Adizem CD

/ Rafa

Adults: For patients new to dilitiazem therapy the usual starting dose is one 240 mg capsule daily. Patients currently receiving a total daily dose of 180 mg diltiazem (as 90 mg b.d. or 60 mg t.i.d.) and transferring to this product should be given the 240 mg capsule (o.d.). A patient receiving 240 mg/day of diltiazem (as 120 mg b.d.) should commence treatment on the 240 mg capsule (o.d.).
Elderly and patients with impaired hepatic and renal function: For patients new to diltiazem therapy, the usual starting dose is one 120 mg capsule daily. If necessary the dose may be gradually increased but careful monitoring of this group of patients is advised.
Elderly patients transferring to this product should receive the same total daily dose of diltiazem, titrating upwards as required
Children: These capsules are not recommended for children. Safety and efficacy in children have not been established.
Method of administration: Oral. To be taken at 24 hour intervals.
The capsules should be swallowed whole and not chewed.
In order to avoid confusion, it is suggested that patients once titrated to an effective dose using ADIZEM CD capsules, should remain on this treatment and should not be changed between different presentations.
ADIZEM CD capsules should not be taken at the same time as an alcoholic beverage.

Chronic stable angina pectoris, angina due to coronary artery spasm, hypertension.

Pregnancy and in women of child bearing capacity. Patients with severe bradycardia (less than 40 bpm), second or third degree heart block, sick sinus syndrome, decompensated cardiac failure, patients with left ventricular failure with pulmonary congestion. Concurrent use with dantrolene infusion because of the risk of ventricular fibrillation. Hypersensitivity to diltiazem or to any of the excipients.

The product should be used with caution in patients with reduced left ventricular function. Patients with 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. 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.
For full details see prescribing information.

Peripheral oedema, hypotension, palpitations, nasal and chest congestion, shortness of breath, nausea, diarrhea, constipation, cramps, flatulence, allergic hepatitis, dizziness, light headedness, nervousness, sleep disturbances, blurred vision, headache, flushing, weakness, equilibrium disturbances, dermatitis, rash, pruritus, urticaria, thrombocytopenia, gingival hyperplasia, muscle cramps, joint stiffness, arthralgia, impotence, fever, chills, sweating, sexual difficulties.

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.
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, ACEinhibitors) 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 (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 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. Diltiazem may increase serum levels of phenytoin.
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. These capsules should not be taken at the same time as alcohol, as it may increase the rate of release of diltiazem from the controlled 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, 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.

The clinical effects of acute overdose can involve pronounced hypotension possibly leading to collapse, sinus bradycardia with or without isorhythmic 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.
Symptomatic bradycardia and high grade atrioventricular block may respond to
atropine and isoprenaline.
The formulation employs a prolonged release system which will continue to release diltiazem for some hours.