SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Diltiazem modified release tablets 60mg.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains diltiazem hydrochloride 60mg.

3    PHARMACEUTICAL FORM

White flat modified release tablets with C/066 on one side and the company logo on the other.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Prophylaxis and treatment of angina pectoris.

4.2.    Posology and method of administration

Adults: 60mg three times daily.

As patient responses may vary the dose can be increased to a maximum of 360mg daily in divided doses.

Higher doses up to 480mg/day have been used with benefit in some patients especially in unstable angina. There is no evidence of any decrease in efficacy at high doses. Diltiazem has not been reported to precipitate angina.

Elderly patients and patients with impaired hepatic or renal function: initially 60mg twice daily, monitoring of the heart rate should be carried out. Do not increase the dose if the rate falls below 50 beats per minute.

Children: Not recommended.

Route of Administration - Oral.

•    Sick sinus syndrome except in the presence of a functioning ventricular pacemaker

•    Second or third degree AV block except in the presence of a functioning ventricular pacemaker

•    Severe bradycardia (below 40 bpm)

•    Left ventricular failure with pulmonary congestion

•    Hypersensitivity to diltiazem or to any of the excipients.

•    Concomitant use of dantrolene infusion (see section 4.5)

•    Pregnant women or those of child bearing potential, lactation

Additionally, for the intravenous forms, patients known to have an accessory bypass (Wolf-Parkinson-White syndrome or short PR syndrome), and who develop atrial fibrillation or flutter, should not be administered intravenous diltiazem.

4.4 Special warnings and precautions for use

Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a first degree AV block or prolonged PR interval detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).

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.

Prior to general anaesthesia, the anaesthetist 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.

Calcium channel blocking agents, such as diltiazem may be associated with mood changes, including depression. Early recognition of relevant symptoms is important, especially in predisposed patients. In such cases, drug discontinuation should be considered.

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 galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interactions

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 anti-hypertensive 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 may cause small increases in the plasma levels of digitalis.

Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.

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.

Ciclosporin: Increase in circulating ciclosporin levels. It is recommended that the ciclosporin dose be reduced, renal function be monitored, circulating ciclosporin 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. Coadministration with other CYP3A4 substrates may result in an increase in plasma concentration of either co-administered drug. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

Diltiazem increases plasma levels of imipramine and possibly other tricyclic antidepressants, tacrolimus, sirolimus and cilostazol.

Diltiazem increases plasma levels of phenytoin; phenytoin and phenobarbital reduce the effects of diltiazem.

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 metabolised by the CYP3A4 pathway in patients using diltiazem.

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: 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 (e.g atorvastatin, fluvastatin, and simvastatin) may be increased with concomitant use of diltiazem. An adjustment of the dose of statin may be necessary (see also product information of the relevant statin). When possible, a non CYP3A4-metabolised statin (e.g pravastatin) should be used together with diltiazem, otherwise close monitoring for signs and symptoms of a potential statin toxicity is required.

Ritonavir and amprenavir may increase the plasma levels of diltiazem.

Diltiazem may increase the hypotensive effects of ACE inhibitors, angiotensin-II antagonists, aldesleukin, alprostadil, MAOIs, antipsychotics and moxisylate and diuretics.

Possible increase in the risk of bradycardia with mefloquine.

Clearance of nifedipine is reduced by diltiazem.

4.6 Use during pregnancy and lactation

The use of diltiazem in pregnancy or in women of child bearing potential is contraindicated. 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 therefore not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.

Diltiazem hydrochloride 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

On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise (common), the ability to drive and use machines could be altered. However, no studies have been performed.

4.8 Undesirable effects

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

Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

	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.			Extrapyrimidal 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 hypotension
Vascular disorders		Flushing	Orthostatic hypotension		Vasculitis (including leukocytoclastic vasculitis)

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		Urticaria	Photosensitivity (including lichenoid keratosis at sun-exposed skin areas), angioneurotic oedema, rash, erythema multiforme (including Steven-Johnson’s syndrome and toxic epidermal necrolysis), sweating, exfoliative dermatitis, acute generalised exanthematous pustulosis, occasionally desquamative erythema with or without fever
Reproductive system and breast disorders					gynaecomastia.
General disorders and administration site conditions	Peripheral oedema	Malaise, asthenia, fatigue.

4.9    Overdose symptoms, emergency procedures, antidotes

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.

Should overdose occur, observation in a coronary care unit is advised. It is reported that spontaneous recovery usually occurs. 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.

5.    PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Selective Calcium Channel Blockers with Direct Cardiac Effects, Benzothiazepine derivatives.

ATC Code: C08D B01

Diltiazem is a calcium channel blocker interfering with the inward displacement of calcium ions through the slow channels of cell membranes. The site of action is particularly the myocardial cells and the cells of vascular smooth muscle.

5.2.    Pharmacokinetic properties

There is sparse information reported on the pharmacokinetics of diltiazem but due to the first pass hepatic uptake effect bioavailability is variable and about 50%. Literature reports suggest that diltiazem has a mean half life of 4-6 hours. Extensive hepatic metabolism occurs and little unchanged drug is excreted in the urine. The drug is 80-85% protein bound.

5.3.    Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Lactose, hydrogenated castor oil, macrogol 6000 and magnesium stearate.

6.2.    Incompatibilities

None known.

6.3.    Shelf life

36 months.

6.4. Special precautions for storage

Protect from light.

6.5. Nature and contents of container

Securitainers, sealed with low density polythene snap-on closure in pack sizes 28, 30, 50, 56, 60, 84, 90, 100, 112 and 250. Alternatively, heat sealed PVC / PVdC / aluminium blister packs 250 micrometres PVC coated (inside) with 40gsm PVdC. Nominal 20 micrometres aluminium. Strips of 10 packed into cartons of 30, 60, 90, 100, and 1,000; strips of 14 packed into cartons of 28, 56, 84 and 112.

6.6. Instruction for use, handling and disposal

The tablets should not be crushed or chewed, but swallowed whole with a glass of water.

7. MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited Units 3 and 4

Quidhampton Business Units Polhampton Lane Overton

Hants RG25 3ED

8. MARKETING AUTHORISATION NUMBER

PL 20416/0066

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

28 May 2004

10 DATE OF REVISION OF THE TEXT

03/06/2016