Timolol Eye Drops Bp 0.25% W/V
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Timolol Eye Drops BP 0.25% w/v
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Name of Ingredient Amount (g/litre)
0.25% w/v
Timolol Maleate Ph Eur 3.417 equivalent to Timolol 2.5
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Ophthalmic solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Timolol maleate ophthalmic solution is a beta-adrenergic receptor antagonist used topically for the reduction of elevated intra-ocular pressure in various conditions including patients with ocular hypertension; patients with chronic open-angle glaucoma including patients with aphakia; and some patients with secondary glaucoma.
4.2 Posology and method of administration Posology:
in the affected eye(s) twice
increased to one drop 0.5% required, timolol maleate
Recommended therapy is one drop 0.25% solution a day.
If clinical response is not adequate, dosage may be solution in the affected eye(s) twice daily. If
ophthalmic solution may be used with miotics, adrenaline or systemically administered carbonic anhydrase inhibitors.
Intra-ocular pressure should be reassessed approximately four weeks after starting treatment because response to timolol maleate may take a few weeks to stabilise.
Provided that the intra-ocular pressure is maintained at satisfactory levels, many patients can then be placed on once-a-day therapy.
Transfer From Other Agents
If transferring from another topical beta-blocking agent, its use should be discontinued after a full day of treatment and treatment with timolol maleate
0.25% started the next day with one drop twice daily in the affected eye(s).
As above, if the clinical response is not adequate, the dosage may be increased to one drop of the 0.5% solution twice daily.
If transferring from a single anti-glaucoma agent which is not a beta-blocker, the agent should be continued and one drop added of the 0.25% timolol maleate in the affected eye(s) twice daily. On the following day the previous agent should be discontinued and timolol maleate continued. The dosage may be increased to the 0.5% solution twice daily if the clinical response is inadequate.
Use in the Older people
There has been wide experience with the use of timolol maleate in elderly patients. The dosage recommendations above reflect the clinical data derived from this experience.
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.
Paediatric population
Due to limited data, timolol maleate 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 maleate.
No specific dosage recommendation can be given as there is only limited clinical data (see also section 5.1).
However, if benefit outweighs the risk, it is recommended to use the lowest active agent concentration available once daily. If intra-ocular pressure (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 in the office and closely monitored for ocular and systemic side effects until surgery is performed.
With regard to paediatric use, the 0.1% active agent concentration might already be sufficient.
Method of administration:
Precautions to be taken before handling or administering the medicinal product:
To limit potential adverse effects only one drop should be instilled per dosing time.
Systemic absorption of topically administered P-blockers can be reduced by nasolacrimal occlusion and by keeping the eyes closed as long as possible (e.g. for 3 -5 minutes) after instillation of drops. See also section 4.4, 5.2.
Duration of treatment:
For a transient treatment in the paediatric population.
4.3 Contraindications
As with all products containing beta-receptor blocking agents, Ttimolol maleate is
contraindicated in patients with:
• 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 atrioventricular (AV) block not controlled with pace-maker
• Overt cardiac failure, cardiogenic shock
• Hypersensitivity to timolol maleate, or to any of the excipients listed in section 6.1 or other beta-blocking agents.
4.4 Special warnings and precautions for use
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 section 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 its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Cardiac failure should be adequately controlled before beginning therapy with timolol maleate . Patients with a history of severe cardiac disease should be closely observed for signs of cardiac failure and have their pulse rates checked.
Vascular disorders
Patients with severe peripheral circulatory disturb ance/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 maleate 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.
Hypoglycaemia/diabetes
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.
Corneal diseases
Ophthalmic P-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 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).
Anaphylactic reactions
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
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Surgical anaesthesia
P-blocking ophthalmological preparations may block systemic P-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol maleate.
Paediatric population
Timolol maleate solutions should generally 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 also be helpful for neonates on timolol maleate.
If timolol maleate is used to reduce elevated intra-ocular pressure in angle closure glaucoma it should be used with a miotic and not alone.
There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic receptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy involving beta-blockade should be gradual.
Timolol maleate contain benzalkonium chloride as a preservative which may be deposited in soft contact lenses. Therefore, timolol maleate should not be used while wearing these lenses. The lenses should be removed before application of the drops and not reinserted earlier than 15 minutes after use.
Timolol maleate have generally been well tolerated in glaucoma patients wearing conventional hard contact lenses. Timolol maleate has not been studied in patients wearing lenses made of material other than polymethylmethacrylate (PMMA) which is used to make hard contact lenses.
No specific drug interaction studies have been performed with timolol maleate.
1. Other eye drops
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
2. Other drugs
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), digitalis glycosides, parasympathomimetics, guanethidine.
CYP2D6 inhibitors (e.g. quinidine, SSRIs)
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 maleate .
4.6 Fertility, pregnancy and lactation
Pregnancy
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 section 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 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 timolol maleate is administered until delivery, the neonate should be carefully monitored during the first days of life.
Breast-feeding
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 section 4.2.
A decision for breast-feeding mothers either to stop taking timolol maleate or stop nursing should be based on the importance of the drug to the mother.
4.7 Effects on 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. Patients should be warned not to drive or operate moving machinery until any blurring of vision after instillation has totally regressed.
4.8 Undesirable effects
Like other topically applied ophthalmic drugs, timolol maleate 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. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
Timolol maleate is usually well tolerated.
Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with timolol maleate.
Immune system disorders:
Systemic lupus erythematosus, systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction.
Metabolism and nutrition disorders:
Hypoglycaemia.
Psychiatric disorders:
Insomnia, depression, nightmares, memory loss.
Nervous system disorders:
Syncope, cerebrovascular accident, cerebral ischaemia, 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), including conjunctivitis, blepharitis, keratitis, blurred vision and choroidal detachment following filtration surgery (see section 4.4 Special
warnings and special precautions for use). Decreased corneal sensitivity, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), dry eyes, corneal erosion, ptosis, diplopia.
Cardiac disorders:
Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, cardiac failure.
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 (such as impotence), decreased libido.
General disorders and administration site conditions:
Asthenia, fatigue.
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.
Causal relationship unknown: The following adverse effects have been reported, but a causal relationship to timolol maleate has not been established: Aphakic cystoid macular oedema, nasal congestion, anorexia, CNS effects (e.g. behavioural change including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence and other psychiatric disturbances), hypertension and retroperitoneal fibrosis.
The adverse reactions seen with oral timolol maleate may occur with timolol maleate due to systemic absorption.
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Overdosage reactions are more likely to follow oral ingestion of timolol maleate than by systemic absorption through its topical use. No specific data on overdosage in humans by either route are available.
A study in patients with renal failure suggests that timolol maleate does not readily dialyse.
The most common signs and symptoms to be expected following overdosage with a beta-blocker are symptomatic bradycardia, hypotension, bronchospasm and acute cardiovascular insufficiency. The standard measures to overcome beta-blockade should be undertaken.
If overdosage occurs, the following measures should be considered:
1. Administration of activated charcoal, if the preparation has been taken orally. Studies have shown that timolol maleate cannot be removed by haemodialysis.
2. Symptomatic bradycardia: Atropine sulphate, 0.25 to 2 mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker should be considered.
3. Hypotension: A sympathomimetic agent such as dopamine, dobutamine or noradrenaline should be given. In refractory cases, the use of glucagon has been useful.
4. Bronchospasm: Isoprenaline hydrochloride should be given. Concomitant therapy with aminophylline may be considered.
5. Acute cardiac failure: Conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is recommended.
This may be followed, if necessary, by glucagon, which has been found useful.
6. Heart blocks: Isoprenaline hydrochloride or a pacemaker should be used.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Timolol maleate ophthalmic solution is a non-selective beta-adrenergic antagonist used for the topical treatment of increased intra-ocular pressure.
Timolol maleate has no intrinsic sympathomimetic activity nor membrane-stabilising activity.
It is thought that the mode of action is by markedly reducing the production of aqueous humor, probably without any effect on the outflow tract.
Timolol maleate ophthalmic solution is effective in a range of concentrations but the usual recommendation is for 0.25% and 0.5% solution strengths.
Paediatric Population:
There is only very limited data available on the use of Timolol maleate (0.25%, 0.5% twice daily one drop) in the paediatric population for a treatment period up to 12 weeks. One small, double blinded, randomized, published clinical study conducted on 105 children (n=71 on Timolol) aged 12 days - 5 years shows to some extent evidence, that Timolol maleate in the indication primary congenital and primary juvenile glaucoma is effective in short term treatment.
5.2 Pharmacokinetic properties
Timolol maleate ophthalmic solution lowers intra-ocular pressure within 30-60minutes of being administered topically, has a maximum IOP-lowering effect 4-5 hours after administration, and the effect persists for 12-14 hours after a single dose.
Minute amounts are absorbed systemically; plasma concentrations of up to 1 ng/ml can be detected after single eye drop administration.
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 maleate 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.
Preclinical safety data
5.3
None presented
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Potassium Dihydrogen Phosphate Ph Eur Disodium Hydrogen Phosphate Dodecahydrate Ph Eur Benzalkonium Chloride Ph Eur Purified Water Ph Eur
6.2 Incompatibilities
None known
6.3 Shelf life
Shelf Life of the Product as Packaged for Sale Three years
Shelf Life After First Opening the Container One month
6.4 Special precautions for storage
Store below 30°C. Protect from light.
6.5 Nature and contents of container
A 5 ml low density polyethylene bottle. The dropper insert is made from low density polyethylene and the bottle is closed by a screw cap manufactured from high density polyethylene. The cap is secured by a tamper evident closure.
6.6 Special precautions for disposal
Disposal:
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Unscrew the cap from the bottle. Pull down the bottom lid of the eye to form a pocket. Place the tip close to the lower eye lid and squeeze the container gently. One drop of solution should fall into the eye.
7. MARKETING AUTHORISATION HOLDER
Norton Healthcare Limited
T/A IVAX Pharmaceuticals UK
Albert Basin
Royal Docks
London
E16 2QJ
8. MARKETING AUTHORISATION NUMBER(S)
PL 00530/0490
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 22 January 1997
10 DATE OF REVISION OF THE TEXT
05/01/2015