1. Name Of The Medicinal Product
VERTAB SR 240 TABLETS
2. Qualitative And Quantitative Composition
Verapamil hydrochloride 240 mg
Also contains microcrystalline cellulose and about 36 mg of sodium.
3. Pharmaceutical Form
Modified-release coated tablets
4. Clinical Particulars
4.1 Therapeutic Indications
Vertab SR 240 is indicated for the treatment of mild to moderate hypertension, and for the treatment and prophylaxis of angina pectoris.
4.2 Posology And Method Of Administration
Adults:
Hypertension: Most patients respond to 240 mg daily (one tablet) 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 Vertab SR 240 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 Vertab SR 240 with other anti-hypertensive agents, in particular diuretics.
Angina pectoris: One tablet of Vertab SR 240 twice daily. A small number of patients respond to a lower dose and where indicated, adjustment down to one tablet of Vertab SR 240 daily could be made.
Children: Vertab SR 240 is not recommended for children.
Elderly patients: The adult dose is recommended unless liver or renal function is impaired (see Precautions).
The tablets should not be chewed.
4.3 Contraindications
Cardiogenic shock; acute myocardial infarction complicated by bradycardia, marked hypotension, left ventricular failure; second or third degree atrioventricular block; sino atrial block; sick sinus syndrome; uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90 mm Hg systolic; concomitant ingestion of grapefruit juice.
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. 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 therefore Verapamil should be used with caution in patients with first degree atrioventricular 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.
4.5 Interaction 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 Verapamil and beta-blockers, antiarrhythmic agents or inhaled anaesthetics may lead to additive cardiovascular effects (e.g. auriculo-ventricular block, bradycardia, hypotension, heart failure). Intravenous beta-blockers should not be given to patients under treatment with Verapamil. The effect of Verapamil may be additive to other antihypertensive 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 may be 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.
- An increase in Verapamil serum level upon concomitant ingestion of grapefruit juice has been reported.
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 patients' ability to drive a vehicle or operate machinery may be impaired. This is particularly true in the initial stages of treatment, or when changing over from another drug. 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
Particularly when given in high doses or in the presence of previous myocardial damage, some cardiovascular effects of Verapamil may occasionally be greater than therapeutically desired: bradycardia, arrhythmias, such as sinus bradycardia, sinus arrest with asystole, second and third degree AV-block, bradyarrythmia in atrial fibrillation, hypotension, development or aggravation of heart failure.
Verapamil is generally well tolerated. Side effects are usually mild and transient and discontinuation of therapy is rarely necessary. Constipation may occur. There have been rare reports of flushing, headache, nausea, vomiting, dizziness, fatigue and ankle oedema. Allergic reactions (e.g. erythema, pruritus, urticaria, Quincke's oedema, Stevens Johnson syndrome) are very rarely seen. 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 gynecomastia has been observed in elderly male patients under long term Verapamil treatment, which was fully reversible in all cases when the drug was discontinued.
Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.
Erythromelalgia and paresthesia may occur. In very rare cases, there may be myalgia and arthralgia. Rises in prolactin levels have been reported.
4.9 Overdose
The course of symptoms in Verapamil intoxication depends on the amount taken, the time at which detoxication measures are taken and myocardial contractility (age related). The main symptoms are as follows: blood pressure fall (at time 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, sinus arrest.
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, it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. 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 Vertab SR 240 is suspected, extensive elimination measures are indicated, such as induced vomiting, removal of the content of the stomach and the small intestine under endoscopy, intestinal lavage, laxative, high enemas. The usual intensive resuscitation measures, 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 and 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 is a calcium antagonist which blocks the inward movement of calcium in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in the cells of the intracardiac conduction system. 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.
Verapamil lowers peripheral vascular resistance with little or no reflex tachycardia. Its efficacy in reducing raised blood pressure, both systolic and diastolic, is thought to be primarily due to this mode of action.
5.2 Pharmacokinetic Properties
Verapamil is well absorbed after oral tablet administration, but undergoes extensive first pass metabolism. Its bioavailability is 20-35%. The volume of distribution is about 5 liters/kg and plasma protein binding is 90%. Only 3% of a Verapamil dose is excreted in the urine as the unmetabolised drug.
5.3 Preclinical Safety Data
Verapamil HCl is a well-established drug for which there is adequate published safety data. This application is an abridged authorization application submitted under article 4.8a (iii) of Directive 65/65/EEC and therefore preclinical data has not been submitted.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium alginate, Microcrystalline cellulose 2208, Povidone, Hydroxypropyl methylcellulose, Colloidal anhydrous silica, and Magnesium stearate.
Each tablet contains approximately 36 mg of sodium.
Film coating constituents: Hydroxypropyl methylcellulose 2910, Titanium dioxide, Polyethylene glycol 400, D & C Yellow No. 10 Aluminium Lake E-104, Indigo Carmine Aluminium Lake E-132 FD & C Blue No 2, Carnauba wax.
6.2 Incompatibilities
None
6.3 Shelf Life
36 months
6.4 Special Precautions For Storage
Store at or below 25oC
6.5 Nature And Contents Of Container
Blister pack: PVC or PVDC-coated-PVC/Aluminium foil.
28 tablets
6.6 Special Precautions For Disposal And Other Handling
No specific statement.
ADMINISTRATIVE DATA
7. Marketing Authorisation Holder
Dexcel-Pharma Ltd,
1 Cottesbrooke Park
Heartlands Business Park
Daventry, Northamptonshire NN11 5YL
United Kingdom
8. Marketing Authorisation Number(S)
PL 14017/0025
9. Date Of First Authorisation/Renewal Of The Authorisation
12 November 1998
10. Date Of Revision Of The Text
October 2001
11. LEGAL CATEGORY
POM
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