SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Retalzem®60mg MR Tablets

2. Qualitative and Quantitative Composition

Each tablet contains 60 mg of the active substance diltiazem hydrochloride Excipients with known effect

Product contains lactose monohydrate, For full list of excipients see section 6.1

3    PHARMACEUTICAL FORM

Modified release tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Prophylaxis and treatment of angina pectoris

4.2 Posology and Method of Administration

The tablets should be swallowed whole with some water, without crushing or chewing.

Adults The usual dose is one tablet (60mg) three times daily. However, patient responses may vary and dosage requirements can differ significantly between individual patients. If necessary the dosage may be increased, up to 360mg/day. Higher doses, up to 480mg/day, have been used with benefit in some patients, especially in the treatment of unstable angina. There is no evidence of any decrease in efficacy at these high doses.

Elderly patients or patients with impaired hepatic or renal function

Plasma levels of diltiazem can be increased in these patients. The recommended initial dose is one tablet (60mg) twice daily. Heart rate should be monitored regularly in these patients and the dose should not be increased if the heart rate falls below 50 beats per minute. In patients suffering from liver problems, periodical checks of liver function are recommended during treatment with Retalzem® 60mg MR Tablets.

Children Not recommended.

4.3 Contraindications

Congestive heart failure, sick sinus syndrome [sinoatrial (SA) and 2nd or 3rd degree atrioventricular (AV) block] in patients without a functioning pacemaker, marked bradycardia (less than 50 beats per minute).

Retalzem® 60mg MR Tables should not be used in pregnancy, in women of child-bearing potential or in mothers who are breast-feeding.

Left ventricular failure with pulmonary stasis

Hypersensitivity to diltiazem or to any of its excipients

Retalzem® 60mg MR Tablets like any calcium-channel blocker should not be administered concurrently with dantrolene infusion, because of the risk of ventricular fibrillation (see section 4.5 Interactions with other medicinal products).

4.4 Special Warnings and Precautions for Use

Retalzem® 60mg MR Tablets should be used with caution in patients with reduced left ventricular function, mild bradycardia (because of risk of exacerbation), first degree AV block or prolonged PR interval detected on electrocardiogram (risk of exacerbation and rarely, of complete block). In case of surgery with general anaesthesia inform anaesthetist about current therapy and dosage. Calcium channel blockers may potentiate the depression of cardiac contractility, conductivity and automaticity and vascular dilatation caused by anaesthetics.

The product should be used with caution in elderly patients and in patients with hepatic and renal dysfunction, since plasma diltiazem levels can be increased. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.

The product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Treatment with 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.

Diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk of developing an intestinal obstruction.

4.5 Interactions with other Medicaments and other Forms of Interaction Combinations 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 Contraindications).

Combinations requiring caution

In common with other calcium-channel blockers, when Retalzem® 60mg MR Tablets is used with drugs which may induce bradycardia or hypotension or with other antiarrhythmic drugs the possibility of an additive effect should be borne in mind.

Alpha-antagonist agents

Increase of hypotensive effects. Combination of diltiazem with alpha-antagonist drugs may produce or aggravate hypotension; therefore strict monitoring is recommended.

Beta-blockers

Possible disturbances of conduction (marked bradycardia, sinus node depression), effects on sinoatrial and atrioventricular conduction and heart failure (synergistic action). Patients receiving such combinations should be regularly monitored by ECG and clinically, especially when initiating the treatment.

Amiodarone, digoxin

Increased risk of bradycardia; caution required in combination with diltiazem, especially in elderly patients, or at high dosages. Diltiazem increases blood levels of digoxin.

Antiarrhythmic drugs

Since diltiazem has antiarrhythmic activity, concurrent prescription of other antiarrhythmic agents may result in increase of cardiac side effects due to additive effects. Such a combination requires caution and it should be initiated under close ECG and clinical monitoring.

Nitro-compounds

Should be prescribed at gradually increasing doses because of increase in hypotensive effects and faintness from the additive effects on vasodilation.

In all patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.

Ciclosporin, Tacrolimus and Sirolimus

Diltiazem causes an increase of blood levels. It is recommended to decrease the dose, check renal function, titrate blood levels and adjust the dose both during the treatment combination and after its discontinuation.

Carbamazepine

Increase of blood levels of carbamazepine. It is recommended that the plasma concentration of carbamazepine be monitored and the dose adjusted as necessary.

Theophylline

Increase of blood levels of theophylline.

Histamine H2-receptor antagonists (cimetidine or ranitidine)

Increase in plasma levels of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H2 agents. A change in the diltiazem dose may be necessary.

Rifampicin

Plasma levels of diltiazem may be decreased after beginning rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.

Lithium

Risk of lithium-induced neurotoxicity Combinations to be taken into account

CYP450 3A4

Diltiazem is metabolised 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. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

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 is increased by concomitant administration of diltiazem with statins metabolised by CYP3A4 (e.g. atorvastatin, fluvastatin and simvastatin). An adjustment to the dose of statin may be necessary (see also product information of the relevant statin). When possible, it is recommended to use a statin not metabolised by CYP3A4 (e.g. pravastatin) with 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)

Diltiazem can increase methylprednisolone levels (through inhibition of CYP3A4 and possible inhibition of P-glycoprotein). The patient should be monitored when initiating methylprednisolone treatment. An adjustment to the dose of methylprednisolone may be necessary.

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.

4.6 Fertility, Pregnancy and Lactation

Diltiazem hydrochloride is teratogenic in some animal species. In the absence of adequate evidence of safety in human pregnancy, Retalzem® 60mg MR Tablets should not be used in pregnancy or in women of child bearing potential. If it is considered essential that diltiazem hydrochloride be given to a woman of child bearing potential, the possibility of pregnancy must be excluded before starting the treatment and adequate contraception must be used throughout the therapy.

Diltiazem hydrochloride is excreted in breast milk. If use of Retalzem® 60mg MR Tablets is considered essential, another method of infant feeding should be instituted.

4.7 Effects on ability to drive and use machines

No studies on ability to drive or use machines have been performed. Side effects such as dizziness or syncope can occur, particularly at start of treatment or after changes in dose and patients should ensure they do not have these effects before driving or operating machinery.

4.8 Undesirable Effects

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

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			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)
Gastrointestinal disorders		Constipation, dyspepsia, gastric pain,	Vomiting, diarrhea	Dry mouth	Gingival hyperplasia

		nausea
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 generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever
Reproductive system and breast disorders					Gynecomastia
General disorders and administration site conditions	Peripheral oedema	Malaise

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

Overdose

Experience of overdosage in man is limited, but cases of spontaneous recovery have been reported. However, it is recommended that patients with suspected overdose should be placed under observation in a coronary care unit with facilities available for treatment of any possible hypotension and conduction disturbances that may occur.

Most patients suffering from overdosage of diltiazem become hypotensive within 8 hours of ingestion. With bradycardia and first to third degree atrioventricular block also developing, cardiac arrest may ensue. Hyperglycaemia is also a recognised complication. The elimination half-life of diltiazem after overdosage is estimated to be about 5.5 - 10.2 hours. If a patient presents early after overdose, gastric lavage should be performed and activated charcoal administered to reduce diltiazem absorption.

Hypotension should be corrected with plasma expanders, intravenous calcium gluconate and inotropic agents (dopamine, dobutamine or isoprenaline). Symptomatic bradycardia and high grade AV block may respond to atropine, isoprenaline or occasionally cardiac pacing which may be useful if cardiac standstill occurs.

Diltiazem MR tablets are extended release tablets and effects may be slow in onset and prolonged, therefore, monitoring should be carried out for longer periods than following overdose with immediate release dosage forms.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:

Calcium channel blocker: ATC code: C08DB01

Diltiazem is a benzothiazepine calcium-channel blocking agent. These agents interfere with the influx of calcium ions through the slow channels of active cell membranes, influencing the myocardial cells, the cells within the specialised conducting system of the heart and the cells of vascular smooth muscle. It is used in the management of classical and vasospastic angina pectoris. The efficacy of diltiazem in the treatment of angina pectoris is probably related to its coronary vasodilating properties (causing an increase in myocardial oxygen supply) and to some of its haemodynamic effects (resulting in a decrease in myocardial work/oxygen demand). Although diltiazem is a potent vasodilator, the reduction in blood pressure that often accompanies its use usually occurs without reflex tachycardia, as diltiazem has little effect on the peripheral vasculature.

Diltiazem causes a small reduction in heart rate which is accompanied by an increase in cardiac output, improved myocardial perfusion and reduction of ventricular work. In animal studies diltiazem protects the myocardium against the effects of ischaemia and reduces the damage produced by excessive entry of calcium in to the myocardial cell during perfusion.

Diltiazem has a less negative inotropic effect than verapamil and significant myocardial depression rarely occurs.

5.2 Pharmacokinetic properties

Diltiazem hydrochloride is effective in angina, protecting the heart against ischaemia, vasodilating coronary arteries and reducing myocardial oxygen requirements. It is well tolerated and does not generally give rise to side effects associated with peripheral vasodilators, nor cause significant myocardial depression.

Diltiazem is rapidly and almost completely (about 90%) absorbed from the gastrointestinal tract after oral administration. However, it is subject to extensive first-pass hepatic metabolism, reported to reduce the bioavailability to about 40%. The absolute bioavailability is dose related.

Peak plasma concentration is reached within about 3 to 4 hours after oral dosing and steady-state plasma concentrations are reached in about 3 days.

The mean volume of distribution is about 5L/kg. Diltiazem is highly lipophilic and appears in cerebrospinal fluid (rabbit studies) and in breast milk. It is highly protein bound (80-90%), as is its most active metabolite, desacetyl diltiazem (60-75%).

Diltiazem is extensively metabolised, the most important metabolites being N-mono-desmethyl diltiazem (with 20% of potency of diltiazem), desacetyl diltiazem (50% relative potency) and N-demethyl desacetyl diltiazem. The metabolites are detectable in plasma within 30 minutes, reaching concentrations of 30-50%, 10-30% and 10-20% of the parent drug, respectively.

The elimination half-life of oral diltiazem is about 4-8 hours and it is longer for the metabolites. Excretion of diltiazem and its metabolites is mainly in the urine. Less than 4% of a dose of diltiazem is excreted in the urine as unchanged drug within 24 hours.

There is a linear relationship between dose and plasma concentration. During long-term administration to any one patient, plasma concentrations of diltiazem remain constant.

Mean plasma concentrations in elderly subjects and patients with renal and hepatic insufficiency are higher than in young subjects.

Diltiazem and its metabolites are poorly dialysed

5.3 Preclinical safety data

Diltiazem has been shown to be teratogenic in some animal species and it is therefore contraindicated in pregnancy and in women of child-bearing potential.

Diltiazem is freely diffusible in breast milk. It should not be given to nursing mothers until more information becomes available concerning safety in infants.

6.1    List of Excipients

Lactose Monohydrate Hydrogenated castor oil Macrogol 6000 Magnesium stearate

6.2    Incompatibilities

None known.

6.3 Shelf life

For product as packaged for sale: 3 years.

6.4 Special precautions for storage

No special precautions.

6.5 Nature and contents of container

Strip (heat-sealed PVC/aluminium foil blister) of:

50 tablets (2 strips of 25 tablets)

84 tablets (4 strips of 21 tablets)

100 tablets (4 strips of 25 tablets) in an outer cardboard carton.

7 MARKETING AUTHORISATION HOLDER

ATHLONE PHARMACEUTICALS LIMITED

BALLYMURRAY

ROSCOMMON

COUNTY ROSCOMMON

IRELAND

8 MARKETING AUTHORISATION NUMBER(S)

PL 30464/0048

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

5 March 1998

10 DATE OF REVISION OF THE TEXT

02/06/2014