INFORMATION FOR HEALTH PROFESSIONALS
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0.5%/2% and 0.5%/4% ophthalmic solution
TIMPILO is dispensed in a unique, two-chambered vial system. One of the chambers contains a concentrated solution of timolol and pilocarpine at a pH of approximately 3.5. This low pH prevents the hydrolysis of pilocarpine prior to dispensing. The other chamber contains a diluent solution with a pH of 7.8 to 8.2 for TIMPILO 2 and 8.5 to 9.5 for TIMPILO 4. The two solutions are separated by an internal plug.
Prior to use of TIMPILO, the two solutions are mixed together. The resulting solution for administration has a pH of 6.4 to 6.8.
TIMPILO 2 contains 2% pilocarpine hydrochloride and 0.5% timolol maleate. After mixing TIMPILO 2 is a sterile colourless to pale yellow clear solution.
TIMPILO 4 contains 4% pilocarpine HCI and 0.5% timolol maleate. After mixing TIMPILO 4 is a sterile colourless to pale yellow clear solution.
Timolol is a non-selective beta blocker. Pilocarpine is a cholinergic agent.
TIMPILO is indicated for the reduction of elevated intraocular pressure in patients whose IOP is not adequately controlled on monotherapy with a beta blocker or pilocarpine or when concomitant therapy is appropriate.
It has been shown to reduce intraocular pressure in:
Instil one drop of TIMPILO 2 twice daily in the affected eye. If the clinical response is inadequate the dosage may be increased by using one drop of TIMPILO 4 twice daily.
When a patient is transferred from prior therapy, the previously administered agents should be discontinued after proper dosing on one day, and treatment with TIMPILO started on the following day.
TIMPILO is dispensed in a unique, two-chambered vial system. One of the chambers contains a concentrated solution of timolol and pilocarpine at a pH of approximately 3.5. This low pH prevents the hydrolysis of pilocarpine prior to dispensing. The other chamber contains a diluent solution with a pH of 7.8 to 8.2 for TIMPILO 2 and 8.5 to 9.5 for TIMPILO 4. The two solutions are separated by an internal plug.
Prior to use of TIMPILO, the two solutions are mixed together. The resulting solution for administration has a pH of 6.4 to 6.8.
To activate the solution for administration of TIMPILO:
There is no need to repeat steps 1 through 5 each time TIMPILO is used: The contents of the bottle do not have to be mixed again.
As with other topically applied ophthalmic medicines, this medicine may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration.
Cardiac failure should be controlled before beginning therapy with TIMPILO. In patients with a history of cardiac disease signs of cardiac failure should be watched for and pulse rate should be checked. Following administration of timolol ophthalmic solution, severe respiratory reactions and cardiac reactions have been reported, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure.
The use of two topical beta-adrenergic blocking agents is not recommended. Patients already receiving a beta blocker systemically and who are given TIMPILO should be observed for a potential additive effect on the intraocular pressure or on the known systemic effects of beta blockers.
Miosis usually causes difficulty in dark adaptation. Caution should be exercised in night driving and other hazardous activities in poor illumination.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (eg. timolol, acetazolamide) after filtration procedures.
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 used to treat anaphylactic reactions.
TIMPILO has not been studied in human pregnancy. The use of TIMPILO in pregnancy requires that the anticipated benefit be weighed against potential hazards.
Timolol is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the medicine, taking into account the importance of the medicine to the mother.
Safety and effectiveness in children have not been established.
TIMPILO contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses Therefore, TIMPILO should not be administered while wearing soft contact lenses. The contact lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.
TIMPILO has not been studied in patients wearing conventional hard contact lenses or soft contact lenses.
TIMOPTOL (timolol maleate) ophthalmic solution has been used in patients with glaucoma wearing conventional (PMMA) hard contact lenses, and has generally been well tolerated. TIMOPTOL has not been studied in patients wearing lenses made with materials other than PMMA.
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.
In patients without a history of cardiac failure continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure TIMPILO should be discontinued.
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycaemia.
Beta-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g. tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.
Beta-adrenergic blockade has been reported to increase muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalised weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenic symptoms.
Because of potential effects of beta-adrenergic blocking 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 TIMPILO, alternative therapy should be considered.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.
Patient should also be instructed that ocular solutions, if handles improperly, can become contaminated by common bacteria known to cause ocular infection. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
Patients should be advised that if they develop an intercurrent ocular condition (eg. trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.
There have been reports of bacterial keratitis associated with the use of multidose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, have a concurrent corneal disease or a disruption of the ocular epithelial surface.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product (see Contraindications).
TIMPILO is generally well tolerated. In clinical studies of TIMPILO, the adverse experiences reported were mainly well known pilocarpine adverse effects: blurring of vision, difficulty with dark adaptation, headache/brow-ache and ocular irritation (see below).
Adverse effects reported in clinical and post-marketing experience with Ophthalmic Solution TIMOPTOL (timolol maleate, MSD), systemic BLOCADREN (timolol maleate, MSD), other timolol maleate formulations, and pilocarpine ophthalmic solution may be considered potential adverse effects of ophthalmic solution TIMPILO.
The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulation, either in clinical trials or since the medicine has been marketed.
Special Senses: Signs and symptoms of ocular irritation, including burning and stinging, conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity, and dry eyes. Visual disturbances, diplopia, and ptosis, choroidal detachment following filtration surgery (see Warnings and Precautions), tinnitus.
Cardiovascular: Bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud's phenomenon, cold hands and feet.
Respiratory: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough.
Body as a Whole: Headache, asthenia, fatigue, chest pain.
Integumentary: Alopecia, psoriasiform rash or exacerbation of psoriasis.
Hypersensitivity: Signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash.
Nervous System / Psychiatric: Dizziness, depression, increase in signs and symptoms of myasthenia gravis, insomnia, nightmares, memory loss.
Digestive: Nausea, diarrhoea, dyspepsia, dry mouth.
Urogenital: Decreased libido, Peyronie's disease.
Immunologic: Systemic lupus erythematosus.
Adverse effects reported in clinical experience with systemic timolol maleate may be considered potential adverse effects of ophthalmic solution TIMPILO.
Ciliary spasm, conjunctival vascular congestion, lacrimation, temporal or supra-orbital headache, induced myopia, reduced visual acuity in poor illumination (especially in the elderly and in patients with lens opacities), retinal detachment (especially in young myopic patients). Lens opacity may occur with prolonged use of pilocarpine.
Systemic: Extremely rare, but have included hypertension, tachycardia, bronchiolar spasm, pulmonary oedema, salivation, sweating, nausea, vomiting and diarrhoea.
Body as a whole: extremity pain, decreased exercise tolerance
Cardiovascular: AV block (2nd or 3rd degree), sinoatrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation
Digestive: vomiting
Endocrine: hyperglycaemia, hypoglycaemia
Integumentary: pruritus, sweating, exfoliative dermatitis
Musculoskeletal: arthralgia
Nervous System: vertigo, local weakness
Psychiatric: nervousness, hallucinations, somnolence, diminished concentration, increased dreaming
Haematologic: nonthrombocytopaenic purpura
Respiratory: rales
Urogenital: impotence, micturition difficulties
Clinically important changes in standard laboratory parameters were rarely associated with the administration of systemic timolol maleate. Slight increases in blood urea nitrogen, serum potassium and serum uric acid and triglycerides, and slight decreases in haemoglobin and haematocrit and HDL-cholesterol occurred, but were not progressive or associated with clinical manifestations.
Systemic beta blockers or calcium blockers or catecholamine-depleting medicines, such as reserpine, may produce additive effects, hypotension and/or marked bradycardia, with possible vertigo, syncope or postural hypotension. Intravenous calcium blockers should be used with caution in patients receiving beta blockers.
Potentiated systemic beta-blockade (eg., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6.
Oral β-adrenergic blocking agents may exacerbate the rebound hypertension, which can follow the withdrawal of clonidine.
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 Adverse Effects)
The following therapeutic measures should be considered:
Cholinergic systemic effects are extremely rare with ocular use of pilocarpine (see Adverse Effects). If accidentally swallowed, pilocarpine is readily absorbed from the alimentary tract, and if a large amount is ingested cholinergic symptoms may appear, including salivation, lacrimation, nausea, vomiting, headache, mental confusion, visual disturbances, abdominal colic, diarrhoea, bronchospasm, and hypotension. Dehydration and shock may develop. Respiratory depression has been reported in severe cases of pilocarpine poisoning.
Treatment is with general measures and atropine.
TIMPILO (timolol maleate/pilocarpine hydrochloride, MSD) is a fixed combination of timolol maleate 0.5% and pilocarpine hydrochloride 2% (TIMPILO 2) or 4% (TIMPILO 4).
Timolol is a non-selective beta blocker with no significant intrinsic sympathomimetic activity; pilocarpine is a cholinergic agent. Each of the two components decreases elevated intraocular pressure (IOP) by different but complementary mechanisms. Timolol lowers IOP primarily by reducing aqueous humor production. Pilocarpine lowers IOP primarily by enhancing the outflow of aqueous humor from the anterior chamber of the eye. Although pilocarpine, given alone, requires administration four times a day, it has been shown that when formulated with timolol in TIMPILO, administration twice daily is adequate.
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. Timolol maleate combines reversibly with a part of the cell membrane, the beta-adrenergic receptor, and thus inhibits the usual biologic response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic receptors by catecholamines having beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of the agonist, which will restore the usual biologic response.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function beta-adrenergic 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 parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.
Pilocarpine hydrochloride is a cholinergic substance, which causes a significant reduction of intraocular pressure. This is thought to be due to contraction of the ciliary muscle, which in turn transmits increased tension to the scleral spur, resulting in a decrease in the resistance of aqueous outflow as the trabecular outflow channels become enlarged.
The onset of action of TIMPILO is usually rapid (for TIMOPTOL (timolol maleate MSD) the onset of action is approximately 20 minutes after topical application to the eye.)
A single dose of TIMPILO 4 lowers IOP up to 12 hours.
A single dose of TIMPILO 2 lowers IOP up to 6 hours.
After topical administration of TIMOPTOL, plasma levels of timolol maleate were low to undetectable (less than 3ng/ml). Although TIMOPTOL often reduces blood pressure and pulse, in clinical studies with TIMPILO there were no clinically important changes in these vital signs.
Pharmacokinetic studies following administration of TIMPILO or ocular pilocarpine have not been performed.
Store at room temperature. Do not freeze. Protect from light. TIMPILO is stable for four weeks after mixing.
Prescription Medicine.
TIMPILO 2 Solution 5ml.
TIMPILO 4 Solution 5ml.
Timolol maleate is a beta-adrenergic receptor blocking agent. Its chemical name is (S)-1 [ (1,1-dimethylethyl) amino ] -3- [ [4- (4-morpholinyl) -1,2, 5-thiadiazol-3-yl] oxy] -2- propanol, (Z)-2-butenedioate (1:1) salt. Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo isomer. Its empirical formula is C13H24N4O3S.C4H4O4 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odourless, crystalline powder, which is soluble in water, methanol, and alcohol.
Pilocarpine hydrochloride is a cholinergic agent. Its chemical name is:(3S-cis)-3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl) methyl]-2(3H)-furanone monohydrochloride. The empirical formula is C11H16N2O2.HCl and its structural formula is:
Pilocarpine hydrochloride has a molecular weight of 244.7. It is a white odourless crystalline powder or may occur as colourless crystals.
Each mL of constituted TIMPILO 0.5 - 2.0% contains 6.8 mg of timolol maleate (5.0 mg of timolol) and 20.0 mg of pilocarpine hydrochloride. Each mL of TIMPILO 0.5 - 4.0% contains 6.8 mg of timolol maleate (5.0 mg of timolol) and 40.0 mg of pilocarpine hydrochloride. Inactive ingredients: sodium phosphate dibasic dodecahydrate, sodium phosphate monobasic dihydrate, and water for injection. Benzalkonium chloride 0.01% is added as preservative.
Merck Sharp & Dohme (New Zealand) Limited
P.O. Box 99851, Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673
20 May 2003
DP-TPL-042003(20503)
®Registered Trademark of Merck & Co Inc., Whitehouse Station, NJ, USA