Diltiazem

Mechanism

Diltiazem is a moderate CYP3A4 inhibitor and a weak P-glycoprotein inhibitor (diltiazem SmPC). Colchicine is cleared through both pathways and has a narrow therapeutic margin (colchicine SmPC). Diltiazem 240 mg/day raised colchicine exposure (area under the curve, AUC) by 93%, almost twofold (colchicine label, US Food and Drug Administration, FDA). Higher levels bring a higher risk of bone marrow suppression and nerve and muscle toxicity.

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 diltiazem in its interactions section (colchicine SmPC). The diltiazem SmPC does not recommend combining it with colchicine (diltiazem SmPC). US labels allow it 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, and neuromuscular toxicity has been reported with diltiazem (colchicine label, FDA). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Diltiazem is a moderate inhibitor of CYP3A4, the enzyme that clears ivabradine. When the two are taken together, ivabradine exposure (area under the concentration curve, AUC) rises 2–3-fold (ivabradine SmPC, EMA). Both drugs slow the heart. Ivabradine slows the sinus node; diltiazem prolongs the refractory periods of the atrioventricular node and can cause bradycardia or second- or third-degree atrioventricular block (diltiazem SmPC). Together they lower the heart rate by a further 5 beats per minute beyond the effect of ivabradine alone and worsen conduction disturbances (ivabradine SmPC, EMA; Corlanor label, FDA).

Symptoms

Bradycardia: resting pulse below 50 beats per minute, dizziness, fatigue, low blood pressure (ivabradine SmPC, EMA). Sinus arrest and atrioventricular block with fainting can occur (Corlanor label, FDA; diltiazem SmPC). Marked bradycardia raises the risk of QT prolongation and torsade de pointes, especially with other QT-prolonging drugs (Corlanor label, FDA).

Management

The combination is contraindicated from both sides: the ivabradine SmPC (EMA) forbids use with diltiazem and verapamil, and the diltiazem SmPC forbids use with ivabradine (section 4.3 of both). The FDA labels require avoiding concomitant use (ivabradine and diltiazem labels, FDA). If a calcium channel blocker is needed, the ivabradine SmPC notes no safety problems with dihydropyridines such as amlodipine (ivabradine SmPC, EMA). If a patient already takes both, one of them is stopped and heart rate and ECG (electrocardiogram) are monitored. With a resting heart rate below 50 beats per minute or symptoms of bradycardia the ivabradine dose is reduced; if bradycardia persists, ivabradine is stopped (ivabradine SmPC, EMA). Ivabradine is not started with a resting heart rate below 70 beats per minute (ivabradine SmPC, EMA).

Mechanism

Both drugs slow the heart rate and conduction; together they can cause excessive bradycardia, sinus arrest and atrioventricular (AV) block (amiodarone labels in Spain and the US). There is also a pharmacokinetic part: CYP3A4 takes part in amiodarone metabolism and diltiazem moderately inhibits it. The Spanish amiodarone label advises avoiding CYP3A4 inhibitors because they can raise amiodarone levels, and the diltiazem label does not rule out higher diltiazem levels with amiodarone. Because of amiodarone's long half-life, interactions persist for weeks to months after it is stopped (amiodarone labels).

Symptoms

Slow pulse, sinus arrest and atrioventricular (AV) block (FDA amiodarone label). A slow pulse causes weakness and dizziness, and in severe cases fainting. The risk of bradycardia is higher in older patients and at high doses (diltiazem label).

Management

The Spanish amiodarone label does not recommend combining it with diltiazem because of the risk of excessive bradycardia and conduction disorders (amiodarone label). The Spanish diltiazem label requires strict clinical and ECG monitoring when it is combined with other antiarrhythmics, and caution with amiodarone, especially in older patients and at high doses (diltiazem label). If the combination cannot be avoided, adjust doses carefully and monitor heart rate (FDA amiodarone label) and the ECG (diltiazem label). Amiodarone interactions persist for weeks to months after it is stopped, so the same caution applies if diltiazem is started soon after amiodarone is withdrawn (amiodarone labels).

Mechanism

CYP3A4 takes part in atorvastatin metabolism (atorvastatin labels), and diltiazem is a moderate CYP3A4 inhibitor (diltiazem and atorvastatin labels). With diltiazem 240 mg daily, atorvastatin AUC rose 1.51-fold (atorvastatin labels in Spain and the US). The risk of muscle damage, up to rhabdomyolysis, rises with statin exposure (diltiazem labels). The effect is stronger with simvastatin, whose AUC diltiazem raised 5-fold (diltiazem labels).

Symptoms

Muscle pain, cramps or weakness, especially with fever and malaise, and raised creatine kinase. In severe cases rhabdomyolysis develops: creatine kinase above 10 times the upper limit of normal, myoglobin in blood and urine (dark urine) and possible kidney failure (atorvastatin label).

Management

When possible, combine diltiazem with a statin that is not metabolized by CYP3A4 (diltiazem labels in Spain and the US). Pravastatin is an example: diltiazem did not change its pharmacokinetics (diltiazem labels). If atorvastatin is kept, start it at the lowest effective dose (diltiazem label) and consider a lower maximum dose (atorvastatin label); the FDA diltiazem label also allows dose adjustment of both drugs. Monitor the patient closely after diltiazem is started and after each dose change (atorvastatin and diltiazem labels). Ask the patient to report muscle pain, cramps or weakness at once. If they appear, measure creatine kinase and stop atorvastatin if it is above 5 times the upper limit of normal (atorvastatin label).

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + beta-blocker (bisoprolol) – additive AV node blockade and negative inotropic effect.

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 bisoprolol + digoxin (without diltiazem) or diltiazem with bisoprolol withdrawn.

Mechanism

The interaction works both ways. Diltiazem inhibits CYP3A4, the main enzyme of carbamazepine metabolism, and blood carbamazepine levels rise by 40–72%, in some patients to toxic levels (diltiazem and carbamazepine labels). Carbamazepine, in turn, is a potent CYP3A4 inducer and can lower levels of drugs metabolized by this enzyme (carbamazepine label). Diltiazem is metabolized by CYP3A4, and CYP3A4 inducers can lower its blood levels (diltiazem label).

Symptoms

Ataxia, diplopia, nausea, drowsiness, tremor. Severe cases: cardiac conduction abnormalities and AV block.

Management

The FDA diltiazem labels advise avoiding diltiazem with any CYP3A4 inducer and considering other treatment, and carbamazepine is a potent CYP3A4 inducer (carbamazepine label). If the combination is still needed, measure the blood carbamazepine level after diltiazem is added and adjust the carbamazepine dose if needed (diltiazem and carbamazepine labels). The usual adult therapeutic range of carbamazepine is 4–12 mcg/mL (FDA carbamazepine label). Warn the patient about signs of carbamazepine excess: dizziness, drowsiness, unsteady gait and double vision (carbamazepine label). The effect of diltiazem may weaken on carbamazepine, and its dose may also need adjustment (FDA carbamazepine label).

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + beta-blocker (carvedilol) – additive AV node blockade and negative inotropic effect. Carvedilol's α1-blockade amplifies 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. Alternative for combined heart failure and angina: carvedilol + amlodipine (dihydropyridine, no AV effect) or diltiazem with carvedilol withdrawn.

Mechanism

Diltiazem blocks CYP3A4 and P-glycoprotein – cyclosporine clearance routes. Cyclosporine plasma levels rise by 50–100%. The combination is sometimes used intentionally in transplant patients to reduce cyclosporine dose (sparing effect), but requires monitoring.

Symptoms

Acute nephrotoxicity: rising creatinine, hypertension, tremor, headache. In transplant patients: accelerated graft function decline.

Management

For intentional sparing, reduce cyclosporine by 25–50% when starting diltiazem; check trough (C0) at days 3 and 7. For incidental combination: monitor cyclosporine and creatinine.

Mechanism

Additive bradycardia and atrioventricular (AV) block. Clonidine lowers sympathetic tone and slows conduction; diltiazem 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 in hypertension: amlodipine or nifedipine (no AV effect). Alternative to clonidine: an ACE-I or ARB with a diuretic.

Mechanism

The transporter P-glycoprotein limits digoxin absorption in the gut and removes it through the kidneys and bile (FDA digoxin label). Diltiazem weakly inhibits this transporter (diltiazem label). In studies, blood digoxin levels rose by about 20%; two studies found a 46–50% rise in digoxin AUC and a third found no significant interaction (diltiazem labels in Spain and the US). The second mechanism does not depend on drug levels: both drugs slow conduction through the atrioventricular (AV) node, and together they can cause bradycardia and AV block up to complete heart block (FDA digoxin label).

Symptoms

Signs of digoxin toxicity: loss of appetite, nausea, vomiting, weakness, dizziness and color vision changes with a yellow-green tint. Cardiac effects are rhythm and conduction disorders: atrioventricular (AV) block of any degree, atrial tachycardia with block, ventricular premature beats, often as bigeminy, and ventricular tachycardia (FDA digoxin label). The combined effect of both drugs on the AV node can slow the pulse even without a rise in digoxin levels; the risk is higher in older patients and at high doses (diltiazem label).

Management

Measure serum digoxin before starting diltiazem. Then reduce the digoxin dose by about 15–30% or give it less often, and keep monitoring levels (FDA digoxin label). Check digoxin levels when diltiazem is started, when its dose changes and when it is stopped, to avoid both over- and under-digitalization (diltiazem labels in Spain and the US). Take blood just before the next digoxin dose or at least 6 hours after the last one. Do not change the dose on a single level without the clinical picture (FDA digoxin label). Both drugs slow the pulse, so watch it closely in older patients and at high doses (diltiazem label).

Mechanism

Diltiazem slows AV conduction + inhibits CYP3A4 (metoprolol metabolism). Additive bradycardia and AV block.

Symptoms

Bradycardia, AV block.

Management

Avoid combination. Alternative – amlodipine.

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + non-selective beta-blocker (propranolol) – marked additive bradycardia, AV block, negative inotropic effect. Risk of symptomatic AV block, especially in older patients and left ventricular dysfunction.

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, propranolol + digoxin (without diltiazem) or diltiazem with propranolol withdrawn. In heart failure, a selective beta-blocker (bisoprolol) or carvedilol is preferable.

Mechanism

Rifampicin is a potent inducer of drug-metabolizing enzymes and transporters, including CYP3A4 and P-glycoprotein (rifampicin label). Diltiazem is metabolized by CYP3A4 (diltiazem label). With rifampicin, diltiazem blood levels fell to undetectable (FDA diltiazem label), so its antianginal and blood pressure-lowering effect can be lost.

Symptoms

Return of hypertension, anginal episodes in ischaemic heart disease. Rate control in atrial fibrillation is lost.

Management

Avoid the combination and consider other treatment (FDA diltiazem labels). When choosing a replacement, note that nifedipine, nimodipine, nisoldipine and nitrendipine are contraindicated with rifampicin (rifampicin label). If diltiazem is kept, monitor the patient closely when rifampicin is started and after it is stopped, checking the effect of diltiazem (diltiazem labels). The diltiazem dose may need adjustment when rifampicin is started or stopped (rifampicin label).

Mechanism

Diltiazem inhibits CYP3A4. Simvastatin concentration rises 2.7-fold. FDA Zocor Section 7 caps simvastatin at 10 mg/day with diltiazem due to myopathy and rhabdomyolysis risk.

Symptoms

Pain in thighs and shoulder girdle, CK above 5× ULN, dark urine.

Management

Cap simvastatin at 10 mg/day. Alternative: pravastatin 40 mg or rosuvastatin 10–20 mg with comparable LDL effect.

Mechanism

Diltiazem impairs platelet function via calcium channel blockade; aspirin is an antiplatelet. Mild additive bleeding risk, rarely clinically significant.

Symptoms

Usually asymptomatic. In patients with bleeding risk factors (peptic ulcer, older age): rare gum bleeding and epistaxis.

Management

Standard combination in ischaemic heart disease. Cardioprotective aspirin doses (75–100 mg) are acceptable without special measures. In patients with bleeding risk factors: PPI cover with pantoprazole.

Mechanism

Diltiazem moderately inhibits CYP3A4; alprazolam is a CYP3A4 substrate. Alprazolam AUC rises by 30–50%, prolonging sedation.

Symptoms

Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Morning sedation is especially pronounced (alprazolam half-life is extended).

Management

On starting the combination, reduce alprazolam by 25–50%. In older patients, start at 0.125 mg at bedtime. Antihypertensive alternatives: amlodipine or a beta-blocker without CYP3A4 effect (metoprolol, bisoprolol). Anxiolytic alternatives: lorazepam or oxazepam (CYP3A4-independent), or buspirone.

Mechanism

Diltiazem weakly inhibits CYP2D6 and CYP3A4; amitriptyline is metabolised by both. TCA levels can rise, amplifying anticholinergic, sedative, and QT effects. Bradycardia is additive.

Symptoms

Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk. Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.

Management

On the combination, begin amitriptyline at 10 mg at bedtime. Avoid the combination in older patients — orthostatic hypotension and arrhythmia risk. For neuropathic pain, alternatives: gabapentin or pregabalin. Antihypertensive alternatives: amlodipine or a beta-blocker without CYP effect.

Mechanism

Diltiazem is a moderate CYP3A4 inhibitor (diltiazem SmPC), and CYP3A4 takes part in amlodipine metabolism. In older patients with hypertension, diltiazem 180 mg a day increased systemic exposure to amlodipine 5 mg by 60% (US Food and Drug Administration (FDA) amlodipine label). Both drugs lower blood pressure, and their effects add up when they are taken together.

Symptoms

Lower blood pressure, dizziness on standing, fatigue, leg oedema. Older patients: fall risk.

Management

The combination is acceptable with monitoring. Clinical monitoring and a lower amlodipine dose may be needed, and the effect can be stronger in older patients (amlodipine SmPC). Watch for signs of hypotension and oedema and use them to decide whether the amlodipine dose should change (US Food and Drug Administration (FDA) amlodipine label).

Mechanism

Diltiazem is a moderate inhibitor of the CYP3A4 enzyme and a weak inhibitor of the P-glycoprotein transporter (diltiazem and apixaban SmPCs), and apixaban is cleared through both routes. Diltiazem 360 mg once daily raised the apixaban area under the curve (AUC) 1.4-fold and peak concentration 1.3-fold (apixaban SmPC of the European Medicines Agency, EMA). Higher apixaban levels mean a higher bleeding risk.

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. Do not change the apixaban dose because of diltiazem: the apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names diltiazem among them (apixaban SmPC, EMA). The diltiazem SmPC asks for caution and monitoring with direct oral anticoagulants, especially in patients at high bleeding risk (diltiazem 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).