Summary of Product Characteristics

1.             Trade 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 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: 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.         Contra-indications

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 90 mmHg 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.

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.

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.

4.5.                Interactions with other medicinal products and other forms of Interaction

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.

The combination of Securon IV and beta-blockers, anti-arrhythmic agents or inhaled anaesthetics 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 or anti-arrhythmic agents by any route.

The effects of Securon IV may be additive to other hypotensive agents.

Interactions between verapamil and the following have been reported:

Carbamazepine, cyclosporin and theophylline: Use of verapamil has resulted in increased serum levels of these medications. This could lead to increased side effects.

Rifampicin: Serum levels of verapamil reduced.

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.

HMG Co-A Reductase Inhibitors (“Statins”):  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.

There is no direct in vivo clinical evidence for an interaction between atorvastatin and verapamil, however, 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.

                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

Increased tendency to bleed. 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 of flecainide 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.

 

Anticonvulsants

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 redcued blood pressure lowering effect.  Erythromycin 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.

 

ImmunologicsImmunosuppressants

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 titrriated 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 may 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 and 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.

 

Antiasthmatics 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.                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 is excreted into the breast milk in small amounts and is unlikely to be harmful.  However, rare hypersensitivity reactions have been reported with verapamil. For this reason, it should only be used during lactation if, in the clinician's judgement, it is essential for the welfare of the patient.

4.7.         Effects on Ability to Drive and Use Machines

 

None stated.

4.8.                Undesirable Effects

 

Securon IV is generally well tolerated but due to the drug’s mode of action, undesired cardiovascular effects may occur, particularly at high doses and in patients with AV block and/or impaired myocardial function. Decreased heart rate, hypotension and decreased myocardial contractility have been reported. On rare occasions, second or third degree AV 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.

A slight transient fall in blood pressure, due to a reduction in peripheral resistance, may be seen. In rare cases, this may lead to severe hypotension.

 

On rare occasions, dizziness, headache, nausea, vomiting, nervousness and flushing have been reported. Allergic reactions (erythema, pruritus, urticaria, bronchospasm) are extremely rare. A reversible impairment of liver function, characterised 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.

 

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. Gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.

 

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, 2^nd and 3^rd 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 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.

 

5                Pharmacological Properties

 

5.1.                Pharmacodynamic Properties

 

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

 

Following intravenous infusion in man, verapamil is eliminated bi-exponentially with a rapid distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2-5 hours). Plasma protein binding of verapamil is about 90%. Renal insufficiency does not affect the kinetics of verapamil.  In patients with liver cirrhosis, elimination half‑life is prolonged.

 

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 as pH adjuster.

 

6.2.                Incompatibilities

 

Securon IV is incompatible with alkaline solutions.

 

6.3.         Shelf Life

 

Ampoule: 60 months.

 

Syringe: 36 months.

 

6.4.         Special Precautions for Storage

 

Store at room temperature. Protect from light.

 

6.5.         Nature and Contents of Container

 

2 ml glass ampoule (hydrolytic type 1) containing 5 mg verapamil. Pack size:
5 ´ 2 ml ampoules.

 

2 ml pre-filled glass syringe (borosilicate type 1) with tip cap and butyl rubber stopper and polystyrene plunger. Pack size: 5 ´ 2 ml syringes.

 

6.6.       Special precautions for disposal of a used medicinal product

 

None.

 

7.                Marketing Authorisation Holder

 

                Abbott Laboratories Ltd

                Queenborough

                Kent

                ME11 5EL

United Kingdom

               

8.                Marketing Authorisation Number

 

PL 00037/0367

 

9.             Date of First Authorisation/Renewal of Authorisation

 

17 June 2003

 

10.          Date of (Partial) Revision of the Text

 

                To be updated. 02^{nd April 2009}

Plasma protein binding of verapamil is about 90%. Renal insufficiency does not affect the kinetics of verapamil.  In patients with liver cirrhosis, elimination half‑life is prolonged.-added