Napp Pharmaceuticals Limited

Section 4.5  The following replaces the first three paragraphs of the previous SPC.

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.

Section 4.7 the following has been added

Therefore, patients should not drive or operate machinery if affected.

 Section 4.8 the following replaces the first paragraph of the previous SPC