Document: spc-doc_PL 40147-0023 change

• spc-doc_PL 00142-0390
• spc-doc_PL 40147-0023

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Diltiazem Hydrochloride Tablets 60mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains diltiazem hydrochloride USP 60mg.

3    PHARMACEUTICAL FORM

White flat tablets scored on one side.

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.

4.3 Contraindications

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

2nd or 3rd degree AV block except in the presence of a functioning pacemaker.

Severe bradycardia (less than 50 beats per minute).

Left ventricular failure with pulmonary congestion.

Concurrent use with dantrolene infusion (see section 4.5 Interactions with other medicinal products and other forms of interactions).

Hypersensitivity to diltiazem or to any of the excipients.

Pregnancy; women of child-bearing potential.

Congestive heart failure.

Severe aortic stenosis.

Cardiogenic shock.

Severe hypotension (systolic Blood Pressure less than 90mmHg).

4.4 Special warnings and precautions for use

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

Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a 1st 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 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.

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 of developing an intestinal obstruction.

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).

COMBINATIONS REQUIRING

CAUTION: 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 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.

The blood levels of beta blockers with a low bioavailability (e.g propranolol) may be increased and small increases in the plasma levels of digitalis glycosides have been observed.

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 vasodilating effects).

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

Ciclospor

in

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.

Carbamazepi

ne

Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.

Theophylli

ne

Increase in circulating theophylline levels. Anti-H₂ agents (cimetidine and 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.

Rifampic

in

Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.

Lithiu

m

Risk of increase in lithium-induced neurotoxicity.

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.

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 (e.g. pravastatin) with diltiazem.

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. 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.

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.

The plasma concentration of phenytoin is increased by diltiazem. Phenobarbital and phenytoin reduce the effect of diltiazem. The effect of diltiazem is probably reduced by primidone.

There is an enhanced hypotensive effect when calcium-channel blockers are given with hydralazine, minoxidil or nitroprusside.

The effect of diltiazem is probably reduced by barbiturates.

There is an enhanced hypotensive effect when calcium-channel blockers are given with the doperminergenic levodopa.

Diltiazem increases the plasma concentration of the hormone antagonist dutasteride.

There is an enhanced hypotensive effect when calcium-channel blockers are given with the muscle relaxants baclofen and tizanidine.

The hypotensive effect of calcium-channel blockers is antagonised by oestrogens. Diltiazem increases the plasma concentration of the immunosuppressants sirolimus and tacrolimus.

The hypotensive effect of calcium-channel blockers is antagonised by carbenoxolone.

Diltiazem increases plasma concentration of imipramine and possibly other tricyclic antidepressants.

Diltiazem has been used safely in combination with diuretics. It is recommended that patients receiving these combinations should be regularly monitored.

There is a possibility that calcium channel blockers may occasionally impair glucose tolerance.

4.6 Fertility, Pregnancy and lactation

Pregnancy: There is 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 child-bearing

potential not using effective contraception

Diltiazem 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 adverse reactions are listed by system organ class and frequency, based on data from clinical trials with diltiazem, using the following convention: very Common    ( 1/10); common ^

1/100 to 3/10); uncommon (    1/1,000 to 1/100); rare ( 1/10,000 to?

1/1000); very rare

(1/10,000); not known (cannot be estimated from the available data).

	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, diarrhoea	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

4.9 Overdose

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

Treatment, under hospital supervision, will include gastric lavage, 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 blocker 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 (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, 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.

When Diltiazem is given alone or with a beta-blocking agent only slight negative inotropic effects have been reported in patients with preserved ventricular function.

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

Lactose

Hydrogenated castor oil Polyethylene glycol 6000 Magnesium stearate

6.2 Incompatibilities

None known.

10 DATE OF REVISION OF THE TEXT

30/04/2015