Summary of Product Characteristics

1.             Trade Name of the Medicinal Product

Securon SR

2.                Qualitative and Quantitative Composition

Verapamil Hydrochloride Ph Eur – 240 mg

3.                Pharmaceutical Form

Modified-release tablets.

The tablets are oblong, pale green, scored and embossed with two Knoll logos (triangles) on one side.

4.             Clinical Particulars

4.1.                Therapeutic Indications

Securon SR is indicated for:

The treatment of mild to moderate hypertension.

The treatment and prophylaxis of angina pectoris.

Secondary prevention of reinfarction after an acute myocardial infarction in patients without heart failure, and not receiving diuretics (apart from low-dose diuretics when used for indications other than heart failure), and where beta-blockers are not appropriate.  Treatment is to be started at least one week after an acute myocardial infarction.

4.2.                Posology and Method of Administration

Securon SR tablets should not be chewed. Securon SR tablets are scored and may be halved without damaging the modified-release formulation.

Adults

Hypertension:  One tablet of Securon SR daily. For patients new to verapamil therapy, the physician should consider halving the initial dose to 120 mg (one tablet Half Securon SR).  Most patients respond to 240 mg daily (one tablet Securon SR) given as a single dose. If control is not achieved after a period of at least one week, the dosage may be increased to a maximum of two Securon SR tablets daily (one in the morning and one in the evening at an interval of about twelve hours).  A further reduction in blood pressure may be achieved by combining Securon SR with other antihypertensive agents, in particular diuretics.  Half Securon SR may be used for dose titration purposes.

Angina pectoris:  One tablet of Securon SR twice daily.  A small number of patients respond to a lower dose and where indicated, adjustment down to one tablet of Securon SR daily could be made. Half Securon SR may be used for dose titration purposes.

Secondary prevention of reinfarction after an acute myocardial infarction in patients without heart failure, and not receiving diuretics (apart from low-dose diuretics when used for indications other than heart failure), and where beta-blockers are not appropriate:  Treatment is to be started at least one week after an acute myocardial infarction.  360 mg/day in divided doses, to be taken either as one Half  Securon SR (120 mg) tablet three times daily, or as one Securon SR (240 mg) tablet in the morning and one Half Securon SR (120 mg) tablet in the evening, on a daily basis.

Elderly patients

The adult dose is recommended unless renal or hepatic function is impaired (see Section 4.4, ‘Special Warnings and Precautions for Use’).

Children

Securon SR and Half Securon SR are not recommended for children.

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 atrioventricular (AV) block (except in patients with a functioning artificial pacemaker); sino-atrial block; sick sinus syndrome (except in patients with a functioning artificial pacemaker);  uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90 mmHg systolic.

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.

Concomitant ingestion of grapefruit juice.

4.4.         Special Warnings and Precautions for Use

Since verapamil is extensively metabolised in the liver, careful dose titration is required in patients with liver disease.  The disposition of verapamil in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended.  Verapamil is not removed during dialysis.

Verapamil may affect impulse conduction and should therefore be used with caution in patients with bradycardia or first degree AV block.  Patients with atrial flutter/fibrillation in association with an accessory pathway (e.g. WPW-syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.  Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated.  In patients with incipient cardiac failure, therefore, verapamil should be given only after such cardiac failure has been controlled with appropriate therapy, e.g. digitalis.

When treating hypertension with verapamil, monitoring of the patient's blood pressure at regular intervals is required.

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 Medicaments 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 verapamil and beta-blockers, antiarrhythmic agents or inhaled anaesthetics 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.  The effects of verapamil may be additive to other hypotensive agents.

Interactions between verapamil and the following medications have been reported:

Carbamazepine, cyclosporin and theophylline  -  use of verapamil has resulted in increased serum levels of these medications, which could lead to increased side effects.

Rifampicin, phenytoin and phenobarbital  -  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).

Cimetidine  -  increase in verapamil serum level is possible.

Neuromuscular blocking agents employed in anaesthesia  -  the effects may be potentiated.

Grapefruit juice – increase in verapamil serum level has been reported.

Alcohol – increase in blood alcohol has been reported.

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 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

               

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 which may lead to hypotension.  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. 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).

               

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.  Erythromycin 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.

 

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 titrariated 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.

Serotonin receptor agonists

Verapamil may increase the plasma concentrations of almotriptan.

 

AntiasthmaticsTheophylline

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 and therefore 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

 

Depending on individual susceptibility, the patient’s ability to drive a vehicle, operate machinery or work under hazardous conditions may be impaired.  This is particularly true in the initial stages of treatment, when changing over from another drug or when the dose is raised.  Like many other common medicines, verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8.                Undesirable Effects

 

Reactions from Postmarketing Surveillance or Phase IV Clinical Trials

The following adverse events reported with verapamil are listed below by system organ class:     

Immune system disorders: allergic reactions (e.g. erythema, pruritus, urticaria) are very rarely seen.

 

Nervous system disorders: headache, dizziness, paresthesia, tremor and extrapyramidal syndrome.

 

Ear and labyrinth disorders: vertigo and tinnitus.

 

Cardiac disorders/vascular disorders: bradycardic arrhythmias such as sinus bradycardia, sinus arrest with asystole, 2^nd and 3^rd degree AV block, bradyarrhythmia in atrial fibrillation, peripheral oedema, palpitations, tachycardia, development or aggravation of heart failure and hypotension.  There have been rare reports of flushing.

 

Gastrointestinal disorders: nausea, vomiting, constipation, ileus and abdominal pain/discomfort.  Gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued. 

 

Skin and subcutaneous tissue disorders: ankle oedema, Quincke’s oedema, Steven-Johnson syndrome, erythema multiforme, erythromelalgia, alopecia and purpura.

 

Musculoskeletal and connective tissue disorders: muscular weakness, myalgia and arthralgia.

 

Reproductive system and breast disorders: impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment, and is fully reversible in all cases when the drug was discontinued.

 

General disorders and administration site conditions: fatigue.

 

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. Rises in blood prolactin levels have been reported. 

 

4.9.                Overdose

 

The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related). The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, 1st and 2nd degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, bradycardia up to high degree AV block and, sinus arrest, hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose.

 

The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms.  In intoxications with large amounts of slow-release preparations (Securon SR and Half Securon SR), it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours.  Verapamil hydrochloride cannot be removed by haemodialysis.  Depending on the time of ingestion, it should be taken into account that there may be some lumps of incompletely dissolved tablets along the entire length of the gastrointestinal tract, which function as active drug depots. 

General measures to be taken: Gastric lavage with the usual precautions, even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable.  Where intoxication by Securon SR or Half Securon SR is suspected, extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage, laxative, high enemas. The usual intensive resuscitation measures apply, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy. 

Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10 ‑20 ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour).

The following measures may also be necessary: In case of 2nd or 3rd degree AV block, sinus bradycardia, asystole - atropine, isoprenaline, orciprenaline or pacemaker therapy.  In case of hypotension - dopamine, dobutamine, noradrenaline. If there are signs of continuing myocardial failure - dopamine, dobutamine, if necessary repeated calcium injections.

5.                Pharmacological Properties

 

5.1.                Pharmacodynamic Properties

 

Verapamil, a phenylalkylamine calcium antagonist, has a balanced profile of cardiac and peripheral effects.  It lowers heart rate, increases myocardial perfusion and reduces coronary spasm.  In a clinical study in patients after myocardial infarction, verapamil reduced total mortality, sudden cardiac death and reinfarction rate.

Verapamil reduces total peripheral resistance and lowers high blood pressure by vasodilation, without reflex tachycardia.  Because of its use‑dependent action on the voltage-operated calcium channel, the effects of verapamil are more pronounced on high than on normal blood pressure.

As early as day one of treatment, blood pressure falls; the effect is found to persist also in long‑term therapy. Verapamil is suitable for the treatment of all types of hypertension: for monotherapy in mild to moderate hypertension; combined with other antihypertensives (in particular with diuretics and, according to more recent findings, with ACE inhibitors) in more severe types of hypertension.  In hypertensive diabetic patients with nephropathy, verapamil in combination with ACE inhibitors led to a marked reduction of albuminuria and to an improvement of creatinine clearance.

5.2.                Pharmacokinetic Properties

 

Absorption: More than 90% of an orally-administered dose of verapamil is absorbed. Due to an intensive hepatic first‑pass metabolism, the absolute bioavailability is about 22% with a variability of about 10 ‑ 35%.  Under multiple dosing, bioavailability increases by about 30%.  Bioavailability is not affected by food consumption.

Distribution, biotransformation and elimination: Plasma concentrations reach their peak 4 - 8 hours after drug intake. Plasma protein binding of verapamil is about 90%. The elimination half‑life is about 5 ‑ 8 hours. The mean residence time of modified-release verapamil is 13 hours.  After repeated single daily doses, steady-state conditions are reached between 3 - 4 days.

Within 5 days, approximately 70% of an orally-administered dose is excreted in the urine and about 16% with the faeces.  Only 3 - 4 % is eliminated renally as unchanged drug.  The drug is extensively metabolized. A number of metabolites are generated in humans (twelve have been identified). 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). Norverapamil represents about 6% of the dose eliminated in urine. Norverapamil can reach steady‑state plasma concentrations approximately equal to those of verapamil itself. Renal insufficiency does not affect the kinetics of verapamil.

At-risk patients: In patients with liver cirrhosis, bioavailability is increased and elimination half‑life is prolonged.  In patients with compensated hepatic insufficiency, no influence on the kinetics of verapamil was observed.

5.3.                Preclinical Safety Data

 

None stated.

 

6.                Pharmaceutical Particulars

 

6.1.         List of Excipients

 

Microcrystalline cellulose, sodium alginate, povidone, magnesium stearate, purified water, hydroxypropyl methylcellulose, polyethylene glycol 400, polyethylene glycol 6000, talc, titanium dioxide (E171), l-green lake [quinoline yellow (E104) and indigo carmine (E132)], montan glycol wax.

6.2.                Incompatibilities

 

None stated.

 

6.3.         Shelf Life

 

5 years.

 

6.4.         Special Precautions for Storage

 

Do not store above 25^oC and store in the original package – blister pack.

 

Do not store above 25^oC and keep the container tightly closed – bottle pack.

 

6.5.         Nature and Contents of Container

 

Calendar pack consisting of a PVC/PVDC blister in a cardboard outer container.  Pack size: 28 tablets.

 

Polypropylene bottle with polyethylene stopper.  Pack size: 100 tablets.

 

6.6.         Special precautions for disposal of a used medicinal product

 

                There are no specific instructions for use/handling. The tablets should not be chewed, but may be halved without affecting the modified-release form.

 

 

7.                Marketing Authorisation Holder

 

Abbott Laboratories Limited

Queenborough

Kent

ME11 5EL

United Kingdom

 

8.                Marketing Authorisation Number

 

PL 00037/0369

 

 

9.             Date of First Authorisation/Renewal of Authorisation

 

14 March 2002

 

10.                Date of (Partial) Revision of the Text

 

To be updated. 02^{nd April 2009}