Document: spc-doc_PL 08829-0022 change

• spc-doc_PL 06934-0195
• spc-doc_PL 08829-0022

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Angitil SR 90

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 90 mg of Diltiazem Hydrochloride

3.    PHARMACEUTICAL FORM

Modified release hard capsule.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the management of angina pectoris. For the management of mild to moderate hypertension.

4.2    Posology and method of administration

Posology:

Individual patients’ responses to diltiazem may vary, necessitating careful titration.

The capsules should be swallowed whole and not chewed. Dosage may be taken with or without food.

Adults: The usual initial dose is 90 mg twice daily. Dosage may be increased gradually to 120 mg twice daily or 180 mg twice daily if required.

Patients currently receiving a total daily dose of 180 mg diltiazem (as 90 mg bd), may be titrated up to 240 mg (od). A patient receiving 240 mg per day of diltiazem (as 120 mg bd), should commence treatment on the 240 mg capsule (od), titrating to the 300 mg capsule (od), if required.

Elderly and patients with impaired renal or hepatic dysfunction', the starting dose should be 60 mg diltiazem twice daily. If necessary, the dose may be increased gradually but careful monitoring of this group of patients is advised. Where the patient is currently prescribed 120 mg this dose may, by careful titration, be increased to 240 mg (od).

Paediatric population: Diltiazem preparations are not recommended for children. Safety and efficacy in children has not been established

In order to avoid confusion, it is suggested that patients once titrated to an effective dose should remain on this treatment and should not be changed between different presentations.

Method of administration Oral use

4.3    Contraindications

•    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)

•    Decompensated cardiac failure

•    Left ventricular failure with pulmonary congestion

•    Hypersensitivity to diltiazem or to any of the excipients

•    Concomitant use of dantrolene infusion (see section 4.5)

•    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 first degree AV block detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).

Prior to general anaesthesia, the anaesthetist 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 blockers 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 in considered unsafe in patients with acute porphyria.

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 dose.

Theophylline: Increase in circulating theophylline levels.

Alpha-antagonists: Increased antihypertensive effects: Concomitant treatment with alpha-antagonists 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: 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 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.

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 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 methyloprednisolone 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 metabolized 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 potential statin toxicity is required.

Angitil capsules should not be taken at the same time as alcohol. In vitro data suggests that in combination with Angitil capsules, alcohol may increase the rate of in vivo release of the product from the prolonged release preparation. Alcohol may increase

dose-dependent effects and lead to potential adverse pharmacodynamic interactions. Alcohol use could therefore increase the rate and seriousness of diltiazem adverse drug reactions such as vasodilatory related events.

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 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

Diltiazem is excreted in breast milk at low concentrations. 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					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;	Bradycardia		Sinoatrial block, congestive heart failure

		bundle branch block may occur), palpitations
Vascular disorders		Flushing	Orthostatic hypotension		Vasculitis (including leukocytoclastic vasculitis)
Gastrointestinal disorders		Constipation, dyspepsia, gastric pain, nausea	Vomiting diarrhoea	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.

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, in a hospital setting, will include gastric lavage and/or 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

Diltiazem is an anti-anginal agent, calcium antagonist. Diltiazem inhibits transmembrane calcium entry in myocardial muscle fibres and in vascular smooth muscle fibres, thereby decreasing the quantity of intracellular calcium available to the contractile proteins.

5.2    Pharmacokinetic properties

Angitil capsules contain slow release forms of microgranules which permit diltiazem hydrochloride to be released along a length of the gastrointestinal tract.

Diltiazem is 80% bound to human plasma proteins (albumin, acid glucoproteins).

The biotransformation routes are:

-    Deacetylation

-    Oxidative O- and N- demethylation

-    Conjugation of the phenolic metabolites

The primary metabolites, n-demethyldiltiazem and desacetyldiltiazem exert less pharmacological activity than diltiazem. The other metabolites are pharmacologically inactive.

After administration of 180mg to 300mg of the diltiazem formulation, a peak plasma concentration of 80ng/ml to 220 ng/ml, respectively, is obtained after 5.5 hours.

The elimination half-life varies from 6 to 8 hours, depending on the strength.

Preclinical safety data

Other than that already mentioned, there is no additional pre-clinical data that is deemed relevant to the prescriber.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule content:

Sucrose and maize starch SP microgranules

Povidone K30

Sucrose

Ethylcellulose

Purified Talc

Dibutyl sebacate

Sodium Lauryl Sulfate

Cetyl Alcohol

Capsule Shell:

Gelatin

Titanium dioxide (E171)

Black Ink:

Shellac, propylene glycol, ammonium hydroxide, potassium hydroxide, E172 black iron oxide.

6.2 Incompatibilities

None reported.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

The capsules should be stored in their original packaging. Do not store above 30°C.

Nature and contents of container

Capsules are enclosed in 250pm PVC/ 20pm aluminium blisters which are boxed in cardboard cartons containing 28 or 56 capsules.

6.6 Instructions for use/handling

There are no special instructions for use/handling.

7.    MARKETING AUTHORISATION HOLDER

Chiesi Limited 333 Styal Road Manchester M22 5LG United Kingdom

8.    MARKETING AUTHORISATION NUMBER(S)

PL 08829/0022

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

25/02/2005

10 DATE OF REVISION OF THE TEXT

07/03/2016