Timolol 0.25% W/V Eye Drops Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Timolol 0.25% w/v Eye Drops Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of the solution contains timolol 2.5 mg (as timolol maleate 3.4 mg)
Excipients: benzalkonium chloride
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Eye drops, solution Clear, colourless solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Reduction of intra-ocular pressure in patients with chronic open-angle glaucoma or ocular hypertension.
4.2 Posology and method of administration
Recommended dosage for adults (including the elderly):
Initially 1 drop of the 0.25% w/v solution is recommended twice daily in the affected eye. The dose can be increased to 1 drop of the 0.5% w/v solution twice daily if necessary.
Intraocular pressure should be reassessed approximately four weeks after starting treatment because response to timolol eye drops may take a few weeks to stabilise.
If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye(s) twice daily.
Administration:
Contact lenses should be removed before instillation of eye drops and may be re-inserted after 15 minutes (see section 4.4, Special warnings and precautions for use).
When using nasolacrimal occlusion or closing the eyelids for as long as possible (e.g. 3-5 minutes, the systemic absorption is reduced (see also section 4.4, 5.2). This may result in a decrease in systemic side effects and an increase in local activity.
If more than one topical ophthalmic product is to be used, the different products must be instilled at least 5 minutes apart.
If the intra-ocular pressure is maintained at satisfactory levels by the dosage described above, a once daily therapy may be considered. However, intraocular pressure should be measured regularly to monitor the response to treatment.
Use in children and adolescents:
Due to limited data, Timolol could only be recommended for use in primary congenital and primary juvenile glaucoma for a transitional period while decision is made on a surgical approach and in case of failed surgery while awaiting further options.
Clinicians should strongly evaluate the risks and benefits when considering medical therapy with Timolol in paediatric patients. A detailed paediatric history and examination to determine the presence of systemic abnormalities should precede the use of Timolol.
No specific dosage recommendation can be given as there is only limited clinical data (see also section 5.1)
To limit potential adverse effects only one drop should be instilled per dosing time.
Systemic absorption of topically administered B-blockers can be reduced by nasolacrimal occlusion and by keeping the eyes closed as long as possible (e.g. for 3-5 minute) and after instillation of the drops.
See also sections 4.4, 5.2
However, if benefit outweighs the risk, it is recommended to use the lowest active agent concentration available once daily. If IOP could not be sufficiently controlled, a careful up titration to a maximum of two drops daily per affected eye has to be considered. If applied twice daily, an interval of 12 hours should be preferred.
Furthermore the patients, especially neonates, should be strongly observed after the first dose for one to two hours and closely monitored for ocular and systemic side effects until surgery is performed.
With regard to paediatric use, the 0.25% eye drop solution might already be sufficient.
Timolol Eye Drop solution should be used for a transient treatment in the paediatric population.
4.3 Contraindications
Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome sino-atrial block, second or third degree atroventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.
Hypersensitivity to timolol, or to any of the excipients.
4.4 Special warnings and precautions for use
Systemic effects:
Like other topically applied ophthalmic agents, timolol is absorbed systemically. Due to beta-adrenergic component, timolol, 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.
Cardiac disorders:
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 it’s negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Vascular disorders:
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.
Respiratory disorders:
Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.
Timolol Eye Drops should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benfit outweighs the potential risk.
Hypoglycaemia/diabetes:
Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to atients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
Beta-blockers may also mask the signs of hyperthyroidism.
Corneal diseases:
Ophthalmic B-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking agents:
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 agents. 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).
Anaphylactic reactions:
While taking beta-blockers, patients with a 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:
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol) after filtration procedures.
Surgical anaesthesia:
B-blocking ophthalmological preparations may block systemic B-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol maleate.
Timolol Eye Drops contain benzalkonium chloride which is commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy and may cause eye irritation. Close monitoring is required with frequent or prolonged use of Timolol Eye Drops in dry eye patients or in conditions where the cornea is compromised.
Soft contact lenses may absorb benzalkonium chloride and discolour. Contact lenses should therefore be removed before applying Timolol Eye Drops but may be reinserted after 15 minutes
Paediatric Population:
Timolol solutions should generall be used cautiously in young glaucoma patients (see also section 5.2).
It is important to notify the parents of potential side effects so they can immediately discontinue the drug therapy. Signs to look for are, for example, coughing and wheezing.
Because of the possibility of apnoea and Cheyne-Stokes breathing, the drug should be used with extreme caution in neonates, infants and younger children. A portable apnoea monitor may be helpful for neonates on Timolol.
4.5 Interaction with other medicinal products and other forms of interaction
No specific drug interaction studies have been performed with timolol.
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, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digital glycosides, parasympathomimetics, guanethidine.
Potentiated systemic beta-blockade (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.
There is also a potential for AV conduction disturbances or left ventricular failure to occur when oral calcium channel blockers like verapamil and diltiazem are used with the beta blocker
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta blockers.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data for the use of timolol in pregnant women. Timolol 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 symptos of beta-blockafe (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If Timolol Eye Drops are administered until delivery, the neonate should be carefully monitored during the first days of life.
Lactation
Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol 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 systemic absorption, see 4.2.
4.7 Effects on ability to drive and use machines
Instillation of eye drops may cause transient blurring of vision. Until this has resolved, the patient must not drive or use machinery.
4.8 Undesirable effects
Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulations, either in clinical trials or since the drug has been marketed.
Additional side effects have been reported in clinical experiences with systemic timolol maleate, and may be considered potential effects of ophthalmic timolol maleate.
Eye disorders
Ocular use: signs and symptoms of ocular irritation, (e.g. burning, stinging, itching, tearing, redness), conjunctivitis, blepharitis, keratitis, dry eyes, decreased corneal sensitivity, blurred vision, corneal erosion. Visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and choroidal detachment following filtration surgery (see 4.4 'Special warnings and precautions for use').
Ear and labyrinth disorders:
Ocular use: tinnitus Cardiac disorders:
Ocular use: bradycardia, chest pain, arrhythmia, heart block, congestive heart failure, palpitations, cardiac arrest, atrioventricular block, cardiac failure, oedema;
Systemic use: AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.
Vascular disorders:
Ocular use: claudication, hypotension, Raynaud's phenomenon, cold hands and feet. Respiratory, thoracic and mediastinal disorders:
Ocular use: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough;
Systemic use: rales.
General disorders and administration site conditions:
Ocular use: asthenia, fatigue;
Systemic use: extremity pain, decreased exercise tolerance.
Skin and subcutaneous tissue disorders:
Ocular use: alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash;
Systemic use: sweating, exfoliative dermatitis.
Immune system disorders:
Ocular use: systemic lupus erythematosus, pruritus;
Systemic use: signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash, anaphylactic reaction.
Psychiatric disorders:
Ocular use: depression, insomnia, nightmares, memory loss;
Systemic use: diminished concentration, increased dreaming.
Nervous system disorders
Ocular use: syncope, cerebrovascular accident, cerebral ischemia, headache, dizziness, increase in signs and symptoms of myasthenia gravis, paraesthesia;
Systemic use: vertigo, local weakness Gastrointestinal disorders:
Ocular use: nausea, diarrhoea, dyspepsia, dry mouth dysgeusia, abdominal pain vomiting. Reproductive system and breast disorders:
Ocular use: decreased libido, Peyronie's disease, sexual dysfunction such as impotence; Systemic use: micturition difficulties.
Metabolism and nutrition disorders:
Ocular use: hypoglycaemia;
Systemic use: hyperglycaemia.
Musculoskeletal and connective tissue disorders:
Ocular use: myalgia;systemic: arthralgia Blood and lymphatic system disorders:
Systemic use: non-thrombocytopenic purpura.
Reporting of suspected adverse reactions
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 Yellow Card Scheme at: www.mhra.gov .uk/yellowcard
4.9 Overdose
No specific data are available.
Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm, headache, dizziness, shortage of breath and cardiac arrest. If such symptoms occur, treatment should be symptomatic and supportive. In some cases, particularly in children and adolescents, CNS-symptoms and respiratory depression may dominate. Studies have shown that timolol does not dialyse readily.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals - antiglaucoma preparations and miotics - betablocking agents, ATC code: S01ED01
Timolol is a beta-1 and beta-2 (non-selective) adrenergic receptor blocking agent that has no intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising (local anaesthetic) activity. Timolol reduces intra-ocular pressure by inhibiting the production of aqueous humour in the ciliary epithelium. The precise mechanism of action is not clearly established but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is
Paediatric Population:
Thre is only very limited data on the use of Timolol (0.25%, 0.5% twice daily one drop), in the paediatric population for a treatment period up to 12 weeks. One small, double blinded, randomised, published clinical study conducted on 105 children (n=71 on Timolol) aged 12 days - 5 years show to some extent evidence that Timolol, in the indication primary congenital and primary juvenile glaucoma is effective in short term treatment.
5.2 Pharmacokinetic properties
The maximum concentration of timolol in the aqueous humour is achieved about one hour after topical administration of eye drops. Part of the dose is absorbed systemically where it is extensively metabolised by the liver. The metabolites are excreted in the urine together with some unchanged timolol. The half life of timolol in plasma is about 6 hours. Timolol is not extensively bound to plasma.
Paediatric Population:
As already confirmed by adult data, 80% of each eye drop passes through the nasolacrimal system where it may be rapidly absorbed into the systemic circulation via the nasal mucosa, conjunctiva, nasolacrimal duct, oropharynx and gut, or the skin from tear overflow.
Due to the fact that the blood volume in children is smaller than that in adults, a higher circulation concentration has to be taken into account. In addition, neonates have immature metabolic enzyme pathways and it may result in an increase in elimination half-life and potentiating adverse events.
Limited data show that plasma timolol levels in children after 0.25% greatly exceed those in adults after 0.5%, especially in infants and are presumed to increase the risk of side effects such as bronchospasm and bradycardia.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Benzalkonium chloride Sodium dihydrogen phosphate dihydrate Disodium phosphate dodecahydrate Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Unopened bottle: 2 years. After first opening bottle: 4 weeks.
6.4 Special precautions for storage
Do not store above 25°C. Store the bottle in the outer carton to protect from light.
6.5 Nature and contents of container
Transparent plastic (LDPE) bottle with a transparent dropper (LDPE) and a white screw cap (HDPE) containing 5 ml of a clear and colourless solution.
1 x 5 ml plastic bottle 3 x 5 ml plastic bottles
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Blumont Pharma Ltd 23 Moortown Close Grantham United Kingdom NG31 9GG
8 MARKETING AUTHORISATION NUMBER(S)
PL 31103/0007
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27/07/2009
10 DATE OF REVISION OF THE TEXT
28/11/2014