SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Vera-Til SR Tablets 240mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

240mg Verapamil hydrochloride

3    PHARMACEUTICAL FORM

Modified release film coated tablet Oblong, light-green, with scores on both sides

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of mild to moderate hypertension.

The treatment and prophylaxis of angina pectoris.

Secondary prevention of re-infarction 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

Adults

Hypertension: The usual dose is one tablet of Vera-Til SR 240mg daily. For patients new to verapamil therapy the doctor should consider halving the dose to one Vera-Til SR 120mg tablet daily. Most patients respond to 240mg daily given as a single dose. If control is not achieved within at least one week the dosage may be increased to a maximum of two Vera-Til SR 240mg tablets daily (one taken in the morning and one in the evening at an interval of about 12 hours). Other anti-hypertensive agents, in particular diuretics, may be used in combination with Vera-Til SR tablets to achieve further reduction in blood pressure.

Angina pectoris: The usual dose is one tablet of Vera-Til SR 240mg twice daily. A small number of patients respond to a lower dose and where indicated, adjustment down to one Vera-Til SR 240mg tablet daily could be made, using Vera-Til SR 120mg tablets for dose titration purposes.

Secondary prevention of re-infarction 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. 360mg/day in divided doses, to be taken either as 120mg three times daily, or as 240mg to be taken in the morning and 120mg to be taken in the evening, on a daily basis.

Elderly

The adult dose is recommended, except in patients with impaired liver or renal function or cardiac conduction problems, where a reduced dosage may be necessary (see “Precautions”).

Vera-Til SR Tablets are to be swallowed whole with some liquid.

Verapamil therapy should be discontinued gradually after long-term treatment.

Paediatric population

The safety and efficacy of Vera-Til SR tablets in children and adolescents have not been established. No data are available.

Vera-Til SR tablets are not recommended for children and adolescents.

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 atrioventricular 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 mm Hg systolic

Patients with atrial fibrillation/flutter with simultaneously existing of an an accessory pathway e.g. Wolff-Parkinson-White syndrome, may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.

4.4 Special warnings and precautions for use

Since verapamil is extensively metabolised in the liver, careful dose titration of verapamil 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 therefore should 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 often 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)

4.5 Interaction with other medicinal products and other forms of interaction

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 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. 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, clarithromycin 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.

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).

Ivabradine

Verapamil increases plasma concentration of ivabradine —avoid concomitant use 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, 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.

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 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 is excreted into the 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. Due to the potential for serious adverse reactions and rarely hypersensitivity reactions in nursing infants with verapamil, , it should only be used during lactation if, in the clinician’s judgement, it is essential for the welfare of the mother.

4.7 Effects on ability to drive and use machines

Depending on individual susceptibility, the patient’s ability to drive a vehicle or 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 medication 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, 2nd and 3rd 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 intoxification depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age related). The main symptoms are:

- blood pressure drop (at times to values not detectable), shock symptoms, loss of consciousness, 1st and 2nd degree AV block (frequently as Wenkebach’s phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, sinus bradycardia up to high degree AV block, 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 intoxication with large amounts of slow release preparations such as Vera-Til SR 240mg tablets, 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 gastro-intestinal 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 Verapamil 240mg and 120mg 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: elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10-20ml of a 10% calcium gluconate solution administered intravenously (2.25-4.5mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5mmol/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 gluconate injections.

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 the cells of the intracardiac conduction system. Verapamil lowers peripheral vascular resistance with no reflex tachycardia. Its efficacy in reducing both raised systolic and diastolic blood pressure is thought to be due to this mode of action. The decrease in systemic and coronary vascular resistance and the sparing effect on intracellular oxygen consumption appear to explain the anti-anginal properties of the drug. 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

After oral administration, 80-90% of verapamil is rapidly absorbed from the small intestine. The systemic availability of the unchanged substance is only approximately 20% due to a marked first pass metabolism. The maximum plasma concentration (C_max) of verapamil is achieved 1-2 hours after oral administration. The proportion of verapamil bound to plasma proteins is 90%.

The active agent is metabolised into a large number of products to a high degree. Only one of these metabolites, norverapamil, demonstrates a low extent of efficacy of 20% in comparison with the parental agent.

The elimination half-life is 3-7 hours. A delayed elimination of verapamil must be expected in patients with cirrhosis of the liver.

70% of verapamil administered is excreted predominantly in the form of metabolites via the urine, the unchanged proportion is 3-4%. Hence, the pharmacokinetics of verapamil are not influenced by renal insufficiency. Up to 16% is excreted with the faeces.

5.3 Preclinical safety data

A long-term toxicological study in rats gave no evidence that verapamil has any tumorigenic potential. In vitro and in vivo studies have shown that verapamil does not exert any mutagenic effects.

Embryotoxic studies in rabbits and rats at daily doses of up to 15mg/kg and 60mg/kg respectively gave no evidence of teratogenic potential. However, embryotoxic effects were observed in rats at this dosage level, which already proved toxic for the maternal animals.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core:

Sodium alginate 80cP x H₂O Microcrystalline cellulose 90pm Povidone

Magnesium stearate Colloidal anhydrous silica

Film-coating:

Opadry, white:

Lactose monohydrate Hypromellose Titanium dioxide (E171)

Macrogol 4000 Yellow ferric oxide (E172)

6.2    Incompatibilities

None known

6.3    Shelf life

36 months

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

Nature and Contents of Container