SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

ADIZEM-SR tablets 120 mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Diltiazem Hydrochloride 120 mg

Excipients: also contains 120 mg lactose and 0.8 mg sucrose per tablet.

For a full list of excipients see section 6.1.

3.    PHARMACEUTICAL FORM

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

4.    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

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

4.2.    Posology and Method of Administration

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.

4.3 Contraindications

Pregnancy and in women of child-bearing capacity. Patients with severe bradycardia (less than 40 bpm), second or third degree heart block, sick sinus syndrome, decompensated cardiac failure, patients with left ventricular failure with pulmonary congestion. Concurrent use with dantrolene infusion because of the risk of ventricular fibrillation (see section 4.5). Hypersensitivity to diltiazem or to any of the excipients.

4.4 Special warnings and precautions for use

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

Diltiazem is considered unsafe in patients with acute porphyria.

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.

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

4.5 Interaction with other medicinal products and other forms of interaction

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 (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 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.

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

4.6 Pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

The following CIOMS frequency rating is used, when applicable: Very common fe.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).

	Very common	Common	Uncommon	Rare	Not known
Blood and lymphatic system disorders					Thrombocytopenia
Psychiatric disorders			Nervousness, insomnia		Mood changes (including depression)
Nervous system disorders		Headache, dizziness			Extrapyramidal syndrome
Cardiac disorders		Atrioventricular block (may be of first, second or third degree; bundle branch block may occur), palpitations	Bradycardia		Sinoatrial block, congestive heart failure
Vascular disorders		Flushing	Orthostatic hypotension		Vasculitis (including leukocytoclastic vasculitis), hypotension
Gastrointestinal disorders		Constipation, dyspepsia, gastric pain, nausea	Vomiting, diarrhoea	Dry mouth	Gingival hyperplasia, gastrointestinal disorder
Hepatobiliary disorders			Hepatic enzymes increase (AST, ALT, LDH, ALP increase)		Hepatitis
Skin and subcutaneous tissue disorders		Erythema		Urticaria	Photosensitivity (including lichenoid keratosis at sun exposed skin areas), angioneurotic oedema, rash, erythema multiforme (including Steven-Johnson's syndrome and toxic epidermal necrolysis), hyperhidrosis, exfoliative dermatitis, acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever, allergic dermatitis

	Very common	Common	Uncommon	Rare	Not known
Reproductive system and breast disorders					Gynecomastia
General disorders and administration site conditions	Peripheral oedema	Malaise, fatigue

4.9. Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Selective calcium channel blocker with direct

cardiac effects

ATC Code: C08D B01

5.1 Pharmacodynamic Properties

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.

5.2 Pharmacokinetic Properties

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.

5.3 Pre-clinical Safety Data

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

6.    PHARMACEUTICAL PARTICULARS

6.1    List of Excipients

Lactose

Hydrogenated castor oil Colloidal aluminium hydroxide Acrylic resin Talc

Magnesium stearate Hypromellose Sucrose Glycerol 85%

Titanium dioxide (E171)

Polysorbate 80

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5 Nature and Contents of Container

Aluminium foil backed PVdC/PVC blister packs containing 8, 28 or 56 tablets.

Amber glass bottles with a pilfer-proof closure containing 56 tablets. Polypropylene containers with polyethylene lids containing 28 or 56 tablets.

6.6 Instructions for Use/Handling None.

ADMINISTRATIVE DATA

7. MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Ltd Cambridge Science Park Milton Road Cambridge CB4 0GW

8. MARKETING AUTHORISATION NUMBER

PL 16950/0009

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21^st December 1989 / 23^rd September 2003

DATE OF REVISION OF THE TEXT

10/12/2010