Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Aventis Pharma Limited, One Onslow Street, Guildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker.
Severe bradycardia (less than 50 beats per minute). Left ventricular failure with pulmonary stasis. Lactation.
Concurrent use with dantrolene infusion (see section 4.5 Interactions with other medicinal products and other forms of interactions).
Hypersensitivity to diltiazem or to any of the excipients.
Combination with ivabradine (see section 4.5).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a 1st 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 (see section 4.5 and 4.8). 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.
Careful monitoring is necessary in patients with latent or manifest diabetes mellitus due to a possible increase in blood glucose.
The use of diltiazem may induce bronchospasm, including asthma aggravation, especially in patients with preexisting bronchial hyper-reactivity. Cases have also been reported after dose increase. Patients should be monitored for signs and symptoms of respiratory impairment during diltiazem therapy.
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).
Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of diltiazem to ivabradine (see section 4.3)
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.
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.
An increased risk of depression has been reported when dilitiazem is co-administered with beta-blockers (see section 4.8)
Increased risk of bradycardia; caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.
Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents 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.
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.
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.
When co-administered with phenytoin, diltiazem may increase phenytoin plasma concentration.
It is recommended that the phenytoin plasma concentrations be monitored
Cardiovascular effects of an intravenous bolus of an ionic X-ray contrast media, such as hypotension, may be increased in patients treated with diltiazem.
Special caution is required in patients who concomitantly receive diltiazem and X-ray contrast media
Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
Increase in circulating theophylline levels.
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.
Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.
Risk of increase in lithium-induced neurotoxicity.
In a pharmacodynamic study, diltiazem was shown to inhibit platelet aggregation. Although the clinical significance of this finding is unknown, potential additive effects when used with antiplatelet drugs should be considered.
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. Grapefruit juice may increase diltiazem exposure (1.2 fold). Patients who consume grapefruit juice should be monitored for increased adverse effects of diltiazem. Grapefruit juice should be avoided if an interaction is suspected. 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. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
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 possible, it is recommended to use a statin not metabolised by CYP3A4 (e.g. pravastatin) with diltiazem.
Inhibition of cilostazol metabolism (CYP3A4). Diltiazem has been shown to increase cilostazol exposure and to enhance its pharmacological activity.
Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing short-acting benzodiazepines matabolised by the CYP3A4 pathway in patients using diltiazem.
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.
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.
There are very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity (see section 5.3) 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.
As this drug is excreted in breast milk, breast feeding whilst taking diltiazem is contraindicated.
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.
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.
Not known: Thrombocytopenia
Uncommon: Nervousness, insomnia
Not known: Mood changes including depression
Common: Headache, dizziness
Not known: Extrapyramidal syndrome
Not known: Bronchospasm (including asthma aggravation)
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 sinus arrest, cardiac arrest (asystole)
Common: Flushing
Uncommon: Orthostatic hypotension
Not known: Vasculitis (including leukocytoclastic vasculitis)
Common: Constipation, dyspepsia, gastric pain, nausea
Uncommon: Vomiting, diarrhea
Rare: Dry mouth
Not known: Gingival hyperplasia
Not known: Hyperglycemia
Uncommon: Hepatic enzymes increase (AST, ALT, LDH, ALP increase)
Not known: Hepatitis
Common: Erythema
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), sweating, exfoliative dermatitis, acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever
Not known: Gynecomastia
Very common: Peripheral oedema
Common: Malaise
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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