Data Sheet

TILMAT

Timolol maleate USP 10mg tablets

Presentation

10mg Tablet: Light blue, circular, flat, bevel-edged, compressed tablets of 8mm diameter; plain on one side and embossed N10 on the other.

Uses

Actions

TILMAT is a hydrophilic, non-selective competitive β₁ and β₂ adrenoceptor blocker (or β-antagonists). It has no significant intrinsic sympathomimetic or local anaesthetic (or membrane stabilising) activities, nor does it depress myocardial function directly. TILMAT antagonises the response of β-adrenoceptors to excessive circulating catecholamines or β-agonists. Therefore it reduces heart beats, cardiac output, causes vasoconstriction and induces bronchoconstriction leading to increased airway resistance.

TILMAT also reduces heart and force rate and blood pressure changes induced by exercise, stress and change of posture. The combined effects of reduced cardiac output, reduced renin activity and sympathetic activity on the CNS contribute to lower blood pressure.

TILMAT reduces atrioventricular conduction resulting in increase of atrioventricular mode refactory period and interval of the ECG. The negative chronotropic and inotropic actions of TILMAT reduces myocardial workload and oxygen demand. This reduces or delays exercise or stress-induced myocardial hypoxia and anginal pain.

β-antagonists have been shown to reduce the infarct size during the acute attack of myocardial infarction.

It potentiates hypoglycaemic action of insulin and may inhibit conversion of thyroxine to triiodothronine. TILMAT can increase serum levels of very low density lipoproteins and triglycerides and reduce serum levels of high density lipoprotein.

Pharmacokinetics

TILMAT tablets are almost completely absorbed (about 90%) following oral administration. As most β-antagonists do, TILMAT distributes rapidly giving a large volume of distribution. Its bioavailability is approximately 50% and it achieves peak plasma concentrations about 1-2 hours after an oral dose. It has a low protein binding capacity.

TILMAT is moderately subject to hepatic first pass metabolism. The metabolites are excreted in urine with some unchanged timolol. It can be detected in placenta and breast milk. The elimination plasma half life is 4-5 hours which is essentially unchanged for those patients with moderately insufficient renal function. Metabolism of TILMAT is subject to genetic polymorphism for some patients.

There is considerable individual variation in β-sympathetic activity and the therapeutic effect of TILMAT is not simply correlated to its plasma drug level. Hence objective monitoring of patient's blood pressure and heart rate is essential as a guideline to dosage adjustment to optimize therapeutic effect individually.

Indications

TILMAT is used to treat essential hypertension including hyperkinetic cardiac syndrome.

TILMAT is also indicated for angina pectoris. TILMAT can reduce risk of both sudden cardiac death and post acute phase reinfarction.

TILMAT can be used to treat cardiac arrhythmias eg. artrial fibrillation, atrial flutter, supraventricular tachycardia and ventricular etopic. It slows down development of systolic blood pressure in dissecting aortic aneurysm and increases stroke volume in obstructive cardiomyopathy.

TILMAT is also useful in prophylaxis of common and classical migraine.

Dosage and Administration

TILMAT 10mg tablets are to be administered orally.

Hypertension: 10mg daily initially, may be gradually increased, at intervals of three days up to one week, to a maximum of 60mg daily according to patient's response. Normal daily maintenance doses are 10-40mg given once or in divided doses. For daily dosage higher than 20mg, it must be given in divided doses.

For concomitant therapy with Hydrozide, one tablet daily, TILMAT tablets can be maintained at 10-20mg once daily.

Angina Pectoris: Initially 5mg twice or three times daily. The dosage can be increased at intervals of at least three days apart. Initial increase should be by 10mg per day at maximum and subsequent increase by up to 15mg per day in divided doses. Most patients respond to a total daily dosage of 35-45mg.

Post Myocardial Infarction Prophylaxis: Initial dose is 5mg twice daily for the first two days. Subsequent doses can be increased to 10mg twice daily provided the therapy is not contraindicated.

Artial Fibrillation: Initial dose 10mg twice daily, increasing to 30mg twice daily with adjustment according to clinical response.

Migraine: For prophylaxis: 10mg to 20mg once daily.

Contraindications

• Patients with a history of bronchospasm, asthma and severe chronic obstructive respiratory disease.
• Patients with overt heart failure, cardiogenic shock, sinus bradycardia and atrioventricular block.
• Patients developing hypersensitivity to β-antagonists or, in particular, to this product.
• Patients having phaeochromocytoma without concomitant treatment with α-antagonists.

Warnings and Precautions

Use in Heart Failure:

Prolonged continual myocardial depression by β-antagonists may precipitate heart failure. TILMAT should be used with a digitalis and/or a diuretic for patients developing heart failure or have a history of heart failure. Both digitalis and TILMAT can slow down atrioventricular conduction. If heart failure persists despite combination therapy, TILMAT should be discontinued.

Use in Thyrotoxicosis:

TILMAT may mask some signs of thyrotoxicosis such as tachycardia. Abrupt withdrawal of TILMAT may induce a thyroid storm.

Abrupt Withdrawal:

Some patients develop hypersensitivity to catecholamines and exacerbation of ischaemic heart disease after abrupt withdrawal of β-antagonists. Therefore, for patients on chronic TILMAT therapy, discontinue the drug by tapering the dosage over two weeks with careful monitoring, even if it is only used for hypertension. Should acute coronary ischaemia develop or worsen, resume TILMAT treatment and take other appropriate measures for unstable angina. Warn patients against stopping TILMAT therapy without doctor's advice.

Use in Major Surgery:

β-antagonists impair cardiac response to reflex stimuli mediated through β-receptor activities. This potentiates the risk of general anaesthesia such as severe hypotension and arrhythmias. Withdrawal of β-antagonists gradually prior to major surgery is advisable. Anaesthetic agents having myocardial depressant property eg. ether, trichloroethylene and cyclopropane, should not be used.

Use in Diabetes Mellitus:

TILMAT can mask the clinical hypoglycaemic signs and symptoms such as tachycardia and tremor in diabetic patients on oral hypoglycaemic agents or insulin therapy. It may block the glycogenolytic and lypolytic responses to intrinsic catecholamines in hypoglycaemic attack.

Patients with Muscle Weakness:

TILMAT may potentiate muscle weakness in patients having myasthenic symptoms such as diplopia, ptosia and generalised weakness.

Use in Impaired Hepatic and Renal Function:

TILMAT should be given in a reduced dosage in these patients. Masked hypotension has been reported in renal dialysis patients following oral timolol maleate.

Use in Cerebrovascular Insufficiency:

TILMAT should be used cautiously in these patients. Stop treatment with TILMAT if signs and symptoms of impaired cerebral blood flow occur.

Use in Pregnant and Lactating Mothers:

There is no proof about the safety of TILMAT use in pregnancy. Potential benefits to the mother should be weighed against potential risks to the foetus when TILMAT is used. Since timolol maleate has been detected in breast milk and may potentially cause serious harm to the baby, either TILMAT should be discontinued when breast feeding or alternative feed be given to the infant.

Use in Paediatrics:

Drug safety and efficacy in infants and children have not be established.

Adverse Effects

Cardiovascular

• Potentiation of existing coronary insufficiency precipitating sudden heart attack and sudden cardiac death
• Cardiac arrhythmia, heart block, heart failure
• Pulmonary oedema, oedema, syncope and hypotension
• Raynaud's syndrome, peripheral claudication, stroke

Endocrine

• Hyperglycaemia, hypoglycaemia

Gastrointestinal and Abdominal

• Nausea, vomiting, diarrhoea, constipation, abdominal cramp
• Sclerosing peritonitis, retroperitoneal fibrosis
• Hepatomegaly, mesenteric arterial thrombosis, ischaemic colitis

Haematological

• Non-thrombocytopenic purpura and thrombocytopenic purpura
• Transient eosinophilia and rarely agranulocytosis

Skin and Musculoskeletal

• Rash, pruritus, perspiration, hyperpigmentation, arthralgia and rarely exfoliative dermatitis. Peripheral myopathy.

Nervous System and Mental Functions

• Peripheral neuropathy and paraesthesia
• Headache, fatigue, confusion, transient amnesia, dizziness, vertigo
• Anxiety, reduced concentration, nightmare, insomnia
• Depression, catatonia, emotional instability, hallucinations

Respiratory

• Bronchospasm, asthma, rale, cough, dyspnoea
• Pneumonia, pulmonary fibrosis, pleurisy

Ophthalmic

• Dry and irritated eyes
• Blurred vision
• Diplopia and ptosis (after ophthalmic administration of timolol maleate)

Reproductive and Urinary

• Male impotence, decreased libido, micturition problems

Miscellaneous

• Lupus erythematous rash, fever, laryngospasm, weight loss,
• Peyronie 's disease, reversible alopecia and generalized asthemia.

Interactions

With Catecholamine - Depleting Drugs:

eg. reserpine. Additive effects leading to marked postural hypotension, bradycardia.

With Non-steroidal Anti-inflammatory Drugs:

(NSAID's): Impairment of hypotensive effect of TILMAT may result from inhibition of vasodilatory prostaglandin production in the kidneys by NSAID's.

With Calcium Antagonists:

Avoid combined treatment in patients with compromised cardiac function. Combined treatment with dihydropyridines such as nifedipine has been reported to cause severe hypotension and heart failure. Verapamil or diltiazem (in presence of digitalis) may precipitate left ventricular failure or AV block.

With Quinidine:

May exacerbate bradycardia and hypotension in combination.

With Adrenaline:

Non-cardioselective β-antagonists raise blood pressure by a-mediated vasoconstriction with reflex bradycardia. Prolonged therapy with non-cardioselective β-antagonists may inhibit the pressor and bronchodilator effect of adrenaline which is administered for anaphylactic shock.

With Amiodarone:

May cause bradycardia, ventricular fibrillation and even cardiac arrest when given concurrently with TILMAT.

With Ergot Alkaloids:

Peripheral vasoconstriction has been reported when propranolol or oxprenolol was administered with ergotamine or methysergide. Although there is no evidence of interaction between an ergot alkaloid and timolol, potentiation of vasoconstriction has to be considered when both ergot alkaloid and timolol are used concomitantly.

Overdosage

LD₅₀ of oral timolol maleate in experimental mice and rats is about 900 - 1200 mg/kg.

Patients may suffer from severe bradycardia, hypotension, AV conduction block acute cardiac failure and cardiogenic shock. Occassionally convulsions, coma, respiratory depression and bronchospasm may occur.

Management of Overdosage:

• Gastric lavage with activated charcoal for recent overdosage.
• Intravenous fluid, glucagon hydrochloride or sympathomimetic agents can be used to treat hypotension. These agents include dopamine, dobutamine, levarteronol. Intravenous isoprenaline as much as 200 mcg/min has been used.
• Bradycardia is treated with intravenous atropine sulphate 0.25 -2mg with or without subsequent treatment by intravenous isoproterenol hydrochloride. If this fails, pacemaker insertion may be considered. These measures also apply when conduction blockage occurs.
• For other arrhythmic conditions, use lignocaine or phenytoin.
• For bronchospasm, use isoproterenol hydrochloride and aminophylline.
• When acute cardiac failure develops, digitalis, diuretics and oxygen should be administered. For refractory cases, intravenous aminophylline and glucagon may be useful.

Pharmaceutical Precautions

Store below 30°C. Protect from light and moisture. Keep out of reach of children.

Medicine Classification

Prescription Medicine.

Package Quantities

Bottles of 100 tablets.

Further Information

Timolol maleate is soluble in 15 parts of water. Its chemical name in full is: (5)-1- tert -butylamino-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)propan-2-ol maleate. Its molecular formula and weight are C₁₃H₂₄N₄O₃S, C₄H₄O₄ and 432.5 respectively. It is stable in solution state up to pH 12.

Name and Address

Douglas Pharmaceuticals Ltd
P.O. Box 45-027
Auckland 8

Ph: (09) 835-0660

Fax: (09) 835-0665

Date of Preparation

13 September 1999