- Approval Id
- 53fafb4ced320fd2
- Drug Approval Emc Name
- Verapamil 2.5 mg/ml Solution for injection
- Drug Name
- Verapamil 2.5 mg/ml Solution for injection
- Company Address
- Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL
- Company Website
- http://www.mylan.com
- Company Telephone
- +44 (0)1707 853 000
- Company Medical Info Direct Line
- +44 (0)1707 853 000
- Company Medical Info Email
- info@mylan.co.uk
- Company Customer Care Direct Line
- +44 (0)1707 853 000 select option 2
- Company Medical Info Fax
- +44 (0)1707 261 803
- Company Stock Availability
- +44 (0)1707 853 000 select option 2
- Atc Code
- C08DA01
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Mylan Products Ltd.
20 Station Close
Potters Bar
Herts
EN6 1TL
United Kingdom
- Authorisation Number
- PL 46302/0026
- Authorisation Date
- 17 June 2003
- Instruction Authorisation Holder
- Mylan Products Ltd.
20 Station Close
Potters Bar
Herts
EN6 1TL
United Kingdom
- Instruction Authorisation Number
- PL 46302/0026
- Instruction Authorisation Date
- 17 June 2003
- Instruction Composition
- verapamil hydrochloride 2.5 mg/ml
- Instruction Dosage Form
- Solution for injection.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Verapamil Injection is indicated for the treatment of paroxysmal supraventricular tachycardia and the reduction of ventricular rate in atrial flutter/fibrillation.4.2 Posology and method of administration
For slow intravenous injection.
\*Adults\*: 5-10 mg by slow intravenous injection over a period of 2 minutes. The patient should be observed continuously, preferably under ECG and blood pressure control. If necessary, \*e.g.\* in paroxysmal tachycardia, a further 5 mg may be given after 5 to 10 minutes.
\*Children\*: Verapamil Injection must always be administered under ECG monitoring in young patients.
0-1 year: 0.1-0.2 mg/kg bodyweight (usual single dose range: 0.75-2 mg).
1-15 years: 0.1-0.3 mg/kg bodyweight (usual single dose range: 2-5 mg).
The dose may be repeated after 30 minutes if necessary. Many cases are controlled by doses at the lower end of the range. The injection should be stopped at the onset of the desired effect.
\*Elderly\*: The dosage should be administered over 3 minutes to minimise the risk of adverse effects.
\*Dosage in impaired liver and renal function\*: Significant hepatic and renal impairment should not increase the effects of a single intravenous dose but may prolong its duration of action.
For use with beta-blocker therapy, see 'Contra-indications' and 'Special Warnings and Precautions for Use'.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Cardiogenic shock; acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure; second or third degree AV block (except in patients with a functioning artificial ventricular pacemaker); sino-atrial block; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90mmHg systolic; simultaneous administration of intravenous beta-blockers.
Patients with atrial flutter/fibrillation in the presence of an accessory pathway (\*e.g.\* WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction).4.4 Special warnings and precautions for use
Verapamil hydrochloride injection should be given as a slow intravenous injection over at least a two-minute period of time under continuous ECG and blood pressure monitoring.
A small fraction of patients treated with verapamil hydrochloride respond with life-threatening adverse responses including (rapid ventricular rate (in atrial flutter/fibrillation in the presence of an accessaory bypass tract), marked hypotension or extreme bradycardia/asystole).
\*\*Heart Block/ 1st Degree AV block/Bradycardia/Asystole\*\*
Verapamil hydrochloride affects the AV and SA nodes and prolongs AV conduction time. Use with caution as development of second-or third-degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation in subsequent doses of verapamil hydrochloride and institution of appropriate therapy, if needed.
Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients.
Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. See \*Undesirable Effects\* Section.
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.
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 at the lowest possible dose of verapamil 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), refer to 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).4.5 Interaction with other medicinal products and other forms of interaction
In rare instances, including when patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil hydrochloride, serious adverse effects have occurred. Concomitant use of verapamil hydrochloride injection with agents that decrease adrenergic function may result in an exaggerated hypotensive response.
\*In vitro\* metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following are potential drug interactions due to pharmacokinetic reasons:
\*\*\*Acetylsalicylic acid\*\*\*
Concomitant use of verapamil with aspirin may increase the risk of bleeding.
\*\*\*Alcohol\*\*\*
Increase in blood \*alcohol\* has been reported.
\*\*\*Alpha blockers\*\*\*
Verapamil may increase the plasma concentrations of \*prazosin\* and \*terazosin\* which may have an additive hypotensive effect.
\*\*\*Antiarrhythmics\*\*\*
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.
The combination of verapamil and \*antiarrhythmic agents\* may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
\*\*\*Anticonvulsants\*\*\*
Verapamil may increase the plasma concentrations of \*carbamazepine\*. This may produce side effects such as diplopia, headache, ataxia or dizziness. \*Phenytoin\* may decrease the plasma concentrations of verapamil.
\*\*\*Antidepressants\*\*\*
Verapamil may increase the plasma concentrations of \*imipramine\*.
\*\*\*Antidiabetics\*\*\*
Verapamil may increase the plasma concentrations of \*glibenclamide (glyburide).\* Co-administration of verapamil with metformin may reduce the efficacy of \*metformin.\*
\*\*\*Antihypertensives, diuretics, vasodilators\*\*\*
Potentiation of the hypotensive effect.
\*\*\*Anti-infectives\*\*\*
\*Rifampicin\* may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect\*.\*When verapermil and \*rifampicin\* are administrated together there is no change in PK. \*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\*\*\*
Verapamil may increase the plasma concentrations of \*metoprolol\* and \*propranolol\* which 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.
\*\*\*Cardiac glycosides\*\*\*
Verapamil may increase the plasma concentrations of \*digitoxin\* and \*digoxin.\* Verapamil has been shown to increase the serum concentration of \*digoxin\* and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.
\*\*\*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.
\*\*\*H2 Receptor antagonists\*\*\*
\*Cimetidine\* may increase the plasma concentrations of verapamil.
\*\*\*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.
\*\*\*Immunosuppressants\*\*\*
Verapamil may increase the plasma concentrations of \*ciclosporin, everolimus, sirolimus\* and \*tacrolimus\*. Concentration determinations and dose adjustments of everolimus and sirolimus may be necessary.
\*\*\*Inhaled anaesthetics\*\*\*
When used concomitantly, \*inhalation anaesthetics\* and calcium antagonists, such as verapamil hydrochloride, should each be titrated carefully to avoid additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
\*\*\*Lipid lowering agents\*\*\*
Verapamil may increase the plasma concentrations \*atorvastatin, lovastatin\* and \*simvastatin.\*
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 retitrate against serum cholesterol concentrations.
\*Atorvastatin\* has been shown to increase verapamil levels. Although there is no direct in vivo clinical evidence, there is 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 metabolized by CYP3A4 and are less likely to interact with verapamil.
\*\*\*Lithium\*\*\*
Serum levels of \*lithium\* may be reduced. However there may be increased sensitivity to \*lithium\* causing enhanced neurotoxicity. Patients receiving both drugs should be monitored carefully.
\*\*\*Neuromuscular blocking agents employed in anaesthesia\*\*\*
The effects may be potentiated.
\*\*\*Protein-bound drugs\*\*\*
As verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly \*protein-bound drugs\*.
\*\*\*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. When verapermil and \*sulfinpyrazone\* are administrated together there is no change in PK.
\*\*\*Anticoagulants\*\*\*
When oral verapamil was co-administered with dabigatran etexilate (150 mg), a P- gp substrate, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on time between administration and the formulation of verapamil. Co- administration of verapamil 240 mg extended-release at the same time as dabigatran etexilate resulted in increased dabigatran exposure (increase of Cmax by about 90 % and AUC by about 70 %).
Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
\*\*\*Other Cardiac therapy\*\*\*
Concomitant use with \*ivabradine\* is contraindicated due to the additional heart rate lowering effect of verapamil to \*ivabradine\* (see section 4.3).
\*\*\*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 lactation
There are no adequate and well-controlled study data in pregnant women. Although animal studies have not shown any teratogenic effects (see section 5.3), 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.
Verapamil hydrochloride is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 – 1% of the mother's oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.4.7 Effects on ability to drive and use machines
None stated.4.8 Undesirable effects
Adverse events observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Frequency\*\* | \*\*Undesirable Effects\*\* |
| Nervous system disorders | | |
| | common | - dizziness - headache |
| Cardiac disorders/vascular disorders | | |
| | common | - bradycardia - hypotension |
| uncommon | - tachycardia |
| Gastrointestinal disorders | | |
| | uncommon | - nausea - abdominal pain |
Cases of seizures during verapamil hydrochloride injection have been reported.
In rare cases of hypersensitivity, bronchospasm accompanied by pruritis and urticaria has been reported.
\*\*Other Reactions from Postmarketing Surveillance or Phase IV Clinical Trials\*\*
Other adverse events reported with verapamil are listed below by system organ class:
\*Psychiatric disorders\*: on rare occasions, nervousness has been reported.
\*Nervous system disorders\*: somnolence and extrapyramidal syndrome.
\*Ear and labyrinth disorders\*: vertigo.
\*Cardiac disorders/vascular disorders\*: decreased myocardial contractility has been reported. On rare occasions, 2nd and 3rd block may occur and in extreme cases, this may lead to asystole. The asystole is usually of short duration and cardiac action returns spontaneously after a few seconds, usually in the form of sinus rhythm. If necessary, the procedures for the treatment of overdosage should be followed as described below. On rare occasions, flushing has been reported.
\*Gastrointestinal disorders\*: gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued. On rare occasions, vomiting has also been reported.
\*Skin and subcutaneous tissue disorders\*: Steven-Johnson syndrome, erythema and hyperhidrosis.
\*Reproductive system and breast disorders\*: On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment; this was fully reversible in all cases when the drug was discontinued.
\*Investigations\*: A reversible impairment of liver function characterized by an increase of transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
\*\*The symptoms of overdosage include hypotension, shock, 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, bradycardia\*\* \*\*up to high degree AV block and, sinus arrest, hyperglycaemia, stupor and metabolic acidosis and acute respiratory distress syndrome.. Fatalities have occurred as a result of overdose.\*\*
Treatment of overdosage depends on the type and severity of symptoms. The specific antidote is calcium, \*e.g.\* 10-20 ml of 10% calcium gluconate solution i.v. (2.25-4.5 mmol) if necessary by repeated injection or continuous infusion (\*e.g.\* 5 mmol/hour). The usual emergency measures for acute cardiovascular collapse should be applied and followed by intensive care. Verapamil hydrochloride cannot be removed by haemodialysis. Similarly, in the case of second or third degree AV block, atropine, orciprenaline, isoprenaline and if required, pacemaker therapy should be considered. If there are signs of myocardial insufficiency, dopamine, dobutamine, cardiac glycosides or calcium gluconate (10-20 ml of a 10% solution) can be administered.
In the case of hypotension, after appropriately positioning the patient, dopamine, dobutamine or noradrenaline may be given.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.
ATC-Code: C08DA01
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 cells of the intracardiac conduction system. 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.5.2 Pharmacokinetic properties
Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolised. Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity of verapamil and accounts for 6% of excreted drug. The steady-state plasma concentrations of norverapamil and verapamil are similar.
Steady state after multiple once daily dosing is reached after three to four days.
\*\*Distribution\*\*
Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of verapamil is approximately 90%.
\*\*Metabolism\*\*
Verapamil is extensively metabolised. In vitro metabolic studies indicate that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N and O-dealkylated products of verapamil. Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.
\*\*Elimination\*\*
Following intravenous infusion, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about four minutes) and a slower terminal elimination phase (half-life two to five hours).
\*\*Special Populations\*\*
\*Paediatric\*:
Limited information on the pharmacokinetics in the paediatric population is available. After intravenous dosing, the mean half-life of verapamil was 9.17 hours and the mean clearance was 30 L/h, whereas it is around 70 L/h for a 70kg adult.
\*Geriatric\*:
Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly. The antihypertensive effect of verapamil was found not to be age-related.
\*Renal insufficiency\*:
Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by hemodialysis.
\*Hepatic insufficiency\*:
Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolised.5.3 Preclinical safety data
Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 (180 mg/m2/day) and 1.2 times (360 mg/m2/day) respectively the equivalent maximum recommended human oral daily dose (300 mg/m2/day) and have revealed no evidence of teratogenicity. In the rat the highest dose was embryocidal and retarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gain of dams). This oral dose has also been shown to cause hypotension in rats.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Water for injections, sodium chloride (8.5 mg/ml), hydrochloric acid 10% as pH adjuster.6.2 Incompatibilities
Verapamil Injection is incompatible with alkaline solutions.6.3 Shelf life
36 months.6.4 Special precautions for storage
Do not store above 30°C. Protect from light.6.5 Nature and contents of container
2 ml glass ampoule (hydrolytic type 1) containing 5 mg verapamil. Pack size:
5 x 2 ml ampoules.6.6 Special precautions for disposal and other handling
None.
- Instruction Content
- ## Composition
verapamil hydrochloride 2.5 mg/ml
## Pharmaceutical Form
Solution for injection.
## Clinical Particulars
4.1 Therapeutic indications
Verapamil Injection is indicated for the treatment of paroxysmal supraventricular tachycardia and the reduction of ventricular rate in atrial flutter/fibrillation.4.2 Posology and method of administration
For slow intravenous injection.
\*Adults\*: 5-10 mg by slow intravenous injection over a period of 2 minutes. The patient should be observed continuously, preferably under ECG and blood pressure control. If necessary, \*e.g.\* in paroxysmal tachycardia, a further 5 mg may be given after 5 to 10 minutes.
\*Children\*: Verapamil Injection must always be administered under ECG monitoring in young patients.
0-1 year: 0.1-0.2 mg/kg bodyweight (usual single dose range: 0.75-2 mg).
1-15 years: 0.1-0.3 mg/kg bodyweight (usual single dose range: 2-5 mg).
The dose may be repeated after 30 minutes if necessary. Many cases are controlled by doses at the lower end of the range. The injection should be stopped at the onset of the desired effect.
\*Elderly\*: The dosage should be administered over 3 minutes to minimise the risk of adverse effects.
\*Dosage in impaired liver and renal function\*: Significant hepatic and renal impairment should not increase the effects of a single intravenous dose but may prolong its duration of action.
For use with beta-blocker therapy, see 'Contra-indications' and 'Special Warnings and Precautions for Use'.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Cardiogenic shock; acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure; second or third degree AV block (except in patients with a functioning artificial ventricular pacemaker); sino-atrial block; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90mmHg systolic; simultaneous administration of intravenous beta-blockers.
Patients with atrial flutter/fibrillation in the presence of an accessory pathway (\*e.g.\* WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction).4.4 Special warnings and precautions for use
Verapamil hydrochloride injection should be given as a slow intravenous injection over at least a two-minute period of time under continuous ECG and blood pressure monitoring.
A small fraction of patients treated with verapamil hydrochloride respond with life-threatening adverse responses including (rapid ventricular rate (in atrial flutter/fibrillation in the presence of an accessaory bypass tract), marked hypotension or extreme bradycardia/asystole).
\*\*Heart Block/ 1st Degree AV block/Bradycardia/Asystole\*\*
Verapamil hydrochloride affects the AV and SA nodes and prolongs AV conduction time. Use with caution as development of second-or third-degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation in subsequent doses of verapamil hydrochloride and institution of appropriate therapy, if needed.
Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients.
Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. See \*Undesirable Effects\* Section.
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.
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 at the lowest possible dose of verapamil 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), refer to 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).4.5 Interaction with other medicinal products and other forms of interaction
In rare instances, including when patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil hydrochloride, serious adverse effects have occurred. Concomitant use of verapamil hydrochloride injection with agents that decrease adrenergic function may result in an exaggerated hypotensive response.
\*In vitro\* metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following are potential drug interactions due to pharmacokinetic reasons:
\*\*\*Acetylsalicylic acid\*\*\*
Concomitant use of verapamil with aspirin may increase the risk of bleeding.
\*\*\*Alcohol\*\*\*
Increase in blood \*alcohol\* has been reported.
\*\*\*Alpha blockers\*\*\*
Verapamil may increase the plasma concentrations of \*prazosin\* and \*terazosin\* which may have an additive hypotensive effect.
\*\*\*Antiarrhythmics\*\*\*
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.
The combination of verapamil and \*antiarrhythmic agents\* may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
\*\*\*Anticonvulsants\*\*\*
Verapamil may increase the plasma concentrations of \*carbamazepine\*. This may produce side effects such as diplopia, headache, ataxia or dizziness. \*Phenytoin\* may decrease the plasma concentrations of verapamil.
\*\*\*Antidepressants\*\*\*
Verapamil may increase the plasma concentrations of \*imipramine\*.
\*\*\*Antidiabetics\*\*\*
Verapamil may increase the plasma concentrations of \*glibenclamide (glyburide).\* Co-administration of verapamil with metformin may reduce the efficacy of \*metformin.\*
\*\*\*Antihypertensives, diuretics, vasodilators\*\*\*
Potentiation of the hypotensive effect.
\*\*\*Anti-infectives\*\*\*
\*Rifampicin\* may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect\*.\*When verapermil and \*rifampicin\* are administrated together there is no change in PK. \*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\*\*\*
Verapamil may increase the plasma concentrations of \*metoprolol\* and \*propranolol\* which 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.
\*\*\*Cardiac glycosides\*\*\*
Verapamil may increase the plasma concentrations of \*digitoxin\* and \*digoxin.\* Verapamil has been shown to increase the serum concentration of \*digoxin\* and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.
\*\*\*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.
\*\*\*H2 Receptor antagonists\*\*\*
\*Cimetidine\* may increase the plasma concentrations of verapamil.
\*\*\*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.
\*\*\*Immunosuppressants\*\*\*
Verapamil may increase the plasma concentrations of \*ciclosporin, everolimus, sirolimus\* and \*tacrolimus\*. Concentration determinations and dose adjustments of everolimus and sirolimus may be necessary.
\*\*\*Inhaled anaesthetics\*\*\*
When used concomitantly, \*inhalation anaesthetics\* and calcium antagonists, such as verapamil hydrochloride, should each be titrated carefully to avoid additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
\*\*\*Lipid lowering agents\*\*\*
Verapamil may increase the plasma concentrations \*atorvastatin, lovastatin\* and \*simvastatin.\*
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 retitrate against serum cholesterol concentrations.
\*Atorvastatin\* has been shown to increase verapamil levels. Although there is no direct in vivo clinical evidence, there is 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 metabolized by CYP3A4 and are less likely to interact with verapamil.
\*\*\*Lithium\*\*\*
Serum levels of \*lithium\* may be reduced. However there may be increased sensitivity to \*lithium\* causing enhanced neurotoxicity. Patients receiving both drugs should be monitored carefully.
\*\*\*Neuromuscular blocking agents employed in anaesthesia\*\*\*
The effects may be potentiated.
\*\*\*Protein-bound drugs\*\*\*
As verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly \*protein-bound drugs\*.
\*\*\*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. When verapermil and \*sulfinpyrazone\* are administrated together there is no change in PK.
\*\*\*Anticoagulants\*\*\*
When oral verapamil was co-administered with dabigatran etexilate (150 mg), a P- gp substrate, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on time between administration and the formulation of verapamil. Co- administration of verapamil 240 mg extended-release at the same time as dabigatran etexilate resulted in increased dabigatran exposure (increase of Cmax by about 90 % and AUC by about 70 %).
Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
\*\*\*Other Cardiac therapy\*\*\*
Concomitant use with \*ivabradine\* is contraindicated due to the additional heart rate lowering effect of verapamil to \*ivabradine\* (see section 4.3).
\*\*\*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 lactation
There are no adequate and well-controlled study data in pregnant women. Although animal studies have not shown any teratogenic effects (see section 5.3), 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.
Verapamil hydrochloride is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 – 1% of the mother's oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.4.7 Effects on ability to drive and use machines
None stated.4.8 Undesirable effects
Adverse events observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Frequency\*\* | \*\*Undesirable Effects\*\* |
| Nervous system disorders | | |
| | common | - dizziness - headache |
| Cardiac disorders/vascular disorders | | |
| | common | - bradycardia - hypotension |
| uncommon | - tachycardia |
| Gastrointestinal disorders | | |
| | uncommon | - nausea - abdominal pain |
Cases of seizures during verapamil hydrochloride injection have been reported.
In rare cases of hypersensitivity, bronchospasm accompanied by pruritis and urticaria has been reported.
\*\*Other Reactions from Postmarketing Surveillance or Phase IV Clinical Trials\*\*
Other adverse events reported with verapamil are listed below by system organ class:
\*Psychiatric disorders\*: on rare occasions, nervousness has been reported.
\*Nervous system disorders\*: somnolence and extrapyramidal syndrome.
\*Ear and labyrinth disorders\*: vertigo.
\*Cardiac disorders/vascular disorders\*: decreased myocardial contractility has been reported. On rare occasions, 2nd and 3rd block may occur and in extreme cases, this may lead to asystole. The asystole is usually of short duration and cardiac action returns spontaneously after a few seconds, usually in the form of sinus rhythm. If necessary, the procedures for the treatment of overdosage should be followed as described below. On rare occasions, flushing has been reported.
\*Gastrointestinal disorders\*: gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued. On rare occasions, vomiting has also been reported.
\*Skin and subcutaneous tissue disorders\*: Steven-Johnson syndrome, erythema and hyperhidrosis.
\*Reproductive system and breast disorders\*: On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment; this was fully reversible in all cases when the drug was discontinued.
\*Investigations\*: A reversible impairment of liver function characterized by an increase of transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
\*\*The symptoms of overdosage include hypotension, shock, 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, bradycardia\*\* \*\*up to high degree AV block and, sinus arrest, hyperglycaemia, stupor and metabolic acidosis and acute respiratory distress syndrome.. Fatalities have occurred as a result of overdose.\*\*
Treatment of overdosage depends on the type and severity of symptoms. The specific antidote is calcium, \*e.g.\* 10-20 ml of 10% calcium gluconate solution i.v. (2.25-4.5 mmol) if necessary by repeated injection or continuous infusion (\*e.g.\* 5 mmol/hour). The usual emergency measures for acute cardiovascular collapse should be applied and followed by intensive care. Verapamil hydrochloride cannot be removed by haemodialysis. Similarly, in the case of second or third degree AV block, atropine, orciprenaline, isoprenaline and if required, pacemaker therapy should be considered. If there are signs of myocardial insufficiency, dopamine, dobutamine, cardiac glycosides or calcium gluconate (10-20 ml of a 10% solution) can be administered.
In the case of hypotension, after appropriately positioning the patient, dopamine, dobutamine or noradrenaline may be given.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.
ATC-Code: C08DA01
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 cells of the intracardiac conduction system. 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.5.2 Pharmacokinetic properties
Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolised. Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity of verapamil and accounts for 6% of excreted drug. The steady-state plasma concentrations of norverapamil and verapamil are similar.
Steady state after multiple once daily dosing is reached after three to four days.
\*\*Distribution\*\*
Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of verapamil is approximately 90%.
\*\*Metabolism\*\*
Verapamil is extensively metabolised. In vitro metabolic studies indicate that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N and O-dealkylated products of verapamil. Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.
\*\*Elimination\*\*
Following intravenous infusion, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about four minutes) and a slower terminal elimination phase (half-life two to five hours).
\*\*Special Populations\*\*
\*Paediatric\*:
Limited information on the pharmacokinetics in the paediatric population is available. After intravenous dosing, the mean half-life of verapamil was 9.17 hours and the mean clearance was 30 L/h, whereas it is around 70 L/h for a 70kg adult.
\*Geriatric\*:
Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly. The antihypertensive effect of verapamil was found not to be age-related.
\*Renal insufficiency\*:
Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by hemodialysis.
\*Hepatic insufficiency\*:
Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolised.5.3 Preclinical safety data
Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 (180 mg/m2/day) and 1.2 times (360 mg/m2/day) respectively the equivalent maximum recommended human oral daily dose (300 mg/m2/day) and have revealed no evidence of teratogenicity. In the rat the highest dose was embryocidal and retarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gain of dams). This oral dose has also been shown to cause hypotension in rats.
## Pharmaceutical Particulars
6.1 List of excipients
Water for injections, sodium chloride (8.5 mg/ml), hydrochloric acid 10% as pH adjuster.6.2 Incompatibilities
Verapamil Injection is incompatible with alkaline solutions.6.3 Shelf life
36 months.6.4 Special precautions for storage
Do not store above 30°C. Protect from light.6.5 Nature and contents of container
2 ml glass ampoule (hydrolytic type 1) containing 5 mg verapamil. Pack size:
5 x 2 ml ampoules.6.6 Special precautions for disposal and other handling
None.
- Company Detail Path
- /organization/mylan-laboratories-limited
