Verapamil

Mechanism

Verapamil inhibits the CYP3A4 enzyme and the P-glycoprotein transporter (verapamil SmPC), the two colchicine clearance pathways. With verapamil, colchicine exposure (area under the curve, AUC) doubles and peak concentration rises 1.3-fold (verapamil SmPC). The risk of myopathy, neuropathy and bone marrow suppression grows; one case of tetraparesis has been reported with this combination (verapamil SmPC).

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards, and names verapamil in its interactions section (colchicine SmPC). The verapamil SmPC requires a lower colchicine dose (verapamil SmPC). US labels allow the combination only if there is no alternative and only with a reduced colchicine dose: for gout flare prophylaxis 0.3 mg twice daily or 0.6 mg once daily instead of 0.6 mg twice daily, for a flare 1.2 mg as a single dose, repeated no earlier than 3 days later (colchicine label, US Food and Drug Administration, FDA). In renal or hepatic impairment the combination is avoided (colchicine SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Verapamil inhibits renal OCT2 transporter that clears dofetilide. Dofetilide doubles, QT prolongs. FDA Tikosyn Section 4.3 strict contraindication.

Symptoms

Torsades de pointes within hours.

Management

Combination contraindicated.

Mechanism

CYP3A4 is the only enzyme that clears ivabradine. Verapamil is a moderate CYP3A4 inhibitor and also slows the sinus rhythm on its own. In interaction studies verapamil or diltiazem raised ivabradine exposure 2- to 3-fold (AUC) and lowered the heart rate by a further 5 beats per minute (ivabradine SmPC, EMA, section 4.5). The two effects add up: more ivabradine in the blood plus a second rate-lowering drug on top.

Symptoms

Marked bradycardia: resting heart rate below 50 beats per minute, dizziness, fatigue, hypotension (ivabradine SmPC, EMA, section 4.4). Conduction disturbances: sinoatrial or atrioventricular block, sinus arrest (ivabradine FDA label, section 5.3). A slow rate prolongs the QT interval and may end in ventricular arrhythmia, including torsade de pointes, especially when the patient also takes QT-prolonging drugs (ivabradine SmPC, EMA, section 4.4; FDA label, section 5.3).

Management

The combination is contraindicated in both labels: the ivabradine SmPC (EMA, section 4.3) names verapamil and diltiazem, and the verapamil SmPC (AEMPS, 4.3) names ivabradine. The contraindication in the ivabradine SmPC has no dose condition, and the FDA label of prolonged-release verapamil also says to avoid the combination (verapamil ER label, FDA). If the patient needs ivabradine, replace verapamil: the ivabradine SmPC reports no safety problems with nitrates, dihydropyridine calcium antagonists such as amlodipine, or beta-blockers (EMA, 4.4 and 4.5); with beta-blockers monitor the heart rate (ivabradine FDA label, 7.2). If verapamil itself is needed, for example for supraventricular tachycardia, stop ivabradine. Before starting ivabradine measure the resting heart rate repeatedly, by ECG or 24-hour monitoring, and do not start it below 70 beats per minute (EMA, 4.3 and 4.4). If the patient has already taken the two drugs together, reduce the ivabradine dose or stop it when the resting rate falls below 50 or bradycardia symptoms appear (EMA, 4.4). The US labels are softer but point the same way: both the ivabradine label (FDA, 5.3 and 7.1) and the verapamil label (FDA, Drug Interactions) say to avoid coadministration.

Mechanism

Additive suppression of sinus node and atrioventricular (AV) conduction. Symptomatic bradycardia, sinoatrial and AV block have been reported.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. In atrial fibrillation, choose one strategy: amiodarone for rhythm control, verapamil for rate control. Alternatives: a beta-blocker + digoxin or catheter ablation.

Mechanism

Dual calcium channel blockade: amlodipine is a dihydropyridine blocker, verapamil is non-dihydropyridine. Additive hypotension, bradycardia, AV block risk.

Symptoms

Blood pressure drop, dizziness, syncope. Bradycardia, ECG first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. In hypertension, choose one calcium channel blocker (amlodipine or verapamil). For difficult hypertension, ACE-I + amlodipine + diuretic (without verapamil) or ACE-I + verapamil.

Mechanism

Verapamil inhibits CYP3A4, the enzyme that breaks down atorvastatin, and may raise atorvastatin levels (both SmPCs). No interaction study of this pair has been done, so the atorvastatin SmPC gives no figure. The interaction also works the other way: atorvastatin increases systemic exposure to verapamil by 43% (verapamil SmPC). The higher the atorvastatin level, the higher the risk of muscle damage (atorvastatin SmPC).

Symptoms

Muscle pain, cramps or weakness, sometimes with fever and malaise, and raised creatine kinase on blood tests. In rhabdomyolysis the urine turns dark and kidney function can suffer.

Management

If the patient already takes verapamil, atorvastatin is started at the lowest possible dose and titrated up: the verapamil SmPC requires this and names atorvastatin. If verapamil is added to existing atorvastatin, a statin dose reduction is considered and cholesterol is rechecked (verapamil SmPC). For verapamil and other moderate CYP3A4 inhibitors, the atorvastatin SmPC advises considering a lower maximum atorvastatin dose and monitoring the patient; the documents set no specific dose limit for this pair. Ask the patient to report muscle pain, cramps or weakness promptly. Check creatine kinase if they occur, and stop atorvastatin if it is more than 5 times the upper limit of normal (atorvastatin SmPC). Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil (verapamil SmPC).

Mechanism

Additive AV slowing and reduced contractility. Bradycardia, AV block.

Symptoms

Bradycardia, AV block.

Management

Avoid combination.

Mechanism

Non-dihydropyridine calcium channel blocker (verapamil) + beta-blocker (carvedilol) – additive AV node blockade and negative inotropic effect. Carvedilol has additional α1-blockade, amplifying hypotension.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. For atrial fibrillation rate control, choose carvedilol + digoxin (instead of verapamil), or verapamil with carvedilol withdrawn. In heart failure, carvedilol is preferred (benefit proven in COPERNICUS and CIBIS).

Mechanism

Additive bradycardia and AV block. Clonidine lowers sympathetic tone; verapamil directly blocks the AV node.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall and fracture risk.

Management

Avoid the combination, especially in older patients. Alternative calcium channel blockers: amlodipine or nifedipine (no AV effect). Alternative to clonidine: an ACE-I or ARB with a diuretic.

Mechanism

Verapamil inhibits P-glycoprotein, which clears digoxin via kidney and intestine. Digoxin plasma concentration rises 50–75%. Digoxin has a narrow therapeutic index (target 0.5–0.9 ng/mL, toxic above 2). Verapamil also amplifies digoxin's bradycardia and AV block.

Symptoms

Nausea, vomiting, visual disturbances (yellow halos), bradycardia below 50, AV blocks, ventricular arrhythmias.

Management

When starting verapamil, reduce digoxin by 30–50% and check level on days 5–7. Alternative calcium channel blocker: amlodipine, which does not inhibit P-glycoprotein. Avoid the combination in the elderly.

Mechanism

Both drugs slow conduction through the atrioventricular (AV) node and sinus node function, lower the heart rate and reduce cardiac contractility; together these effects add up (metoprolol and verapamil labels). There is also a pharmacokinetic part: in patients with angina, verapamil increased metoprolol AUC by 32.5% and peak concentration by 41% (verapamil label). The FDA verapamil label also describes reduced metoprolol clearance.

Symptoms

Marked bradycardia, high-degree atrioventricular (AV) block up to complete heart block, low blood pressure with dizziness, new or worsening heart failure (verapamil and metoprolol labels).

Management

Do not give intravenous verapamil to patients taking beta-blockers, including metoprolol (metoprolol labels). Intravenous verapamil is contraindicated with intravenous beta-blockers; the two should not be given within a few hours of each other (intravenous verapamil labels in Spain and the US). Avoid oral verapamil with a beta-blocker in any degree of ventricular dysfunction; in hypertension the risks of the combination may outweigh the benefits (FDA verapamil label). If tablets are combined, use caution and monitor pulse and blood pressure closely (metoprolol and verapamil labels). If the pulse falls below 50–55 beats per minute, reduce metoprolol gradually or withdraw it slowly (metoprolol label). Marked first-degree atrioventricular (AV) block or progression to second- or third-degree block requires a lower verapamil dose, and rarely stopping it (FDA verapamil label).

Mechanism

Verapamil and propranolol both slow the heart rate and conduction through the atrioventricular (AV) node and reduce myocardial contractility; taken together, these effects add up (verapamil and propranolol SmPCs). With verapamil and beta-blockers, marked bradycardia, AV block up to complete heart block, heart failure and cardiovascular collapse have been reported (verapamil and propranolol labels of the US Food and Drug Administration, FDA). The risk is higher with impaired ventricular function and with sinoatrial or AV conduction disorders (propranolol SmPC).

Symptoms

Slow pulse, dizziness, weakness, fainting, a sharp fall in blood pressure. Shortness of breath and swelling if heart failure develops. On the electrocardiogram (ECG): high-grade atrioventricular block (verapamil and propranolol SmPCs).

Management

Avoid the combination, especially in decompensated heart failure (propranolol SmPC). Avoid verapamil in patients on a beta-blocker who have any degree of ventricular dysfunction (verapamil label of the US Food and Drug Administration, FDA). Intravenous verapamil is contraindicated in patients receiving an intravenous beta-blocker, and the intravenous forms of the two drugs are not given within a few hours of each other (FDA label for verapamil injection). If the patient is taking one of the drugs, stop it 48 hours before giving the other intravenously and 7 days before starting the other by mouth (propranolol SmPC). If the combination is still used for hypertension, use it only with caution and close monitoring (verapamil FDA label); if second- or third-degree atrioventricular block develops, withhold further verapamil doses (verapamil SmPC).

Mechanism

Verapamil inhibits CYP3A4 and P-glycoprotein. Simvastatin rises 2–3 fold with myopathy and rhabdomyolysis risk. FDA Zocor Section 7 caps simvastatin at 10 mg/day with verapamil.

Symptoms

Myalgia, weakness, rising CK within 1–3 weeks.

Management

Cap simvastatin at 10 mg/day. Alternative: pravastatin or rosuvastatin.

Mechanism

At high doses, aspirin weakens verapamil's antihypertensive effect via vasodilator prostaglandin suppression. At cardioprotective doses, there is no clinically significant effect.

Symptoms

Gradual blood pressure rise at high aspirin doses. At cardioprotective doses, no significant changes.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high doses, monitor blood pressure and increase verapamil if needed. Alternative analgesic: paracetamol.

Mechanism

Verapamil blocks CYP3A4 (one of the amitriptyline metabolic routes). TCA plasma levels may rise slightly. Plus additive bradycardia and PR prolongation.

Symptoms

Bradycardia, postural dizziness, syncope. ECG: PR prolongation. Older patients: delirium risk.

Management

In older patients, check pulse and ECG 1–2 weeks after starting amitriptyline. Alternative calcium channel blocker without CYP effect: amlodipine (with amitriptyline's α1-blockade – see the related pair). For neuropathic pain, alternative: gabapentin or pregabalin.

Mechanism

Verapamil inhibits the CYP3A4 enzyme and the P-glycoprotein transporter (verapamil SmPC), and apixaban is cleared through both routes. Apixaban blood levels may therefore rise, and with them the bleeding risk. The size of the effect is unknown: there are no pharmacokinetic data for this pair (practical guide of the European Heart Rhythm Association, EHRA 2021). The apixaban SmPC of the European Medicines Agency (EMA) lists verapamil among inhibitors expected to raise apixaban levels to a lesser degree than strong inhibitors.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is allowed with caution. The apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names verapamil among them (apixaban SmPC, EMA). The verapamil SmPC notes a possible rise in bleeding risk with direct oral anticoagulants, especially in patients with risk factors, and advises reducing the anticoagulant dose if needed, following its own SmPC (verapamil SmPC). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily only by its own criteria: two of three (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or creatinine clearance 15–29 mL/min (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021).

Mechanism

Verapamil inhibits CYP3A4, the main enzyme of carbamazepine metabolism (verapamil and carbamazepine labels). In patients with epilepsy, carbamazepine AUC rose by 46%, which can cause its side effects (verapamil label). The reverse effect is also possible: carbamazepine is a potent CYP3A4 inducer (carbamazepine label), and CYP3A4 inducers lower verapamil levels (verapamil labels).

Symptoms

Double vision, headache, ataxia, dizziness, drowsiness and nausea (verapamil and carbamazepine labels). Severe cases: cardiac conduction disorders and atrioventricular (AV) block (carbamazepine label).

Management

The combination is allowed but is managed by carbamazepine levels. After verapamil is added, measure the blood carbamazepine level and adjust its dose if needed (carbamazepine label). The usual adult therapeutic range of carbamazepine is 4–12 mcg/mL (FDA carbamazepine label). Warn the patient about signs of carbamazepine excess: double vision, headache, unsteady gait and dizziness (verapamil labels). Also monitor the effect of verapamil, because CYP3A4 inducers lower its levels (verapamil label).