Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

ADIZEM^®-SR 90 mg, 120 mg and 180 mg prolonged release capsules.

Each capsule contains diltiazem hydrochloride 90 mg, 120 mg or 180 mg.

Excipients: also contains sucrose 18.26 mg per capsule (90 mg only)

Excipients: also contains sucrose 24.35 mg per capsule (120 mg only)

Excipients: also contains sucrose 36.53 mg per capsule (180 mg only)

For a full list of excipients, see section 6.1

Prolonged release capsules, hard.

ADIZEM-SR capsules 90 mg are size 3 hard gelatin capsules with an opaque white body and an opaque white cap, printed 90 mg.

ADIZEM-SR capsules 120 mg are size 3 hard gelatin capsules with an opaque white body and an opaque brown cap, printed 120 mg.

ADIZEM-SR capsules 180 mg are size 2 hard gelatin capsules with an opaque white body and light brown cap, printed 180 mg.

In the management of stable angina pectoris.

In the management of hypertension.

Route of administration

Oral.

Recommended dosage schedules

Adults only:

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

In the elderly, dosage should commence at the lowest level of 90 mg twice daily and be increased very slowly.

Dosage adjustments are not necessary in the presence of renal dysfunction.

Dosage may be taken with or without food.

Adizem-SR should not be taken at the same time as an alcoholic beverage (refer to Section 4.5, Interactions with other medicinal products and other forms of interaction).

Use in pregnant women or women of child bearing potential not using effective contraception. Use in patients with sever bradycardia (less than 40 b.p.m.), second or third degree heart block or sick sinus syndrome, decompensated cardiac failure or left ventricular failure with pulmonary congestion.

Concurrent use with dantrolene infusion is contraindicated because of the risk of ventricular fibrillation (see section 4.5). Hypersensitivity to diltiazem or to any of the excipients.

The product must be used with caution in patients with reduced left ventricular function, first degree AV block or bradycardia (risk of exacerbation). First degree AV block or prolonged PR interval should be observed closely.

Diltiazem is considered unsafe in patients with acute porphyria.

Isolated cases of moderate and transient increased liver transaminases have been observed at the start of treatment. Isolated cases of clinical hepatitis have been reported, which resolved when diltiazem was withdrawn.

The use of diltiazem hydrochloride in diabetic patients may require adjustment of their control

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.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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).

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

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. Diltiazem hydrochloride may cause small increases in plasma levels of digoxin, requiring careful monitoring of AV conduction.

Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Patients with pre-existing conduction defects should not receive the combination of diltiazem and beta-blockers. Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.

Other antihypertensive drugs: Enhanced antihypertensive effect may occur with concomitant use of other antihypertensive drugs (e.g. beta-blockers, diuretics, ACE-inhibitors) or drugs that cause hypotension such as aldesleukin and antipsychotics.

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.

Protease inhibitors (e.g. atazanavir, ritonavir): Increase in plasma diltiazem concentrations.

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.

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. Co-administration with other CYP3A4 substrates may result in an increase in plasma concentration of either co-administered drug (e.g. cilostazol, ivabradine, sirolimus, tacrolimus). Care should be exercised in patients taking these drugs. Concomitant use of diltiazem hydrochloride with cilostazol and ivabradine should be avoided.

Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

Barbiturates (phenobarbital, primidone): serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers.

Phenytoin: serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers.

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.

Diltiazem may increase bioavailability of tricyclic antidepressants.

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 (simvastatin, atorvastatin, lovastatin): 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.

ADIZEM-SR should not be taken at the same time as alcohol, as it may increase the release of diltiazem from the prolonged release preparation. In addition the combination of alcohol and diltiazem may have an additive vasodilatory effect.

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 contraindicated during pregnancy (see section 4.3), as well as in women of child-bearing potential not using effective contraception.

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.

Diltiazem has been reported to cause adverse reactions such as dizziness (common) and malaise (common), which may impair patients' ability to drive or operate machinery to a varying extent depending on the dosage and individual susceptibility. However, no studies have been performed. Therefore, patients should not drive or operate machinery if affected.

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).

The clinical symptoms of massive acute intoxication may include pronounced hypotension or even collapse, sinus bradycardia with or without isorhythmic dissociation, atrioventricular conduction defects.

Treatment, which should be given in hospital, will include gastric lavage and osmotic diuresis. The patient should be closely monitored in hospital to exclude arrhythmias or atrioventricular conduction defects. Symptomatic bradycardia and high grade atrioventricular block may respond to atropine or isoprenaline.

Conduction disorders may benefit from temporary electro-systolic stimulation.

Hypotension may require correction with plasma volume expanders, intravenous calcium gluconate and positive inotropic agents.

Other proposed antidotes are adrenaline and glucagon.

The formulation employs a prolonged release system which will continue to release diltiazem for some hours.

Pharmacotherapeutic group: Selective calcium channel blocker with direct cardiac effects.

ATC code: C08D B01

A calcium channel blocking agent, well absorbed and undergoing first pass metabolism in the liver to active and inactive metabolites by deacetylation and oxidative O- and N-demethylation. The drug is excreted mainly in the faeces and to a lesser extent in the urine.

With administration of 180 to 300 mg of these formulations, peak plasma levels of 80 to 220 mg/ml respectively are reached at 5.5 hours. With repeat doses of 300 mg daily, plasma levels of over 100 ng/ml are maintained for 24 hours once steady state is reached. The T½ of elimination is 6 to 8 hours.

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

Sucrose

Maize starch

Povidone

Ethylcellulose

Dibutyl sebacate

Talc

Sodium laurilsulfate

Cetyl alcohol

Capsule shell

Titanium dioxide (E171)

Iron oxide (E172)

Indigo carmine (E132) (120 mg capsules only)

Gelatin

Not applicable.

Three years.

Do not store above 25°C.

Aluminium/PVC blister packs containing 56 capsules per pack.

No special requirements.

Mundipharma Pharmaceuticals Ltd

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland

PA 1688/1/1-3

Date of first authorisation: 20 April 1995

Date of last renewal: 16 December 2009

January 2012

® ADIZEM, MUNDIPHARMA and the 'mundipharma' device are Registered Trade Marks.

© Napp Pharmaceuticals Ltd, 2011.