- diltiazem hydrochloride
POM: Prescription only medicine
This information is intended for use by health professionals
Excipient with known effectSucrose 25.2mg in each XL 120mg capsule. For the full list of excipients, see section 6.1.
PosologyOral use only.
AdultsHypertension: The usual initial dose is one 180mg capsule per day (corresponding to 180mg of diltiazem hydrochloride once daily). Depending upon the clinical response the dosage may be increased stepwise to 360mg/day if required.Angina Pectoris: The usual initial dose is one 180mg capsule per day (corresponding to 180mg of diltiazem hydrochloride once daily). Depending upon the clinical response the dosage may be increased stepwise to 360mg/day if required.
Elderly patients and those with renal or hepatic impairmentDosage should commence at the lower level of 120mg once daily and be increased slowly. Do not increase the dose if the heart rate falls below 50 beats per minute.
ChildrenThis product is not recommended for use in children.
Method of administrationOral use only.
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).
IvabradineConcomitant 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:Anaesthetics: Anaesthetists should be warned that a patient is taking diltiazem. The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anaesthetics may be potentiated by calcium channel blockers. When used concomitantly, anaesthetics and calcium channel blockers should be titrated carefully.
StatinsDiltiazem 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.
LithiumRisk of increase in lithium-induced neurotoxicity.
WarfarinThere have been reports in the literature of diltiazem interactions with warfarin.
Nitrate derivativesIncreased 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.
TheophyllineIncrease in circulating theophylline levels. It is recommended that the plasma theophylline concentrations be assayed and that the dose should be adjusted if necessary.
Alpha-antagonistsIncreased 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, digoxinIncreased risk of bradycardia: Caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used. Amiodarone in combination with diltiazem may also cause AV block and myocardial depression. It is recommended that the plasma digoxin concentrations be assayed and that the dose should be adjusted if necessary. Cardiac glycosides may cause a greater degree of AV blocking, reduce the heart rate or induce a hypotensive effect.
Beta-blockersPossibility 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 agentsSince 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.
Diuretics, ACE inhibitors or other antihypertensive agentsPatients should be carefully monitored when taking diltiazem concomitantly with these agents.
Carbamazepine: Increase in circulating carbamazepine levelsIt is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
RifampicinRisk 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.
CiclosporinIncrease 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.
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.
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.
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.Oral administration of diltiazem can raise the plasma concentration of drugs exclusively metabolised by CYP3A4. The concomitant therapy of diltiazem and such drugs may increase the risk of adverse reactions (e.g. muscular disorders with statins).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. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.Simultaneous administration with enzyme inducers such as rifampicin and phenobarbital may lead to reduced activity of diltiazem.
AntihypertensivesDiltiazem hydrochloride should only be administered with great care to patients receiving concurrent treatment with antihypertensives or other hypotensive agents including halogenated anaesthetics or drugs with moderate protein binding.Diltiazem hydrochloride will not protect against effects of withdrawal of ß-adrenoceptor blocking agents, nor the rebound effects seen with various antihypertensives.There may be an additive effect when diltiazem is used with drugs which may induce bradycardia or with other antihypertensives.
PregnancyThere 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 and rabbit). Diltiazem is therefore not recommended during pregnancy,, as well as in women of child bearing potential not using effective contraception (see section 4.3).
Breast-feedingDiltiazem 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.
|Very common||Common||Uncommon||Rare||Not known|
|Blood and lymphatic system disorders||Thrombocytopenia, lymphadenopathy, eosinophilia|
|Psychiatric disorders||Nervousness, insomnia||Hallucinations, mood changes (including depression), personality change|
|Nervous system disorders||Headache, dizziness||Extrapyramidal syndrome, gait abnormality, syncope, amnesia, paraesthesia, somnolence, tremor|
|Cardiac disorders||Atrioventricular block (may be of first, second or third degree; bundle branch block may occur), palpitations||Bradycardia||Sinoatrial block, development or aggravation of congestive heart failure, arrhythmia, angina|
|Vascular disorders||Flushing||Orthostatic hypotension||Vasculitis (including leukocytoclastic vasculitis), The manifestations of vasodilatation (headache, flushing and in particular oedema of the lower limbs) are dose-dependent and appear more frequent in elderly subjects and related to the pharmacological activity of the product, hypotension|
|Gastrointestinal disorders||Constipation, dyspepsia, gastric pain, nausea||Vomiting, diarrhoea||Dry mouth||Gingival hyperplasia, gingivitis|
|Skin and subcutaneous tissue disorders||Erythema||Hepatic enzymes increase (AST, ALT, LDH, ALP increase) Moderate and transient elevation of liver transaminases have been observed at the start of treatment.||Urticaria||Allergic skin reactions, photosensitivity (including lichenoid keratosis at sun exposed skin areas) have been reported and recovering when the treatment is discontinued,, 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, petechiae, pruritus|
|Reproductive system and breast disorders||Gynecomastia, sexual difficulties|
|General disorders and administration site conditions||Peripheral oedema||Oedema, asthenia /fatigue, malaise|
|Eye disorders||Amblyopia, eye irritation|
|Investigations||Hepatic enzymes increase (AST, ALT, LDH, ALP increase)||CK elevation, weight increase|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea, epistaxis, nasal congestion|
|Metabolism and nutrition disorders||Anorexia, hyperglycaemia|
|Renal and urinary disorders||Nocturia, polyuria|
|Musculoskeletal and connective tissue disorders||Osteoarticular pain, muscle pain, muscle weakness|
|Ear and labyrinth disorders||Tinnitus|
Reporting of suspected adverse reactionsReporting 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.
Mechanism of actionDiltiazem is a calcium channel antagonist which restricts the entry of calcium ions into the cell through the slow voltage dependent channels and reduces the liberation of calcium from the endoplasmic reticulum. This results in a reduced amount of available intracellular calcium. The haemodynamic actions of diltiazem are:- Peripheral and coronary vasodilatation.- Decrease in myocardial oxygen consumption.- Reduction of blood pressure particularly in hypertension.Diltiazem has pharmacologic actions similar to those of other calcium channel blocking agents such as nifedipine or verapamil. The principal physiologic action of diltiazem is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells.Calcium plays important roles in the excitation-contraction coupling processes of the heart and vascular smooth muscle cells and in the electrical discharge of the specialised conduction cells of the heart. The membranes of these cells contain numerous channels that carry a slow inward current and that are selective for calcium.By inhibiting calcium influx, diltiazem inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries. Dilation of systemic arteries by diltiazem results in a decrease in total peripheral resistance, a decrease in systemic blood pressure and a decrease in the afterload of the heart. The reduction in afterload, seen at rest and with exercise, and its resultant decrease in myocardial oxygen consumption are thought to be responsible for the beneficial effects of diltiazem in patients with chronic stable angina pectoris. In patients with prinzmetal variant angina, inhibition of spontaneous and ergonovine-induced coronary artery spasm by diltiazem results in increased myocardial oxygen delivery.
AbsorptionWhen taken orally diltiazem is almost completely absorbed. Despite this, the absolute bioavailability is 40% due to extensive first pass metabolism. Bioavailability is not affected by age. Diltiazem is 78-87% bound to plasma proteins but only 35-40% to albumin. The peak plasma concentration is reached in about three hours after single dose of diltiazem 90 mg CR tablets. The Cmax value was 50-65 ng/ml. Capsules seem to have a similar bioavailability to tablets (30-40%), with peak concentrations for the prolonged release product after 8-11 hours compared with 1-2 hours after the conventional release product. The relatively low bioavailability is due to first pass metabolism in the liver to an active metabolite.
DistributionDiltiazem hydrochloride is lipophilic and has a high volume of distribution. Typical study results are in the range of 3-8 litres/kg. Protein binding is about 80% and is not concentration-dependent at levels likely to be found clinically. Protein binding does not appear to be influenced by phenylbutazone, warfarin, propranolol, salicylic acid or digoxin.
MetabolismDiltiazem hydrochloride is extensively metabolised in the liver by deacetylation and N-demethylation followed by O-demethylation or deacetylation. N-monodesmethyl diltiazem is the predominant metabolite followed quantitatively by the desacetyl metabolite, which has some hypotensive potency. The efficacy of the metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem is 25-50% and about 20% respectively of that of diltiazem. In liver function disorders delayed metabolism in the liver is likely. These metabolites are converted to conjugates, generally the glucuronide or the sulphate.
EliminationDiltiazem is excreted in the form of its metabolites (about 35%) and in the non-metabolised form (about 2-4%) via the kidneys while about 60% is excreted via the faeces. Diltiazem is mainly excreted as metabolites in the urine and faeces and only 1-3% of the dose is excreted as the parent compound in urine. The average elimination half life period for diltiazem is 6-8 hours but may vary between 2 and 11 hours. Although the elimination half life is not changed after repeated oral administration, diltiazem and also the desacetyl metabolite show a slight accumulation in the plasma.b) Characteristics in PatientsDecreased first-pass metabolism in the elderly tends to result in increased plasma concentrations of calcium antagonists but no major changes have been found with diltiazem. Renal impairment did not cause significant changes in diltiazem pharmacokinetics. Plasma concentrations of diltiazem also tend to be higher in hepatic cirrhosis due to impaired oxidative metabolism.
Teva UK Limited, Field House, Station Approach, Harlow, Essex, CM20 2FB
+44 (0) 207 540 7000
0800 590 502
+44 (0) 207 540 7117
+44 (0) 207 000 1216