Securon Iv
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Securon IV
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Verapamil Hydrochloride BP 2.5 mg/ml
3 PHARMACEUTICAL FORM
Aqueous solution for intravenous injection.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Securon IV 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 EGG and blood pressure control. If necessary, e.g. in paroxysmal tachycardia, a further 5 mg may be given after 5 to 10 minutes.
Children: Securon IV 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 may affect impulse conduction. For this reason, Securon IV should be used with caution in patients with bradycardia or first degree AV block. 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 poor ventricular function, therefore, Securon IV should only be given after cardiac failure has been controlled with appropriate therapy, e.g. digitalis.
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. Interactions 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 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 associated with verapamil:
Acetylsalicylic acid
Concomitant use of verapamil with aspirin may increase the risk of bleeding
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 offlecainide whereas flecainide has no effect on the verapamil plasma clearance.
Verapamil may increase the plasma concentrations of quinidine.
The combination of verapamil and antiarrhythmic agents may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure). Care must be exercised if Securon IV is combined with anti-arrhythmic agents by any route.
Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness. Verapamil may also increase the plasma concentrations of phenytoin.
Antidepressants
Verapamil may increase the plasma concentrations of imipramine.
Antidiabetics
Verapamil may increase the plasma concentrations of glibenclamide (glyburide).
Anti-infectives
Rifampicin may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect. Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.
Antineoplastics
There is no significant difference between the pharmacokinetic parameters of doxorubicin with intravenous verapamil administration.
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).
Securon IV should not be given in combination with intravenous beta-blocker therapy and care must be exercised if Securon IV is combined with oral beta-blocker therapy.
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 following intravenous verapamil administration.
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.
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.
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.
Anticoagulants
Dabigatran | dabigatran (Cmax up to 180%) and AUC (up to 150%)
The Risk of bleeding may increase. The Dose of dabigatran with oral verapamil may need to be reduced. (See dabigatran label for dosing instructions).
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).
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
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. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil 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. However, there are currently no reports of verapamil injection or infusion use during 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.
Frequency
Nervous system disorders
common
Cardiac disorders/vascular disorders
common
uncommon
dizziness headache
■ bradycardia
■ hypotension
■ 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.
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. 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 hemodialysis. 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.
5 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
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections, sodium chloride (8.5 mg/ml), hydrochloric acid 10% as pH adjuster.
Incompatibilities
6.2
Securon IV 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
None.
7 MARKETING AUTHORISATION HOLDER
BGP Products Ltd.
Abbott House,
Vanwall Business Park,
Vanwall Road,
Maidenhead,
Berkshire,
SL6 4XE,
United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 43900/0026
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17 June 2003
10 DATE OF REVISION OF THE TEXT
01/02/2016