DILTIAZEM MODIFIED RELEASE TABLETS 60 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Diltiazem modified release tablets 60mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 60 mg of diltiazem hydrochloride.

Excipient(s) with known effect:

Also contains 103 mg of lactose and 60 mg of hydrogenated castor oil.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Modified-release tablet.

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

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Prophylaxis and treatment of angina pectoris.

4.2 Posology and method of administration

Posology

Adults: The usual maintenance dose is one tablet (60 mg) three times daily. As patient responses may vary the dose can be increased to a maximum of 360 mg daily in divided doses.

Higher doses up to 480 mg/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 60 mg 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.

Paediatric population:

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Shock

Acute cardiac infarct with complications (bradycardia, severe hypotension, left heart insufficiency)

Bradycardia (pulse rate, at rest, of less than 50 bpm), hypotension (less than 90 mmHg systole), Second or third degree AV block or sick sinus syndrome except in the presence of a functioning ventricular pacemaker

Severe bradycardia (below 40 bpm)

Atrial fibrillation/flut­ter and simultaneous presence of a WPW (Wolff-Parkinson-White) syndrome (increased risk of triggering a ventricular tachycardia)

Manifest myocardial insufficiency

Concomitant use of dantrolene infusion due to the risk of ventricular fibrillation (see section 4.5)

Pregnant women, women of child bearing potential and lactation (see section 4.6)

Combination with ivabradine (see section 4.5).

4.4 Special warnings and precautions for use

The use of diltiazem hydrochloride in diabetic patients may require adjustment of their control due to possible increase in blood glucose.

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 (see section 4.3) detected on the electrocardiogram (risk of exacerbation and rarely, of complete block). Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second or third degree AV block (see section 4.5).

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.

The product should be used with caution in patients with hepatic dysfunction.

Abnormalities of liver function may occur during therapy. Very occasional reports of abnormal liver function have been received; these reactions have been reversible upon discontinuation of therapy.

Prior to general anaesthesia, the anaesthetist must be informed of ongoing diltiazem treatment (see section 4.5). Depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Diltiazem is not recommended for use in patients with acute porphyria unless other safer alternatives are not available.

There have been reports of calcium-channel blockers exacerbating muscle weakness in patients with myasthenia gravis. Diltiazem should be used with caution in such patients.

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.

As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.

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

Diltiazem modified- release tablets contain hydrogenated castor oil which may cause stomach upset and diarrhoea.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use 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).

Ivabradine:

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

Concomitant use requiring caution:

Anaesthetics:

Anaesthetists should be warned that a patient is taking diltiazem. The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anaesthetics may be potentiated by calcium channel blockers. When used concomitantly, anaesthetics and calcium channel blockers should be titrated carefully.

Lithium:

Risk of increase in lithium-induced neurotoxicity.

Nitrate derivatives:

Increased hypotensive effects and faintness (additive vasodilating 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 alphaantagonist 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.

Amiodarone in combination with diltiazem may also cause AV block and myocardial depression.

It is recommended that the plasma digoxin concentrations be assayed and that the dose should be adjusted if necessary. Cardiac glycosides may cause a greater degree of AV blocking, reduce the heart rate or induce a hypotensive effect.

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.

Acetylsalicylates [ASA/LAS]:

Because of the increased risk of bleeding due to potential additive effect on platelet aggregation: the concomitant administration of acetylsalicylates [ASA/LAS] with diltiazem should be undertaken with caution.

X-Ray Contrast Media:

Cardiovascular 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.

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. Grapefruit juice may increase diltiazem exposure (1.2 fold). Patients who consume grapefruit juice should be monitored for increased adverse reactions of diltiazem. Grapefruit juice should be avoided if an interaction is suspected. 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.

Antihypertensives:

Diltiazem hydrochloride should only be administered with great care to patients receiving concurrent treatment with antihypertensives or other hypotensive agents including halogenated anaesthetics or drugs with moderate protein binding.

Diltiazem hydrochloride will not protect against effects of withdrawal of beta-adrenoceptor blocking agents, nor the rebound effects seen with various antihypertensives.

There may be an additive effect when diltiazem is used with drugs which may induce bradycardia or with other antihypertensives.

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. It is recommended that the phenytoin plasma concentrations be monitored.

Benzodiazepines (midazolam, triazolam):

Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing shortacting 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 Fertility, pregnancy and lactation

Pregnancy

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 (see section 4.3).

Breastfeeding

Diltiazem hydrochloride is excreted in breast milk at low concentrations. Breast feeding while taking this drug is contraindicated. 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 (>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 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

Experience of overdose 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.

Conduction disturbances may be managed by temporary cardiac pacing. Most patients suffering from overdose 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 overdose is estimated to be about 5.5 10.2 hours. If a patient presents early after overdose, gastric lavage, osmotic diuresis should be performed under hospital supervision 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.

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 ATC Code: C08D B01

Mechanism of action

Diltiazem is a calcium channel antagonist which restricts the entry of calcium ions into the cell through the slow voltage dependent channels and reduces the liberation of calcium from the endoplasmic reticulum. This results in a reduced amount of available intracellular calcium. The haemodynamic actions of diltiazem are:

– Peripheral and coronary vasodilatation.

– Decrease in myocardial oxygen consumption.

– Reduction of blood pressure particularly in hypertension.

– Increase in renal blood flow and urinary sodium excretion.

Diltiazem has pharmacologic actions similar to those of other calcium channel blocking agents such as nifedipine or verapamil. The principal physiologic action of diltiazem is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells.

Calcium plays important roles in the excitation-contraction coupling processes of the heart and vascular smooth muscle cells and in the electrical discharge of the specialised conduction cells of the heart. The membranes of these cells contain numerous channels that carry a slow inward current and that are selective for calcium.

By inhibiting calcium influx, diltiazem inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries. Dilation of systemic arteries by diltiazem results in a decrease in total peripheral resistance, a decrease in systemic blood pressure and a decrease in the afterload of the heart. The reduction in afterload, seen at rest and with exercise, and its resultant decrease in myocardial oxygen consumption are thought to be responsible for the beneficial effects of diltiazem in patients with chronic stable angina pectoris. In patients with prinzmetal variant angina, inhibition of spontaneous and ergonovine-induced coronary artery spasm by diltiazem results in increased myocardial oxygen delivery.

5.2 Pharmacokinetic properties

a) General characteristics

Absorption

When taken orally diltiazem is almost completely absorbed. Despite this, the absolute bioavailability is 40% due to extensive first pass metabolism. Bioavailability is not affected by age. Diltiazem is 78–87% bound to plasma proteins but only 35–40% to albumin. The peak plasma concentration is reached in about three hours after single dose of diltiazem 90 mg CR tablets. The Cmax value was 50–65 ng/ml. Capsules seem to have a similar bioavailability to tablets (30–40%), with peak concentrations for the prolonged release product after 8–11 hours compared with 1–2 hours after the conventional release product. The relatively low bioavailability is due to first pass metabolism in the liver to an active metabolite.

Distribution

Diltiazem hydrochloride is lipophilic and has a high volume of distribution. Typical study results are in the range of 3–8 litres/kg. Protein binding is about 80% and is not concentration-dependent at levels likely to be found clinically. Protein binding does not appear to be influenced by phenylbutazone, warfarin, propranolol, salicylic acid or digoxin.

Biotransformation

Diltiazem hydrochloride is extensively metabolised in the liver by deacetylation and N-demethylation followed by O-demethylation or deacetylation. N-monodesmethyl diltiazem is the predominant metabolite followed quantitatively by the desacetyl metabolite, which has some hypotensive potency. The efficacy of the metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem is 25–50% and about 20% respectively of that of diltiazem. In liver function disorders delayed metabolism in the liver is likely. These metabolites are converted to conjugates, generally the glucuronide or the sulphate.

Elimination

Diltiazem is excreted in the form of its metabolites (about 35%) and in the non metabolised form (about 2–4%) via the kidneys while about 60% is excreted via the faeces Diltiazem is mainly excreted as metabolites in the urine and faeces and only 1–3% of the dose is excreted as the parent compound in urine. The average elimination half-life period for diltiazem is 6–8 hours but may vary between 2 and 11 hours.

Although the elimination half-life is not changed after repeated oral administration, diltiazem and also the desacetyl metabolite show a slight accumulation in the plasma.

b) Characteristics in specific groups of patients

Decreased first-pass metabolism in the elderly tends to result in increased plasma concentrations of calcium antagonists but no major changes have been found with diltiazem. Renal impairment did not cause significant changes in diltiazem pharmacokinetics. Plasma concentrations of diltiazem also tend to be higher in hepatic cirrhosis due to impaired oxidative metabolism.

5.3 Preclinical safety data

Chronic toxicity studies in rats revealed no remarkable changes at oral doses up to 125 mg/kg/day although there was 60% mortality at this dose. In dogs chronically treated with oral doses of 20 mg/kg/day, transient rises in serum glutamic pyruvic transaminase (SGPT) were observed.

Embryotoxicity has been reported in mice, rats and rabbits following intraperitoneal administration of diltiazem. Main types of malformations included limb and tail defects with a small number of vertebral and rib deformities also noted.

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 foetal lethality. These studies revealed, in one species or another, a propensity to cause foetal 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.

6.1 List of excipients

Lactose

Hydrogenated castor oil Macrogol 6000 Magnesium stearate.

6.2. Incompatibilities

None known.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to 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 Special precautions for disposal

No special requirements for disposal.

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