ADIZEM^®-SR tablets 120 mg

Diltiazem Hydrochloride 120 mg

For excipients see section 6.1

White film-coated capsule-shaped, prolonged release tablets. The tablets are marked 120/DL on one side and with a scoreline on the other.

For the management of angina pectoris. For the treatment of mild to moderate hypertension.

Route of administration

Oral.

Dosage may be taken with or without food, and should be swallowed whole and not chewed.

Angina

Adults:

The usual initial dose is 90 mg twice-daily. Dosage may be increased gradually to 120 mg twice-daily, or 180 mg twice-daily if required. Patients' responses may vary and dosage requirements can differ significantly between individual patients.

Elderly and patients with impaired renal or hepatic function:

In the elderly, dosage should commence at 60 mg diltiazem hydrochloride twice-daily and the dose carefully titrated as required.

Hypertension

Adults:

The usual dose is one ADIZEM-SR 120 mg tablet or capsule twice-daily. Patients may benefit by titrating from a lower total daily dose.

Elderly and patients with impaired renal or hepatic function:

The starting dose should be 60 mg diltiazem hydrochloride twice-daily, increasing to one ADIZEM-SR 90 mg capsule twice-daily and then to one ADIZEM-SR 120 mg tablet or capsule twice-daily if clinically indicated.

Children:

The ADIZEM preparations are not recommended for children. Safety and efficacy in children has not been established.

In order to avoid confusion, it is suggested that patients, once titrated to an effective dose using either ADIZEM tablets or capsules, should remain on this treatment and should not be changed between different presentations.

Pregnancy and in women of child-bearing capacity. Patients with bradycardia (less than 50 bpm), second or third degree heart block, sick sinus syndrome, decompensated cardiac failure, patients with left ventricular dysfunction following myocardial infarction. Concurrent use with dantrolene infusion because of the risk of ventricular fibrillation.

The product should be used with caution in patients with reduced left ventricular function. Patients with mild bradycardia, first degree AV block or prolonged PR interval should be observed closely. Diltiazem is considered unsafe in patients with acute porphyria.

Diltiazem is extensively metabolised by CYP3A4, and as a result serum levels of diltiazem may be:

•Increased by concomitant usage of CYP3A4 inhibitors such as H2 antagonists (e.g. cimetidine, ranitidine) and protease inhibitors (e.g. atazanavir, ritonavir)

Decreased by concomitant usage of CYP3A4 inducers such as barbiturates (phenobarbital, primidone), phenytoin and rifampicin.

Diltiazem is also an inhibitor of CYP3A4, and may therefore increase serum levels of CYP3A4 substrates such as benzodiazepines (especially midazolam and triazolam), carbamazepine, ciclosporin, cilostazol, ivabradine, statins (simvastatin, atorvastatin, lovastatin), sirolimus, tacrolimus and theophylline. Care should be exercised in patients taking these drugs. Concomitant use of diltiazem with cilostazol and ivabradine should be avoided.

There may be an additive effect (increased depression of cardiac conduction with risk of bradycardia and AV block) when diltiazem is prescribed with drugs which may induce bradycardia or other anti-arrhythmic drugs (e.g. amiodarone and beta blockers). Patients with pre-existing conduction defects should not receive the combination of diltiazem and beta-blockers.

Enhanced antihypertensive effect may occur with concomitant use of other antihypertensive drugs (e.g. beta-blockers, diuretics, ACE-inhibitors) or drugs that cause hypotension such as aldesleukin and antipsychotics. Concomitant use with alpha-blockers (e.g. prazosin) should be strictly monitored because of the possible synergistic hypotensive effect of this combination.

Diltiazem hydrochloride may cause small increases in plasma levels of digoxin, requiring careful monitoring of AV conduction.

Diltiazem may increase serum levels of phenytoin.

Diltiazem may increase bioavailability of tricyclic antidepressants.

Treatment with diltiazem has been continued without problem during anaesthesia, but the anaesthetist should be made aware of the treatment regimen.

The combination of alcohol and diltiazem may have an additive vasodilatory effect

Diltiazem hydrochloride is contra-indicated in pregnant women or women of child-bearing potential, and is not recommended in nursing mothers.

Diltiazem may cause adverse reactions such as dizziness, which may impair patients' ability to drive or operate machinery to a varying extent depending on the dosage and individual susceptibility. Therefore, patients should not drive or operate machinery if affected.

The adverse events listed below are classified by body system according to their incidence (common or uncommon). Common adverse events have an incidence of >1% and uncommon adverse events have an incidence of <1%.

The clinical symptoms of acute intoxication may include pronounced hypotension or even collapse and sinus bradycardia with or without atrioventricular conduction defects.

The patient should be closely monitored in hospital to exclude arrhythmias or atrioventricular conduction defects. Gastric lavage and osmotic diuresis should be undertaken when considered appropriate. Symptomatic bradycardia and high grade atrioventricular block may respond to atropine, isoprenaline or occasionally temporary cardiac pacing.

Hypotension may require correction with plasma volume expanders, intravenous calcium gluconate and positive inotropic agents. The formulation employs a prolonged release system which will continue to release diltiazem for some hours.

Pharmacotherapeutic group: Selective calcium channel blocker with direct cardiac effects

ATC Code: C08D B01

Diltiazem is a calcium antagonist which restricts the slow channel entry of calcium ions into the cell and so reduces the liberation of calcium from stores in the endoplasmic reticulum. This results in a reduction in the amount of available intra-cellular calcium and consequently:

1) Reduction of myocardial oxygen consumption.

2) Dilation of small and large coronary arteries.

3) Mild peripheral vasodilation.

4) A negative dromotropic effect.

5) The reflex positive chronotropic and inotropic effects due to reflex sympathetic activity are partially inhibited. This results in a slight reduction or no change in heart rate.

The antianginal effect is due to a reduction in cardiac oxygen demand with maintenance of coronary blood flow. Cardiac contractility and ventricular ejection fraction are unchanged. Treatment with diltiazem increases exercise capacity, improves the indices of myocardial ischaemia in the angina patient and relieves the spasm of vasospastic (Prinzmetal's) angina.

An oral dose of diltiazem is almost completely absorbed. Despite this, diltiazem has a low bioavailability owing to hepatic first pass metabolism. Diltiazem is metabolised extensively and only 1.0 to 3.0% of the dose is excreted in the urine as unchanged diltiazem. The release of the drug has been prolonged in the 120 mg tablet by special pharmaceutical technology. The high peak concentrations of the absorption phase have been eliminated. This allows the tablet to be administered twice-daily.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Lactose

Hydrogenated castor oil

Colloidal aluminium hydroxide

Acrylic resin

Talc

Magnesium stearate

Hypromellose

Sucrose

Glycerol 85%

Titanium dioxide (E171)

Polysorbate 80

None known.

36 months.

Do not store above 30°C.

Store in the original package.

Aluminium foil backed PVdC/PVC blister packs containing 56 tablets.

None.

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

PL 16950/0009

21 December 1989/23 September 2003

December 2008

POM

® ADIZEM and the Napp device are Registered Trade Marks.

© Napp Pharmaceuticals Ltd 2008