ADIZEM^®-SR capsules 90 mg, 120 mg, 180 mg

Diltiazem hydrochloride 90 mg, 120 mg, 180 mg

For excipients, see section 6.1

Prolonged release capsules

ADIZEM-SR capsules 90 mg are white capsules marked “90 mg”

ADIZEM-SR capsules 120 mg are white/brown capsules marked “120 mg”

ADIZEM-SR capsules 180 mg are white/pale brown capsules marked “180 mg”

The capsules contain prolonged release microgranules.

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-SR tablets or capsules should remain on this treatment and should not be changed between different presentations.

ADIZEM-SR capsules should not be taken at the same time as an alcoholic beverage (refer to section 4.5, Interactions with other Medicinal Products and Other Forms of Interaction).

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.

ADIZEM-SR capsules should not be taken at the same time as alcohol, as it may increase the rate of release of diltiazem from the prolonged release preparation. In addition the combination of alcohol and diltiazem may have an additive vasodilatory effect.

Diltiazem hydrochloride is contraindicated 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 an antianginal agent and calcium antagonist. Diltiazem inhibits transmembrane calcium entry in myocardial muscle fibres and in vascular smooth muscle fibres, thereby decreasing the quantity of intracellular calcium available to the contractile proteins.

ADIZEM-SR capsules is a form characterised by prolonged release of diltiazem hydrochloride in the digestive tract. Diltiazem is 80% bound to human plasma proteins (albumin, acid glucoproteins).

The biotransformation routes are:

- Deacetylation

- Oxidative o- and n-demethylation

- Conjugation of the phenolic metabolites.

The primary metabolites, n-demethyldiltiazem and desacetyldiltiazem exert less pharmacological activity than diltiazem. The other metabolites are pharmacologically inactive.

After administration of 180 to 300 mg of ADIZEM-SR capsules, a peak plasma concentration of 80 to 220 ng/ml, respectively, is obtained after about 5.5 hours.

The elimination half-life varies from 6 to 8 hours, depending on the strength.

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

Capsule contents

Sucrose and maize starch SP microgranules

Povidone

Sucrose

Ethylcellulose

Talc

Aquacoat ECD 30

Dibutyl sebacate

Capsule shells

Titanium dioxide (E171)

Gelatin

Iron oxide (E172) – 120 mg and 180 mg capsules only.

Indigotine (E132) - 120 mg capsules only.

None known.

Three years.

Do not store above 25°C.

Blister packs (aluminium/PVC) boxed in cardboard cartons.

Pack sizes: 56 capsules

Not applicable

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

PL 16950/0006-0008

2 October 1992/23 September 2003

December 2008

POM

® The Napp device and ADIZEM are Registered Trade Marks

© Napp Pharmaceuticals Ltd 2008.