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.
Experience of overdosage in man is limited but cases of spontaneous recovery have been reported. However, it is recommended that patients with suspected overdose should be placed under observation in a coronary care unit with facilities available for treatment of any possible hypotension and conduction disturbances that may occur. Conduction disturbances may be managed by temporary cardiac pacing. Most patients suffering from overdosage of diltiazem become hypotensive within 8 hours of ingestion. With bradycardia and first to third degree atrioventricular block also developing cardiac arrest may ensue. Hyperglycaemia is also a recognised complication. The elimination half-life of diltiazem after overdosage is estimated to be about 5.5 - 10.2 hours. If a patient presents early after overdose, gastric lavage should be performed under hospital supervision and activated charcoal administered to reduce diltiazem absorption.
Hypotension should be corrected with plasma expanders, intravenous calcium gluconate and inotropic agents (dopamine, dobutamine or isoprenaline). Symptomatic bradycardia and high grade AV block may respond to atropine, isoprenaline or occasionally cardiac pacing which may be useful if cardiac standstill occurs.
Proposed corrective treatments: atropine, vasopressors, inotropic agents, glucagon and calcium gluconate infusion.
Symptoms
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. It is recommended that patients with suspected overdose should be placed under observation in a coronary care unit.
Most patients suffering from overdosage of diltiazem become hypotensive within 8 hours of ingestion. With bradycardia and first to third degree atrioventricular block also developing, cardiac arrest may ensue. Hyperglycaemia is also a recognised complication. The elimination half-life of diltiazem after overdosage is estimated to be about 5.5-10.2 hours.
The following may be linked to renal impairment in patients; polyuri, pollakiuria, nocturia, acute kidney injury, acute interstitiel nephritis.
Management
Treatment, in a hospital setting, will include gastric lavage with administration of activated charcoal to reduce diltiazem absorption and/or osmotic diuresis. Conduction disturbances may be managed by temporary cardiac pacing. Proposed corrective treatments: Hypotension should be corrected with plasma expanders, vasopressors, glucagon, calcium gluconate infusion and inotropic agents (e.g. dopamine, dobutamine or isoprenaline). Symptomatic bradycardia and high grade AV block may respond to atropine, isoprenaline or occasionally cardiac pacing which may be useful if cardiac standstill occurs.
Diltiazem Retard SR capsules are prolonged release capsules and effects may be slow in onset and prolonged, therefore, monitoring should be carried out for longer periods than following overdose with immediate-release dosage forms.
Not applicable.
Tabulated list of adverse reactions
The frequencies of adverse reactions are ranked according to the following: 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.
| 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 | |
| Hepatobiliary disorders | Hepatic enzymes increase (AST, ALT, LDH, ALP increase) Moderate and transient elevation of liver transaminases have been observed at the start of treatment. | Hepatitis | |||
| Skin and subcutaneous tissue disorders | Erythema | 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 reactions
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.
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.
| Very Common | Common | Uncommon | Rare | Not Known | |
| Blood and lymphatic system disorders | Thrombocytopenia | ||||
| Immune system disorders | Hypersensitivity | ||||
| Psychiatric disorders | Nervousness, insomnia | Mood changes (including depression), anorexia | |||
| Nervous system disorders | Headache, dizziness | Extrapyramidal syndrome, Parkinsonian syndrome, paraesthesia | |||
| Cardiac disorders | Atrioventricular block (may be of first, second or third degree; bundle branch block may occur), palpitations | Bradycardia | Sinoatrial block, congestive heart failure | ||
| Vascular disorders | Flushing | Orthostatic hypotension | Vasculitis (including leukocytoclastic vasculitis) Hypotension | ||
| Gastrointestinal disorders | Constipation, dyspepsia, gastric pain, nausea | Vomiting, diarrhoea | Dry mouth | Gingival hyperplasia Gastrointestinal disorder | |
| Hepatobiliary disorders | Hepatic enzymes increase (AST, ALT, LDH, ALP increase) | Hepatitis | |||
| Skin and subcutaneous tissue disorders | Erythema, pruritus | Urticaria | 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 generalised exanthematous pustulosis, desquamative erythema with or without fever, allergic dermatitis hyperpigmentation | ||
| Reproductive system and breast disorders | Gynecomastia | ||||
| General disorders and administration site conditions | Peripheral oedema | Malaise, fatigue |
Reporting of suspected adverse reactions
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
Chronic toxicity studies in rats revealed no remarkable changes at oral doses up to 125 mg/kg/day although there was 60% mortality at this dose. In dogs chronically treated with oral doses of 20 mg/kg/day, transient rises in SGPT were observed. Embryotoxicity has been reported in mice, rats and rabbits following i.p. administration of diltiazem. Main types of malformations included limb and tail defects with a small number of vertebral and rib deformities also noted.
There are no additional data of relevance to the prescriber.
Pharmacotherapeutic group: Calcium channel Blocker, ATC code: C08D B01
Mechanism of action
Diltiazem 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.
Increase in renal blood flow and urinary sodium excretion
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.
Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects:
ATC code: C08DB01
Diltiazem hydrochloride is a calcium-channel blocking agent. It is a peripheral and coronary vasodilator with some negative inotropic activity. Diltiazem inhibits cardiac conduction particularly at the sino-atrial and atrioventricular nodes. It is used in the management of classical and vasospastic angina pectoris and it is also used in the treatment of essential hypertension.
a) General Characteristics
Absorption
When 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.
Distribution
Diltiazem 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.
Metabolism
Diltiazem 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.
Elimination
Diltiazem 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 Patients
Decreased 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.
Absorption
Diltiazem is rapidly and almost completely absorbed from the gastro-intestinal tract following oral administration, but undergoes extensive first-pass hepatic metabolism. The bioavailability has been reported to be about 40%, although there is considerable inter-individual variation in plasma concentrations.
Distribution
Diltiazem is about 80% bound to plasma proteins.
Biotransformation
It is extensively metabolised in the liver; one of the metabolites, desacetyl diltiazem has been reported to have 25 to 50% of the activity of the parent compound. The half-life is reported to be about 3 to 4 hours.
Elimination
Approximately 60% of the dose is excreted in the bile and 35 to 40% in the urine, and 2 to 4% as unchanged diltiazem.
The prolonged-release formulation is designed for twice daily dosage.
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.
Not applicable.
No special requirements.
