VERAPAMIL Film-coated tablets Ref.[7556] Active ingredients: Verapamil

Verapamil may affect left ventricular contractility as a result of its mode of action. The 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 should therefore only be administered after appropriate therapy for cardiac failure such as digitalis, etc.

Verapamil 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 stage 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.

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.

H₂ Receptor antagonists: Cimetidine increases serum levels of verapamil.

Anticonvulsants: Increased serum levels of carbamazepine which could lead to increased side-effects.

Reduced serum levels of verapamil when taken with phenytoin.

Barbiturates: Reduced serum levels of verapamil when taken with Phenobarbital.

Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect). There may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).

Alcohol: Verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

Antihypertensive drugs: Verapamil may have an additive effect with other antihypertensive drugs; thus, in many cases with verapamil, a reduction in the dosage of the other antihypertensive drug may be possible:

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.

Alpha blockers: Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.

Antiarrhythmics: 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).

Benzodiazepines and anxiolytics: Verapamil may increase the plasma concentrations of midazolam.

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 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.

Acetylsalicylic acid: Concomitant use of verapamil with aspirin may increase the risk of bleeding.

Dabigatran etexilate: When oral verapamil was co-administered with dabigitran etexilate (150mg), a P-gp substrate, the C_max 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 C_max 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 C_max 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.

Anti-infectives: Reduced serum levels of verapamil when taken with rifampicin.

Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.

Anaesthesia: Long-term verapamil therapy may give rise to potentiation of neuromuscular blocking agents during anaesthesia.

Interactions have been reported during the concomitant use of verapamil and the following medications:

Theophylline: Increased serum levels of theophylline which could lead to increased side-effects.

Immunosuppressants: Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus which could lead to increased side-effects.

Digoxin: Verapamil has been shown to increase the serum concentration of digoxin and caution should therefore be exercised with regard to digitalis toxicity.

Dantrolene: Concomitant use of verapamil with intravenous dantrolene may cause hypotension, myocardial depression, and hyperkalaemia. This combination should be avoided.

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.

Other: An increase in verapamil serum level has been reported when taken with grapefruit juice.

Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of verapamil to ivabradine (see section 4.3).

Animal studies have shown no teratogenic effect. Verapamil should not be administered during pregnancy unless, in the clinicians judgement, it is essential for the welfare of the patient. The possibility that verapamil can cause relaxation of the uterine muscle should be considered at term.

Verapamil is excreted in breast milk at concentrations approximately equal to 0.5-1.0 times that coexisting in maternal plasma. However, the amount ingested in such circumstances is less than 1% of the recommended therapeutic infant dose, assuming normal suckling rates.

Depending on individual susceptibility, the patient’s ability to drive or operate machines may be impaired due to feelings of drowsiness. This is particularly true in the initial stages of treatment, or when changing over from another drug. Verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

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

Nervous system disorders: headaches occur rarely, dizziness, paraesthesia, tremor, extrapyramidal syndrome (e.g. parkinsonism), dystonia.

Ear and labyrinth disorders: vertigo, tinnitus.

Cardiac disorders: bradycardic arrhythmias such as sinus bradycardia, sinus arrest with asystole, 2nd and 3rd degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure, hypotension.

Vascular disorders: flushing, peripheral oedema.

Gastrointestinal disorders: nausea, vomiting, constipation is not uncommon, ileus and abdominal pain/discomfort. Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods. This is fully reversible when the drug is discontinued.

Skin and subcutaneous tissue disorders: alopecia, ankle oedema, Quincke’s oedema, Steven-Johnson syndrome, erythema multiforme, erythromelalgia, 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. Gynaecomastia was observed on very rare occasions in elderly male patients under longer term verapamil treatment which was fully reversible in all cases when the drug was discontinued.

General disorders and administration site conditions: fatigue.

Investigations: On very rare occasions, a reversible impairment of liver function characterised by an increase in transaminases and/or alkaline phosphatase, may occur during verapamil treatment and is most probably a hypersensitivity reaction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

None known.