Clarithromycin

Mechanism

Clarithromycin blocks CYP3A4 – the main alprazolam metabolic route. Alprazolam plasma levels rise 2- to 3-fold, with prolonged and stronger effect.

Symptoms

Prolonged sedation, drowsiness, dizziness, ataxia. Falls and fracture risk in older patients. Symptoms appear within 1–2 days.

Management

During clarithromycin therapy, halve the alprazolam dose. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 impact). Alternative benzodiazepines without CYP3A4 dependence: lorazepam, oxazepam.

Mechanism

Dual mechanism: both prolong QT, and clarithromycin blocks CYP3A4 – a partial amiodarone clearance route. Amiodarone and its active metabolite (N-desethyl-amiodarone) plasma levels rise.

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: azithromycin or doxycycline (minimal CYP3A4 interaction). If clarithromycin is needed, ECG before start and every 3 days during therapy, with potassium and magnesium maintained.

Mechanism

Clarithromycin blocks CYP3A4 and prolongs QT itself. Amitriptyline plasma levels 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 antibiotics: azithromycin or doxycycline (minimal CYP3A4 and QT effect). Alternative for neuropathic pain instead of TCA: gabapentin or pregabalin.

Mechanism

Clarithromycin blocks CYP3A4 – the main amlodipine metabolic route. Amlodipine plasma levels rise by 50–60%. Symptomatic hypotension and acute kidney injury have been reported in older patients.

Symptoms

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

Management

During clarithromycin therapy, halve amlodipine and monitor blood pressure. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 effect).

Mechanism

Clarithromycin blocks CYP3A4 and P-glycoprotein – two apixaban clearance routes. Apixaban levels rise by about 60%, and bleeding risk increases.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid where possible. Alternative antibiotics: azithromycin or doxycycline. If clarithromycin is required, reduce apixaban to 2.5 mg twice daily only when at least two of these apply: age ≥80, weight ≤60 kg, serum creatinine ≥133 µmol/L.

Mechanism

Atorvastatin clearance depends on hepatic CYP3A4, but unlike simvastatin only ~70% of the dose follows this route – the rest uses alternative pathways. Clarithromycin strongly inhibits CYP3A4. Atorvastatin plasma levels rise 4- to 5-fold. The exposure increase is smaller than with simvastatin but still clinically significant for muscle injury risk.

Symptoms

Pain and weakness in large muscle groups, dark urine. Laboratory: elevated creatine kinase. Symptoms appear 3–7 days into concurrent therapy. Acute rhabdomyolysis is less common than the clarithromycin + simvastatin pair but has been reported.

Management

Hold atorvastatin for the clarithromycin course or switch the patient to pravastatin or rosuvastatin. If statin therapy cannot be paused, replace the antibiotic: azithromycin (minimal CYP3A4 interaction) or a non-macrolide class based on susceptibility.

Mechanism

Clarithromycin blocks CYP3A4 – the main hepatic metabolic route for budesonide. Systemic budesonide exposure (oral or inhaled) rises 4- to 8-fold. Cushing's syndrome and adrenal insufficiency have been reported.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: risk of adrenal insufficiency with hypotension and weakness.

Management

For short clarithromycin courses (5–7 days), halve budesonide temporarily. For prolonged therapy, switch antibiotics (azithromycin, doxycycline) or replace budesonide with fluticasone/mometasone (less CYP3A4-dependent).

Mechanism

Clarithromycin blocks CYP3A4 – the main carbamazepine metabolic route. Carbamazepine plasma levels rise by 30–50%, with neurotoxicity risk.

Symptoms

Ataxia, diplopia, nausea, drowsiness, tremor. Severe cases include cardiac conduction abnormalities and coma. Symptoms appear within 3–5 days of co-administration.

Management

Avoid the combination. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 impact). If clarithromycin is needed, measure carbamazepine plasma levels at days 3 and 7.

Mechanism

Cyclosporine (an immunosuppressant used after solid-organ transplantation and in severe autoimmune disease) is cleared through hepatic CYP3A4 and actively transported by P-glycoprotein. Clarithromycin inhibits both the enzyme and the transporter. Cyclosporine plasma levels rise 2- to 4-fold. The narrow therapeutic window (minimal margin between therapeutic and toxic dose) makes any concentration rise clinically dangerous.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Hypertension, headache, tremor. In transplant patients, accelerated graft function decline. Symptoms appear within a few days of concurrent dosing.

Management

Avoid the combination. Replace clarithromycin with azithromycin – minimal CYP3A4 and P-glycoprotein interaction with comparable activity. If clarithromycin is essential, reduce the cyclosporine dose by 30–50% immediately, measure cyclosporine trough or C2 levels (per the transplant centre protocol) every 2–3 days, and monitor creatinine.

Mechanism

Clarithromycin prolongs QT and is a potent CYP3A4 inhibitor. Citalopram is metabolised by CYP3A4 only minorly, so pharmacokinetic effect is small, but QT prolongation adds 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. Alternative antibiotics: azithromycin (weaker QT effect) or doxycycline/a cephalosporin. If clarithromycin is needed: do not increase citalopram; ECG before start and every 3 days during therapy.

Mechanism

Clarithromycin blocks intestinal P-glycoprotein, the main transporter of dabigatran. Dabigatran plasma levels rise by 49–60%, and bleeding risk becomes clinically significant.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid where possible. Do not prescribe the combination if creatinine clearance is below 50 mL/min. During clarithromycin therapy, reduce dabigatran to 110 mg twice daily. Alternative antibiotic: azithromycin (minimal P-glycoprotein interaction).

Mechanism

Clarithromycin blocks intestinal P-glycoprotein and suppresses gut flora that partly inactivates digoxin. Digoxin plasma levels rise 1.7- to 2.5-fold.

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

During clarithromycin therapy, reduce digoxin by 50%; check level at 5–7 days. Alternative antibiotics without P-glycoprotein block: azithromycin or doxycycline.

Mechanism

Both prolong QT, and clarithromycin blocks CYP3A4 (a minor escitalopram metabolic route). Escitalopram levels rise moderately. In patients with hypokalaemia or other arrhythmia risk factors, torsades de pointes risk increases.

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 where possible. Alternative antibiotics: azithromycin (with caution given its own QT risk) or doxycycline. During clarithromycin therapy, cap escitalopram at 10 mg/day.

Mechanism

Additive QT prolongation. Clarithromycin also blocks CYP3A4 – the main haloperidol clearance route – and haloperidol levels rise.

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: azithromycin or doxycycline. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.

Mechanism

Clarithromycin blocks CYP3A4 – the main methylprednisolone metabolic route. Methylprednisolone plasma levels rise 2- to 3-fold, with risk of iatrogenic Cushing's syndrome and hyperglycaemia.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: adrenal insufficiency risk with hypotension and weakness.

Management

For short clarithromycin courses (5–7 days), halve methylprednisolone temporarily. For prolonged therapy, switch antibiotics (azithromycin, doxycycline) or replace methylprednisolone with hydrocortisone (less CYP3A4-dependent).

Mechanism

Clarithromycin blocks CYP3A4 – the main quetiapine metabolic route. Quetiapine plasma levels rise 6-fold, with stronger sedation, orthostatic hypotension, and QT effect.

Symptoms

Marked sedation, drowsiness, orthostatic hypotension with syncope on standing. Tachycardia, QT prolongation. In older patients: fall and fracture risk.

Management

During clarithromycin therapy, reduce quetiapine 4- to 6-fold and monitor ECG (QT) and blood pressure. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 impact). Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.

Mechanism

Dual CYP3A4 inhibition (clarithromycin + ritonavir). Plasma levels of both drugs rise, plus additive QT prolongation.

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 antibiotics without CYP3A4 inhibition: azithromycin or doxycycline. If clarithromycin is needed: ECG before start and every 3 days during therapy; do not increase clarithromycin dose.

Mechanism

Clarithromycin blocks CYP3A4 and P-glycoprotein – the two main rivaroxaban clearance routes. Rivaroxaban levels rise by roughly 50%, and bleeding risk grows in patients with renal impairment.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid where possible. Do not prescribe if creatinine clearance is below 30 mL/min. Alternative antibiotics: azithromycin or doxycycline (minimal CYP3A4 and P-glycoprotein interaction).

Mechanism

Clarithromycin blocks CYP3A4 – the main sildenafil metabolic route. Sildenafil plasma levels rise 3- to 5-fold. The hypotensive effect intensifies; priapism and ischaemic optic neuropathy risks rise.

Symptoms

Sudden blood pressure drop: dizziness, syncope. Priapism – painful erection lasting more than 4 hours, requiring emergency care. Worsening of visual disturbances (cyanopsia) and tinnitus.

Management

During clarithromycin therapy, cap sildenafil at 25 mg (instead of the standard 50–100 mg) and limit to one dose every 24 hours. Alternative antibiotics: azithromycin or doxycycline.

Mechanism

Clarithromycin blocks CYP3A4 – the main tamsulosin metabolic route. Tamsulosin plasma levels rise; orthostatic hypotension emerges.

Symptoms

Sudden blood pressure drop on standing, syncope, dizziness. Older patients: fall and fracture risk.

Management

During clarithromycin therapy, halve tamsulosin temporarily or use an alternative: finasteride/dutasteride (minimal CYP3A4 dependence). Alternative antibiotics: azithromycin or doxycycline.

Mechanism

Clarithromycin blocks CYP1A2 and CYP3A4 – theophylline metabolic routes. Theophylline plasma levels rise 2- to 3-fold. Theophylline has a narrow therapeutic window.

Symptoms

Nausea, tachycardia, tremor, insomnia, agitation. At levels above 30 mg/L: seizures and ventricular arrhythmias.

Management

Avoid the combination. Alternative antibiotics without CYP1A2/CYP3A4 inhibition: a cephalosporin, amoxicillin-clavulanate, or doxycycline. If clarithromycin is needed, halve theophylline and check level at 3 days.

Mechanism

Clarithromycin inhibits CYP3A4 (a minor warfarin clearance route) and suppresses vitamin K-producing gut flora. INR rises 1.5- to 2-fold within 3–5 days of co-administration.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

During clarithromycin therapy, empirically reduce warfarin by 20–30% and check INR 3–4 days after starting and 7 days after stopping the antibiotic. Alternative: azithromycin (minimal CYP3A4 and gut-flora impact).