Summary of medicine characteristics - VERAPAMIL HYDROCHLORIDE BP TABLETS 40 MG
1 NAME OF THE MEDICINAL PRODUCT
Verapamil Hydrochloride BP Tablets 40mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 40mg tablet contains verapamil hydrochloride BP 40mg
Excipients with known effect
Each tablet contains 28mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
Yellow, round, biconvex tablets plain on both the sides with an approximate diameter of 7 mm.
4 CLINICAL PARTICULARS
4 CLINICAL PARTICULARS4.1 Therapeutic indications
Verapamil hydrochloride is useful in:
1. the treatment and prophylaxis of angina pectoris, and variant angina;
2. the treatment and prophylaxis of paroxysmal supraventricular tachycardia and atrial flutter/fibrillation (verapamil should not be used when atrial flutter/fibrillation complicates Wolff-Parkinson-White syndrome); and
3. the treatment of mild to moderate hypertension.
4.2 Posology and method of administration
Elderly or patients with impaired liver or kidney function, or cardiac conduction problems may require a reduced dosage.
Angina:
| Adults: | 120mg, 3 times daily is recommended. Some patients with angina of effort may respond to 80mg, 3 times daily, but this dose is not likely to be effective in angina at rest and variant angina. |
Supraventricular tachycardias:
| Adults: | 40mg to 120mg, 3 times daily according to the severity of the condition. |
| Children, 2 years and above: | 40mg to 120mg, 2 to 3 times daily, according to age and effectiveness. |
Hypertension:
| Adults: | 160mg twice daily. A small number of patients may be controlled successfully on 120mg twice daily, whereas others may require up to 480mg daily, given in divided doses. A further reduction in blood pressure may be obtained by combining Verapamil Tablets with other antihypertensive agents, eg thiazide diuretics. Verapamil hydrochloride and beta-blockers may be additive, both with respect to conduction and contraction. Verapamil hydrochloride should, therefore, be given with care to those who are receiving beta-blockers. |
| Children: | Up to 10mg/kg/day, in divided doses, according to the severity of the condition. |
| Method of administration: | Oral. |
4.3 Contraindications
Hypersensitivity to the active substance or any of the other excipients listed in section 6.1.
Hypotension (of less than 90mmHg systolic).
Second or third degree atrioventricular block, sick sinus syndrome (except in patients with a functioning artificial pacemaker), uncompensated heart failure marked bradycardia (less than 50 beats/minute).
Combination with beta-blockers is contraindicated in patients with poor ventricular function.
Wolff-Parkinson-White Syndrome.
Concomitant ingestion of grapefruit juice is contraindicated.
Acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure.
Combination with ivabradine (see section 4.5)
4.4 Special warnings and precautions for use
Verapamil hydrochloride may affect left ventricular contractility as a result of its mode of action. This effect is small and not normally important, however, cardiac failure may be aggravated or precipitated if it exists. In cases with poor ventricular function, verapamil hydrochloride should only be administered after appropriate therapy for cardiac failure such as digitalis, etc.
Verapamil hydrochloride may affect impulse conduction and should be administered with caution in patients with first degree atrioventricular block. The effects of verapamil and beta-blockers or other drugs may be additive both in respect of conduction and contraction, therefore care should be exercised when these are administered concurrently or closely together. This is especially true when either drug is administered intravenously.
Caution should be observed in the acute phase of myocardial infarction.
Patients with atrial fibrillation/flutter and an accessory pathway (e.g. Wolff-Parkinson-White syndrome) may rarely develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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.
Concomitant use of verapamil with aspirin may increase the risk of bleeding
Verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.
Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.
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).
Increased serum levels of carbamazepine which could lead to increased sideeffects. Reduced serum levels of verapamil when taken with phenytoin.
Verapamil may have an additive effect when given with other antihypertensive drugs, thus in many cases with verapamil, and a reduction in the dosage of the other antihypertensive drug may be possible.
Reduced serum levels of verapamil when taken with rifampicin. Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.
Long-term verapamil therapy may give rise to potentiation of neuromuscular blocking agents during anaesthesia.
Reduced serum levels of verapamil when taken with Phenobarbital.
Verapamil may increase the plasma concentrations of midazolam.
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 on verapamil.
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.
Dabigatran etexilate
When oral verapamil was co-administered with dabigatran etexilate (150mg), a P-gp substrate, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on time between administration and the formulation of verapamil. When verapamil 120mg immediate-release was co-administered one hour before a single dose of dabigatran etexilate, the dabigatran Cmax was increased by about 180% and AUC by about 150%. No meaningful interaction was observed when verapamil was administered 2 hours after dabigatran etexilate (increase of Cmax by about 10% and AUC by about 20%).
Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
Verapamil has been shown to increase the serum concentration of digoxin and caution should therefore be exercised with regard to digitalis toxicity.
Concomitant use of verapamil with intravenous dantrolene may cause hypotension, myocardial depression, and hyperkalaemia. This combination should be avoided.
H2 Receptor antagonists
Cimetidine may increase the serum levels of verapamil.
Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus, which could lead to increased side-effects.
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.
Serum levels of lithium may be reduced (pharmacokinetic effect). There may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).
Increased serum levels of theophylline which could lead to increased side effects.
5. PHARMACOLOGICAL PROPERTIES
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose, lactose monohydrate, maize starch, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose (E464), quinoline yellow (E104) and titanium dioxide (E171).
6.2 Incompatibilities
None stated.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Store in a cool dry place.
6.5 Nature and contents of container
Blisters of 250^m Opaque PVC and Aluminium Foil.
Pack sizes: 28, 30, 56, 60, 84, 90, 100, 112 and 120 tablets.
6.6
Special precautions for disposal Not applicable.
7 MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited
Unit G4,
Riverside Industrial Estate,
Riverside Way,
Dartford
DA1 5BS
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0084
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10 June 1987 / 16 June 1992