Verapamil Other names: Verapamil hydrochloride

St. John’s Wort may reduce the plasma concentrations of verapamil.

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. Coadministration of verapamil with a drug known to be primarily metabolized by CYP3A4 or known to be a P‐gp substrate may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.

In patients with impaired liver function, metabolism of the drug is delayed to a greater or lesser extent depending on the severity of hepatic dysfunction, thus potentiating and prolonging the effects of verapamil hydrochloride. Therefore, the dosage needs to be adjusted with special caution in patients with impaired liver function and low doses should be given initially.

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.

Increase in blood alcohol has been reported.

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).

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.

Metoprolol: ↑ metoprolol AUC (~32.5%) and C_max (~41%) in angina patients.

Propranolol: ↑ propranolol AUC (~65%) and C_max (~94%) in angina patients.

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. Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.

Clinical data and animal studies suggest that verapamil hydrochloride may potentiate the activity of neuromuscular blocking agents (curare‐like and depolarizing). It may be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

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).

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

Verapamil may increase the plasma concentrations of almotriptan.

Verapamil may increase the plasma concentrations of buspirone and midazolam.

Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness.

Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus. Concentration determinations and dose adjustments of everolimus and sirolimus may be necessary.

Cimetidine may increase the plasma concentrations of verapamil.

Clarithromycin may increase the plasma concentrations of 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. Reduce colchicine dose.

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.

Increased absorption of DOACs since they are P‐gp substrates and, if applicable, also reduced elimination of DOACs which are metabolized by Cyp3A4, may increase the systemic bioavailability of DOACs.

Some data suggest a possible increase of the risk of bleeding, especially in patients with further risk factors.

Verapamil may increase the plasma concentration of digitoxin.

↓ digitoxin total body clearance (~27%) and extrarenal clearance (~29%).

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.

Healthy subjects:

↑ C_max (~44%)
↑ digoxin C_12h (~53%)
↑ C_ss (~44%) and ↑ AUC (~50%)

Until data on possible interactions between verapamil hydrochloride and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil hydrochloride administration.

Verapamil may increase the plasma concentrations of doxorubicin.

↑ doxorubicin AUC (104%) and C_max (61%) with oral verapamil administration.

No significant change in doxorubicin PK with intravenous verapamil administration.

Erythromycin may increase the plasma concentrations of verapamil.

Verapamil may increase the plasma concentrations of glibenclamide (glyburide).

Verapamil may increase the plasma concentrations of imipramine.

Serum levels of lithium may be reduced. However there may be increased sensitivity to lithium causing enhanced neurotoxicity. Patients receiving both drugs should be monitored carefully.

Co-administration of verapamil with metformin may reduce the efficacy of metformin.

Phenobarbital may reduce the plasma concentrations of verapamil.

↑ oral verapamil clearance (~5‐fold).

Phenytoin may decrease the plasma concentrations of verapamil.

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

Rifampicin may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect. When verapamil and rifampicin are administrated together there is no change in PK.

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.

Blood pressure lowering effect may be reduced.

No change in PK with intravenous verapamil administration.

Telithromycin may increase the plasma concentrations of verapamil.

Verapamil may increase the plasma concentrations of theophylline.

Verapamil hydrochloride should be used with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert‐Eaton syndrome, advanced Duchenne muscular dystrophy). Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of verapamil.

Verapamil may affect impulse conduction and therefore verapamil solution should be used with caution in patients with bradycardia or first degree AV block.

Use with caution in acute myocardial infarction complicated by bradycardia, marked hypotension, or left ventricular dysfunction.

Heart failure patients with ejection fraction higher than 35% should be compensated before starting verapamil treatment and should be adequately treated throughout.

Teratogenic Effects

There are no adequate and well‐controlled study data in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Because animal reproduction studies are not always predictive of human response, during pregnancy (especially in the first trimester), verapamil should only be used if considered essential by the physician. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Verapamil hydrochloride/metabolites are excreted in human milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1‐1% of the mother’s oral dose) and that verapamil use may be compatible with breastfeeding.

A risk to the newborns/infants cannot be excluded. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.

Due to its antihypertensive effect, depending on the individual response, verapamil hydrochloride may affect the ability to react to the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This applies all the more at the start of treatment, when the dose is raised, when switching from another drug and in conjunction with alcohol. Verapamil may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

The following adverse events reactions have been reported with verapamil from clinical studies, postmarketing surveillance or Phase IV clinical trials and are listed below by system organ class.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

The most commonly reported ADRs were: headache, dizziness, gastrointestinal disorders: nausea, constipation and abdominal pain, bradycardia, tachycardia, palpitations, hypotension, flushing, oedema peripheral, fatigue.

Adverse reactions reported from clinical studies with verapamil and post-marketing surveillance activities:

¹ There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood‐brain barrier due to CYP3A4 and P‐gp inhibition by verapamil.