SECURON Solution for injection Ref.[7144] Active ingredients: Verapamil

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).

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 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 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 (C_max 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).

Other:

St. John’s Wort may reduce the plasma concentrations of verapamil, whereas grapefruit juice may increase the plasma concentrations of verapamil.

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.

None stated.

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.

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.

Securon IV is incompatible with alkaline solutions.