Tildiem Retard 90mg Prolonged-Release Tablets

Tildiem Retard 120mg Prolonged-Release Tablets

Each 90mg tablet contains 90mg of the active substance diltiazem hydrochloride.

Also contains 49.7mg of sucrose and 13.45mg of sodium

Each 120mg tablet contains 120mg of the active substance diltiazem hydrochloride.

Also contains 69.4mg of sucrose and 17.97mg of sodium.

For full list of excipients, see Section 6.1

Prolonged-release tablet.

White to off-white, round convex coated tablet.

Mild to moderate hypertension and angina pectoris.

Tildiem Retard tablets should be swallowed whole with a little water and not crushed or chewed.

Patients should be advised that the tablet membrane may pass through the gastro-intestinal tract unchanged.

Tildiem (diltiazem hydrochloride) is available in a range of presentations to enable dosage to be adjusted to meet the individual requirements of the patient. Careful titration of the dose should be considered where appropriate, as individual patient response may vary. When changing from one type of Tildiem formulation to another it may be necessary to adjust the dosage until a satisfactory response is obtained. To ensure consistency of response once established, particularly in the sustained release formulations, Tildiem Retard 90mg and 120mg should continue to be prescribed by brand name.

Adults:

Angina and hypertension:

The usual starting dose is one tablet (90mg or 120mg) twice daily. Patient responses may vary and dosage requirements can differ significantly between individual patients. Higher divided doses up to 480mg/day have been used with benefit in some angina patients especially in unstable angina. Doses of 360mg/day may be required to provide adequate BP control in hypertensive patients.

Elderly and patients with impaired hepatic or renal function:

Angina:

The recommended starting dose is one Tildiem 60mg tablet twice daily. This dose may be increased to one 90mg or 120mg Tildiem Retard tablet twice daily.

Hypertension:

The starting dose should be one 120mg Tildiem Retard tablet daily. Dose adjustment to one 90mg or one 120mg Tildiem Retard tablet twice daily may be required.

Children:

Safety and efficacy in children have not been established. Therefore diltiazem is not recommended for use in children.

Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker.

Severe bradycardia (less than 50 beats per minute).

Left ventricular failure with pulmonary stasis.

Lactation.

Concurrent use with dantrolene infusion (see section 4.5 Interactions with other medicinal products and other forms of interaction).

Hypersensitivity to diltiazem or to any of the excipients.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a 1st degree AV block or prolonged PR interval detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).

Increase of plasma concentrations of diltiazem may be observed in the elderly and patients with renal or hepatic insufficiency. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.

In the case of general anaesthesia, the anaesthetist must be informed that the patient is taking diltiazem. The depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Treatment with diltiazem may be associated with mood changes, including depression. Early recognition of relevant symptoms is important, especially in predisposed patients. In such cases, drug discontinuation should be considered.

Diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk of developing an intestinal obstruction.

Combination Contraindicated For Safety Reasons:

Dantrolene (infusion)

Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and dantrolene are administered concomitantly.

The combination of a calcium antagonist and dantrolene is therefore potentially dangerous (see section 4.3 Contraindications).

Combinations Requiring Caution:

Alpha-antagonists

Increased anti-hypertensive effects. Concomitant treatment with alpha-antagonists may produce or aggravate hypotension. The combination of diltiazem with an alpha antagonist should be considered only with strict monitoring of blood pressure.

Beta-blockers

Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect).

Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.

Amiodarone, Digoxin

Increased risk of bradycardia; caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.

Antiarrhythmic agents

Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended due to the risk of increased cardiac adverse effects due to an additive effect. This combination should only be used under close clinical and ECG monitoring.

Nitrate derivatives:

Increased hypotensive effects and faintness (additive vasodilating effects).

In all patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.

Ciclosporin

Increase in circulating ciclosporin levels. It is recommended that the ciclosporin dose be reduced, renal function be monitored, circulating ciclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation.

Carbamazepine

Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.

Theophylline

Increase in circulating theophylline levels.

Anti-H₂ agents (cimetidine and ranitidine)

Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H₂ agents. An adjustment in diltiazem daily dose may be necessary.

Rifampicin

Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.

Lithium

Risk of increase in lithium-induced neurotoxicity.

Combinations To Be Taken Into Account:

Diltiazem is metabolised by CYP3A4. A moderate (less than 2-fold) increase of diltiazem plasma concentration in cases of co-administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other CYP3A4 substrates may result in an increase in plasma concentration of either co-administered drug. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

Statins:

Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins. The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with statins metabolised by CYP3A4 (e.g. atorvastatin, fluvastatin, and simvastatin). An adjustment of the dose of statin may be necessary (see also product information of the relevant statin). When possible, it is recommended to use a statin not metabolised by CYP3A4 (e.g. pravastatin) with diltiazem.

Benzodiazepines (midazolam, triazolam)

Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing short-acting benzodiazepines matabolised by the CYP3A4 pathway in patients using diltiazem.

Corticosteroids (methylprednisolone):

Diltiazem can increase methylprednisolone levels (through inhibition of CYP3A4 and possible inhibition of P-glycoprotein). The patient should be monitored when initiating methylprednisolone treatment. An adjustment to the dose of methylprednisolone may be necessary.

General Information To Be Taken Into Account:

Due to the potential for additive effects, caution and careful titration are necessary in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction.

Pregnancy: There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity (see section 5.3) in certain animal species (rat, mice, rabbit). Diltiazem is therefore not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.

Breast feeding: as this drug is excreted in breast milk, breast feeding whilst taking diltiazem is contraindicated.

No studies on the effects on the ability to drive and use machines have been performed

The following adverse reactions are listed by system organ class and frequency, based on data from clinical trials with diltiazem, using the following convention: very common ( 1/10); common ( 1/100 to 1/10); uncommon ( 1/1,000 to 1/100); rare ( 1/10,000 to 1/1000); very rare ( 1/10,000); not known (cannot be estimated from the available data)

Psychiatric disorders

Uncommon: nervousness, insomnia.

Nervous system disorders

Common: headache, dizziness

Cardiac disorders

Common: atrioventricular block, palpitations

Uncommon: bradycardia

Vascular disorders

Common: flushing

Uncommon: orthostatic hypotension

Gastrointestinal disorders

Common: constipation, dyspepsia, gastric pain, nausea

Uncommon: vomiting, diarrhoea

Rare: dry mouth

Hepatobiliary disorders

Uncommon: hepatic enzymes increase (AST, ALT, LDH, ALP increase)

Skin and subcutaneous tissue disorders

Common: erythema

Rare: urticaria

General disorders and administration site conditions

Very common: lower limb oedema

Common: malaise, asthenia/fatigue

POST-MARKETING EXPERIENCE

In addition to the above, the following adverse reactions have been reported during post-marketing surveillance. They are derived from spontaneous reports and, therefore, the frequency of these adverse reactions is not known.

Blood and lymphatic system disorders

Thrombocytopenia

Psychiatric disorders

Mood changes (including depression), extrapyramidal syndrome

Cardiac disorders

Sinoatrial block, congestive heart failure

Vascular disorders

Vasculitis (including leukocytoclastic vasculitis)

Gastrointestinal disorders

Gingival hyperplasia

Hepatobiliary disorders

Hepatitis

Skin and subcutaneous disorders

Photosensitivity (including lichenoid keratosis on sun-exposed skin areas), angioneurotic oedema, erythema multiforme (including Steven-Johnson's syndrome and toxic epidermal necrolysis), sweating, exfoliative dermatitis, acute generalised exanthematous pustulosis, occasionally desquamative erythema with or without fever

Reproductive system and breast disorders

Gynaecomastia

The clinical effects of acute overdose can involve pronounced hypotension leading to collapse, sinus bradycardia with or without isorhythmic dissociation, and atrioventricular conduction disturbances.

Treatment, under hospital supervision, will include gastric lavage and osmotic diuresis. Conduction disturbances may be managed by temporary cardiac pacing.

Proposed corrective treatments: atropine, vasopressors, inotropic agents, glucagon and calcium gluconate infusion.

Pharmacotherapeutic group: Calcium Channel Blockers; Benzothiazepine derivatives, ATC code: C08D B01

Tildiem is a calcium antagonist. It restricts the slow channel entry of calcium into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction of the amount of available intracellular calcium reducing myocardial oxygen consumption. It increases exercise capacity and improves all indices of myocardial ischaemia in the angina patient. Tildiem relaxes large and small coronary arteries and relieves the spasm of vasospastic (Prinzmetal's) angina and the response to catecholamines but has little effect on the peripheral vasculature. There is therefore no possibility of reflex tachycardia. A small reduction in heart rate occurs which is accompanied by an increase in cardiac output, improved myocardial perfusion and reduction of ventricular work. In animal studies, Tildiem protects the myocardium against the effects of ischaemia and reduces the damage produced by excessive entry of calcium into the myocardial cell during reperfusion.

Diltiazem is well absorbed (90%) in healthy volunteers following oral administration.

These formulations of diltiazem hydrochloride provide prolonged absorption of the active ingredient. Peak plasma concentrations occur between 4 and 8 hours post-dose.

Bioavailability of this formulation of diltiazem is approximately 90% of that of the conventional tablet. The mean apparent plasma half-life is 7 - 8 hours.

Diltiazem is 80 to 85% bound to plasma proteins. It is extensively metabolised by the liver.

The major circulating metabolite, N-monodesmethyl diltiazem accounts for approximately 35% of the circulating diltiazem.

Less than 5% of diltiazem is excreted unchanged in the urine.

During long term administration to any one patient, plasma concentrations of diltiazem remain constant.

Mean plasma concentrations in elderly subjects and patients with renal and hepatic insufficiency are higher than in young subjects.

Diltiazem and its metabolites are poorly dialysed.

Twice daily formulations of diltiazem have been shown to have different pharmacokinetic profiles and therefore it is not advised to substitute different brands for one another.

Pregnancy: Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg q.d. or 8 mg/kg q.d. for a 60-kg patient) resulted in embryo and fetal lethality. These studies revealed, in one species or another, a propensity to cause fetal abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights, pup survival, as well as prolonged delivery times and an increased incidence of stillbirths.

Tablet core:

Sodium dihydrogen citrate,

Sucrose,

Povidone,

Magnesium stearate,

Macrogol 6000.

Coating:

Sucrose,

Coating polymer,

Acetyl tributyl citrate,

Castor oil polymerised,

Sodium hydrogen carbonate,

Ethyl vanillin,

Titanium dioxide (E171).

Not applicable

3 years.

Do not store above 30°C. Store in the original package.

Tildiem Retard tablets are coated with a porous polymer membrane which enables the diltiazem to diffuse out of the tablet at a gradual rate. This membrane may pass through the gastro-intestinal tract unchanged. This has no bearing on the efficacy of the product.

56 tablets in PVC/foil strips

No special requirements.

sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

Date of first authorisation: 18 April 1991

Date of latest renewal: 28 August 2003

29 March 2011

POM