Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

ADIZEM^®-XL 120 mg, 180 mg, 240 mg and 300 mg prolonged release capsules.

Each capsule contains 120 mg, 180 mg, 240 mg or 300 mg diltiazem hydrochloride.

For a full list of excipients, see section 6.1.

Prolonged release capsules, hard.

ADIZEM-XL capsules 120 mg are size 3, hard gelatin capsules with a pale pink body and a navy blue cap, marked DCR 120.

ADIZEM-XL capsules 180 mg are size 2, hard gelatin capsules with a dark pink body and a royal blue cap, marked DCR 180.

ADIZEM-XL capsules 240 mg are size 1, hard gelatin capsules with a dark red body and a blue cap, marked DCR 240.

ADIZEM-XL capsules 300 mg are size 0, hard gelatin capsules with a dark maroon body and a pale blue cap, marked DCR 300.

1. Management of angina pectoris.

2. Treatment of mild to moderate hypertension.

Oral. The capsules should be swallowed whole and not chewed.

Adults:

The usual starting dose is one 240 mg capsule daily. However, patients' responses may vary and dosage requirements can differ significantly between individual patients. There is no evidence of any decrease in efficacy at higher doses. If necessary the dosage may be gradually increased to 300 mg or 360 mg per day. Doses of 480 mg/day have been used with benefit in some angina patients.

Elderly:

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.

Children:

Not recommended for use in children.

ADIZEM-XL 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).

Sick sinus syndrome, second or third degree AV-block, severe bradycardia (less than 40 beats per minute). Congestive heart failure and in patients with left ventricular failure with pulmonary congestion. Pregnant women or those of child bearing potential. Concurrent use with dantrolene infusion is contraindicated because of the risk of ventricular fibrillation (see section 4.5). Hypersensitivity to diltiazem or to any of the excipients.

Patients with bradycardia (risk of exacerbation), first degree AV block or a prolonged PR interval should be observed closely. Diltiazem should be used with caution in patients with reduced left ventricular function.

Diltiazem is considered unsafe in patients with acute porphyria.

Isolated cases of moderate and transient increased liver transaminases have been observed at the start of treatment. Isolated cases of clinical hepatitis have been reported, which resolved when diltiazem was withdrawn.

The use of diltiazem in diabetic patients may require adjustment of their control.

Prior to general anaesthesia, the anaesthesist must be informed of ongoing diltiazem treatment. Depression of cardiac contractility, conductivity and automaticity, as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Increase of plasma concentrations of diltiazem may be observed in the elderly and in 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.

Calcium channel blocking agents, such as diltiazem, may be associated with mood changes, including depression.

Like other calcium channel antagonists, diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk to develop an intestinal obstruction. Tablet residues from slow release formulations of the product may pass into the patient's stools; however, this finding has no clinical relevance.

Concomitant use contraindicated:

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).

Concomitant use requiring caution:

Lithium: Risk of increase in lithium-induced neurotoxicity.

Nitrate derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects): In all the patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.

Theophylline: Increase in circulating theophylline levels.

Alpha-antagonists: Increased antihypertensive effects:

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

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

Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Patients with pre-existing conduction defects should not receive the combination of diltiazem and beta-blockers. Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.

Other antihypertensive drugs: 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.

Other antiarrhythmic agents:

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

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.

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.

Anti-H₂ agents (cimetidine, 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.

Protease inhibitors (e.g. atazanavir, ritonavir): Increase in plasma diltiazem concentrations.

Ciclosporin: Increase in circulating cyclosporin levels:

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

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.

Diltiazem is metabolized 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 (e.g. cilostazol, ivabradine, sirolimus, tacrolimus). Care should be exercised in patients taking these drugs. Concomitant use of diltiazem with cilostazol and ivabradine should be avoided.

Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

Barbiturates (phenobarbital, primidone): serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers.

Phenytoin: serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers.

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 metabolized by the CYP3A4 pathway in patients using diltiazem.

Diltiazem hydrochloride may increase bioavailability of tricyclic antidepressants.

Corticosteroids (methylprednisolone): Inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein: The patient should be monitored when initiating methylprednisolone treatment. An adjustment in the dose of methylprednisolone may be necessary.

Statins (simvastatin, atorvastatin, lovastatin): Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins. The risk of myopathy and rhabdomyolysis due to statins metabolised by CYP3A4 may be increased with concomitant use of diltiazem. When possible, a non CYP3A4-metabolised statin should be used together with diltiazem, otherwise close monitoring for signs and symptoms of a potential statin toxicity is required.

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

There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity in certain animal species (rat, mice, rabbit). Diltiazem is contraindicated during pregnancy (see section 4.3), as well as in women of child-bearing potential not using effective contraception.

Diltiazem is excreted in breast milk at low concentrations. Breast-feeding while taking this drug should be avoided. If use of diltiazem is considered medically essential, an alternative method of infant feeding should be instituted.

Diltiazem has been reported to cause adverse reactions such as dizziness (common) and malaise (common), which may impair patients' ability to drive or operate machinery to a varying extent depending on the dosage and individual susceptibility. However, no studies have been performed . Therefore, patients should not drive or operate machinery if affected.

The following CIOMS frequency rating is used, when applicable: Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

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. 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 hepatic first-pass metabolism. Diltiazem is metabolised extensively and only 1.0-3.0% of the dose is excreted in urine as unmetabolised diltiazem.

The release of the drug has been prolonged in the capsules by special pharmaceutical technology. The high peak concentrations of the absorption phase have been eliminated. This allows the capsules to be administered once 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.

Microcrystalline cellulose

Ethylcellulose N10

Colloidal anhydrous silica

Polysorbate 80

Dibutyl sebacate

Magnesium stearate

Capsule shell

Erythrosine (E127)

Iron oxide red (E172)

Iron oxide black (E172) (180 mg capsule only)

Iron oxide yellow (E172) (240 mg capsule only)

Indigo carmine (E132)

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

Titanium dioxide (E171)

Gelatin

Sodium laurilsulfate

Printing ink

Shellac

Simeticone

Propylene glycol

Titanium dioxide (E171)

Not applicable.

Two years.

Do not store above 25°C.

PVdC coated PVC blister packs with aluminium foil backing containing 28 capsules.

No special requirements.

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland

PA 1688/1/4-7

Date of first authorisation: 16 December 1994

Date of last renewal: 16 December 2009

November 2011

® ADIZEM, MUNDIPHARMA and the 'mundipharma' device are Registered Trade Marks.

© Napp Pharmaceuticals Ltd, 2010-2011.