1. Name Of The Medicinal Product
Timolol Eye Drops, 0.5%
2. Qualitative And Quantitative Composition
Timolol 0.50% w/v (as timolol maleate).
For excipients, see 6.1.
3. Pharmaceutical Form
Eye Drops, Solution
A clear, colourless sterile, multi-dose drops, solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Timolol Eye Drops 0.5% are indicated for the treatment of open-angle glaucoma, aphakic glaucoma, some patients with secondary glaucoma, and other patients with elevated intraocular pressure who are at sufficient risk to require lowering of their ocular pressure.
Timolol Eye Drops 0.50% may be used alone or in combination with other glaucoma medications
4.2 Posology And Method Of Administration
Apply one drop in the eye(s) twice a day.
Since the intraocular pressure lowering response to timolol may require several weeks to stabilise, intraocular pressure should be re-assessed approximately one month after starting treatment with timolol.
Transfer from Other Agents:
When a patient is transferred from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent already used and add one drop of timolol in the affected eye(s) twice a day. On the following day, discontinue the previous anti-glaucoma agent completely and continue with timolol.
When a patient is transferred from a single topical beta-blocking agent, discontinue its use after a full day of therapy and start treatment with timolol on the next day.
When a patient is transferred from several concomitantly administered anti-glaucoma agents, individualisation is required. Adjustment should involve one agent at a time made at intervals of not less that one week. A recommended approach is to continue the agents being used and add one drop of timolol in the affected eye(s) twice a day. On the following day, discontinue one of the other anti-glaucoma agents. The remaining anti-glaucoma agents may be decreased or discontinued according to the patient's response to treatment. The physician may be able to discontinue some or all of the other anti-glaucoma agents.
Elderly and Paediatric Use:
There are currently no clinical data indicating that dosage modifications are required for use in the elderly.
Safety and effectiveness in children have not been established by adequate and well-controlled studies.
Patients should be instructed to remove soft contact lenses before using timolol.
4.3 Contraindications
Timolol Eye Drops 0.50% are contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease; sinus bradycardia; second and third degree atrioventricular block; overt cardiac failure; and cardiogenic shock.
This product is contraindicated in patients who are hypersensitive to any of its components.
4.4 Special Warnings And Precautions For Use
As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following administration of Timolol Eye Drops 0.50%.
Patients who are receiving a beta-adrenergic blocking agent orally and Timolol Eye Drops 0.50% should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta blockade.
Patients should not receive two topical ophthalmic beta-adrenergic blocking agents concurrently.
Because of potential effects of beta-adrenergic blockade agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol Eye Drops 0.50%, alternative therapy should be considered.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalized weakness). Timolol Eye Drops have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Timolol Eye Drops 0.50% have little or no effect on the pupil. When Timolol Eye Drops 0.50% are used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used with a miotic and not alone.
As with the use of other antiglaucoma drugs, diminished responsiveness to Timolol Eye Drops 0.50% after prolonged therapy has been reported in some patients. However, in one long-term study in which 96 patients have been followed for at least 3 years, no significant difference in mean intraocular pressure has been observed after initial stabilisation.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Although Timolol Eye Drops 0.50% used alone have little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timolol Eye Drops and epinephrine has been reported occasionally.
Close observation of the patients is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Caution should be used in the co-administration of beta-adrenergic agents, such as Timolol Eye Drops 0.50%, with oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.
The concomitant use of beta-adrenergic blocking agents with digitalis may have additive effects in prolonging atrioventricular conduction time.
4.6 Pregnancy And Lactation
Teratogenicity studies with timolol in mice and rabbits at doses up to 50 mg/kg/day (40 times the maximum recommended human oral dose*) showed no evidence of foetal malformations. Although delayed foetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (approx. 830 time the maximum recommended human oral dose) were maternotoxic in mice and resulted in an increased number of foetal resorptions. Increased foetal resorptions were also seen in rabbits at doses of 40 times the maximum recommended human oral dose, in this case without apparent maternotoxicity. There are no adequate and well- controlled studies in pregnant women. Timolol Eye Drops 0.50% should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Nursing Mothers: Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
*The maximum recommended daily oral dose is 60 mg of timolol. One drop of Timolol Eye Drops 0.50% contains about 1/300 of this dose which is about 0.2 mg.
4.7 Effects On Ability To Drive And Use Machines
There are currently no data available on the effects of this product with regard to the ability to drive. It has to be taken into account that during driving and using machines the possibility of transient ocular irritation, blurred vision and lacrimation may occur occasionally.
4.8 Undesirable Effects
Timolol Eye Drops 0.50% are usually well tolerated. The following adverse reactions have been reported either in clinical trials of up to 3 years duration prior to release in 1978 or since the drug has been marketed:
Body as a whole: headache, asthenia, chest pain
Cardiovascular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, palpitation, cardiac arrest
Digestive: nausea, diarrhoea
Nervous System/Psychiatric: dizziness, depression, increase in signs and symptoms of myasthenia gravis, parasthesia
Skin: hypersensitivity, including localised and generalized rash; urticaria, alopecia
Respiratory: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, nasal congestion, cough
Endocrine: masked symptoms of hypoglycaemia in insulin-dependant diabetics
Special Senses: Signs and symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis.
Causal Relationship Unknown: The following adverse effects have been reported, and a causal relationship to therapy with Timolol Eye Drops has not been established: Body as a whole: Fatigue; Cardiovascular: Hypertension, pulmonary oedema, worsening of angina pectoris; Digestive: Dyspepsia, anorexia, dry mouth; Nervous System/Psychiatric: Behavioural changes including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence, and other psychic disturbances; Special Senses: Aphakic systoid macular oedema; Urogenital: Retroperitoneal fibrosis, impotence.
The following additional adverse effects have been reported in clinical experience with oral timolol maleate, and may be considered potential effects of ophthalmic timolol maleate: Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Oedema, worsening of arterial insufficiency, Raynaud's phenomenon, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting; Haematologic: Nonthrombocytopenic purpura; Endocrine: Hyper-glycaemia, hypoglycaemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating, cold hands and feet; Musculoskeletal: Arthralgia, claudication; Nervous System/Psychiatric: Vertigo, local weakness, decreased libido, nightmares, insomnia, diminished concentration; Respiratory: Rales, bronchial obstruction; Special Senses: Tinnitus, dry eyes; Urogenital: Urination difficulties.
Potential Adverse Effects: In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential effects of ophthalmic timolol maleate: Digestive: Mesenteric arterial thrombosis, ischemic colitis; Haematologic: Agranulocytosis, thrombocytopenic purpura; Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Urogenital: Peyronie's disease.
There have been reports of a syndrome comprising psoriasiform skin rash, conjunctivitis sicca, otitis and sclerosing serositis attributed to the beta-adrenergic receptor blocking agent, practolol. This syndrome has not been reported with timolol maleate.
4.9 Overdose
No data are available in regard to overdosage in humans. The oral LD50 of the drug is 1190 and 900 mg/kg in female mice and female rats, respectively.
A. Signs and Overdosage Overdosage may lead to hypotension, cardiac failure, cardiogenic shock, bradycardia to the extreme of cardiac arrest. In addition respiratory distress, bronchospasms, vomiting, disturbed consciousness and generalized seizures may occur.
B. Treatment of Overdosage Apart from general measures, monitoring and if necessary, correction of vital signs under intensive care conditions are imperative. Antidotes include:
atropine:
0.5 to 2 mg IV bolus injection
glucagon:
Initial treatment with 1-10 mg IV, to be followed by 2-2.5 mg/h as continuous drip infusion.
ß-sympathomimetic agents according to body weight and (desired) effect: dobutamine, isoprenaline, orciprenaline or adrenaline
Pacemaker control should be considered in refractory bradycardia.
ß2-sympathomimetics (as aerosol or, intravenously, if the aerosol effect proves inadequate) or intravenous aminophylline can be used in bronchospasms.
Slow intravenous injection of diazepam is recommended to control seizures.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Therapeutic Group: Ophthalmologicals: Antiglaucoma Preparations & Miotics. ATC Code: S01E D01
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, betaadrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed para-sympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.
Timolol Eye Drops 0.50%, when applied topically in the eye, has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma.
Elevated intraocular pressure is major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.
The precise mechanism of the ocular hypotensive action of Timolol Eye Drops is not clearly established at this time. Tonography and fluoro-photometry studies in man suggest that this predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. Unlike miotics, Timolol Eye Drops 0.50% reduces intraocular pressure with little or no effect on accommodation or pupil size. Thus, changes in visual acuity due to increased accommodation are uncommon, and dim or blurred vision and night blindness produced by miotics are not evident. In addition, in patients with cataracts the inability to see around lenticular opacities when the pupil is constricted is avoided.
5.2 Pharmacokinetic Properties
The onset of reduction in intraocular pressure following administration of Timolol can usually be detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated observations over a period of one year indicate that the intraocular pressure-lowering effect of Timolol Eye Drops 0.50% is well maintained.
5.3 Preclinical Safety Data
Carcinogenicity/Tumorigenicity - In a two-year study of timolol maleate in rats, there was a statistically significant increase in the incidence of adrenal phaeochromocytomas in male rats administered 300 mg/kg/day (250 time the maximum recommended human oral dose). The maximum recommended single oral dose is 60 mg of timolol. One drop of Timolol Eye Drops 0.50%, contains about 1/300 of this dose which is about 0.2 mg. Similar differences were not observed in rats administered oral doses equivalent to 20 or 80 times the maximum recommended human oral dose. In a life-time oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumours and benign uterine polyps in female mice at 500 mg/kg/day (approximately 400 times the recommended daily human oral dose), but not at 5 or 50 mg/kg/day. In a subsequent study in female mice, in which post-mortem examinations were limited to uterus and lungs, a statistically significant increase in the incidence of pulmonary tumours was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.
Mutagenicity - Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 µg/mL). In Ames tests the highest concentrations of timolol employed, 5000 or 10,000 µg/plate, were associated with statistically significant elevation of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, nor did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Reproduction - Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 125 times the maximum recommended human oral dose.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium dihydrogen phosphate dihydrate
Disodium phosphate dodecahydrate
Benzalkonium chloride
Sodium hydroxide and/or hydrochloric acid (to adjust pH)
Purified water
6.2 Incompatibilities
Not known
6.3 Shelf Life
36 months for the 5 ml and 10 ml bottles (unopened), one month after the bottle is opened.
6.4 Special Precautions For Storage
Do not store above 25°C
6.5 Nature And Contents Of Container
Multi-dose opaque or natural low density polyethylene DROP-TAINER® bottles containing 5 ml or 10 ml of the ophthalmic solution.
6.6 Special Precautions For Disposal And Other Handling
Do not touch dropper tip to any surface as this may contaminate the contents. If the drop of medication is not retained in the eye upon dosing for any reason, instil another drop.
ADMINISTRATIVE DATA
7. Marketing Authorisation Holder
Cusi (UK) Ltd
Pentagon Park
Boundary Way
Hemel Hempstead
Herts., HP2 7UD
U.K.
8. Marketing Authorisation Number(S)
PL 16020/0003
9. Date Of First Authorisation/Renewal Of The Authorisation
9th June 1998
10. Date Of Revision Of The Text
May 2003
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