SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zemret 300 XL Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 300 mg diltiazem hydrochloride For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Modified release capsule.

Size “0” hard gelatine capsule with light blue cap and white body, marked 300, containing white and whitish pellets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of mild to moderate hypertension. Prophylaxis and treatment of angina pectoris.

4.2 Posology and method of administration

Posology

Zemret 180 XL is a prolonged release product for once daily dosing. The dosage requirements may differ in patients with angina or hypertension.

Zemret XL 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 Zemret XL 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 prolonged release formulations, Zemret 240 and 300 XL should continue to be prescribed by brand name.

Adults:

Angina and hypertension: The usual starting dose is Zemret XL 180 once daily. This dose may be increased to Zemret XL 300 once daily, or 2 capsules of Zemret XL 180 daily (360 mg), and if clinically indicated a higher dose of one Zemret XL 300 plus one Zemret XL 180 capsule (total 480 mg) may be considered.

Older people and patients with impaired hepatic or renal function:

Heart rate should be monitored and if it falls below 50 beats per minute the dose should not be increased. Plasma levels of diltiazem can be increased in this group of patients.

Angina and hypertension: the initial dose should be one Zemret XL 180 capsule daily. This dose may be increased to one capsule of Zemret XL 300 daily if clinically indicated.

Paediatric population:

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

Methods of administration

Capsules should be swallowed whole (not chewed/crushed) with half a glass of fluid, ideally before or during a meal.

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 galactose intolerance, the Lapp lactase deficiency, or glucosegalactose 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.

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

Concomitant use 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).

Ivabradine: 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:

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 artrioventricular 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 contractilityand/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.

Breast-feeding: as this drug is excreted in breast milk, 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 CIOMSfrequency 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, 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 (lower limb oedema)	Malaise			Asthenia/fatigue

Events related to the vasodilatory action of diltiazem are dose-dependent and may be more frequent in elderly patients.Skin rashes are usually localised and limited to erythema and urticaria, or occasionally desquamative erythema, and regress after treatment cessation. Isolated cases of moderate but transient elevation of liver transaminases have been described at the start of treatment. Isolated cases of clinical hepatitis have been noted; these resolved on treatment discontinuation.

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

In overdosage diltiazem can cause sever hypotension leading to collapse and sinus bradycardia, which may be accompanied by isorhythmic dissociation and atrioventricular conduction disturbances. Observation in a coronary care unit is advisable. Vasopressors such as adrenaline may be given in those with severe hypotension. Calcium gluconate infusion may help reverse the effects of calcium entry blockade. The bradycardia and/or conduction disturbances may be managed by atropine, inotropic agents and glucagon and temporary cardiac pacing. Treatment, in a hospital setting, will include gastric lavage and/or osmotic diuresis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcium channel blockers; Benzothiazepine derivatives, ATC code: C08DB01

Calcium antagonist, antihypertensive agent.

Diltiazem restricts calcium entry into the slow calcium channel of vascular smooth muscle and myocardial muscle fibres in a voltage-dependent manner. By this mechanism, diltiazem reduces the concentration of intracellular calcium in contractile protein.

In animals: diltiazem increases coronary blood flow without inducing any coronary steal phenomena. It acts both on small, large and collateral arteries. This vasodilator effect, which is moderate on peripheral systemic arterial territories, can be seen at doses that are not negatively inotropic.

The two major active circulating metabolites, i.e. deacetyl diltiazem and N-monodemethyl diltiazem, possess pharmacological activity in angina corresponding to 10 and 20% respectively of that of the parent compound.

In humans: diltiazem increases coronary blood flow by reducing coronary resistance.

Due to its moderate bradycardia-inducing activity and the reduction in systemic arterial resistance, diltiazem reduces cardiac workload.

Zemret XL does not have a significant myocardial depressant action in man.

5.2 Pharmacokinetic properties

Diltiazem is well absorbed (90%) in healthy volunteers following oral administration.

The prolonged release capsule provides prolonged absorption of the active constituent, producing steady state plasma concentrations between 2 and 14 hours post-dose, during which time peak plasma levels occur.

Bioavailability of Tildiem LA relative to the Tildiem 60mg formulation is approximately 80%. The mean apparent plasma half-life is 8 hours.

Diltiazem in plasma is 80 to 85% protein bound and is poorly dialysed. 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.

Twenty four hours after intake, plasma concentrations remain, even after the 200 mg dose administration, at the level of 50 ng/ml, in patients. During long term administration in any one patient, plasma concentrations of diltiazem remained constant.

Mean plasma concentrations in the elderly and patients with renal and hepatic insufficiency are higher than in young subjects.

Food intake does not significantly affect the kinetics of Tildiem LA, however, when administered with food, absorption was observed to be higher in the first few hours post-dose.

Diltiazem and its metabolites are poorly dialysed.

Once 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 (sucrose and starch), ammonio methacrylate copolymers types ‘A’ and ‘B’, paraffin, talc, gelatin, E171, E172, E127.

Incompatibilities

None known.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Blister packs composed of 250 pm PVC/40 gm² PVDC sealed to 25 pm aluminium/20 gm² PVDC containing 28, 30, 56, 60 or 100 capsules.

Not all packs sizes 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 11311/0451

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:15/08/2008

10    DATE OF REVISION OF THE TEXT

14/07/2016