Securon

Half Securon SR

Verapamil Hydrochloride Ph Eur - 120 mg

Modified-release tablets.

The tablets are round, white, biconvex and embossed with the word 'Knoll' on one side and '120 SR' on the reverse.

Half 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.

For oral use only.

Half Securon SR tablets should be taken without sucking or chewing, with sufficient liquid, preferably with or shortly after meals.

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

Children

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

Liver impairment

In patients with impaired liver function, metabolism of the drug is delayed to a greater or lesser extent depending on the severity of hepatic dysfunction, thus potentiating and prolonging the effects of verapamil hydrochloride. Therefore, the dosage needs to be adjusted with special caution in patients with impaired liver function and low doses should be given initially (see Special Warnings and Precautions for Use Section).

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.

Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction).

Children

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

Liver impairment

In patients with impaired liver function, metabolism of the drug is delayed to a greater or lesser extent depending on the severity of hepatic dysfunction, thus potentiating and prolonging the effects of verapamil hydrochloride. Therefore, the dosage needs to be adjusted with special caution in patients with impaired liver function and low doses should be given initially (see Special Warnings and Precautions for Use Section).

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.

Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction).

Since verapamil is extensively metabolised in the liver, careful dose titration is required in patients with liver disease. 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.

Verapamil may affect impulse conduction and should therefore 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 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.

Use with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)

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.

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.

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.

Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.

ATC-Code: C08DA01

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.

Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolized. 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.

Absorption

Greater than 90% of verapamil is rapidly absorbed from the small intestine after oral administration. Mean systemic availability of the unchanged compound after a single dose of SR verapamil is approximately 33%, owing to an extensive hepatic first-pass metabolism. Bioavailability is about two times higher with repeated administration. Peak verapamil plasma levels are reached four to five hours after SR administration. The peak plasma concentration of norverapamil is attained approximately five hours after SR administration. The presence of food has no effect on the bioavailability of verapamil.

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 metabolized. In vitro metabolic studies indicate that verapamil is metabolized 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 oral administration, the elimination half-life is three to seven hours. Approximately 50% of an administered dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Special Populations

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:

The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.

Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 and 1.2 times respectively the maximum recommended human oral daily dose based on a body surface area comparison (mg/m²) and have revealed no evidence of teratogenicity. In the rat, however, a dose similar to the clinical dose was embryocidal and retarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and reduced weight gain of dams). This oral dose has also been shown to cause hypotension in rats.

Microcrystalline cellulose,

Sodium alginate,

Povidone K30,

Magnesium stearate,

Purified water,

Hypromellose 2910,

Macrogol 400,

Macrogol 6000,

Talc,

Titanium dioxide (E171),

Montan glycol wax.

None stated.

3 years.

Do not store above 25°C and store in the original package - blister pack.

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

No special requirements. The tablets should not be chewed or sucked.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Mylan Products Ltd.

20 Station Close

Potters Bar

Herts

EN6 1TL

United Kingdom

PL 46302/0025

14 March 2002

10^th May 2017