ADIZEM^®-XL capsules 120, 180, 200, 240, 300 mg

Diltiazem Hydrochloride 120, 180, 200, 240, 300 mg

For excipients, see section 6.1.

Prolonged release capsules.

ADIZEM-XL capsules 120 mg have a pale pink body and a navy blue cap, marked DCR 120.

ADIZEM-XL capsules 180 mg have a dark pink body and a royal blue cap marked DCR 180.

ADIZEM-XL capsules 200 mg have a brown body and a brown cap marked DCR 200.

ADIZEM-XL capsules 240 mg have a dark red body and a blue cap marked DCR 240.

ADIZEM-XL capsules 300 mg have a dark maroon body and a pale blue cap marked DCR 300.

Management of angina pectoris.

Treatment of mild to moderate hypertension.

Route of administration

Oral

Posology

Dosage requirements may differ between patients with angina and patients with hypertension. In addition, individual patients' responses may vary necessitating careful titration. This range of capsule strengths facilitates titration to the optimal dose.

The capsules should be swallowed whole and not chewed.

Adults:

For patients new to diltiazem therapy the usual starting dose is one 240 mg capsule daily.

Patients currently receiving a total daily dose of 180 mg diltiazem (as 90 mg b.d. or 60 mg t.i.d.) and transferring to ADIZEM-XL capsules should be given the 240 mg capsule (o.d.). A patient receiving 240 mg/day of diltiazem (as 120 mg b.d.) should commence treatment on the 240 mg capsule (o.d.), titrating to the 300 mg capsule (o.d.) if required.

Elderly and patients with impaired hepatic and renal function:

For patients new to diltiazem therapy, the usual starting dose is one 120 mg capsule daily. If necessary the dose may be gradually increased but careful monitoring of this group of patients is advised.

Elderly patients transferring to ADIZEM-XL capsules should receive the same total daily dose of diltiazem, titrating upwards as required.

Children:

ADIZEM-XL capsules are not recommended for children. Safety and efficacy in children have not been established.

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

ADIZEM-XL 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. Peanut or soya allergies. Hypersensitivity to diltiazem or to any of the excipients.

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-XL 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

5.1 Pharmacodynamic Properties

Diltiazem is a calcium antagonist. It restricts the slow channel entry of calcium ions into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction in the amount of available intra-cellular calcium and consequently a (1) reduction of myocardial oxygen consumption, (2) dilation of small and large coronary arteries, (3) mild peripheral vasodilation, (4) negative dromotropic effects, (5) reflex positive chronotropic and inotropic effects due to reflex sympathetic activity are partially inhibited and result in a slight reduction or no change in heart rate.

The antihypertensive effect is due to the reduction in peripheral vascular resistance.

The antianginal effect is due to a reduction in the peripheral resistance, thereby decreasing the after-load, whilst a reduction in the vasomotor tone of the coronary circulation maintains the coronary blood flow. Cardiac contractility and ventricular ejection fraction are unchanged. Diltiazem increases exercise capacity and improves indices of myocardial ischaemia in the angina patient. Diltiazem relieves the spasm of vasospastic (Prinzmetal) angina.

An oral dose of diltiazem is almost completely absorbed. Despite this, diltiazem has a low bioavailability owing to extensive first pass metabolism. This process is saturable at higher doses of the drug resulting in a non-linear accumulation and higher blood concentrations at steady state than would be anticipated from those following a single dose.

ADIZEM-XL capsules reduce the degree of saturation by presenting diltiazem in a retarded fashion therefore eliminating the high peak concentrations of the absorption phase. This allows the capsule to be administered once daily.

In pharmacokinetic studies in healthy volunteers, diltiazem was well absorbed. The controlled release capsules provided prolonged absorption of the drug, producing peak steady state plasma concentrations between 4 and 14 hours post-dose. The availability of diltiazem from ADIZEM-XL capsules 120 mg (o.d.) relative to a prolonged release 60 mg diltiazem preparation (b.d.) was approximately 79% at steady state. Similarly, the availability of diltiazem from the 240 mg capsule (o.d.) relative to ADIZEM-SR tablets 120 mg (b.d.) was approximately 78%. The extent of absorption of diltiazem was not affected when ADIZEM-XL capsules were co-administered with a high-fat meal.

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

Microcrystalline Cellulose

Ethylcellulose N10

Colloidal Anhydrous Silica

Polysorbate 80

Dibutyl Sebacate

Magnesium Stearate

Capsule shells

Iron oxide (E172)

Titanium dioxide (E171)

Sodium dodecylsulphate

Gelatin

Erythrosine (E127) (not present in the 200 mg capsule)

Indigo carmine (E132) (not present in the 200 mg capsule)

Patent blue V (E131) (300 mg capsule only)

Printing ink

Shellac

Soya lecithin

2-ethoxyethanol

Dimeticone

Titanium dioxide (E171)

None known

2 years

Do not store above 25^°C

PVC/PVdC blister packs with aluminium foil (containing 28 capsules).

None.

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

PL 16950/0010-0013, 0121

ADIZEM-XL capsules 120 mg, 180 mg, 240 mg, 300 mg:

11 August 1993 / 23 September 2003

ADIZEM-XL capsules 200 mg:

10 September 2001/23 September 2003

July 2009

POM

ADIZEM-XL capsules are the subject of UK Patent GB 2 258 613.

® The Napp device and ADIZEM are Registered Trade Marks.

© Napp Pharmaceuticals Ltd 2009.