Calcium-channel blockers (class III calcium antagonists).

Diltiazem - angina

Diltiazem hydrochloride 90 mg, 120 mg, 180 mg

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.

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.

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.

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.

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%.

Blood and the lymphatic system disorders
Uncommon:  thrombocytopenia
 
Nervous system disorders
Common:  dizziness, headache
Uncommon: extrapyramidal disorder
  
Cardiac disorders
Uncommon: atrioventricular block, bradycardia, palpitations, sinoatrial block  

Vascular disorders 
Common: facial flushing, hypotension
Uncommon: vasculitis

Gastrointestinal disorders
Common:  gastrointestinal disorder, nausea 
Uncommon:  gingival hyperplasia
  
Hepatobiliary disorders
Uncommon:  increased hepatic enzyme, clinical hepatitis

Skin and subcutaneous tissue disorders
Uncommon: allergic dermatitis, erythema multiforme, exfoliative dermatitis, photosensitivity reaction
 
Reproductive system and breast disorders
Uncommon: gynaecomastia
 
General disorders and administration site conditions
Common: fatigue, oedema legs
 

Napp Pharmaceuticals Limited

(POM)

25 June 2009