This information is intended for use by health professionals

1. Name of the medicinal product

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

2. Qualitative and quantitative composition

Each capsule contains 90 mg, 120 mg or 180 mg diltiazem hydrochloride.

Excipients: also contains sucrose 18.26 mg per capsule. (90 mg only)

Excipients: also contains sucrose 24.35 mg per capsule. (120 mg only)

Excipients: also contains sucrose 36.53 mg per capsule. (180 mg only)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged release capsule

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

ADIZEM-SR capsules 120 mg are capsules with white bodies and brown caps marked “120 mg”

ADIZEM-SR capsules 180 mg are capsules with white bodies and pale brown caps marked “180 mg”

The capsules contain prolonged release microgranules.

4. Clinical particulars
4.1 Therapeutic indications

For the management of angina pectoris.

For the treatment of mild to moderate hypertension.

ADIZEM-SR capsules are indicated for use in adults only.

4.2 Posology and method of administration

Posology

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.

Paediatric population:

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

Method of administration

Oral.

To be taken at 12 hour intervals.

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

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 (see section 4.5).

4.3 Contraindications

Hypersensitivity to diltiazem or to any of the excipients.

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).

4.4 Special warnings and precautions for use

The product should be used with caution in patients with reduced left ventricular function. Patients with mild 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 (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. Diltiazem may increase serum levels of phenytoin.

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.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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 frequencies are the basis for assessing undesirable effects:

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).

Very common

Common

Uncommon

Rare

Not known

Blood and lymphatic system disorders

Thrombocytopenia

Immune system disorders

Hypersensitivity

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

Hepatobiliary disorders

Hepatic enzymes increase (AST, ALT, LDH, ALP increase)

Hepatitis

Skin and subcutaneous tissue disorders

Erythema,

pruritus

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, desquamative erythema with or without fever, allergic dermatitis

Reproductive system and breast disorders

Gynaecomastia

General disorders and administration site conditions

Peripheral oedema

Malaise, fatigue

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

The clinical effects of acute overdose can involve pronounced hypotension possibly leading to collapse, sinus bradycardia with or without isorhythmic dissociation and atrioventricular conduction disturbances.

Treatment in a hospital setting will include gastric lavage and/or osmotic diuresis.

Conduction disturbances may be managed by temporary cardiac pacing.

Proposed corrective treatments: atropine, vasopressors, inotropic agents, glucagon and calcium gluconate infusion.

Symptomatic bradycardia and high grade atrioventricular block may respond to atropine and isoprenaline.

The formulation employs a prolonged release system which will continue to release diltiazem for some hours.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical 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

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.

6.2 Incompatibilities

None known.

6.3 Shelf life

Three years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

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

Pack sizes: 56 capsules

6.6 Special precautions for disposal and other handling

Not applicable

7. Marketing authorisation holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

8. Marketing authorisation number(s)

PL 16950/0006-0008

9. Date of first authorisation/renewal of the authorisation

2 October 1992/23 September 2003

10. Date of revision of the text

22 March 2017

11. Legal category

POM

® The Napp device and ADIZEM are Registered Trade Marks

© 2008-2017 Napp Pharmaceuticals Ltd.