Dronedarone

Mechanism

Dronedarone is a strong CYP3A4 inhibitor, the main alprazolam metabolic route. Alprazolam plasma levels may rise 2- to 4-fold. Deep sedation, fall risk in older patients.

Symptoms

Deep sedation, drowsiness, ataxia. Older patients: fall and fracture risk. Symptoms appear within 1–2 days.

Management

During dronedarone therapy, halve alprazolam or use lorazepam/oxazepam (glucuronidated, no CYP3A4 dependence).

Mechanism

Dronedarone is a strong CYP3A4 inhibitor, the main amlodipine metabolic route. Amlodipine plasma levels may double.

Symptoms

Blood pressure drop: postural dizziness, syncope. Ankle oedema (typical of amlodipine), facial flushing, reflex tachycardia are possible.

Management

Cap amlodipine at 5 mg/day when combined. Alternative calcium channel blocker: diltiazem (with caution combined with an antiarrhythmic), or replace amlodipine with an ACE-I/ARB.

Mechanism

Dronedarone is a strong P-glycoprotein and CYP3A4 inhibitor – two apixaban clearance routes. Apixaban plasma levels rise by 30–60%; bleeding risk increases.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

The combination is acceptable without dose change in patients under 80, weight above 60 kg, serum creatinine below 133 µmol/L. In older patients with two of these factors, reduce apixaban to 2.5 mg twice daily.

Mechanism

Additive QT prolongation. Azithromycin received a dedicated FDA warning in 2013 for fatal ventricular arrhythmia risk. Dronedarone itself prolongs QT, and combined the effects add up.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

Avoid the combination. Alternative antibiotics: doxycycline or a cephalosporin (no QT effect). If azithromycin is needed, ECG before start and potassium and magnesium in range.

Mechanism

Additive QT prolongation. Dronedarone is on the FDA list of drugs that contraindicate strong QT-prolonging antibiotics. Ciprofloxacin prolongs QT dose-dependently.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

Avoid the combination. Alternative antibiotics: a cephalosporin (no QT effect) or nitrofurantoin for urinary tract infection.

Mechanism

Dronedarone prolongs QT (FDA Multaq carries a boxed warning). Citalopram does so dose-dependently. Additive torsades de pointes risk.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

Avoid the combination. Alternative antidepressants with minimal QT effect: mirtazapine or agomelatine. Alternative antiarrhythmic: a beta-blocker for rate control.

Mechanism

Dronedarone strongly blocks both P-glycoprotein and CYP3A4 – two colchicine clearance routes. Colchicine plasma levels rise; myopathy, neuropathy, and pancytopenia risks grow.

Symptoms

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

Management

In chronic kidney disease or hepatic impairment, do not prescribe the combination. With preserved function: colchicine 0.3 mg every other day for no more than 5 days. Alternative for gout on dronedarone: intra-articular or short systemic glucocorticoid.

Mechanism

Dronedarone blocks intestinal P-glycoprotein – the main route of digoxin absorption and elimination. Digoxin plasma levels rise 1.7- to 2.5-fold. Dronedarone also enhances contractile and bradycardic effects.

Symptoms

Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias ranging from premature beats to ventricular tachycardia. Older adults: confusion, dizziness. Symptoms appear within 1–2 weeks of co-administration.

Management

When dronedarone starts, halve the digoxin dose; check level at 1 week. If sinus node or AV conduction symptoms appear, hold digoxin temporarily.

Mechanism

Both drugs prolong QT. Escitalopram does so dose-dependently (FDA Lexapro caps at 20 mg/day), dronedarone does too. Effects add up.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

Avoid the combination. If escitalopram is needed, cap at 10 mg/day; ECG before start and at 2 weeks; maintain potassium and magnesium. Alternative antidepressants: mirtazapine or agomelatine.

Mechanism

Dual mechanism. Fluconazole blocks CYP3A4 (the main dronedarone clearance route) and prolongs QT itself. Dronedarone plasma levels rise; QT effects add up.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antifungals: echinocandins (micafungin, caspofungin) for systemic mycoses or terbinafine for dermatophytosis. If fluconazole is needed: ECG before start and every 3 days during therapy.

Mechanism

Fluoxetine blocks CYP2D6 (strongly) and CYP3A4 (moderately). Dronedarone plasma levels may rise. Additive QT risk.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antidepressants without CYP3A4/CYP2D6 inhibition: sertraline or escitalopram. Alternative antiarrhythmic: a beta-blocker for rate control.

Mechanism

Furosemide (loop diuretic) increases urinary potassium loss. Low potassium amplifies dronedarone's QT effect, which itself carries an FDA boxed warning for this risk.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

The combination is common (atrial fibrillation + heart failure). Check potassium and magnesium every 1–3 months; if potassium drops below 4.0 mmol/L, add a potassium-sparing diuretic or potassium supplement.

Mechanism

Additive QT prolongation. Torsades de pointes has been reported with dronedarone plus other QT-prolonging drugs. Haloperidol is particularly dangerous parenterally (IV).

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination, especially IV haloperidol. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole. For acute delirium: dexmedetomidine.

Mechanism

Hydrochlorothiazide (thiazide diuretic) increases urinary potassium loss. Low potassium amplifies dronedarone's QT effect.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

The combination is common (hypertension + atrial fibrillation). Check potassium and magnesium every 3 months; if potassium drops below 4.0 mmol/L, add a potassium-sparing diuretic or potassium supplement.

Mechanism

Indapamide (thiazide-like diuretic) increases urinary potassium loss. Low potassium amplifies dronedarone's QT effect.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

The combination is common (hypertension + atrial fibrillation). Check potassium and magnesium every 3 months; if potassium drops below 4.0 mmol/L, add a potassium-sparing diuretic or potassium supplement.

Mechanism

Mirtazapine prolongs QT dose-dependently (especially above 30 mg/day). Combined with dronedarone, torsades de pointes risk rises.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

The combination is acceptable at low mirtazapine doses (≤30 mg/day) and normal potassium. ECG before start and at 2 weeks. Alternative antidepressants with minimal QT effect: agomelatine or sertraline (up to 100 mg).

Mechanism

Additive QT prolongation (both prolong QTc). Dronedarone carries an FDA boxed warning for QT risk.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole. Alternative antiarrhythmic: a beta-blocker for rate control or catheter ablation.

Mechanism

Sertraline at high doses (above 150 mg/day) moderately prolongs QT. Combined with dronedarone, risk of torsades de pointes rises, especially in older patients.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination with sertraline above 100 mg. At low doses (50–100 mg) with normal potassium and magnesium, the combination is acceptable with ECG monitoring at 2 weeks. Alternative antidepressants: mirtazapine or agomelatine.

Mechanism

Dronedarone inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise 4-fold. FDA Zocor 2012 caps simvastatin at 10 mg/day with dronedarone.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

Cap simvastatin at 10 mg/day when combined. If LDL targets are missed, switch to pravastatin or rosuvastatin (no CYP3A4 dependence).

Mechanism

Dronedarone blocks the P-glycoprotein transporter – the main tacrolimus clearance route. Tacrolimus plasma levels rise. Additional risk of additive QT prolongation.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

Avoid the combination. Alternative antiarrhythmics in transplant patients: a beta-blocker for rate control or catheter ablation. If unavoidable, reduce tacrolimus by 30% and check level at days 3 and 7.

Mechanism

Additive QT risk. Tramadol weakly prolongs QT and blocks serotonin/norepinephrine reuptake. Dronedarone is a potent QT prolonger. Tramadol also lowers seizure threshold.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. For analgesia on dronedarone, use paracetamol, an NSAID, or morphine/oxycodone (no QT effect).

Mechanism

Additive QT prolongation. Venlafaxine prolongs QT at high doses; dronedarone carries an FDA boxed warning for this effect.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antidepressants with minimal QT effect: mirtazapine or agomelatine. Alternative antiarrhythmic: a beta-blocker for rate control.