DILTIAZEM HYDROCHLORIDE TABLETS 60 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

DILTIAZEM HYDROCHLORIDE TABLETS 60mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 60mg Diltiazem Hydrochloride.

Excipient(s) with known effect: Each tablet contains 111.50mg lactose and 42.00mg hydrogenated castor oil.

For the full list of excipients, see section 6.1

White uncoated modified-release tablets.

White circular, biconvex, uncoated, modified-release tablets impressed “C” on one face, and the identifying letters “DU” on the reverse.

4.1 Therapeutic indications

1) Prevention and long term treatment of angina pectoris. NOT indicated for acute attacks of angina.

2) Treatment of mild to moderate arterial hypertension.

4.2. Posology and method of administration

Posology

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 divided dose may be increased to 360mg/daily. Higher doses of up to 480mg/daily have been used with benefit in some patients, especially in unstable angina. There is no evidence of any decrease in efficacy at these high doses.

Elderly and patients with impaired hepatic or renal function:

The recommended starting dose is one tablet (60mg) twice daily. The heart rate should be measured regularly in these groups of patients and the dose should not be increased if the heart rate falls below 50 beats/minute.

Paediatric population:

Safety and efficacy in children have not been established. Therefore diltiazem is not recommended for use in children.

Method of Administration

For oral administration. Tablets should be swallowed whole with a little water.

4.3 Contraindications

Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker

Lactation

Severe bradycardia (less than 50 beats per minute)

Left ventricular failure with pulmonary stasis

Concurrent use with dantrolene infusion (see section 4.5)

Hypersensitivity to diltiazem or to any of the excipients listed in section 6.1

Combination with ivabradine (see section 4.5).

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.

Cases of acute renal failure secondary to decreased renal perfusion have been reported in patients with reduced left ventricular function, severe bradycardia or severe hypotension.

In the case of general anaesthesia, the anaesthetist must be informed that the patient is taking diltiazem. The depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Treatment with diltiazem may be associated with mood changes, including depression (see section 4.5 and 4.8). 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. Careful monitoring is necessary in patients with latent or manifest diabetes mellitus due to a possible increase in blood glucose.

The use of diltiazem may induce bronchospasm, including asthma aggravation, especially in patients with pre-existing bronchial hyper-reactivity. Cases have also been reported after dose increase. Patients should be monitored for signs and symptoms of respiratory impairment during diltiazem therapy.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Diltiazem Hydrochloride Tablets contain hydrogenated castor oil. May cause stomach upset and diarrhoea.

4.5 Interaction with other medicinal products and other forms of interaction

Combination Contraindicated For Safety Reasons:

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).

Ivabradine:

Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of diltiazem to ivabradine (see section 4.3).

Combinations Requiring Caution:Alpha-antagoni sts

Increased antihypertensive effects: concomitant treatment with alphaantagonists may produce or aggravate hypotension. The combination of diltiazem with an alpha-antagonist should be considered only with the strict monitoring of blood pressure.

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.

An increased risk of depression has been reported when dilitiazem is coadministered with beta-blockers (see section 4.8).

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.

Antiarrhythmic agents

Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended due to the risk of increased cardiac adverse effects due to an additive effect. This combination should only be used under close clinical and ECG monitoring.

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.

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.

Phenytoin

When co-administered with phenytoin, diltiazem may increase phenytoin plasma concentration. It is recommended that the phenytoin plasma concentrations be monitored.

X-Ray contrast Media

Cardiovscular effects of an intravenous bolus of an ionic X-ray contrast media, such as hypotension, may be increased in patients treated with diltiazem.

Special caution is required in patients who concomitantly receive diltiazem and X-ray contrast media.

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.

Theophylline

Increase in circulating theophylline levels.

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 H2 antagonists. An adjustment in diltiazem daily dose may be 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.

Lithium

Risk of increase in lithium-induced neurotoxicity.

Antiplatelet drugs

In a pharmacodynamics study, diltiazem was shown to inhibit platelet aggregation. Although the clinical significance of this finding is unknown, potential additive effects when used with antiplatelet drugs should be considered.

Combinations To Be Taken Into Account: 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. Grapefruit juice may increase diltiazem exposure (1.2 fold). Patients who consume grapefruit juice should be monitored for increased adverse effects of diltiazem. Grapefruit juice should be avoided if an interaction is suspected. 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.

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 of 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 (eg. pravastatin) with diltiazem.

Cilostazol

Inhibition of cilostazol metabolism (CYP3A4). Diltiazem has been shown to increase cilostazol exposure and to enhance its pharmacological activity.

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.

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 in the dose of methylprednisolone may be necessary.

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. Pregnancy and Lactation

Pregnancy

There are very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity (see section 5.3) in certain animal species (rat, mice, rabbit). Diltiazem is therefore not recommended during pregnancy, as well as in women of childbearing potential not using effective contraception.

Breast-feeding

As this drug is excreted in breast milk, breast-feeding while taking diltiazem is contraindicated.

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 (> 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.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

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

Treatment

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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcium channel blockers; Benzothdiazepine derivatives, ATC code : C08DB01

Diltiazem is a calcium antagonist. It restricts the slow channel entry of calcium into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction of the amount of available intracellular calcium reducing myocardial oxygen consumption. It increases exercise capacity and improves all indices of myocardial ischaemia in the angina patient.

Diltiazem relaxes large and small coronary arteries and relieves the spasm of vasospastic (prinzmetals) angina and the response to catecholamines but has little effect on the peripheral vasculature. There is therefore no possibility of reflex tachycardia. A small reduction in heart rate occurs 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 into the myocardial cell during reperfusion.

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 well absorbed (90%) in healthy volunteers following oral administration.

Peak plasma concentrations occur 3 to 4 hours after dosing.

Due to a first pass effect, the bioavailability of the 60 mg tablet is about 40 %.

The mean apparent plasma half-life is 4– 8 hours.

Diltiazem is 80 to 85% bound to plasma proteins. It is extensively metabolised by the liver.

The major circulating metabolite, N-monodesmethyl diltiazem accounts for approximately 35% of the circulating diltiazem.

Less than 5% of diltiazem is excreted unchanged in the urine.

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

Pregnancy: Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg q.d. or 8 mg/kg q.d. for a 60-kg patient) resulted in embryo and fetal lethality. These studies revealed, in one species or another, a propensity to cause fetal abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights, pup survival, as well as prolonged delivery times and an increased incidence of stillbirths.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Also contains: castor oil, lactose, magnesium stearate, polyethylene glycol.

6.2 Incompatibilities

None known

6.3 Shelf life

Three years from the date of manufacture.

6.4 Special precautions for storage

Blister packs:

Do not store above 25°C.

Store in the original package.

Keep container in the outer carton

Polypropylene containers, polyethylene containers and amber glass bottles: Do not store above 25°C.

Store in the original container.

Keep the container tightly closed

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps. An alternative closure for polyethylene containers is a polypropylene, twist on, push down and twist off child-resistant, tamper-evident lid.

The product may also be supplied in blister packs and cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250^m white rigid PVC. (ii) Surface printed 20^m hard temper aluminium foil with 5–6g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8 MARKETING AUTHORISATION NUMBER(S)

PL 0142/0390