Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Napp Pharmaceuticals Ltd, Cambridge Science Park, Milton Road, Cambridge CB4 0GW
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 (see section 4.5). 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 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 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 of developing 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.
This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
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).
Risk of increase in lithium-induced neurotoxicity.
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.
Increase in circulating theophylline levels.
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.
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.
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.
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.
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.
Increase in circulating carbamazepine levels.
It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin.
The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.
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.
Increase in plasma diltiazem concentrations.
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.
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.
ADIZEM-XL capsules should not be taken at the same time as alcohol, as it may increase the rate of 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 frequencies are the basis for assessing undesirable effects: 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).
Not known: Thrombocytopenia
Uncommon: Hypersensitivity
Uncommon: Nervousness, insomnia
Not known: Mood changes (including depression)
Common: Headache, dizziness
Not known: Extrapyramidal syndrome
Common: Atrioventricular block (may be of first, second or third degree; bundle branch block may occur), palpitations
Uncommon: Bradycardia
Not known: Sinoatrial block, congestive heart failure
Common: Flushing
Uncommon: Orthostatic hypotension
Not known: Vasculitis (including leukocytoclastic vasculitis), hypotension
Common: Constipation, dyspepsia, gastric pain, nausea
Uncommon: Vomiting, diarrhoea
Rare: Dry mouth
Not known: Gingival hyperplasia
Uncommon: Hepatic enzymes increase (AST, ALT, LDH, ALP increase)
Not known: Hepatitis
Common: Erythema, Pruritus
Rare: Urticaria
Not known: Photosensitivity (including lichenoid keratosis at sun exposed skin areas), angioneurotic oedema, rash, erythema multiforme (including Steven-Johnson’s syndrome and toxic epidermal necrolysis), hyperhidrosis, exfoliative dermatitis, acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever, allergic dermatitis
Not known: Gynecomastia
Very common: Peripheral oedema
Common: Malaise, fatigue
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.
None known.
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