Slozem 120mg Capsules

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Slozem 120mg Capsules each contain 120mg diltiazem hydrochloride Slozem 180mg Capsules each contain 180mg diltiazem hydrochloride Slozem 240mg Capsules each contain 240mg diltiazem hydrochloride Slozem 300mg Capsules each contain 300mg diltiazem hydrochloride

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged release capsule, hard.

Slozem 120mg Capsules have a natural transparent cap with a pink transparent body and contain white-grey to light yellow approximately spherical pellets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Mild to moderate hypertension. Angina pectoris.

4.2 Posology and method of administration

Posology

Adults

240mg once daily

Dosage titration in 60mg to 120mg steps at 2-weekly intervals may be required to obtain satisfactory clinical response (usually 240mg to 360mg daily will suffice).

Dosage should be reduced in the presence of adverse reactions or if the pulse rate falls below 50 per minute.

Older people and patients with hepatic or renal impairment

Starting dose 120mg once daily.

Paediatric population Not recommended

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.

□ 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).

□ Additionally, for the intravenous forms, patients known to have an accessory bypass (Wolf-Parkinson-White syndrome or short PR syndrome), and who develop atrial fibrillation or flutter, should not be administered intravenous diltiazem.

□ Combination with ivabradine (see section 4.5)

4.4 Special warnings and precautions for use

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

As Slozem contains sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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).

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:

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. Care should be exercised in patients taking these drugs.

Alpha-antagonists: Increased antihypertensive effects:

Concomitant treatment with alpha-antagonists such as prazosin 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, small increases in plasma levels of digoxin. Caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.

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.

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.

Anti-H2 agents (cimetidine, 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.

Ciclosporin: Increase in circulating cyclosporin levels:

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

Tricyclic antidepressants: diltiazem increases plasma concentration of imipramine. Diltiazem possibly increases plasma concentration of tricyclic antidepressants.

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. Coadministration 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 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.

Oral administration of diltiazem can raise blood levels of drugs exclusively metabolised by the iso-enzyme CYP3A4 - this can lead to increased plasma levels for carbamazepine, tacrolimus, sirolimus, and erythromycin.

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 (teratogenic) in some animal species (rat, mice, rabbit). In the absence of adequate evidence of safety in human pregnancy, dilitiazem is therefore not recommended during pregnancy as well as in women of child-bearing potential not using effective contraception.

Breast-feeding

Diltiazem hydrochloride is excreted in breast milk at low concentrations. One report suggests that concentrations in breast milk reach similar levels to those in serum. 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					Thrombocytope nia
Psychiatri c disorders			Nervousness, insomnia		Mood changes (including depression)
Nervous system disorders		Headache, dizziness			Extrapy rami dal syndrome. Drug-induced Parkinsonism
Cardiac disorders		Atrioventricu lar 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)
Gastroint estinal disorders		Constipation, dyspepsia, gastric pain, nausea	Vomiting, diarrhea	Dry mouth	Gingival hyperplasia
Hepatobil iary disorders			Hepatic enzymes increase (AST, ALT, LDH, ALP increase)		Hepatitis

	Very common	Common	Uncommon	Rare	Not known
Skin and subcutane ous tissue disorders		Erythema		Urticari a	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 and hyperpigmentation in sun-exposed areas have also been reported. Occasionally desquamative erythema with or without fever.
Reproduct ive system and breast disorders					Gynecomastia
General disorders and administr ation site conditions	Periphera l oedema	Malaise

Hepatic enzymes increase (AST, ALT, LDH, ALP increase) typically observed at the start of the treatment.

Isolated cases of clinical hepatitis have been reported which resolved on cessation of therapy.

Skin reactions are generally mild and resolve on cessation of therapy.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs and symptoms:

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

Hyperglycaemia may require treatment. Onset of symptoms may be delayed for several hours after ingestion and have been described after as little as 900mg diltiazem.

Treatment:

Treatment in a hospital setting will include gastric lavage and/or osmotic diuresis

Observation in a coronary or intensive care unit is advisable if a substantial overdose has been ingested. Soon after ingestion, gastric lavage followed by activated charcoal may reduce absorption.

Profound hypotension requires plasma expanders, I V calcium gluconate and inotropic agents (e.g. dopamine, dobutamine or isoprenaline). Symptomatic bradycardia and heart block may respond to atropine, vasopressors, inotropic agents, isoprenaline, glucagon, calcium gluconate infusion or, if necessary, cardiac pacing. Slozem capsules are extended release capsules and effects may be slow in onset and prolonged.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Diltiazem hydrochloride is a calcium antagonist. It 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 active contractile proteins. In vascular tissue, diltiazem relaxes arterial smooth muscle, reducing systemic peripheral resistance and dilating the coronary arteries, In cardiac muscle diltiazem reduces contractility and slows the heart rate through its negative chronotropic and inotropic actions. Cardiac work and oxygen

demand can therefore be reduced and high blood pressure lowered without reflex tachycardia.

5.2 Pharmacokinetic properties

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%.

Diltiazem in plasma is 80-85% protein bound. Plasma levels above 40-50ng/ml are associated with pharmacological activity.

Diltiazem is extensively metabolised by the liver, the plasma elimination half-life being on average 3-4.5 hours.

The two major active circulating metabolites, desacetyl-diltiazem and N-monodesmethyl diltiazem possess coronary artery vasodilatory activity equivalent to about 50% of that of diltiazem. Only 0.2 to 4% diltiazem is found unchanged in the urine.

The prolonged release pellets in this presentation usually achieve maximum plasma diltiazem levels six to eight hours after dosing and have an apparent plasma half-life of approximately 7 hours, allowing once daily dosing

The bioavailability of diltiazem from the Slozem formulation given once a day is equivalent to that obtained from a conventional release tablet given three times a day, when the same total daily dose is administered.

Data from studies in patients and healthy volunteers have also demonstrated that trough plasma levels (i.e. 24 hours post dosing) can be maintained within the minimum therapeutic range by appropriate dose titration.

Plasma concentrations in elderly patients and in hepatic failure are in general higher than in young subjects, due to an increase in apparent bioavailability. In renal failure, a reduction in dosage is only necessary as a function of the clinical response

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.1 List of excipients

Maize starch, sucrose, povidone, shellac, ethylcellulose, talc, gelatin, erythrosine (E127), indigo carmine (E132), titanium dioxide (E171) and black iron oxide (E172), shellac, propylene glycol.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

4, 28 or 56 capsules in PVC/PVDC/Aluminium blisters enclosed in a cardboard carton.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Merck Serono Ltd Bedfont Cross, Stanwell Road,

Feltham, Middlesex,

TW14 8NX, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 11648/0045

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/02/2001 / 21/06/2005

10 DATE OF REVISION OF THE TEXT

08/10/2015