SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

BI-CARZEM SR 120 mg prolonged release capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 120 mg diltiazem hydrochloride.

Excipients with known effect: Each capsule contains 50 mg of sucrose For the full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Prolonged release capsule, hard (capsule)

Size S1 Opaque pink and orange hard gelatine capsule containing diltiazem hydrochloride in sustained release sugar beads.

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

BI-CARZEM SR should be swallowed whole with a little water and not crushed or chewed.

Patients should be advised that the capsule membrane may pass through the gastro-intestinal tract unchanged.

BI-CARZEM SR (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 BI-CARZEM SR 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, BI-CARZEM SR 90mg and 120mg should continue to be prescribed by brand name.

Adults:

Angina and hypertension:

The usual starting dose is one BI-CARZEM SR (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 BI-CARZEM SR 60mg capsule twice daily. This dose may be increased to one 90mg or 120mg BI-CARZEM SR capsule twice daily.

Hypertension:

The starting dose should be one 120mg BI-CARZEM SR capsule daily. Dose adjustment to one 90mg or one 120mg BI-CARZEM SR capsule twice daily may be required.

Children:

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

4.3 Contraindications

Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker.

Severe bradycardia (less than 50 beats per minute).

Left ventricular failure with pulmonary stasis.

Lactation.

Concurrent use with dantrolene infusion (see section 4.5).

Hypersensitivity to diltiazem or to any of the excipients listed in section 6.1. Combination with ivabradine (see section 4.5).

4.4 Special warnings and precautions for use

Patients with rare hereditary problems of fructose and galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption or sucrase-isomaltase insufficiency 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.

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

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 dangerous (see 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 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.

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.

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. Grapefruit juice may increase diltiazem exposure (1.2 fold). Patients who consume grapefruit juice should be monitored for increased adverse effects 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. Coadministration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

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.

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 matabolised 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.

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

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.

Breastfeeding

As this drug is excreted in breast milk at low concentrations, breast feeding whilst taking diltiazem is contraindicated.

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 CIOMS frequency, based on data from clinical trials with diltiazem, using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); 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)

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, diarrhea	Dry mouth	Gingival hyperplasia
Metabolism and nutrition disorders					Hyperglycemia
Hepatobiliary disorders			Hepatic enzymes increase (AST, ALT, LDH, ALP increase)		Hepatitis

	Very common	Common	Uncommon	Rare	Not known
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 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 possibly leading to collapse, with sinus bradycardia with or without isorhythmic dissociation and first to third degree atrioventricular block also developing, atrioventricular conduction disturbances and cardiac arrest may 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 and/or osmotic diuresis should be performed and activated charcoal administered to reduce diltiazem absorption.

Hypotension should be corrected with plasma expanders, intravenous calcium gluconate, glucagon and inotropic agents, vasopressors (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/ Conduction disturbances occurs.

Diltiazem 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

Calcium antagonist, antianginal and antihypertensive agent.

Pharmacotherapeutic group: Calcium Channel Blocker, ATC Code: C08D B01 Bi-Carzem 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. Bi-Carzem 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, Bi-Carzem 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 well absorbed (90%) in healthy volunteers following oral administration.

These formulations of diltiazem hydrochloride provide prolonged absorption of the active ingredient. Peak plasma concentrations occur between 4 and 8 hours post-dose.

Bioavailability of this formulation of diltiazem is approximately 90% of that of the conventional tablet. 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 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

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, Yellow iron oxide)

6.2 Incompatibilities

Not Applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Store below 25° C in a dry place away from heat. Store in the original package in order to protect from moisture.

6.5    Nature and contents of container

•    PVC/aluminium foil blister strips containing 56 capsules

•    High density, white polyethylene “tablet containers” with white polypropylene screw caps containing 100 capsules.

Both containers are enclosed in outer cardboard cartons, which also contain a patient information leaflet.

Not all packs sizes or pack types may be marketed.

6.6    Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots

Cambridgeshire PE19 8ET

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0470

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 28/05/2010

10 DATE OF REVISION OF THE TEXT

14/07/2016