Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Essential Pharma Ltd, 7 Egham Business Village, Crabtree Road, Egham, Surrey, TW20 8RB, UK
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 verapamil solution 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 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.
Verapamil is extensively metabolised in the liver and special care should be taken in cases where liver damage exists, as plasma levels of verapamil may be increased (See section 4.2)
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 on the lowest possible dose of verapamil and titrated upwards. If verapamil treatment is to be added to patients already taking HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), refer to the 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).
This product contains:
Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.
In vitro metabolic 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 have been reported with inhibitors of CYP3A4 (such as ketoconazole, erythromycin and ritonavir) 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.
Interactions between verapamil and the following medications have been reported:
Acetylsalicylic acid: Concomitant use of verapamil may increase the risk of bleeding.
Alcohol: Plasma concentration may be increased (see Effects on ability to drive and use machines)
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).
Anticoagulants: When oral verapamil was co-administered with dabigatran etexilate (150 mg), 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. Co-administration of verapamil 240 mg extended-release at the same time as dabigatran etexilate resulted in increased dabigatran exposure (increase of Cmax by about 90% and AUC by about 70%).
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.
Anticonvulsants: Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness. Levels of verapamil may be reduced when taken with 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 concentration 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 has been shown to increase the serum concentration of digoxin and digitoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.
Cimetidine: Increase in verapamil serum level is possible.
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, Pglycoprotein (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.
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.
HMG Co-A Reductase Inhibitors (Statins): Verapamil may increase the plasma concentrations of simvastatin, atorvastatin and lovastatin. 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 re-titrate against serum cholesterol concentrations.
There is no direct in vivo clinical evidence of an interaction between atorvastatin and verapamil; however there is a 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 metabolised by CYP 3A4 and are less likely to interact with verapamil.
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).
Intravenous dantrolene: The association of this muscle relaxant given intravenously and verapamil is potentially dangerous (can cause fatal ventricular fibrillation in animals) and is contraindicated.
Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect); there may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).
Neuromuscular blocking agents employed in anaesthesia: The effects may be potentiated. The effects of verapamil may be additive to other hypotensive agents.
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 Cardiac therapy: Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of verapamil to ivabradine (see section 4.3).
Other: St. John’s Wort may reduce the plasma concentrations of verapamil, whereas grapefruit juice may increase the plasma concentrations of verapamil.
Co-administration of verapamil with metformin may reduce the efficacy of metformin.
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.
No information is available regarding the effects of verapamil on fertility.
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, or when changing over from another medication. 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.
Verapamil is generally well tolerated. Side effects are usually mild and transient and discontinuation of therapy is rarely necessary.
Immune System Disorders: Allergic reactions (e.g. erythema, pruritus, urticaria, Quincke’s oedema, StevensJohnson syndrome, erythema multiforme, alopecia and purpura) are very rarely seen.
Nervous System Disorders: Tremor and extrapyramidal syndrome. Headaches and dizziness have been reported rarely. Paraesthesia may occur.
Ear and Labyrinth Disorders: Vertigo and tinnitus.
Cardiac Disorders: 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: bradycardic arrhythmias, such as sinus bradycardia, sinus arrest with asystole, second and third degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure.
Vascular Disorders: Peripheral oedema, hypotension. Flushing is observed occasionally. Erythromelalgia may occur.
Gastrointestinal Disorders: Constipation may occur. Nausea, vomiting, ileus, abdominal pain/discomfort have been reported rarely.
Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.
Hepatobiliary Disorders: A reversible impairment of liver function, characterised by an increase in transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction.
Musculoskeletal and Connective Tissue Disorders: In very rare cases, there may be 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, which was fully reversible in all cases when the drug was discontinued. Rises in prolactin levels have been reported.
General Disorders and Administration Site Conditions: Fatigue and ankle oedema have been reported rarely.
Investigations: Rises in blood prolactin levels have been reported.
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA, Yellow Card in the Google Play or Apple App Store.
Not applicable.
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