Clarithromycin

Mechanism

CYP3A4 inhibition – bromocriptine rises 4-5 fold.

Symptoms

MI, stroke.

Management

Combination contraindicated.

Mechanism

Clarithromycin inhibits CYP3A4 – cisapride rises 5-7 fold. Well-known fatal combination, the main reason for cisapride withdrawal in 2000.

Symptoms

Torsades de pointes, sudden cardiac death.

Management

Combination contraindicated.

Mechanism

Clarithromycin is a macrolide, and its own SmPC puts concomitant drugs associated with QT prolongation among its contraindications. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions. Clarithromycin inhibits CYP3A4, a minor metabolic path for citalopram, so a small rise in antidepressant levels comes on top of the additive QT.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Both labels carry the ban, so the antibiotic course is planned not to overlap with the antidepressant. H. pylori eradication and respiratory infections have macrolide-free regimens.

Mechanism

Colchicine is cleared via hepatic CYP3A4 and the P-glycoprotein transporter. Clarithromycin inhibits both. Colchicine plasma levels rise several-fold. The narrow therapeutic window makes any increase clinically dangerous. FDA Colcrys carries a boxed warning for fatal toxicity.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

For patients with renal impairment (creatinine clearance below 60 mL/min) or hepatic impairment, the combination is not prescribed. With preserved renal and hepatic function, use colchicine 0.3 mg every other day, no more than 5 days. Alternative antibiotic: azithromycin (minimal interaction).

Mechanism

Clarithromycin inhibits CYP3A4 – dihydroergotamine accumulates 5-10 fold. Fatal ergotism.

Symptoms

Limb ischaemia, myocardial infarction.

Management

Combination contraindicated.

Mechanism

The liver breaks down domperidone mainly through the enzyme CYP3A4, and clarithromycin strongly inhibits this enzyme (domperidone and clarithromycin prescribing information). In vitro data suggest that drugs which markedly inhibit CYP3A4 raise domperidone plasma levels. The documents give no study or numbers with clarithromycin. Both drugs prolong the QT interval on the electrocardiogram on their own, so the arrhythmia risk rises in two ways: through higher domperidone levels and through added effects on the heart (domperidone prescribing information).

Symptoms

The main risk is heart rhythm disorders: QT interval prolongation on the electrocardiogram, ventricular tachycardia, ventricular fibrillation and torsade de pointes (clarithromycin prescribing information). Epidemiological studies have linked domperidone to serious ventricular arrhythmias and sudden cardiac death. The risk was higher in people over 60, at daily doses above 30 mg and with concomitant QT-prolonging drugs or inhibitors of the enzyme CYP3A4 (domperidone prescribing information). An arrhythmia attack shows as sudden strong palpitations, dizziness or fainting.

Management

The combination is contraindicated (clarithromycin and domperidone prescribing information, Spanish Agency of Medicines and Medical Devices, AEMPS). The clarithromycin document names domperidone among contraindicated drugs. The domperidone document contraindicates strong inhibitors of the enzyme CYP3A4 and gives clarithromycin as an example (AEMPS). Among macrolide antibiotics, the domperidone document allows only azithromycin and roxithromycin with caution and places clarithromycin among the contraindicated drugs. Each drug on its own is contraindicated in people with a prolonged QT interval or low potassium or magnesium, and domperidone also with bradycardia or congestive heart failure (clarithromycin and domperidone prescribing information). Use domperidone at the lowest effective dose, no more than 30 mg a day in adults and usually for no longer than one week (domperidone prescribing information). Stop domperidone if signs of arrhythmia appear during treatment, and tell patients in advance to report any cardiac symptoms as soon as possible (domperidone prescribing information).

Mechanism

Clarithromycin is a strong CYP3A4 inhibitor and prolongs QT itself. Dronedarone is cleared via CYP3A4 and also prolongs QT. Double mechanism: dronedarone levels rise 4-fold plus additive QT prolongation. FDA Multaq Section 4.3 specifically lists strong CYP3A4 inhibitors.

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 rises with hypokalaemia and hypomagnesaemia.

Management

The combination is not prescribed. Alternative antibiotics: azithromycin (minimal CYP3A4 effect and weaker QT effect) or doxycycline by susceptibility.

Mechanism

The liver breaks down eletriptan mainly through the enzyme CYP3A4, and clarithromycin strongly inhibits this enzyme. According to its own prescribing information, clarithromycin can raise the levels of drugs broken down by CYP3A enzymes and increase or prolong their adverse effects. The labels give no study of this exact pair. The closest guide is erythromycin, another macrolide antibiotic. At 1000 mg, it raised the eletriptan area under the curve (AUC) 3.6-fold and lengthened its half-life from 4.6 to 7.1 hours. Ketoconazole 400 mg raised the AUC 5.9-fold. Like other triptans, eletriptan can cause coronary artery spasm. In clinical trials, doses of 60 mg or more caused short-lived rises in blood pressure.

Symptoms

Tightness, pain or pressure in the chest, throat, neck and jaw is common after eletriptan. It is usually not cardiac but can be a sign of coronary artery spasm. Myocardial infarction, ventricular tachycardia and ventricular fibrillation have been reported within a few hours of triptan use, sometimes in people without known heart disease. Rarely, blood pressure rises sharply, even to a hypertensive crisis. Spasm of other arteries can cause Raynaud's syndrome or bowel ischaemia with abdominal pain and bloody diarrhoea. Stroke and brain haemorrhage have occurred after triptans.

Management

The combination is contraindicated (eletriptan label, US Food and Drug Administration, FDA). The eletriptan summary of product characteristics (SmPC) says not to use eletriptan with clarithromycin or other strong inhibitors of the enzyme CYP3A4 (Spanish Agency of Medicines and Medical Devices, AEMPS). Wait at least 72 hours after the last dose of clarithromycin before giving eletriptan (eletriptan label, FDA). If eletriptan has been taken during clarithromycin treatment and chest pain or tightness suggesting cardiac ischaemia appears, give no further doses and evaluate the heart (eletriptan SmPC, AEMPS). Stop eletriptan if arrhythmias occur and monitor blood pressure during treatment (eletriptan label, FDA). If signs of spasm in other arteries appear, such as abdominal pain with blood in the stool or white, cold fingers, rule out vasospasm before the next dose (eletriptan label, FDA).

Mechanism

According to the Inspra summary of product characteristics (SmPC) from the Spanish Agency of Medicines and Medical Devices (AEMPS), eplerenone is cleared mainly through the enzyme CYP3A4 (section 5.2). The clarithromycin SmPC itself calls clarithromycin a strong inhibitor of this enzyme (Klacid SmPC, AEMPS, section 4.3). According to the same SmPC, clarithromycin can raise the levels of drugs broken down by CYP3A enzymes and increase or prolong both their therapeutic and adverse effects (Klacid SmPC, AEMPS, section 4.5). The labels give no eplerenone data with clarithromycin itself. The closest guide is ketoconazole, another strong CYP3A4 inhibitor. At 200 mg twice daily, it raised the eplerenone area under the curve (AUC) by 441%, or 5.4-fold (Inspra SmPC, AEMPS, section 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 12.3). Eplerenone blocks mineralocorticoid receptors, so excess drug increases potassium retention and lowers blood pressure further. The SmPC names hypotension and hyperkalaemia as the most likely signs of overdose (Inspra SmPC, AEMPS, section 4.9). Eplerenone does not affect clarithromycin: it inhibits neither the main cytochrome P450 (CYP) enzymes nor P-glycoprotein (Inspra SmPC, AEMPS, section 4.5).

Symptoms

The main danger is hyperkalaemia. The eplerenone label of the US Food and Drug Administration (FDA) says the risk is higher even with moderate inhibitors of the enzyme CYP3A4. The same label lists clarithromycin among the strong ones (sections 4 and 5.1). High potassium causes muscle weakness, bradycardia and arrhythmias up to cardiac arrest, with peaked T waves and a widened QRS complex on the electrocardiogram (ECG). Low blood pressure causes dizziness and fainting, especially on standing (Inspra summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.8 and 4.9). The risk of hyperkalaemia is higher in older people, in reduced kidney function or diabetes, and with concurrent angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (Inspra SmPC, AEMPS, section 4.4).

Management

The combination is contraindicated. The Inspra summary of product characteristics (SmPC) and prescribing information bar eplerenone in patients taking strong inhibitors of the enzyme CYP3A4 and name clarithromycin explicitly (Inspra SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.3 and 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 4). The clarithromycin labels do not name eplerenone and ask only for caution with drugs broken down by CYP3A enzymes (AEMPS, section 4.5; FDA, section 7). This does not lift the contraindication in the eplerenone labels. The eplerenone ceiling of 25 mg daily applies only to weak and moderate CYP3A4 inhibitors, and among macrolides this group includes erythromycin (Inspra SmPC, AEMPS, sections 4.2 and 4.5; FDA, sections 2.4 and 7.1). The ceiling does not apply to clarithromycin, and a lower dose does not make the combination acceptable. If the two drugs have already been taken together, stop one of them and check potassium and creatinine at once. The eplerenone labels require a potassium check at any dose change, and a potassium and creatinine check within 3–7 days of adding even a moderate CYP3A4 inhibitor (Inspra SmPC, AEMPS, section 4.4; FDA, section 2.3). Stop eplerenone if serum potassium reaches 6.0 mmol/L or higher (Inspra SmPC, AEMPS, section 4.2).

Mechanism

Clarithromycin inhibits CYP3A4. Ergotamine is metabolised exclusively by CYP3A4; concentration rises 10+ fold. Fatal ergotism: digital ischaemia, MI, stroke. FDA boxed warning.

Symptoms

Within 1–3 days: digital numbness, pallor, limb pain; in severe cases gangrene. Fatal cases reported.

Management

Combination contraindicated. For migraine in a clarithromycin patient – switch ergotamine to triptan after course completion, or use paracetamol for acute attack.

Mechanism

Clarithromycin is a macrolide, and its own SmPC puts concomitant drugs associated with QT prolongation among its contraindications. The escitalopram SmPC contraindicates any QT-prolonging drug alongside it: the ban is written broadly, and the classes in brackets are examples. Clarithromycin inhibits CYP3A4, a minor metabolic path for escitalopram, so a small rise in antidepressant levels comes on top of the additive QT.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the escitalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Both labels carry the ban, so the antibiotic course is planned not to overlap with the antidepressant. H. pylori eradication and respiratory infections have macrolide-free regimens.

Mechanism

Clarithromycin inhibits CYP3A4 and P-gp. Everolimus rises 5+ fold – severe immunosuppression, pneumonitis, nephrotoxicity.

Symptoms

Dyspnoea, rising creatinine, cytopenia.

Management

Combination contraindicated. Alternative – azithromycin.

Mechanism

Both drugs prolong the QT interval on the electrocardiogram. The clarithromycin SmPC reports QT prolongation and a risk of torsades de pointes with macrolides, clarithromycin included. The haloperidol SmPC reports QT prolongation, ventricular arrhythmias and sudden death; the risk is higher with high doses and high plasma levels. There is a second mechanism: clarithromycin is a strong CYP3A4 inhibitor (clarithromycin SmPC), and haloperidol is partly cleared by this enzyme, although its main pathways are different. With CYP3A4 inhibitors haloperidol levels may rise by 20–40%, in some cases by up to 100%, and the risk of QT prolongation rises with them (haloperidol SmPC).

Symptoms

QT prolongation on the electrocardiogram (ECG) causes no symptoms by itself. Palpitations, dizziness or fainting may occur. The dangerous complication is torsades de pointes, which can progress to ventricular fibrillation (clarithromycin SmPC). The risk is higher with low potassium or magnesium, coronary artery disease, severe heart failure, conduction disorders or marked bradycardia (clarithromycin and haloperidol SmPCs).

Management

The combination is contraindicated: the Spanish haloperidol SmPC contraindicates haloperidol with drugs that prolong the QT interval and names clarithromycin (haloperidol SmPC). The clarithromycin label approved by the US Food and Drug Administration (FDA) says to avoid clarithromycin in patients who take QT-prolonging drugs (clarithromycin FDA label). Clarithromycin itself is contraindicated with low potassium or magnesium and with a history of QT prolongation (clarithromycin SmPC). The haloperidol SmPC also contraindicates azithromycin, erythromycin, levofloxacin and moxifloxacin. Before haloperidol is started, an electrocardiogram (ECG) is recorded and low potassium and magnesium are corrected; if the corrected QT interval (QTc) lengthens, the haloperidol dose is reduced, and haloperidol is stopped if QTc exceeds 500 ms (haloperidol SmPC).

Mechanism

In the liver and gut, a single enzyme, CYP3A4 (cytochrome P450 3A4), breaks down ivabradine, and clarithromycin strongly inhibits this enzyme (ivabradine and clarithromycin summaries of product characteristics, SmPCs). When the two are taken together, ivabradine levels in the blood rise, and high levels can lead to excessive bradycardia (ivabradine SmPC, European Medicines Agency, EMA). The documents give no figures for clarithromycin itself. Figures exist for other strong inhibitors: ketoconazole 200 mg once daily and the macrolide antibiotic josamycin 1 g twice daily raised mean ivabradine plasma exposure 7- to 8-fold (ivabradine SmPC, EMA). The second mechanism involves the QT interval. Clarithromycin prolongs QT on its own, and the slower heart rate caused by ivabradine can worsen this prolongation and lead to a serious arrhythmia (clarithromycin and ivabradine SmPCs, EMA).

Symptoms

Excessive bradycardia shows as a resting heart rate below 50 beats per minute, dizziness, fatigue and low blood pressure (ivabradine summary of product characteristics, European Medicines Agency, EMA). Sinus arrest and heart block can occur (Corlanor label, US Food and Drug Administration, FDA). The QT interval on the electrocardiogram (ECG) can lengthen, and a severe ventricular arrhythmia, including torsade de pointes, may follow (ivabradine and clarithromycin summaries of product characteristics). The risk is higher in people who also take other QT-prolonging drugs (Corlanor label, FDA).

Management

The combination is contraindicated on both sides. The ivabradine summary of product characteristics (SmPC) lists clarithromycin among the strong inhibitors of the enzyme CYP3A4 (cytochrome P450 3A4) that must not be taken with ivabradine (European Medicines Agency, EMA, sections 4.3 and 4.5). The clarithromycin SmPC lists ivabradine among contraindicated drugs (Spanish Agency of Medicines and Medical Devices, AEMPS, 4.3 and 4.5). The US ivabradine label also contraindicates strong CYP3A4 inhibitors and gives clarithromycin as an example (US Food and Drug Administration, FDA, sections 4 and 7.1). So during a course of clarithromycin, choose another antibiotic or pause ivabradine (this follows from the contraindication in both labels). The documents give no interval after clarithromycin before ivabradine can be restarted. When choosing the antibiotic, note that oral erythromycin, josamycin and telithromycin are also contraindicated with ivabradine, and drugs that prolong the QT interval should be avoided with it (ivabradine SmPC, EMA, sections 4.3–4.5). Clarithromycin itself is contraindicated with a history of QT prolongation and with low potassium or magnesium (clarithromycin SmPC, AEMPS, 4.3). Avoid it in clinically significant bradycardia (clarithromycin label, FDA, 5.2). If the drugs have already been taken together, stop one of them and monitor the heart rate and electrocardiogram (ECG). With a resting heart rate below 50 beats per minute or symptoms of bradycardia, reduce the ivabradine dose, and if bradycardia persists, stop ivabradine (ivabradine SmPC, EMA, 4.2 and 4.4). Treat severe bradycardia in a specialised unit. If it compromises the circulation, give intravenous beta-stimulants such as isoprenaline, and use temporary cardiac pacing if that is not enough (ivabradine SmPC, EMA, 4.9). Before restarting ivabradine, measure the resting heart rate several times, by ECG or 24-hour monitoring, and do not start the drug below 70 beats per minute (ivabradine SmPC, EMA, 4.3 and 4.4).

Mechanism

Clarithromycin inhibits CYP3A4 – lovastatin (sensitive substrate) rises 8-fold. Rhabdomyolysis risk.

Symptoms

Myalgia, weakness, dark urine, rising CK within 5-10 days.

Management

Combination contraindicated. Switch lovastatin to pravastatin or rosuvastatin during the course.

Mechanism

Clarithromycin inhibits CYP3A4 (raises methadone) and itself prolongs QT. Dual torsades risk in OST patient.

Symptoms

QT above 500 ms, syncope.

Management

Combination contraindicated. Alternative – azithromycin.

Mechanism

Clarithromycin is a strong CYP3A4 inhibitor. Pimozide is 80% metabolised by CYP3A4; concentration rises 5–7 fold during co-administration. FDA Orap Section 4 strict contraindication – risk of QT prolongation, torsades de pointes and sudden cardiac death.

Symptoms

Within 3–7 days: palpitations, dizziness, syncope. ECG QTc above 500 ms, ventricular ectopy; in severe cases torsades de pointes progressing to ventricular fibrillation.

Management

Combination contraindicated. For infection in a pimozide patient use azithromycin (no CYP3A4 inhibition) or another antibiotic class (amoxicillin for typical pneumonia). If clarithromycin is needed, hold pimozide for the course and resume 7 days after the last dose.

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

The AEMPS label for quetiapine lists the combination with CYP3A4 inhibitors, clarithromycin included, as contraindicated. The FDA label reduces the quetiapine dose sixfold with ECG monitoring instead. Alternative antibiotics: azithromycin or doxycycline, with little effect on CYP3A4. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.

Mechanism

The gut and liver break down ranolazine mainly through the enzyme CYP3A4, and clarithromycin strongly inhibits this enzyme. The labels give no figures for this exact pair. The closest guide is ketoconazole 200 mg twice daily, another strong CYP3A4 inhibitor. It raised the ranolazine area under the curve (AUC) 3.0–3.9-fold. As ranolazine levels rise, so do its dose-dependent adverse effects and QT interval prolongation on the electrocardiogram. Clarithromycin prolongs the QT interval on its own. The ranolazine prescribing information warns that combining ranolazine with such drugs may in theory raise the risk of ventricular arrhythmias.

Symptoms

Excess ranolazine causes dizziness, nausea and vomiting, and at high concentrations double vision, lethargy, confusion and fainting. Reported effects of oral ranolazine overdose include low blood pressure, slow heart rate, QT interval prolongation on the electrocardiogram, severe tremor, unsteady gait and hallucinations. Clarithromycin also prolongs the QT interval. Torsade de pointes and deaths have been reported in patients taking it.

Management

The combination is contraindicated (clarithromycin summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS; ranolazine SmPC, European Medicines Agency, EMA; ranolazine label, US Food and Drug Administration, FDA). None of these documents sets a dose condition, so the contraindication covers any dose of either drug. Ranolazine is used for stable angina (ranolazine SmPC, EMA). In coronary artery disease, weigh the benefit of clarithromycin against a rare risk of arrhythmia, myocardial infarction and cardiovascular death (clarithromycin SmPC, AEMPS). Also weigh it against higher all-cause mortality one year or more after the course (clarithromycin label, FDA). Clarithromycin is contraindicated in patients with low blood potassium or magnesium and in those with a history of QT interval prolongation or ventricular arrhythmia (clarithromycin SmPC, AEMPS). If a patient has taken both drugs and develops dizziness, vomiting, double vision or fainting, observe the patient closely and give symptomatic and supportive care (ranolazine SmPC, EMA). Monitor the electrocardiogram continuously if needed (ranolazine label, FDA).

Mechanism

Simvastatin clearance is 98% dependent on hepatic CYP3A4. Clarithromycin is a potent inhibitor of this enzyme; simvastatin plasma concentrations rise 10-fold or more. The FDA lists this combination as an absolute contraindication.

Symptoms

Pain and weakness in large muscle groups, dark urine, elevated creatine kinase on lab work. Severe cases progress to rhabdomyolysis with acute kidney injury. First signs appear within 3–7 days of concurrent dosing.

Management

The combination is not prescribed. Hold simvastatin for the duration of clarithromycin therapy or switch the patient to pravastatin or rosuvastatin – these statins use a different metabolic pathway and do not interact. If simvastatin cannot be paused, replace the antibiotic: azithromycin or a non-macrolide class based on susceptibility.

Mechanism

Clarithromycin is a strong CYP3A4 inhibitor. Ticagrelor rises 5-fold.

Symptoms

Bleeding.

Management

Combination contraindicated. Alternative – azithromycin (no CYP3A4 inhibition).

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

Both drugs prolong the QT interval, and their effects on the heart add up, raising the risk of torsades de pointes (amiodarone SmPC). Clarithromycin inhibits CYP3A4, which clears amiodarone, so amiodarone levels may rise (amiodarone SmPC). The US Food and Drug Administration (FDA) also describes the reverse effect: amiodarone slows the clearance of macrolides other than azithromycin (amiodarone FDA label). Amiodarone is eliminated very slowly, and its interactions can persist for months after it is stopped (amiodarone SmPC).

Symptoms

QT prolongation on the electrocardiogram, palpitations, dizziness, fainting. In severe cases, torsades de pointes with a risk of ventricular fibrillation and sudden cardiac death. The risk is higher with low potassium or magnesium, marked bradycardia, coronary artery disease and in older patients.

Management

Avoid the combination. The US Food and Drug Administration (FDA) advises against clarithromycin in patients taking class III antiarrhythmics, including amiodarone (clarithromycin FDA label). The amiodarone FDA label advises avoiding certain macrolides with amiodarone, both as QT-prolonging drugs and as inhibitors of its metabolism (amiodarone FDA label). CYP3A4 inhibitors should be avoided during amiodarone treatment (amiodarone SmPC). QT-prolonging drugs, clarithromycin included, are combined with amiodarone only after a careful assessment of benefit and risk for the individual patient and with QT monitoring (amiodarone SmPC). Clarithromycin is contraindicated in patients with a history of QT prolongation or ventricular arrhythmia and in those with low potassium or magnesium (clarithromycin SmPC). The interaction remains possible for several months after amiodarone is stopped (amiodarone SmPC).

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 is a strong inhibitor of CYP3A4 and P-glycoprotein. Atorvastatin plasma levels rise 4–5-fold, and so does the risk of rhabdomyolysis with acute kidney injury. The labels do not ban the pair. The FDA caps atorvastatin at 20 mg/day while clarithromycin is taken. The AEMPS label advises avoiding the combination where possible and, if it cannot be avoided, using lower starting and maximum statin doses.

Symptoms

Within 5–10 days: muscle pain, especially thighs and shoulder girdle, dark urine, creatine kinase above 10× ULN, rising creatinine.

Management

Hold atorvastatin or reduce it to 10–20 mg/day for the duration of clarithromycin (typically 7–14 days). Alternative: switch clarithromycin to azithromycin, which does not inhibit CYP3A4.

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

Cyclosporine is cleared through CYP3A4, and clarithromycin inhibits this enzyme. Clarithromycin roughly doubles cyclosporine exposure (cyclosporine SmPC). Excess cyclosporine damages the kidneys and raises blood pressure (cyclosporine SmPC).

Symptoms

Rising creatinine and urea, high blood pressure, tremor, headache, high blood potassium.

Management

During the clarithromycin course, adjust the cyclosporine dose according to its blood concentration. The US Food and Drug Administration (FDA) lists clarithromycin among drugs that increase cyclosporine concentrations and states that dose adjustment to the desired concentration is essential when a drug significantly alters cyclosporine levels (cyclosporine FDA label). In transplant recipients, measure cyclosporine levels frequently, especially when clarithromycin is started and stopped, and adjust the dose as needed (cyclosporine SmPC). In patients without a transplant, check kidney function more often and watch for cyclosporine adverse effects (cyclosporine SmPC).

Mechanism

Clarithromycin inhibits P-glycoprotein (P-gp), the efflux transporter for dabigatran. In healthy volunteers, clarithromycin 500 mg twice daily increased dabigatran AUC about 1.19-fold and Cmax about 1.15-fold (EMA SmPC). The increase alone is small, but P-gp inhibition and impaired renal function are the two major independent factors that raise dabigatran exposure (FDA label), and their effects add up.

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

With creatinine clearance (CrCl) of 50 mL/min or more, keep the dabigatran dose. In atrial fibrillation the dose also stays the same at CrCl 30–50 mL/min: the FDA label lists clarithromycin among P-gp inhibitors that need no dabigatran dose adjustment. Per the FDA label, avoid the combination in two cases: CrCl below 50 mL/min when dabigatran is used to treat or prevent deep vein thrombosis and pulmonary embolism, and CrCl 15–30 mL/min in atrial fibrillation. Calculate CrCl with the Cockcroft–Gault formula before the course. During the course, watch for signs of bleeding and anaemia, especially with reduced renal function (EMA SmPC). If the combination is unsuitable, choose an antibiotic that is not listed as a P-gp inhibitor in the dabigatran label.

Mechanism

Digoxin is cleared with the help of the P-glycoprotein (P-gp) transporter, and clarithromycin inhibits it, so digoxin blood levels rise (clarithromycin SmPC). The US Food and Drug Administration (FDA) reports a 70% increase in the area under the digoxin concentration curve (digoxin FDA label). Digoxin has a narrow therapeutic index, and older age, low body weight, impaired kidney function, low potassium or magnesium and high calcium predispose to toxicity (digoxin FDA label).

Symptoms

Loss of appetite, nausea, vomiting, visual changes and heart rhythm disorders: bradycardia, heart block, ventricular extrasystoles, ventricular tachycardia and ventricular fibrillation. Life-threatening arrhythmias have been reported with this combination after marketing.

Management

The US Food and Drug Administration (FDA) lists clarithromycin among drugs that raise digoxin levels by more than 50% and for them recommends measuring serum digoxin before starting, reducing the digoxin dose by about 30–50% or giving it less often, and continuing to monitor (digoxin FDA label). Monitor digoxin levels carefully throughout the clarithromycin course (clarithromycin SmPC): after marketing, some patients on this combination showed signs of digoxin toxicity, including life-threatening arrhythmias (clarithromycin SmPC). Monitor more closely when clarithromycin is started and stopped (digoxin FDA label). If signs of toxicity appear, measure the digoxin level and interrupt or adjust the dose (digoxin FDA label).

Mechanism

Disopyramide is broken down in the liver by CYP3A4, and clarithromycin inhibits this enzyme, so disopyramide blood levels rise. Both drugs prolong the QT interval, and their effects on the heart add up.

Symptoms

QT prolongation on the ECG, palpitations, fainting, torsades de pointes. Post-marketing reports also describe hypoglycemia with this combination: sweating, tremor, hunger, confusion.

Management

Avoid the combination. The disopyramide label lists macrolides that inhibit CYP3A4 among combinations that are not recommended (disopyramide label). The US Food and Drug Administration (FDA) advises against clarithromycin in patients on class IA antiarrhythmics, including disopyramide (clarithromycin FDA label). Clarithromycin is contraindicated in patients with a history of QT prolongation or ventricular arrhythmia and in those with low potassium or magnesium (clarithromycin label). If the combination cannot be avoided, monitor the ECG, disopyramide blood levels and blood glucose during co-administration (clarithromycin label). Stop disopyramide if the QT interval or QRS duration lengthens by more than 25% (disopyramide label). Check potassium and correct it if needed (disopyramide label).

Mechanism

Methylprednisolone is broken down in the liver by CYP3A4, and clarithromycin inhibits this enzyme. A considerable rise in methylprednisolone blood levels has been observed with clarithromycin (methylprednisolone SmPC). Higher levels increase the risk of systemic corticosteroid adverse effects (methylprednisolone SmPC).

Symptoms

Moon face, central obesity, abdominal striae, high blood pressure, high blood glucose (Cushing's syndrome). After prolonged combined use and abrupt withdrawal, adrenal insufficiency with low blood pressure and weakness may occur.

Management

Avoid the combination unless the benefit outweighs the risk of systemic corticosteroid adverse effects: the methylprednisolone SmPC sets this rule for all CYP3A4 inhibitors and names clarithromycin separately as a drug that considerably raises methylprednisolone levels (methylprednisolone SmPC). If the combination is needed, monitor the patient closely for systemic corticosteroid adverse effects throughout the clarithromycin course (methylprednisolone SmPC; clarithromycin SmPC). The US Food and Drug Administration (FDA) advises titrating the methylprednisolone dose to avoid steroid toxicity when drugs that slow its clearance are added (methylprednisolone FDA label).

Mechanism

Clarithromycin inhibits CYP3A4 – pimavanserin rises 2-3 fold. Added QT prolongation.

Symptoms

QT prolongation, dizziness, peripheral edema.

Management

Reduce pimavanserin to 10 mg/day. Better – azithromycin.

Mechanism

Clarithromycin inhibits CYP3A4. Rifabutin rises 2.5-fold – increased uveitis risk, especially in MAC infection patients.

Symptoms

Eye pain, photophobia, reduced vision.

Management

Reduce rifabutin to 300 mg/day (standard 450 mg). Regular ophthalmology review.

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

Cytochrome P450 enzymes play almost no part in breaking down rosuvastatin, so the rosuvastatin SmPC does not expect interactions through these enzymes. The documents contain no study of rosuvastatin with clarithromycin. The rosuvastatin SmPC lists macrolide antibiotics among drugs that increased the incidence of myositis and myopathy with other statins, and the clarithromycin SmPC reports rhabdomyolysis in patients taking clarithromycin with statins.

Symptoms

Unexplained muscle pain, weakness or cramps, especially with malaise or fever, and raised creatine kinase on blood tests (rosuvastatin SmPC). In rhabdomyolysis the urine turns dark and kidney function can suffer.

Management

The clarithromycin SmPC asks for caution when clarithromycin is combined with any statin and for monitoring for signs of myopathy. If the combination cannot be avoided, the statin is prescribed at the lowest registered dose (clarithromycin SmPC), which for rosuvastatin is 5 mg. The same SmPC suggests considering a statin that does not depend on CYP3A4, such as fluvastatin. Ask the patient to report unexplained muscle pain, weakness or cramps promptly. Check creatine kinase if they occur; stop rosuvastatin if it is more than 5 times the upper limit of normal or if muscle symptoms are severe and cause daily discomfort (rosuvastatin SmPC).

Mechanism

Sildenafil is cleared mainly through CYP3A4 (sildenafil SmPC). The European Medicines Agency (EMA) places clarithromycin among the more potent inhibitors of this enzyme and assumes about a 7-fold increase in sildenafil exposure with it (sildenafil SmPC for pulmonary hypertension, EMA). The US Food and Drug Administration (FDA) warns that low blood pressure, fainting and prolonged erection may occur at higher sildenafil exposure (sildenafil FDA label).

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

Avoid the combination: the US Food and Drug Administration (FDA) does not recommend sildenafil together with clarithromycin (clarithromycin FDA label), and for pulmonary arterial hypertension it does not recommend sildenafil with any strong CYP3A4 inhibitor (sildenafil FDA label for pulmonary hypertension). If sildenafil for pulmonary hypertension is still needed during a clarithromycin course, the European Medicines Agency (EMA) recommends reducing the dose to 20 mg once daily (sildenafil SmPC for pulmonary hypertension, EMA). For erectile dysfunction, consider a 25 mg starting dose in patients taking CYP3A4 inhibitors (sildenafil SmPC, EMA; sildenafil FDA label), with no more than one dose per day (sildenafil SmPC, EMA). The clarithromycin SmPC also advises considering a lower sildenafil dose (clarithromycin SmPC). Tell the patient to seek urgent medical help if an erection lasts longer than 4 hours (sildenafil SmPC, EMA).

Mechanism

Sirolimus is cleared by CYP3A4 in the gut and liver and by P-glycoprotein. Clarithromycin strongly inhibits CYP3A4, so sirolimus blood levels rise. The sirolimus SmPC (Rapamune) lists clarithromycin among strong inhibitors it does not recommend combining with, and the FDA sirolimus label says to avoid the pair. The labels give no figure for this specific pair; for ketoconazole, another strong CYP3A4 inhibitor, the sirolimus SmPC reports a 10.9-fold rise in AUC.

Symptoms

Rising creatinine, thrombocytopenia, hepatitis within 5–7 days.

Management

The combination is avoided. Clarithromycin is replaced by an antibiotic with less effect on sirolimus, usually azithromycin if the spectrum fits. If clarithromycin cannot be avoided, per the sirolimus SmPC trough sirolimus levels are measured during co-administration and after clarithromycin stops, and the sirolimus dose follows the result. The patient's clinical status and renal function are checked on the same schedule. A transplant specialist runs the regimen.

Mechanism

Tacrolimus, an immunosuppressant used after organ transplantation, is cleared by CYP3A4 in the liver and gut. Clarithromycin strongly inhibits CYP3A4. According to the tacrolimus SmPC, a strong CYP3A4 inhibitor raises tacrolimus levels rapidly and sharply, within 1–3 days and even after an immediate dose reduction, and overall exposure may increase more than 5-fold. With a narrow therapeutic range such a rise is dangerous: the label lists nephrotoxicity, neurotoxicity and 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

The tacrolimus SmPC advises avoiding the combination, so the first step is to replace clarithromycin, usually with azithromycin if the spectrum fits. If clarithromycin cannot be avoided, a transplant specialist runs the regimen. Per the label, omitting the tacrolimus dose on the day clarithromycin starts is considered, and tacrolimus is restarted the next day at a reduced dose guided by blood levels. Trough levels are measured at baseline, frequently from the first days of co-administration, when clarithromycin stops and afterwards, because the effect lasts several days. Creatinine and the QT interval on ECG are monitored in parallel.

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 inhibits CYP3A4, the enzyme that clears amlodipine, so amlodipine blood levels rise and so does the risk of hypotension (amlodipine SmPC). The labels give no exact figure for this pair. The US Food and Drug Administration (FDA) expects clarithromycin, as a strong inhibitor of the enzyme, to raise amlodipine levels more than diltiazem, which increases them by 60% (amlodipine FDA label). Clarithromycin levels may also rise (clarithromycin SmPC). The effect is stronger in older patients (amlodipine SmPC).

Symptoms

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

Management

The combination can be used, but with caution because of the risk of hypotension (clarithromycin SmPC). During the clarithromycin course, monitor blood pressure and how the patient feels, and lower the amlodipine dose if needed (amlodipine SmPC). The US Food and Drug Administration (FDA) advises using signs of hypotension and swelling to decide whether a dose change is needed (amlodipine FDA label). Watch older patients more closely: the effect is stronger in them (amlodipine SmPC), and most reports of acute kidney injury with clarithromycin and these calcium channel blockers involved patients aged 65 or older (clarithromycin FDA label).

Mechanism

Apixaban is cleared partly through the CYP3A4 enzyme and the P-glycoprotein (P-gp) transporter, and clarithromycin inhibits both. The European Medicines Agency (EMA) does not class clarithromycin as a strong inhibitor of both pathways at once: at 500 mg twice daily it raised the apixaban area under the curve 1.6-fold and peak concentration 1.3-fold, compared with 2-fold and 1.6-fold for ketoconazole (apixaban SmPC, EMA). Higher apixaban levels mean a higher risk of bleeding.

Symptoms

Bleeding gums, nosebleeds, bruising without injury, blood in the urine or stool, heavy periods. In severe cases, gastrointestinal or intracranial bleeding. The risk is higher in patients aged 75 or over, with chronic kidney disease, previous bleeding or anaemia, and with concomitant antiplatelet drugs, non-steroidal anti-inflammatory drugs or systemic corticosteroids.

Management

The combination can be used with caution. The European Medicines Agency (EMA) requires no apixaban dose change with inhibitors that do not strongly block both of its elimination pathways and names clarithromycin among them (apixaban SmPC, EMA). The US Food and Drug Administration (FDA) also requires no dose adjustment with clarithromycin (apixaban FDA label). Caution matters most in patients at high risk of bleeding (clarithromycin SmPC). The European Heart Rhythm Association (EHRA) advises particular caution with polypharmacy and when two or more risk factors are present, such as age 75 or over, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic corticosteroids or previous bleeding (EHRA 2021). In that case, first consider whether another anticoagulant or antibiotic with fewer interactions is suitable (EHRA 2021). Watch the patient for signs of bleeding and stop apixaban if severe bleeding occurs (apixaban SmPC, EMA).

Mechanism

Dual macrolide therapy – doubled QT effect and redundant antibacterial activity without clinical rationale.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

The combination is not prescribed. Choose one macrolide: azithromycin for upper respiratory infections and chlamydia (short course); clarithromycin for H. pylori and atypical pneumonia. When choosing, mind the interaction profile (clarithromycin is a strong CYP3A4 inhibitor).

Mechanism

Carbamazepine is broken down in the liver mainly by CYP3A4, and clarithromycin inhibits this enzyme, so carbamazepine blood levels rise (carbamazepine SmPC). In clinical studies the increase was modest but statistically significant (clarithromycin SmPC). The interaction also works the other way: carbamazepine speeds up the breakdown of clarithromycin, and antibiotic levels may fall below the therapeutic range (clarithromycin SmPC).

Symptoms

Dizziness, drowsiness, unsteady gait, double vision, nausea. On the antibiotic side, a weaker response to treatment of the infection because of low clarithromycin levels.

Management

The combination can be used with monitoring. While the patient takes both drugs, monitor carbamazepine blood levels and adjust the dose if needed (carbamazepine SmPC). The US Food and Drug Administration (FDA) also advises close monitoring of carbamazepine levels and notes that the dose may need adjusting (carbamazepine FDA label). High carbamazepine levels cause dizziness, drowsiness, unsteady gait and double vision (carbamazepine SmPC). Use clarithromycin with caution in patients on carbamazepine because the antibiotic may be less effective (clarithromycin SmPC).

Mechanism

The metformin label does not name clarithromycin, and the risk lies elsewhere: metformin is cleared unchanged by the kidney, and its label warns of lactic acidosis when renal function drops. An infection with fever, vomiting or diarrhoea causes dehydration and lowers filtration, so the danger comes from the illness being treated rather than from the antibiotic itself.

Symptoms

Nausea, vomiting, abdominal pain, deep rapid breathing, muscle cramps, drowsiness: this is how lactic acidosis starts, and it is mistaken for the infection itself. Clarithromycin brings a metallic taste and digestive upset, which is a different thing.

Management

Metformin continues while the patient eats and drinks normally. If vomiting, diarrhoea or high fever prevent hydration, hold it temporarily and restart once intake and renal function are back to normal, as the label directs for iodinated contrast procedures.

Mechanism

Metoprolol is mainly metabolised by CYP2D6; clarithromycin does not clinically significantly inhibit CYP2D6. The effect on metoprolol levels is minimal. Additive bradycardia is possible from clarithromycin's direct effect on the cardiac conduction system.

Symptoms

Bradycardia, dizziness, fatigue. Symptoms appear during clarithromycin courses in older patients and concurrent heart failure.

Management

For short clarithromycin courses (7–14 days) with normal heart rate, no adjustment needed. In older patients and prior first-degree AV block, check ECG at one week. For long-term clarithromycin (e.g. Mycobacterium avium complex), antibiotic alternative: azithromycin (minimal HR effect).

Mechanism

Rivaroxaban is cleared partly through the CYP3A4 enzyme and the P-glycoprotein (P-gp) transporter. The European Medicines Agency (EMA) classes clarithromycin as a strong CYP3A4 inhibitor and a moderate P-gp inhibitor: at 500 mg twice daily it raised the rivaroxaban area under the curve 1.5-fold and peak concentration 1.4-fold (rivaroxaban SmPC, EMA). In severe kidney impairment, rivaroxaban levels are higher even without interacting drugs, on average 1.6-fold (rivaroxaban SmPC, EMA).

Symptoms

Bleeding gums, nosebleeds, bruising without injury, blood in the urine or stool, heavy periods. In severe cases, gastrointestinal or intracranial bleeding. The risk is higher in patients aged 75 or over, with chronic kidney disease, previous bleeding or anaemia, and with concomitant antiplatelet drugs, non-steroidal anti-inflammatory drugs or systemic corticosteroids.

Management

The combination can be used with caution. The European Medicines Agency (EMA) considers the interaction clinically irrelevant for most patients but potentially significant in high-risk patients (rivaroxaban SmPC, EMA). The US Food and Drug Administration (FDA) requires no special measures (rivaroxaban FDA label). Caution matters most in patients at high risk of bleeding (clarithromycin SmPC) and in those with reduced kidney function: rivaroxaban is used with caution in patients with renal impairment who take drugs that raise its levels (rivaroxaban SmPC, EMA), and the European Society of Cardiology (ESC) flags clarithromycin specifically when kidney function is impaired (ESC 2024). The European Heart Rhythm Association (EHRA) advises particular caution with polypharmacy and when two or more risk factors are present, such as age 75 or over, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic corticosteroids or previous bleeding; in that case, first consider whether another anticoagulant or antibiotic with fewer interactions is suitable (EHRA 2021). Watch the patient for signs of bleeding and stop rivaroxaban if severe bleeding occurs (rivaroxaban SmPC, EMA).

Mechanism

Clarithromycin slows the clearance of theophylline by liver enzymes, so theophylline blood levels rise (theophylline SmPC). The US Food and Drug Administration (FDA) gives an average increase of 25% (theophylline FDA label), and the clarithromycin SmPC calls the increase modest but statistically significant (clarithromycin SmPC). Theophylline has a narrow therapeutic range: above 20 mcg/mL, adverse reactions become more frequent and more severe (theophylline FDA label).

Symptoms

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

Management

The combination can be used with monitoring. The theophylline SmPC lists clarithromycin among drugs that raise the risk of theophylline overdose and requires these patients to be monitored (theophylline SmPC). The US Food and Drug Administration (FDA) advises measuring the serum theophylline concentration when clarithromycin is added or stopped (theophylline FDA label), especially with high theophylline doses or a baseline level near the upper end of the therapeutic range (clarithromycin FDA label). The therapeutic range is 10–20 mcg/mL (theophylline SmPC). Lower the theophylline dose if needed (clarithromycin SmPC). Ask the patient to report nausea, vomiting, persistent headache, insomnia or a fast heartbeat (theophylline FDA label). If the theophylline dose was lowered, restore it after clarithromycin is stopped, otherwise theophylline levels will fall (theophylline FDA label).

Mechanism

Clarithromycin is one of the enzyme inhibitors that slow the liver metabolism of warfarin and increase its anticoagulant effect and bleeding risk (warfarin SmPC). The US Food and Drug Administration (FDA) lists clarithromycin as an inhibitor of CYP3A4, which clears one of the two warfarin isomers (warfarin FDA label). Serious bleeding and marked rises in the international normalised ratio (INR) and prothrombin time can occur with this combination (clarithromycin SmPC).

Symptoms

Bleeding gums, nosebleeds, bruising and pinpoint skin bleeds, blood in the urine, black stools, heavy periods. In severe cases, gastrointestinal or intracranial bleeding.

Management

The combination can be used with frequent coagulation checks. Check the international normalised ratio (INR) and prothrombin time frequently throughout the clarithromycin course (clarithromycin SmPC). The US Food and Drug Administration (FDA) advises close INR monitoring when any antibiotic is started or stopped (warfarin FDA label). The European Society of Cardiology (ESC) lists macrolides among drugs that call for careful INR monitoring in patients on vitamin K antagonists (ESC 2024). Adjust the warfarin dose according to the INR (warfarin SmPC). Ask the patient to report any signs of bleeding (warfarin FDA label).