ECG monitoring during 24 hours after the first dose.
Automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).
Clinical and ECG monitoring is recommended.
Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).
Clinical and ECG monitoring is recommended.
Reduction in compensatory cardiovascular mechanisms by beta-blockers. Beta-adrenergic inhibition may be counteracted during surgery by beta-mimetics.
As a general rule, do not discontinue beta-blocker therapy, and in any event, avoid a sudden discontinuation. The anaesthetist should be advised of this treatment.
Enhancement of hypotension risk, notably orthostatic.
Blood pressure monitoring and, if necessary, dosage adjustment of the antihypertensive.
Significant increase in arterial pressure if treatment with a central anti-hypertensive is suddenly discontinued.
Avoid sudden withdrawal of treatment with a central anti-hypertensive. Clinical monitoring.
All beta-blockers may mask certain symptoms of hypoglycaemia: palpitations and tachycardia.
Warn the patient and, particularly at the beginning of treatment, self-monitoring of glycaemia by the patient should be increased.
With lidocaine used intravenously: increase in plasmatic concentrations of lidocaine with a possibility of adverse neurological and cardiac side effects (reduction in hepatic clearance of lidocaine).
Clinical and ECG monitoring and possibly testing of the plasmatic concentrations of lidocaine during the combined therapy and after the beta-blocker has been withdrawn. Adaptation if necessary of dosage regimen of lidocaine.
Enhanced risk of ventricular arrhythmia, particularly torsades de pointes.
Clinical and ECG monitoring is recommended.
Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).
Clinical and ECG monitoring is recommended.
Enhancement of hypotensive effect. Increased risk of orthostatic hypotension.
Enhancement of hypotension risk, notably orthostatic.
Enhancement of hypotension risk, notably orthostatic.
Enhancement of hypotension risk, notably orthostatic. Vasodilatator effect and risk of hypotension, notably orthostatic (additional effect).
Reduction in the antihypertensive effect (inhibition of vasodilator prostaglandins by non-steroidal anti-inflammatory drugs and of water and salt retention by phenylbutazone).
Risk of excessive bradycardia (additive effects).
Hypotension, cardiac failure in patients with latent or uncontrolled cardiac insufficiency (additional negative inotropic effects). Moreover, the beta-blocker can minimise the sympathetic reflex reaction, which comes into play in the event of excessive haemodynamic repercussion.
With the dipyridamole by intravenous route: enhancement of the anti-hypertensive effect.
Risk of excessive bradycardia (additive bradycardial effects).
Enhancement of hypotension risk, notably orthostatic.
There are no adequate data for the use of timolol maleate in pregnant women. Timolol maleate should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see 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 betablockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If TIOPEX 1 mg/g is administered until delivery, the neonate should be carefully monitored during the first days of life.
Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol maleate 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 the systemic absorption, see 4.2.
Timolol maleate has not been found to have any effect on fertility in animal studies (see section 5.3).
TIOPEX 1 mg/g has minor influence on the ability to drive and use machines.
No studies on the effect of this medicinal product on the ability to drive have been conducted. While driving vehicles or operating different machines, it should be taken into account that occasionally visual disturbances may occur including refractive changes, diplopia, ptosis, frequent episodes of mild and transient blurred vision and occasional episodes of dizziness or fatigue.
Like other topically applied ophthalmic drugs, timolol maleate is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic betablocking 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.
Immune system disorders: Systemic lupus erythematosus, systemic allergic reactions including angio-oedema, urticaria, localised and generalised rash, pruritus, anaphylactic reaction.
Metabolism and nutrition disorders: Hypoglycaemia.
Psychiatric disorders: Insomnia, depression, nightmares, memory loss.
Nervous system disorders: Syncope, cerebrovascular accident, cerebral ischemia, increases in signs and symptoms of myasthenia gravis, dizziness, paraesthesia, and headache.
Eye disorders: Signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), blepharitis, conjunctival hyperaemia, conjunctivitis, keratitis, blurred vision and choroidal detachment following filtration surgery (see 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, dry eyes, corneal erosion ptosis, diplopia, refractive changes (due to withdrawal of miotic therapy in some cases).
Cardiac disorders: Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, cardiac failure, claudication.
Vascular disorders: Hypotension, Raynaud’s phenomenon, cold hands and feet.
Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), dyspnoea, cough.
Gastrointestinal disorders: Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.
Skin and subcutaneous tissue disorders: Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash.
Musculoskeletal and connective tissue disorders: Myalgia.
Reproductive system and breast disorders: Sexual dysfunction, libido decreased, impotence.
General disorders and administration site conditions: Asthenia/fatigue.
Investigations: Antinuclear antibodies positive.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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