Diltiazem Hydrochloride Tablets 60mg

Document: spc-doc_PL 00142-0390 change

SUMMARY OF PRODUCT 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

3 PHARMACEUTICAL FORM

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 CLINICAL PARTICULARS

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 maintenance 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 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 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:

Not recommended.

Method of Administration

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

4.3 Contraindications

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

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

• pregnancy; women of child-bearing potential

• congestive heart failure

• severe aortic stenosis

• cardiogenic shock

• severe hypotension (systolic Blood Pressure less than 90mmHg)

• Second- or third-degree AV block except in the presence of a functioning ventricular pacemaker

• Severe bradycardia (below 40 bpm)

• Left ventricular failure with pulmonary congestion

• Concomitant use of dantrolene infusion (see section 4.5).

• Combination with ivabradine (see section 4.5)

• Acute porphyria.

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) prolonged PR interval, or with a first degree AV block detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).

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

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.

Calcium channel blocking agents, such as diltiazem, may be associated with mood changes, including depression.

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.

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).

• 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:

• Lithium: Risk of increase in lithium-induced neurotoxicity

• 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.

• Theophylline: Increase in circulating theophylline levels.

• Alpha-antagonists: Increased antihypertensive effects: concomitant treatment with alpha-antagonists may produce or aggravate hypotension. The combination of diltiazem with an alpha-antagonist 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. In common with other calcium antagonists diltiazem may cause small increases in plasma levels of digoxin.

• 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 (eg propranolol) may be increased and small increases in the plasma levels of digitalis glycosides have been observed.

• 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.

• H₂ antagonists (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.

• 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.

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. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other CYP3A4 substrates may result in an increase in plasma concentration of either coadministered 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 halflife. Special care should be taken when prescribing short-acting benzodiazepines metabolized 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 may be increased with concomitant use of diltiazem. When possible, a non CYP3A4-metabolised statin should be used together with diltiazem, otherwise close

monitoring for signs and symptoms of a potential statin toxicity is required.

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

• Drugs that increase hepatic microsomal activity (eg phenobarbital, phenytoin) lead to decreased plasma diltiazem levels.

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

• Diltiazem hydrochloride treatment has been continued without problem during anaesthesia, but the anaesthetist should be informed that the patient is receiving a calcium antagonist. (see section 4.4)

• 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 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

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 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, nausea	Vomiting, diarrhoea	Dry mouth	Gingival hyperplasia
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

The current literature suggests that the effects of vasodilation particularly ankle oedema are dose dependent and are more frequent in the elderly.

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

Symptoms

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

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective calcium channel blocker with direct cardiac effects, benzothiazepine derivative.

ATC Code: C08DB01

Diltiazem selectively reduces calcium entry through voltage-dependent calcium channels into vascular smooth muscle cells and myocardial cells. This lowers the concentration of intracellular calcium which is available to activate contractile proteins. This action of Diltiazem results in dilation of coronary arteries causing an increase in myocardial oxygen supply. It reduces cardiac work by moderating the heart rate and reducing systemic vascular resistance thus reducing oxygen demand.

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

Absorption

Diltiazem is rapidly and almost completely absorbed from the GI tract following oral administration, but undergoes extensive first-pass hepatic metabolism.

Distribution

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.

Biotransformation

Diltiazem is extensively metabolised in the liver; one of the metabolites, desacetyl diltiazem has been reported to have 25-50% of the activity of the parent compound.

Elimination

The half-life is reported to be about 3-5 hours. Approximately 2-4% of a dose is excreted in urine as unchanged Diltiazem and the remainder excreted as metabolites in bile and urine.

5.3 Preclinical safety data

Not applicable.

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) 250pm white rigid PVC. (ii) Surface printed 20pm 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

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley Barnstaple North Devon EX32 8NS

8 MARKETING AUTHORISATION NUMBER(S)

PL 0142/0390

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 09/01/1996 Date of latest renewal: 25/04/2001

DATE OF REVISION OF THE TEXT

28/04/2016