studies indicate that verapamil hydrochloride is metabolised 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 hove 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 listing provides a list of potential interactions with verapamil: See Table 3.
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Other drug interactions and additional drug interaction information:
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 and the dose of verapamil may be decreased.
Correspondingly, verapamil hydrochloride may induce increased plasma level of these medicinal agents by influencing degradation.
Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil hydrochloride-lithium therapy with either no change or an increase in serum lithium levels.
The addition of verapamil hydrochloride, however, has also resulted in the lowering of the serum lithium levels in patients receiving chronic oral lithium. Patients receiving both medicinal products should therefore be monitored carefully.
Clinical data and animal studies suggest that verapamil hydrochloride may potentiate the activity of muscle relaxants (curare-like and depolarising). It may be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocking agent when the medicinal products are used concomitantly.
Increased haemorrhagic diathesis.
Delayed ethanol elimination and elevation of ethanol plasma levels, resulting in enhanced effect of alcohol by verapamil.
HMG Co-A reductase inhibitors ("statins"):
In patients taking verapamil, treatment with HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) 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), a reduction in the statin dose should be considered, whereby the dose should be re-titrated based on serum cholesterol concentrations.
If verapamil and simvastatin are used concurrently at higher doses, the risk of myopathy/rhabdomyolysis is increased. The dose of simvastatin should be adjusted accordingly (see Precautions).
Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil.
Antihypertensives, diuretics, vasodilators:
Increase of the antihypertensive effect with risk of accelerated fall in blood pressure.
Anti-arrhythmics (e.g. Flecainide, disopyramide), beta-adrenergic blocking agents (e.g. metoprolol, propranolol), inhalation anaesthetics:
Reciprocal increase in cardiovascular effects (higher-degree AV block, higher-degree decrease in the heart rate, occurrence of cardiac insufficiency, potentiated fall in blood pressure).
Beta-blockers must not be used concurrently intravenously in patients treated with verapamil (except intensive care medicine) (see Contraindications).
Concomitant administration of intravenous verapamil hydrochloride with anti-adrenergic substances can result in exaggerated hypotensive response. Especially in patients with a history of cardiovascular disease, e.g. severe cardiomyopathy, congestive heart failure or recent myocardial infarction, the risk of this side effect was increased with concomitant administration of intravenous beta-blocker or disopyramide with intravenous verapamil as both substance classes reduce the myocardial contractility and AV-conduction (see Adverse Reactions).
Concomitant use with ivabradine is contraindicated due to the additional heart rate-lowering effect of verapamil to ivabradine (see Contraindications).