1. Name Of The Medicinal Product
TIMOPTOL®-LA 0.25% w/v Gel-Forming Eye Drops Solution
TIMOPTOL®-LA 0.5% w/v Gel-Forming Eye Drops Solution
2. Qualitative And Quantitative Composition
Each millilitre of 0.25% w/v solution contains an amount of timolol maleate equivalent to 2.5 mg/ml timolol.
Each millilitre of 0.5% w/v solution contains an amount of timolol maleate equivalent to 5 mg/ml timolol.
3. Pharmaceutical Form
Sterile gel-forming eye drops solution.
4. Clinical Particulars
4.1 Therapeutic Indications
A beta-adrenoreceptor blocker used topically in the reduction of elevated intra-ocular pressure in various conditions including the following: patients with ocular hypertension; patients with chronic open-angle glaucoma including aphakic patients; some patients with secondary glaucoma.
4.2 Posology And Method Of Administration
Invert the closed container and shake once before each use. It is not necessary to shake the container more than once.
Recommended therapy is one drop 0.25% solution in each affected eye once a day.
If clinical response is not adequate, dosage may be changed to one drop 0.5% solution in each affected eye once a day.
If needed, 'Timoptol'-LA may be used with other agent(s) for lowering intra-ocular pressure. Other topically applied medication should be administered not less than 10 minutes before 'Timoptol'-LA. The use of two topical beta-adrenergic blocking agents is not recommended (see section 4.4 'Special warnings and precautions for use').
Intra-ocular pressure should be reassessed approximately four weeks after starting treatment because response to 'Timoptol'-LA may take a few weeks to stabilise.
Transfer from other agents: When transferring a patient from 'Timoptol' to 'Timoptol'-LA, discontinue 'Timoptol' after a full day of therapy, starting treatment with the same concentration of 'Timoptol'-LA on the following day.
When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with 'Timoptol'-LA the next day with one drop of 0.25% 'Timoptol'-LA in each affected eye once a day. The dosage may be increased to one drop of 0.5% solution in each affected eye once a day if the response is not adequate.
When transferring a patient from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent and add one drop of 0.25% 'Timoptol'-LA in each affected eye once a day. On the following day, discontinue the previous agent completely, and continue with 'Timoptol'-LA. If a higher dosage of 'Timoptol'-LA is required, substitute one drop of 0.5% solution in each affected eye once a day (see section 5.1 'Pharmacodynamic properties').
Paediatric use: is not currently indicated.
Use in the elderly: there has been wide-experience with the use of timolol maleate in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.
4.3 Contraindications
Bronchial asthma, history of bronchial asthma or severe chronic obstructive pulmonary disease; sinus bradycardia, second- or third-degree AV block, overt cardiac failure, cardiogenic shock; and hypersensitivity to any component of this product or other beta-blocking agents. 'Timoptol'-LA should not be used in patients wearing contact lenses as it has not been studied in these patients.
4.4 Special Warnings And Precautions For Use
Like other topically applied ophthalmic drugs, this drug may be absorbed systemically and adverse reactions seen with oral beta-blockers may occur.
Cardiac failure should be adequately controlled before beginning therapy with 'Timoptol'-LA. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates monitored.
Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure, are potential complications of therapy with 'Timoptol'-LA.
The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when 'Timoptol'-LA 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.
There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoreceptor 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.
The dispenser of 'Timoptol'-LA contains benzododecinium bromide as a preservative. In a clinical study, the time required to eliminate 50% of the gellan solution from the eye was up to 30 minutes.
In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. 'Timoptol'-LA has little or no effect on the pupil. When 'Timoptol'-LA is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Transient blurred vision following instillation may occur, generally lasting from 30 seconds to 5 minutes, and in rare cases up to 30 minutes or longer. Blurred vision and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.
Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container (see section 6.6 'Special precautions for disposal and other handling').
There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
Risk from 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, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Although 'Timoptol' alone has little or no effect on pupil size, mydriasis has occasionally been reported when 'Timoptol' is given with epinephrine (adrenaline). The potential for mydriasis exists from concomitant therapy with 'Timoptol'-LA and epinephrine.
Close observation of the patient 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.
The potential exists for hypotension, atrioventricular (AV) conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium-channel blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium-channel blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker.
The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging AV conduction time.
Oral calcium-channel antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.
Intravenous calcium-channel blockers should be used with caution in patients receiving beta-adrenergic blocking agents.
Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g.quinidine, SSRIs) and timolol.
Oral-β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.
4.6 Pregnancy And Lactation
Use in pregnancy: 'Timoptol'-LA has not been studied in human pregnancy. The use of 'Timoptol'-LA requires that the anticipated benefit be weighed against possible hazards.
Breast-feeding mothers: Timolol is detectable in human milk. Because of the potential for adverse reactions to 'Timoptol'-LA in 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.
4.7 Effects On Ability To Drive And Use Machines
Transient blurred vision following instillation may occur, generally lasting from 30 seconds to 5 minutes, and in rare cases, up to 30 minutes or longer. Blurred vision and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.
4.8 Undesirable Effects
Side effects
'Timoptol'-LA is usually well tolerated. The most frequent drug-related complaint in clinical studies was transient blurred vision (6.0%), lasting from 30 seconds to 5 minutes following instillation.
The following possibly, probably, or definitely drug-related adverse reactions occurred with frequency of at least 1% in parallel active treatment controlled clinical trials:
Ocular: burning and stinging, discharge, foreign body sensation, itching.
The following side effects reported with 'Timoptol', either in clinical trials or since the drug has been marketed, are potential side effects of 'Timoptol'-LA. Additional side effects have been reported in clinical experiences with systemic timolol maleate, and may be considered potential effects of ophthalmic timolol maleate
Special senses:
ocular: signs and symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity and dry eyes. Tinnitus, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, and ptosis. Choroidal detachment following filtration surgery (see section 4.4 'Special warnings and precautions for use').
Cardiovascular:
ocular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud's phenomenon, cold hands and feet.
systemic: AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.
Respiratory:
ocular: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough.
systemic: rales
Body as a whole:
ocular: headache, asthenia, fatigue, chest pain.
systemic: extremity pain, decreased exercise tolerance.
Integumentary:
ocular: alopecia, psoriasiform rash or exacerbation of psoriasis.
systemic: pruritis, sweating, exfoliative dermatitis.
Hypersensitivity:
ocular: signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash.
Nervous system/psychiatric:
ocular: dizziness, depression, insomnia, nightmares, memory loss, paraesthesia.
systemic: vertigo, local weakness, diminished concentration, increased dreaming.
Neuromuscular:
ocular: increase in signs and symptoms of myasthenia gravis.
Digestive:
ocular: nausea, diarrhoea, dyspepsia, dry mouth.
systemic: vomiting.
Urogenital:
ocular: decreased libido, Peyronie's disease.
systemic: impotence, micturition difficulties.
Immunologic:
ocular: systemic lupus erythematosus.
Endocrine:
systemic: hyperglycaemia, hypoglycaemia.
Musculoskeletal:
systemic: arthralgia.
Haematological:
systemic: non-thrombocytopenic purpura.
4.9 Overdose
There have been reports of inadvertent overdosage with 'Timoptol' resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see section 4.8 'Undesirable effects' - Side effects).
If overdosage occurs, the following measures should be considered:
1. 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 may be considered.
2. Hypotension: a sympathomimetic pressor agent such as dopamine, dobutamine or norepinephrine (noradrenaline) should be used. In refractory cases, the use of glucagon has been reported to be useful.
3. Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.
4. Acute cardiac failure: conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon, which has been reported useful.
5. Heart block (second
Timolol does not dialyse readily.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group
Beta-adrenergic receptor blocking agent.
Mechanism of action
The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established. A fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.
'Timoptol'-LA is an ophthalmic formulation comprising timolol maleate, which reduces intra-ocular pressure, whether or not associated with glaucoma, and a new delivery vehicle. Gellan solution contains a highly purified anionic heteropolysaccharide derived from gellan gum. Aqueous solutions of gellan gum form a clear transparent gel at low polymer concentrations in the presence of cations. When 'Timoptol'-LA contacts the precorneal tear film, it becomes a gel. Gellan gum increases the contact time of the drug with the eye.
Pharmacodynamics
In parallel active treatment controlled, double-masked, multiclinic studies in patients with untreated elevated intra-ocular pressure of greater than 22 mmHg in one or both eyes, 0.25% and 0.5% 'Timoptol'-LA administered once daily had an intra-ocular pressure-lowering effect equivalent to the same concentration of 'Timoptol' administered twice daily (see table below).
For the five independent comparative studies listed in the table below, the entrance criterion was an intra-ocular pressure of greater than 22 mmHg in one or both eyes after a washout period of one week for most antiglaucoma medications and up to three weeks for ophthalmic beta-adrenergic antagonists. The dosage used was one drop of 'Timoptol'-LA in each affected eye once daily versus one drop of 'Timoptol' in each affected eye twice daily.
Mean change in intra-ocular pressure (mmHg) from baseline at trough (immediately before the morning dose) for the final week of the double-masked study
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
*The baseline intra-ocular pressure was elevated in comparison to the other studies due to the higher intra-ocular pressure of patients with pseudoexfoliative glaucoma.
Onset of action of timolol maleate is usually rapid, occurring approximately 20 minutes after topical application to the eye.
Maximum reduction of intra-ocular pressure occurs in two to four hours with 'Timoptol'-LA. Significant lowering of intra-ocular pressure has been maintained for 24 hours with both 0.25% and 0.5% 'Timoptol'-LA.
As compared with 0.5% 'Timoptol' administered twice daily, in three clinical studies 0.5% 'Timoptol'-LA administered once daily reduced mean heart rate less and produced bradycardia less frequently (see section 4.4 'Special warnings and specialprecautions for use'). At trough (24 hours post-dose 'Timoptol'-LA, 12 hours post-dose 'Timoptol'), the mean reduction in heart rate was 0.8 beats/minute for 'Timoptol'-LA and 3.6 beats/minute for 'Timoptol'; whereas at two hours post-dose, the mean reduction was comparable (3.8 beats/minute for 'Timoptol'-LA and 5 beats/minute for 'Timoptol').
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity.
Unlike miotics, timolol maleate reduces intra-ocular pressure with little or no effect on accommodation or pupil size. Thus, changes in visual acuity due to increased accommodation are uncommon, and the 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 by miotics is avoided. When changing patients from miotics to 'Timoptol'-LA, refraction may be necessary after the effects of the miotic have passed.
As with other antiglaucoma drugs, diminished responsiveness to timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies of 'Timoptol' in which 164 patients were followed for at least three years, no significant difference in mean intra-ocular pressure was observed after initial stabilisation. This indicates that the intra-ocular pressure-lowering effects of timolol maleate is well maintained.
5.2 Pharmacokinetic Properties
Onset of action of timolol maleate is usually rapid, occurring approximately 20 minutes after topical application to the eye.
Maximum reduction of intra-ocular pressure occurs in two to four hours with 'Timoptol'-LA. Significant lowering of intra-ocular pressure has been maintained for 24 hours with both 0.25% and 0.5% 'Timoptol'-LA. In a study of plasma timolol concentrations, the systemic exposure to timolol was less when normal healthy volunteers received 0.5% 'Timoptol'-LA once daily than when they received 0.5% 'Timoptol' twice daily.
5.3 Preclinical Safety Data
No adverse ocular effects were observed in monkeys and rabbits administered 'Timoptol'-LA topically in studies lasting 12 months and one month, respectively. The oral LD50 of timolol is 1,190 and 900 mg/kg in female mice and female rats, respectively. The oral LD50 of gellan gum is greater than 5,000 mg/kg in rats.
In a two-year oral study of timolol maleate in rats there was a statistically significant (p*). Similar differences were not observed in rats administered oral doses equivalent to 25 or 100 times the maximum recommended human oral dose.
In a lifetime oral study in mice, there were statistically significant (p
The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg/day, 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.
In oral studies of gellan gum administered to rats for up to 105 weeks at concentrations up to 5% of their diet and to mice for 96-98 weeks at concentrations up to 3% of their diet, no overt signs of toxicity and no increase in the incidence of tumours was observed.
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 mcg/ml). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant (p
Gellan gum was devoid of mutagenic potential when evaluated in vivo (mouse) in micronucleus assay using doses up to 450 mg/kg. In addition, gellan gum in concentrations up to 20 mg/ml was not detectably mutagenic in the following in-vitro assays:
(1) unscheduled DNA synthesis in rat hepatocytes assay, (2) V-79 mammalian cell mutagenesis assay, and (3) chromosomal aberrations in Chinese hamster ovary cells assay.
In Ames tests, gellan gum (in concentrations up to 1,000 mcg/plate, which is its limit of solubility) did not induce a twofold or greater increase in revertants relative to the solvent control. It is therefore not detectably mutagenic.
*The maximum recommended daily oral dose of timolol is 60 mg. One drop of 0.5% 'Timoptol'-LA contains about 1/300 of this dose, which is about 0.2 mg.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Gellan gum, trometamol, mannitol E421, and water for injection. Benzododecinium bromide (0.012%) is added as preservative.
6.2 Incompatibilities
None known.
6.3 Shelf Life
The shelf life is 24 months. After opening the shelf life is 28 days.
6.4 Special Precautions For Storage
Do not store above 25°C. Do not freeze. Store bottle in the outer carton.
6.5 Nature And Contents Of Container
The OCUMETER Plus ophthalmic dispenser consists of a translucent high-density polyethylene container with a sealed dropper tip, a flexible fluted side area, which is depressed to dispense the drops, and a two-piece assembly. The two-piece cap mechanism punctures the sealed dropper tip upon initial use, then locks together to provide a single cap during the usage period. Tamper evidence is provided by a safety strip on the container label. The OCUMETER Plus ophthalmic dispenser contains 2.5 ml of solution.
'Timoptol'-LA Gel-Forming Eye Drops Solution is available in single bottles containing 2.5 ml of solution.
6.6 Special Precautions For Disposal And Other Handling
Invert the container and shake once before each use. It is not necessary to shake the container more than once.
Discard 28 days after opening.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
7. Marketing Authorisation Holder
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK.
8. Marketing Authorisation Number(S)
0.25% PL 0025/0310
0.5% PL 0025/0311
9. Date Of First Authorisation/Renewal Of The Authorisation
Granted: 2 April 1996/Renewed: 2 April 2001
10. Date Of Revision Of The Text
February 2008
LEGAL CATEGORY
POM.
® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
© Merck Sharp & Dohme Limited 2008. All rights reserved.
SPC.TOTX.06.UK.2343 F.T. 060608
No comments:
Post a Comment