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1. Kenzem 120mg Sr Capsules
2. Kenzem 120mg Sr Capsules

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Kenzem 120mg SR Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 120mg of diltiazem hydrochloride Excipients with known effect:

Product contains sucrose.

For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Modified release capsule

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The treatment of angina pectoris.

The treatment of mild to moderate hypertension.

4.2 Posology and method of administration

Method of administration

The method of administration is by oral use.

Capsules should be swallowed whole with little water without crushing or chewing.

Kenzem (Diltiazem hydrochloride) is available in a range of presentations to enable dosage to be adjusted to meet individual requirements of the patient. Careful titration of the dose should be considered where appropriate, as individual patient response may vary. When changing from one type of diltiazem formulation to another it may be necessary to adjust the dosage until a satisfactory response is obtained. To ensure consistency of response once established, particularly in the sustained release formulations, Kenzem should continue to be prescribed by the brand name.

Adult Dosage

For all indications the usual starting dose is one (90mg or 120 mg) capsule twice daily. Patient responses may vary and dosage requirements can differ significantly between individual patients. Higher divided doses up to 480mg/day have been used with benefit in some angina patients especially in unstable angina. Doses of 360mg/day may be required to provide adequate BP control in hypertensive patients.

Elderly and patients with impaired hepatic or renal function:

Heart rate should be monitored in these patients and if it falls below 50 beats per minute the dose should not be increased.

Angina:

The recommended starting dose is one Kenzem 60mg capsule twice daily. This dose may be increased to one 90mg or 120mg Kenzem capsule twice daily in order to achieve the required level of control.

Hypertension:

The starting dose should be one 120mg Kenzem capsule daily. Dose adjustment to 90mg or 120mg twice daily may be required.

Paediatric population

Not recommended as safety and efficacy have not been established.

4.3. Contraindications

•    Hypersensitivity to diltiazem or to any of the excipients.

•    Women of child bearing potential or lactating mothers

•    Patients with severe bradycardia (less than 50 beats per minute)

•    Second or third degree heart block, in patients without a functioning pacemaker or sick sinus syndrome

•    Patients with impaired renal function.

•    Patients with moderate to severe hepatic dysfunction

•    Patients with cardiac failure after myocardial infarction; left ventricular failure with pulmonary stasis

•    Concomitant administration of dantrolene infusion (see section 4.5 Interactions with other medicinal products and other forms of interaction)

•    Concomitant use of alcohol

4.4 Special warnings and precautions for use

Rare instances of hyperglycaemia have been reported in association with diltiazem hydrochloride. The use of diltiazem hydrochloride in diabetic patients may require adjustment of their control.

Cautions should be taken in patients with reduced left ventricular function. Patients should be observed closely if they have bradycardia (risk of exacerbation), first degree atrio-ventricular block detected on the electrocardiogram (risk of exacerbation and rarely of complete block) or prolonged PR interval.

Plasma diltiazem concentrations can be increased in the elderly and 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.

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.

This product contains sucrose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency 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.

Careful monitoring is necessary in patients with latent or manifest diabetes mellitus due to a possible increase in blood glucose.

4.5 Interaction with other medicinal products and other forms of interaction

General information to be taken into account:

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

Diltiazem hydrochloride will not protect against effects of withdrawal of beta-adrenoceptor blocking agents, or the rebound effects seen with various antihypertensives.

Combination with beta- adrenoceptor blockers having significant ‘first pass’ loss, e.g. propranolol, may require a decrease in their dose.

Patients receiving diuretics, ACE inhibitors or other antihypertensive agents should be regularly monitored. Use with alpha-blockers should be strictly monitored.

Diltiazem hydrochloride has been continued in anaesthesia without problems, but the anaesthetist should be made aware that the patient is taking this medication because of the potential for synergism or interactions with other agents used in anaesthesia.

Combinations 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 contraindications).

•    Alcohol:

Diltiazem capsules should not be taken at the same time as alcohol. In combination with Diltiazem, alcohol may increase the rate of in vivo release of the product from the prolonged release preparation. This may increase dose-dependent effects and lead to potential adverse pharmacodynamic interactions. Alcohol use could therefore increase the rate and seriousness of diltiazem adverse drug reactions such as vasodilatory related events.

Combinations requiring caution:

•    Alpha antagonists:

Increased antihypertensive effects can occur with alpha-antagonists. Concomitant treatment with alpha-antagonists may produce or aggravate hypotension.. The combination of diltiazem with an alpha antagonist should be considered only with strict monitoring of blood pressure.

•    Beta blockers:

Patients receiving beta-blockers should be regularly monitored. With Beta-blockers, there is a possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sinoatrial and astrio-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.

•    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:

There may be an additive effect when used with drugs, which may induce bradycardia, or with other antihypertensives or other antiarrhythmic drugs. Since diltiazem exerts an antiarrhythmic effect, its co-prescription with other antiarrhythmic drugs 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 vasodilating effects) can occur with nitrate derivatives. In all patients treated with calcium antagonists, the prescription of nitrate derivatives should 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 assessed and that the dose should be adjusted during combined therapy and after its discontinuation.

•    Carbamazepine and theophylline

Diltiazem may cause an increase in the circulating levels of carbamazepine and theophylline when taken concomitantly. It is recommended that the plasma drug concentrations be assayed and that the dose should be adjusted if necessary.

•    Lithium

Risk of increase in lithium-induced neurotoxicity

•    Anti-H₂ agents (cimetidine and ranitidine)

Concomitant H2 antagonist therapy (specifically cimetidine and, to a lesser extent, ranitidine) may increase 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.

•    Rifampicin

There is a risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored where initiating or discontinuing rifampicin treatment.

Combinations to be taken into account

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. Coadministration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

•    Statins

Oral administration of diltiazem can increase the plasma concentrations of drugs exclusively metabolised by CYP3A4 with an increased risk of adverse reactions, (e.g. muscular disorders with statins). The risk of myopathy and rhabdomyolysis is increased by concomitant administration if 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 (e.g. pravastatin) with diltiazem.

•    Benzodiazepines (midazolam, triazolam)

Diltiazem significantly increases plasma concentrations of some benzodiazepines (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 of 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 should not be given during pregnancy and lactation. Diltiazem must not be used at any time during pregnancy, as it is teratogenic in some animal species. There is no experience of its effects in humans. As diltiazem is known to readily enter the breast milk and there is no experience of possible effects in infants, infants should be weaned if treatment with diltiazem is necessary.

4.7 Effects on ability to drive and use machines

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

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					Thrombocytopeni a
Psychiatric disorders			Nervousness , insomnia		Mood changes (including depression), extrapyramidal

					syndrome
Nervous system disorders		Headache, dizziness, tremors, paraesthesia			Extrapyramidal syndrome
Cardiac disorders		Atrioventricula r block (may be of first, second or third degree; bundle branch block may occur), palpitations, sinoatrial block	Bradycardia		Sinoatrial block, congestive heart failure,
Vascular disorders		Flushing	Orthostatic hypotension		Vasculitis (including leukocytoclastic vasculitis)
Gastrointestina l disorders		Constipation, dyspepsia, gastric pain, nausea	Vomiting, diarrhea	Dry mouth	Gingival hyperplasia
Metabolism and nutrition disorders					Hyperglycemia
Hepatobiliary disorders			Hepatic enzymes increased (AST, ALT, LDH, ALP increase)		Hepatitis
Skin and subcutaneous tissue disorders		Erythema		Urticari a	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					Gynaecomastia
General disorders and administration site conditions	Periphera l oedema	Malaise, asthenia/fatigu e

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

4.9. 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 be 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.

Kenzem SR Capsules are extended release capsules 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: C08D B01.

Diltiazem hydrochloride is a calcium-channel blocking agent. It is a peripheral and coronary vasodilator with some negative inotropic activity. Diltiazem inhibits cardiac conduction particularly at the sino-atrial and atrioventricular nodes. It is used in the management of classical and vasospastic angina pectoris and it is also used in the treatment of essential hypertension.

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. Kenzem relaxes large and small coronary arteries and relieves the spasm of vasospastic (Prinzmetal’s) 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, Kenzem 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 is rapidly and almost completely absorbed from the gastro-intestinal tract following oral administration, but undergoes extensive first-pass hepatic metabolism. The bioavailability has been reported to be about 40%, although there is considerable inter-individual variation in plasma concentrations. Diltiazem is about 80% bound to plasma proteins. It is extensively metabolised in the liver; one of the metabolites, desacetyl diltiazem has been reported to have 25 to 50% of the activity of the parent compound. The half-life is reported to be about 3 to 4 hours. Approximately 60% of the dose is excreted in the bile and 35 to 40% in the urine, and 2 to 4% as unchanged diltiazem.

The sustained-release formulation is designed for twice daily dosage. These formulations of diltiazem hydrochloride provide prolonged absorption of the active ingredient. Peak plasma concentrations occur between 4-8 hours post dose. The mean apparent plasma half-life is 7-8 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. 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.

Twice daily formulations of diltiazem have been shown to have different pharmacokinetic profiles and therefore it is not advised to substitute different brands for one another.

5.3 Preclinical safety data

Pregnancy: Reproduction studies have been conducted in mice, rats and rabbits. Administration of doses ranging from 4-6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480mg q.d. or 8mg/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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sugar spheres (75% sucrose; 25% corn starch)

Povidone

Methacrylic acid copolymer

Ethylcellulose

Diethyl phthalate

Talc

Hard gelatin capsules:

- Containing E171 (Titanium dioxide), E172 (red iron oxide), E172 (yellow iron oxide)

6.2 Incompatibilities

No known incompatibilities.

6.3 Shelf life

The shelf-life of the product, as packaged for sale, is four years.

There are no recommendations for dilution or reconstitution.

There are no data available on the shelf-life of the product after first opening the container.