SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zatim XL 200 mg Prolonged-release Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged release capsule contains 200 mg Diltiazem Hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release oral capsules

Opaque capsules with a white body and cap, containing white to whitish pellets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Mild to moderate hypertension and angina pectoris

4.2 Posology and method of administration

Posology

Zatim XL 200 mg and Zatim XL 300 mg are prolonged release capsules for once daily dosing. The capsules should not be chewed but swallowed whole with water, ideally before or during a meal. The dosage requirements may differ in patients with angina or hypertension.

Adults:

Angina and hypertension: The usual starting dose is Zatim XL 200 mg once daily. This dose maybe increased to Zatim XL 300 mg once daily, or 2 capsules of Zatim XL 200 mg daily (400 mg), and if clinically indicated, a higher dose of one Zatim XL 300 mg plus one Zatim XL 200 mg capsule (total 500 mg) may be considered.

Elderly 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. Zatim XL capsules should be used with caution in patients with renal or hepatic impairment (see section 4.4).

Careful titration of the dose should be considered where appropriate, as individual patient response may vary.

Method of administration

Angina and hypertension: the initial dose should be one Zatim XL 200 mg capsule daily. This dose may be increased to one capsule of Zatim XL 300 mg daily if clinically indicated.

Paediatric population:

The safety and efficacy of Zatim XL in children have not been established. Therefore Zatim XL 200 mg Prolonged-release Capsules is not recommended for use in children.

4.3 Contraindications

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

Myocardial infarction with complications (severe bradycardia (less than 50 beats per minute), severe hypotension, left ventricular failure with pulmonary stasis).

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).

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

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 1^st 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.

4.5 Interaction with other medicinal products and other forms of interaction

COMBINATIONS 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).

Nifedipine

The combination of diltiazem with nifedipine may lead to a substantial increase of nifedipine plasma concentrations, due to the inhibition of nifedipine metabolism by diltiazem.

Ergot derivatives (ergotamine, dihydroergotamine)

Diltiazem may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism.

Cisapride

Increased risk of ventricular arrhythmia, notably torsades de pointes.

Sertindole

Increased risk of ventricular arrhythmia, notably torsades de pointes.

Pimozide

Increased risk of ventricular arrhythmia, notably torsades de pointes.

Ivabradine

Due to its metabolism inhibition by diltiazem, ivabradine plasmatic exposure may significantly increase (2 to 3 fold increase in its AUC) leading to increase its adverse effects, notably, cardiac events, further to the bradycardiac properties of each drug.

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 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 (such as dronedarone)

Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents (e.g. dronedarone) 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.

Immunosuppressants (ciclosporine, tacrolimus, sirolimus, everolimus)

Increase in circulating immunosuppressants levels. It is recommended that the immunosuppressants dose be reduced, renal function be monitored, circulating immunosuppressants 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-H 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. Ad adjustment in diltiazem daily dose may be necessary.

Rifampicin

Risk of decrease of diltiazem plasma levels after intiating therapy with rifampicin.

The patients should be carefully monitored when initiating or discontinuing rifampicin treatment.

Lithium

Risk of increase in lithium-induced neurotoxicity.

Medicinal products inducing torsades de pointes

Medicinal products inducing torsades de pointes such as phenothiazines, bepridil, certain oral macrolides (such as erythromycin), terfenadine and Class I and III antiarrhythmics , methadone etc.

Increased risk of ventricular arrhythmia, notably torsades de pointes. This combination should be used under close clinical and ECG monitoring.

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. Diltiazem is also a CYP3A4 isoform inhibitor.

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 possibile, it is recommended to use a statin not metabolised by CYP3A4 (e.g. pravastatin) with diltiazem, otherwise close monitoring for signs ans symptoms of a potential statin toxicity is required.

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 metabolised 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. However, diltiazem has been shown to have reproductive toxicity in animal species (see section 5.3). Diltiazem is therefore not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.

Breastfeeding: Diltiazem is excreted in breast milk at low concentrations. Breastfeeding while taking this drug should be avoided. If use of diltiazem is considered medically essential, an alternative method of infant feeding should be instituted.

Fertility: No evidence of impaired fertility was observed in animal studies. Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by channel blockers.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise (common), the ability to drive and use machines could be altered.

4.8 Undesirable effects

The following adverse reactions are listed by system organ class and 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 < 1/1,000); 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					Thromb ocytop eni a

system disorders
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
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

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 leading to collapse, sinus bradycardia with or without isorhythmic dissociation and atrioventricular conduction disturbances.

Treatment:

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: 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. desacetyl diltiazem and N-monodesmethyl diltiazem, possess pharmacological activity in angina corresponding to 10 and 20% respectively of that of the parent compound.

In humans

Antianginal properties

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.

Electrophysiologically, diltiazem causes moderate bradycardia in normal subjects, marginally prolongs intranodal conduction and has no effect on hisian and infrahisian conduction.

Antihypertensive properties

At a vascular level, the calcium antagonist effect of diltiazem produces moderate arterial vasodilataion and improves large artery compliance. The vasodilatation leads to a decrease in blood pressure in the hypertensive subject, due to lowered peripheral resistance, without producing reflex tachycardia.

On the contrary, there is a bradycardia inducing activity which is more pronounced on elevated heart rates.

Diltiazem reduces cardiac work by the moderate bradycardiac effect coupled with the lowering systemic arterial resistance.

Diltiazem may exert a depressant effect on a diseased sinus node. It slows atrioventricular conduction and there is thus a risk of AV block.

5.2 Pharmacokinetic properties

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

The sustained 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 Prolonged Release Diltiazem formulation relative to the immediate release 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 Diltiazem Prolonged Release formulation, 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

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of oral 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 fetal abnormalities, namely, of the skeleton. Also observed were reductions in early individual pup weights, pup survival, as well as prolonged delivery times and an increased incidence of stillbirths.

Single and repeated dose toxicity, genotoxicity and carcinogenicity studies reveal no special hazard to humans additional to those already included in other sections of the SmPC.

No evidence of impaired fertility was observed.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Povidone,

Talc,

Ethylcellulose,

Stearic Acid

Capsule shell:

Gelatin,

Titanium dioxide (E171)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years

6.4    Special precautions for storage

No special precaution.

6.5    Nature and contents of container

7 or 28 capsules, in a PVC/PVDC-Alu-foil blister pack

6.6    Special precautions for disposal

No special requirements.

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

7    MARKETING AUTHORISATION HOLDER

Neopharma Limited 57 High Street Odiham Hampshire RG29 1LF

8    MARKETING AUTHORISATION NUMBER(S)

PL 33579/0004

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/03/2015

10    DATE OF REVISION OF THE TEXT

05/10/2015