SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Calcicard CR Tablets 120mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Diltiazem Hydrochloride 120mg

Excipients with known effect Lactose, sucrose

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

White, film-coated, round, biconvex, slow release tablets for oral administration.

Clinical Particulars

4.1. Therapeutic Indications

Angina pectoris and treatment of mild to moderate hypertension.

4.2 Posology and method of administration

Posology

Calcicard CR Tablets should be swallowed whole with a little water and not crushed or chewed.

Patients should be advised that the tablet membrane may pass through the gastrointestinal tract unchanged.

Calcicard (diltiazem hydrochloride) is available in a range of presentations to enable dosage to be adjusted to meet the 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 Calcicard formulation to another it may be necessary to adjust the dosage until a satisfactory response is obtained.

Adults

Angina and hypertension:

The usual starting dose is one tablet (90mg or 120mg) 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 Calcicard CR Tablet 60mg twice daily. This dose may be increased to one 90mg or 120mg Calcicard CR Tablet twice daily.

Hypertension:

The starting dose should be one 120mg Calcicard CR Tablet daily. Dose adjustment to one 90mg or one 120mg Calcicard CR Tablet twice daily may be required.

Paediactric population

Children

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

Method of administration

Oral

4.3 Contraindications

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

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

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

•    Severe bradycardia (less than 40 beats per minute).

Left ventricular failure with pulmonary congestion.

•    Complicated myocardial infarct.

•    Pregnancy, women of child-bearing potential and lactation (see section 4.6 Pregnancy and lactation).

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

•    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 1st degree AV 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.

Prior to 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.

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.

Diltiazem does not affect the glucose or endogenous insulin responses to hypoglycaemia.

With reference to the presence of lactose and sucrose in the formulation, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, the Lapp lactase deficiency, or sucrose-isomaltase insufficiency should not take this medicine.

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 dangerousfsee section 4.3 Contraindications).

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-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.

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.

Ciclosporin

Increase in circulating ciclosporin levels. It is recommended that the ciclosporin dose is reduced, renal function is monitored, circulating ciclosporin levels are assayed and that the dose should be adjusted during combined therapy and after its discontinuation.

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 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.

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.

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.

Oral administration of diltiazem can raise the plasma concentration of drugs exclusively metabolised by CYP3A4. The concomitant therapy of diltiazem and such drugs may increase the risk of adverse reactions (e.g. muscular disorders with statins). 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 shortacting benzodiazepines metabolized by the CYP3A4 pathway in patients using diltiazem.

Corticosteroids (mcthvlprcdnisolonc)

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

Diltiazcm 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 diltiazcm. When possible, a non CYP3A4-metabolised statin should be used together with diltiazcm, otherwise close monitoring for signs and symptoms of a potential statin toxicity is required.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is very limited data from the use of diltiazcm in pregnant patients. Diltiazcm has been shown to have reproductive toxicity in certain animal species (rat, mice and rabbit). Diltiazcm is therefore not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.

Breast feeding

Diltiazcm is excreted in breast milk at low concentrations. Breast-feeding while taking this drug should be avoided. If use of diltiazcm 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.c. dizziness (common), malaise (common), the ability to drive and use machines could be altered. However, no studies have been performed.

4.8 Undesirable effects

Tabulated list of adverse reactions

The frequencies of adverse events arc ranked according to the following: 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 arc 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, development or aggravation of congestive heart failure
Vascular disorders		Flushing	Orthostatic hypotension		Vasculitis (including leukocytoclastic vasculitis) The manifestations of vasodilatation (headache, flushing and in particular oedema of the lower limbs) are dose-dependent and appear more frequent in elderly subjects and related to the pharmacological activity of the product.
Gastrointestinal disorders		Constipation, dyspepsia, gastric pain, nausea	Vomiting, diarrhoea	Dry mouth	Gingival hyperplasia

	Very common	Common	Uncommon	Rare	Not known
Hepatobiliary disorders			Hepatic enzymes increase (AST, ALT, LDH, ALP increase) Moderate and transient elevation of liver transaminases have been observed at the start of treatment.		Hepatitis Isolated cases of clinical hepatitis have been reported which resolved on cessation of diltiazem therapy.
Skin and subcutaneous tissue disorders		Erythema		Urticaria	Photosensitivity (including lichenoid keratosis at sun exposed skin areas) have been reported and recovering when the treatment is discontinued, 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			Asthenia/ fatigue

As with some other calcium channel blockers, exceptional cases of extrapyramidal symptoms and gynaecomastia have been reported, reversible after discontinuation of calcium antagonists.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of 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 possibly leading to collapse, sinus bradycardia with or without isorythmic 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    PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcium channel Blocker, 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:

(i) Peripheral and coronary vasodilatation.

(ii) Decrease in myocardial oxygen consumption.

(iii) Reduction of blood pressure particularly in hypertension.

(iv) Increase in renal blood flow and urinary sodium excretion.

Therefore, like other calcium channel blocking agents, diltiazem is effective in the management of angina pectoris and treatment of mild to moderate hypertension.

5.2. Pharmacokinetic Properties

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 C_max value was 50-65 ng/ml. Diltiazem undergoes extensive hepatic metabolism by deacetylation and N-demethylation followed by O-demethylation or deacetylation. The major metabolites are desacetyldiltiazem and N-monodemethyldiltiazem of which desacetyldiltiazem has some hypotensive potency. 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.

5.3. Preclinical Safety Data

Diltiazem is a well established calcium antagonist subject to a USP monograph. It is documented in Martindale, The Extra Pharmacopoeia 30th Edition. The preclinical safety is well documented. The most significant finding relates to use during pregnancy. In pregnant mice and in Wistar strain rats, diltiazem had no adverse effect either on maternal mortality or post-natal growth, but its administration was associated with diminished fetal weight and vertebral and skeletal malformations in one study (Ariyuki F, 1974 Effects of diltiazem hydrochloride (CRD-401) on pre- and post-natal development of mice and rats. Clinical Reports 8: 3401-3416).

There are no data on the teratological effects of diltiazem in human beings, although, because it has been associated with fetal abnormalities in animals, its use is not recommended in pregnant women or in women of child-bearing potential.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Tablet core Lactose

Hydrogenated castor oil Colloidal aluminium hydroxide Acrylic resin Talc

Magnesium stearate Film-coat

Methylhydroxypropylcellulose 6 cps

Sucrose

Glycerol 85%

Titanium dioxide (E 171) Magnesium stearate Polysorbate 80 Purified water Ethanol 96%

6.2 Incompatibilities

Not applicable.

6.3.    Shelf Life

Three years.

6.4.    Special Precautions for Storage

Store at room temperature (15-25°C) and protect from light.

6.5.    Nature and Contents of Container

PVC/PVDC thermoformed blister pack backed with aluminium foil. (PVC: 0.25mm, PVDC: 40g/m², Aluminium foil: 0.02mm). The package quantities will be 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 and 120 tablets.

6.6 Special precautions for disposal

No special requirements. Any unused medicinal product or waste material should be disposed of in accordance to local requirements.

7    MARKETING AUTHORISATION HOLDER

Norton Healthcare Limited T/A IVAX Pharmaceuticals UK

Ridings Point

Whistler Drive

Castleford

West Yorkshire

WF10 5HX

8.    MARKETING AUTHORISATION NUMBER(S)

PL 0530/0483

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/01/2009

10 DATE OF REVISION OF THE TEXT

10/11/2015