TILAZEM. Diltiazem hydrochloride 240 mg

Transcription

1 Tilazem Capsules Page 1 of 9 TILAZEM Diltiazem hydrochloride SCHEDULING STATUS: S3 PROPRIETARY NAME (AND DOSAGE FORM): TILAZEM 180 CR (controlled-release capsule) TILAZEM 240 CR (controlled-release capsule) COMPOSITION: Each controlled-release capsule contains: TILAZEM 180 CR: TILAZEM 240 CR: Diltiazem hydrochloride 180 mg Diltiazem hydrochloride 240 mg TILAZEM controlled-release capsules contain the following inactive ingredients: fumaric acid, talc, povidone, sugar/starch spheres, methacrylic acid RS, methacrylic acid RL, ethanol, isopropyl alcohol, titanium dioxide and gelatine. PHARMACOLOGICAL CLASSIFICATION: A 7.1 Vasodilators, hypotensive medicines. PHARMACOLOGICAL ACTION: Diltiazem is a calcium antagonist (calcium-channel blocker) that blocks the slow inward influx of calcium ions across membranes of cardiac muscle, and of smooth muscle in coronary and peripheral arteries. By this means, diltiazem reduces myocardial oxygen demand, increases myocardial oxygen

2 Tilazem Capsules Page 2 of 9 supply, and reduces blood pressure. Pharmacokinetics Diltiazem is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40 %. Diltiazem undergoes extensive hepatic metabolism; therefore, only 2 % to 4 % of the unchanged substance appears in the urine. In cases of serious liver damage, delayed biotransformation may be anticipated. In-vitro studies show that 70 % - 80 % of diltiazem is bound to plasma proteins. Single oral doses of 30 to 120 mg result in detectable plasma levels within 30 to 60 minutes and peak plasma levels two to three hours after diltiazem administration. The plasma elimination half-life following single or multiple diltiazem administration is approximately 3,5 hours. Desacetyl-diltiazem is also present in the plasma at levels of 10 % to 20 % of the parent substance and has 25 % to 50 % coronary vasodilatation activity of diltiazem. There is a departure from dose-linearity when single doses of diltiazem above 60 mg are given; a 120 mg dose gave plasma levels three times that of the 60 mg dose. INDICATIONS: Prophylaxis of angina pectoris, including Prinzmetal's angina. For the treatment of mild to moderate hypertension.

3 Tilazem Capsules Page 3 of 9 CONTRA-INDICATIONS: TILAZEM should not be administered to patients known to be sensitive to any component of this medication. TILAZEM should not be administered to patients with decompensated cardiac insufficiency, sick sinus syndrome, conduction disturbances (sino-atrial or atrio-ventricular block) and bradycardia (pulse rate less than 55/min). TILAZEM should not be administered to patients with severe impairment of liver and kidney function. It is not safe to administer TILAZEM to patients suffering from porphyria. Pregnancy and lactation - see PREGNANCY AND LACTATION. WARNINGS: TILAZEM prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block. Concomitant use of TILAZEM with beta-blockers or digitalis may result in additive effects on cardiac conduction. See INTERACTIONS. INTERACTIONS: Patients receiving TILAZEM in combination with diuretics, ACE-inhibitors and other antihypertensive agents should be regularly monitored. Concomitant use with alpha-blockers such as prazosin should be strictly monitored because of the possible marked synergistic hypotensive effect of this combination.

4 Tilazem Capsules Page 4 of 9 TILAZEM should be administered with caution to patients taking beta receptor blocker agents or digitalis glycosides as these may have an additive effect on depression of AV conduction. The combination of TILAZEM with the beta-blocker propranolol may enhance the bioavailability of the propranolol significantly, and thus produce elevated levels of propranolol in the serum. Adjustment in the propranolol dosage may be warranted. The combination of TILAZEM with digitalis glycosides can inhibit digitalis glycoside metabolism and elevate serum levels which may cause digitalis glycoside toxicity. Case reports have suggested that blood levels of carbamazepine, cyclosporin, and theophylline may be increased when given concurrently with TILAZEM. Care should be exercised in patients taking these medicines. TILAZEM undergoes biotransformation by cytochrome P-450 (CYP) 3A4, mixed function oxidase. TILAZEM may competitively inhibit the metabolism of concomitant medicines that undergo the same route of biotransformation, thus increasing their plasma concentration. The extent of interaction and potentiation of effects depends on the variability of effect on (CYP) 3A4. Cimetidine's inhibition of the hepatic cytochrome P-450 system causes an increase in plasma diltiazem concentrations. An adjustment in the TILAZEM dose may be warranted. Patients who are taking TILAZEM should inform the anaesthetist accordingly before receiving anaesthesia.

5 Tilazem Capsules Page 5 of 9 PREGNANCY AND LACTATION: Since teratogenic effects were noted in animals, TILAZEM should not be administered to pregnant women or to women of child-bearing age. TILAZEM is excreted in human milk, and therefore should not be administered to lactating women. DOSAGE AND DIRECTIONS FOR USE: Adults: For the treatment of hypertension and angina. The daily dosage for TILAZEM is 180 mg or more per day. The total daily dosage should be titrated upward to a maximum of 360 mg per day to meet the requirements of the individual patient. TILAZEM 180 CR: One 180 mg capsule once daily or one 180 mg capsule twice daily. The 180 CR capsules should be swallowed intact with some liquid. TILAZEM 240 CR: One 240 mg capsule once daily. The 240 CR capsule should be swallowed intact with some liquid. Use in Children: Safety in children has not been established.

6 Tilazem Capsules Page 6 of 9 SIDE EFFECTS AND SPECIAL PRECAUTIONS: Side effects: In studies carried out to date, serious adverse reactions with TILAZEM have been rare, however, it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies. Side effects reported in clinical trials were categorized utilizing the incidence rate as follows: Very Common: 1/10 ( 10 %) Common: 1/100 and <1/10 ( 1 % and <10 %) : 1/1000 and <1/100 ( 0,1 % and <1 %) Rare: 1/ and < 1/1000 ( 0,01 % and <0,1 %) MedDRA System Organ Class Metabolism and nutrition disorders Frequency Adverse Event Creatine kinase elevation, hyperglycaemia, mild elevations of alkaline phosphatase and LDH Nervous system disorders Common Headache, dizziness* Amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paraesthesia, personality change, somnolence, tinnitus, tremor Eye disorders Amblyopia, eye irritation Cardiac disorders Common First degree AV block, sinus bradycardia*, flushing Angina, dysrhythmia, AV block (second or third degree - see conduction warning), congestive heart failure, hypotension,

7 Tilazem Capsules Page 7 of 9 palpitations, syncope Respiratory, thoracic and mediastinal disorders: dyspnoea, epistaxis, nasal congestion Gastrointestinal disorders Common Nausea Anorexia, constipation, diarrhoea, dyspepsia, vomiting, weight increase Hepato-biliary disorders Elevations in ALT and AST Skin and subcutaneous tissue disorders Musculoskeletal, connective tissue and bone disorders Common Common Rash Erythema multiforme, petechiae, pruritus, photosensitivity, urticaria Asthenia Osteoarticular pain Renal and urinary disorders Common Oedema* Reproductive system and breast disorders Nocturia, polyuria Sexual difficulties *Only oedema and perhaps bradycardia and dizziness were dose related. In post-marketing experience, the following additional side-effects have been reported: Gastrointestinal: gum hyperplasia Special Precautions: TILAZEM should be administered with caution to elderly patients and patients with impairment

8 Tilazem Capsules Page 8 of 9 of liver and kidney function. In these patients treatment should commence with reduced doses. If bradycardia is noted, dosage should be decreased then discontinued if bradycardia persists. Administer with caution to patients with pre-existing hypotension and also to those with impaired left ventricular function due to potential negative inotropic properties of TILAZEM. Effects on Ability to Drive and Use Machines: The effect of TILAZEM on the ability to drive or use machinery has not been systematically evaluated. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Treatment is symptomatic and supportive. Further gastro-intestinal absorption can be limited by gastric lavage. TILAZEM CR are extended-release capsules and effects may be slow in onset and prolonged. IDENTIFICATION: TILAZEM 180 CR: White capsule imprinted 'D180' in black, containing off-white, roughly- spherical controlled-release beads. TILAZEM 240 CR: White capsule imprinted 'D240' in black, containing off-white, roughly-spherical controlled-release beads. PRESENTATION: TILAZEM 180 CR: TILAZEM 240 CR: Available in containers and blister packs containing 30 capsules. Available in containers and blister packs containing 30 capsules.

9 Tilazem Capsules Page 9 of 9 STORAGE INSTRUCTIONS: Store in a cool (below 25 ºC) dry place. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBERS: TILAZEM 180 CR: 28/7.1/0579 TILAZEM 240 CR: 28/7.1/0580 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: Pfizer Laboratories (Pty) Ltd 85 Bute Lane Sandton, 2196 South Africa DATE OF PUBLICATION OF THIS PACKAGE INSERT: 7 June 2012