The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related).
The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, first and second degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, sinus bradycardia, sinus arrest hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose. The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms. Gastric lavage, taking the usual precautionary measures may be appropriate even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable.
The usual intensive resuscitation measures, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy. Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10 - 20ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5mmol/hour).
The following measures may also be necessary: In case of second and third degree AV block, sinus bradycardia, asystole: atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension after appropriate positioning of the patient: dopamine, dobutamine, noradrenaline. If there are signs of continuing myocardial failure: dopamine, dobutamine, cardiac glycosides or if necessary, repeated calcium gluconate injections.
The course of symptoms in Lekoptin intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related). The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, 1st and 2nd degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, bradycardia up to high degree AV block and, sinus arrest, hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose.
The therapeutic measures to be taken depend on the point in time at which Lekoptin was taken and the type and severity of intoxication symptoms. In intoxications with large amounts of slow-release preparations, it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Lekoptin hydrochloride cannot be removed by haemodialysis. Depending on the time of ingestion, it should be taken into account that there may be some lumps of incompletely dissolved tablets along the entire length of the gastrointestinal tract, which function as active drug depots.
General measures to be taken: Gastric lavage with the usual precautions, even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable. Where intoxication by a modified release preparation is suspected, extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage, laxative, high enemas. The usual intensive resuscitation measures apply, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy.
Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10 20ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5mmol/hour).
The following measures may also be necessary: In case of 2nd or 3rd degree AV block, sinus bradycardia, asystole - atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension - dopamine, dobutamine, noradrenaline (norepinephrine). If there are signs of continuing myocardial failure - dopamine, dobutamine, if necessary repeated calcium injections.
Cardiogenic shock
Acute myocardial infarction complicated by bradycardia, hypotension or left ventricular failure
Second or third degree atrioventricular block
Sino-atrial block
Sick sinus syndrome
Uncompensated heart failure
Bradycardia of less than 50 beats/minute (Except in patients with functioning artificial ventricular pacemaker)
Intravenous dantrolene
Hypotension of less than 90mm Hg systolic
Atrial flutter or fibrillation associated with an accessory pathway (e.g. Wolff-Parkinson-White syndrome, Lown-Ganong-Levine syndrome)
Porphyria
Concomitant ingestion of grapefruit juice.
-
- Hypotension (of less than 90mmHg systolic)
- Second or third degree atrioventricular block; sick sinus syndrome (except in patients with a functioning artifical pacemaker); uncompensated heart failure; marked bradycardia (less than 50 beats/minute).
- Combination with beta-blockers is contraindicated in patients with poor ventricular function.
- Wolff-Parkinson-White syndrome.
- Concomitant ingestion of grapefruit juice is contraindicated.
- Acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure.
- Combination with ivabradine
Not applicable.
None known.
Verapamil is generally well tolerated. Side effects are usually mild and transient and discontinuation of therapy is rarely necessary.
Immune System Disorders: Allergic reactions (e.g. erythema, pruritus, urticaria, Quincke's oedema, Stevens-Johnson syndrome, erythema multiforme, alopecia and purpura) are very rarely seen.
Nervous System Disorders: Tremor and extrapyramidal syndrome. Headaches and dizziness have been reported rarely. Paraesthesia may occur.
Ear and Labyrinth Disorders: Vertigo and tinnitus.
Cardiac Disorders: Particularly when given in high doses or in the presence of previous myocardial damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias, such as sinus bradycardia, sinus arrest with asystole, second and third degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure.
Vascular Disorders: Peripheral oedema, hypotension. Flushing is observed occasionally. Erythromelalgia may occur.
Gastrointestinal Disorders: Constipation may occur. Nausea, vomiting, ileus, abdominal pain/discomfort have been reported rarely.
Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.
Hepatobiliary Disorders: A reversible impairment of liver function, characterised by an increase in transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction.
Musculoskeletal and Connective Tissue Disorders: In very rare cases, there may be muscular weakness, myalgia and arthralgia.
Reproductive System and Breast Disorders: Impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment, which was fully reversible in all cases when the drug was discontinued. Rises in prolactin levels have been reported.
General Disorders and Administration Site Conditions: Fatigue and ankle oedema have been reported rarely.
Investigations: Rises in blood prolactin levels have been reported.
Immune system disorders: allergic reactions (e.g. erythema, pruritus, urticaria) are very rarely seen.
Nervous system disorders: headaches occur rarely, dizziness, paraesthesia, tremor, extrapyramidal syndrome (e.g. parkinsonism), dystonia.
Ear and labyrinth disorders: vertigo, tinnitus.
Cardiac disorders: bradycardic arrhythmias such as sinus bradycardia, sinus arrest with asystole, 2nd and 3rd degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure, hypotension.
Vascular disorders: flushing, peripheral oedema.
Gastrointestinal disorders: nausea, vomiting, constipation is not uncommon, ileus and abdominal pain/discomfort. Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods. This is fully reversible when the drug is discontinued.
Skin and subcutaneous tissue disorders: alopecia, ankle oedema, Quincke's oedema, Steven-Johnson syndrome, erythema multiforme, erythromelalgia, purpura.
Musculoskeletal and connective tissue disorders: muscular weakness, myalgia and arthralgia.
Reproductive system and breast disorders: impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. Gynaecomastia was observed on very rare occasions in elderly male patients under longer term Lekoptin treatment which was fully reversible in all cases when the drug was discontinued.
General disorders and administration site conditions: fatigue.
Investigations: On very rare occasions, a reversible impairment of liver function characterised by an increase in transaminases and/or alkaline phosphatase, may occur during Lekoptin treatment and is most probably a hypersensitivity reaction.
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; website: www.mhra.gov.uk/yellowcard
Verapamil is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.
Not applicable.
1. Treatment of mild to moderate hypertension.
2. Treatment and prophylaxis of chronic stable angina, vasospastic angina and unstable angina.
3. Treatment and prophylaxis of paroxysmal supraventricular tachycardia and the reduction of ventricular rate in atrial flutter/fibrillation. Verapamil should not be used when atrial flutter/fibrillation complicates Wolff-Parkinson-White syndrome (see Contraindications).
-blockers).2) For the management and prophylaxis of angina pectoris (including variant angina).
3) The treatment and prophylaxis of paroxysmal supraventricular tachycardia and the reduction of the ventricular rate in atrial fibrillation/flutter. Lekoptin should not be used for atrial fibrillation/flutter in patients with Wolff-Parkinson-White syndrome.
Verapamil is a calcium antagonist which blocks the inward movement of calcium ions in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in the cells of the intracardiac conduction system. Verapamil lowers peripheral vascular resistance with no reflex tachycardia. Its efficacy in reducing both raised systolic and diastolic blood pressure is thought to be due to this mode of action. The decrease in systemic and coronary vascular resistance and the sparing effect on intracellular oxygen consumption appear to explain the anti-anginal properties of the drug. Because of its effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.
Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.
ATC code: C08 DA01
Lekoptin hydrochloride is a calcium channel blocker and is classified as a class IV anti-arrhythmic agent.
Mechanism of action
Lekoptin inhibits the entry of calcium into smooth muscle cells of the systemic and coronary arteries and in the cells of cardiac muscle and the intracardiac conduction system.
Lekoptin lowers peripheral vascular resistance with little or no reflex tachycardia. Its efficacy in reducing both raised systolic and diastolic blood pressure is thought to be primarily due to this mode of action.
The decrease in systemic and coronary vascular resistance and the sparing effect on intracellular oxygen consumption appear to explain the anti-anginal properties of the product.
Due to the effect on the movement of calcium in the intracardiac conduction system, Lekoptin reduces automaticity, decreases conduction velocity and increases the refractory period.
Absorption
Over 90% of verapamil is absorbed following administration with peak plasma concentrations occurring between 1 and 2 hours and does not appear to be affected markedly by food.
Distribution, biotransformation and elimination
Verapamil is subject to pre-systemic hepatic metabolism with up to 80% of the dose eliminated this way. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20 - 35%. Verapamil is widely distributed throughout the body with a distribution half-life of 15 - 30 mins. Verapamil is 90% bound to plasma proteins, mainly to albumin and 1 glycoprotein. The half life of verapamil after a single oral dose is between 2 and 7h. However, after repeated administration it increases to 4.5 to 12h resulting in accumulation of the drug.
Absorption
Lekoptin is approximately 90% absorbed from the gastrointestinal tract.
Distribution
Lekoptin acts within 1-2 hours after oral administration with a peak plasma concentration after 1-2 hours. There is considerable interindividual variation in plasma concentrations. Lekoptin is about 90% bound to plasma proteins.
Biotransformation
Lekoptin is subject to very considerable first-pass metabolism in the liver and the bioavailability is only about 20%. It is extensively metabolised in the liver to at least 12 metabolites of which norLekoptin has been shown to have some activity.
Elimination
Lekoptin exhibits bi- or tri-phasic elimination kinetics and is reported to have a terminal plasma half-life of 2-8 hours following a single oral dose. After repeated oral doses this increases to 4.5-12 hours. About 70% of a dose is excreted by the kidneys in the form of its metabolites but about 16% is also excreted in the bile into the faeces. Less than 4% is excreted unchanged.
Pregnancy and breast-feeding
Lekoptin crosses the placenta and is excreted in breast milk.
Since verapamil is extensively metabolised in the liver, careful dose titration of verapamil is required in patients with liver disease. Although the pharmacokinetics of verapamil in patients with renal impairment are not affected, caution should be exercised and careful patient monitoring is recommended. Verapamil is not removed during dialysis.
Verapamil may affect impulse conduction and therefore verapamil solution should be used with caution in patients with bradycardia or first degree AV block. Patients with atrial flutter/fibrillation in association with an accessory pathway (e.g. WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated. In patients with incipient cardiac failure, therefore, verapamil should be given only after such cardiac failure has been controlled with appropriate therapy, e.g. digitalis.
When treating hypertension with verapamil, monitoring of the patient's blood pressure at regular intervals is required.
This product also contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Verapamil is extensively metabolised in the liver and special care should be taken in cases where liver damage exists, as plasma levels of verapamil may be increased
Caution should be exercised in treatment with HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) for patients taking verapamil. These patients should be started on the lowest possible dose of verapamil and titrated upwards. If verapamil treatment is to be added to patients already taking HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), refer to the advice in the respective statin product information.
Use with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).
Lekoptin may affect left ventricular contractility as a result of its mode of action. The effect is small and not normally important. However, cardiac failure may be aggravated or precipitated if it exists. In cases with poor ventricular function, Lekoptin should therefore only be administered after appropriate therapy for cardiac failure such as digitalis, etc.
Lekoptin may affect impulse conduction and should be administered with caution in patients with first degree atrioventricular block. The effects of Lekoptin and beta-blockers or other drugs may be additive both in respect of conduction and contraction, therefore care should be exercised when these are administered concurrently or closely together. This is especially true when either drug is administered intravenously.
Caution should be observed in the acute stage of myocardial infarction.
Patients with atrial fibrillation/flutter and an accessory pathway (eg Wolff-Parkinson-White syndrome) may rarely develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
Since Lekoptin is extensively metabolised in the liver, careful dose titration of Lekoptin is required in patients with liver disease. The disposition of Lekoptin in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended. Lekoptin is not removed during dialysis.
Alpha blockers: Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.
Anticonvulsants: Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness. Levels of verapamil may be reduced when taken with phenytoin.
Antidepressants: Verapamil may increase the plasma concentrations of imipramine.
Antidiabetics: Verapamil may increase the plasma concentrations of glibenclamide (glyburide).
Antihypertensives, diuretics, vasodilators: Potentiation of the hypotensive effect.
Anti-infectives: Rifampicin may reduce the plasma concentration of verapamil which may produce a reduced blood pressure lowering effect. Erythromycin, clarithromycin and telithromycin: May increase the plasma concentrations of verapamil.
Antineoplastics: Verapamil may increase the plasma concentrations of doxorubicin.
Barbiturates: Phenobarbital may reduce the plasma concentrations of verapamil.
Benzodiazepines and other anxiolytics: Verapamil may increase the plasma concentrations of buspirone and midazolam.
Beta-blockers, anti-arrhythmic agents or inhaled anaesthetics: The combination with verapamil may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure). Intravenous beta-blockers should not be given to patients under treatment with verapamil. Verapamil may slightly decrease the plasma clearance of flecainide whereas flecainide has no effect on the verapamil plasma clearance. Verapamil may increase the plasma concentrations of quinidine. Pulmonary oedema may occur in patients with hypertrophic cardiomyopathy.
Cardiac glycosides: Verapamil has been shown to increase the serum concentration of digoxin and digitoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.
Cimetidine: Increase in verapamil serum level is possible.
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.
HIV antiviral agents: Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or dose of verapamil may be decreased.
HMG Co-A Reductase Inhibitors (Statins): Verapamil may increase the plasma concentrations of simvastatin, atorvastatin and lovastatin. Treatment with HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and re-titrate against serum cholesterol concentrations.
There is no direct in vivo clinical evidence of an interaction between atorvastatin and verapamil; however there is a strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.
Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP 3A4 and are less likely to interact with verapamil.
Immunosuppressants: Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus.
Intravenous dantrolene: The association of this muscle relaxant given intravenously and verapamil is potentially dangerous (can cause fatal ventricular fibrillation in animals) and is contraindicated.
Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect); there may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).
Neuromuscular blocking agents employed in anaesthesia: The effects may be potentiated. The effects of verapamil may be additive to other hypotensive agents.
Serotonin receptor agonists: Verapamil may increase the plasma concentrations of almotriptan.
Theophylline: Verapamil may increase the plasma concentrations of theophylline.
Uricosurics: Sulfinpyrazone may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect.
Other: St. John's Wort may reduce the plasma concentrations of verapamil, whereas grapefruit juice may increase the plasma concentrations of verapamil.
4.6 Fertility, pregnancy and lactationPregnancy
Although animal studies have not shown any teratogenic effects, verapamil should not be given during the first trimester of pregnancy unless, in the clinician's judgement, it is essential for the welfare of the patient.
Lactation
Verapamil is excreted into the breast milk in small amounts and is unlikely to be harmful. However, rare hypersensitivity reactions have been reported with verapamil and, therefore, it should only be used during lactation if, in the clinician's judgement, it is essential for the welfare of the patient.
Fertility
No information is available regarding the effects of verapamil on fertility.
4.7 Effects on ability to drive and use machinesDepending on individual susceptibility, the patient's ability to drive a vehicle or operate machinery or work under hazardous conditions may be impaired. This is particularly true in the initial stages of treatment, or when changing over from another medication. Like many other common medicines, verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.
Depending on individual susceptibility, the patient's ability to drive or operate machines may be impaired due to feelings of drowsiness. This is particularly true in the initial stages of treatment, or when changing over from another drug. Lekoptin has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.
Adults:
Hypertension: Initially 120mg b.d. increasing to 160mg b.d. when necessary. In some cases, dosages of up to 480mg daily, in divided doses, have been used. A further reduction in blood pressure may be obtained by combining verapamil with other antihypertensive agents, in particular diuretics. For concomitant administration with beta-blockers see Precautions.
Angina: 120mg t.d.s. is recommended. 80mg t.d.s. can be completely satisfactory in some patients with angina of effort. Less than 120mg t.d.s is not likely to be effective in variant angina.
Supraventricular tachycardias: 40-120mg, t.d.s. according to the severity of the condition.
Hepatic Impairment: Verapamil is extensively metabolised in liver and for those patients with impaired liver function, the dose should be reduced and carefully titrated.
Renal Impairment: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil should be prescribed cautiously when renal function is impaired. Careful patient monitoring is recommended.
Children:
Up to 2 years: 20mg, 2-3 times a day.
2 years and above: 40-120mg, 2-3 times a day, according to age and effectiveness.
Elderly:
The adult dose is recommended unless liver or renal function is impaired (see Precautions).
Posology
Adults:
Angina: 120mg three times daily is recommended. 80mg three times daily may be completely satisfactory in some patients with angina of effort. Less than 120mg three times daily is unlikely to be effective in variant angina.
Supraventricular tachycardias: 40-120mg three times daily depending on the severity of the condition.
Paediatric population:
A paradoxical increase in the rate of arrhythmias in children has been noted. Therefore, Lekoptin should only be used under expert supervision.
Up to 2 years: 20mg 2-3 times a day.
2 years and above: 40-120mg 2-3 times a day according to age and effectiveness.
Elderly: The adult dose is recommended unless liver or renal function is impaired.
Method of Administration
For oral administration.
Not applicable.
