Erythromycin

Mechanism

Erythromycin inhibits CYP3A4. Atorvastatin rises 2-3 fold. FDA recommends dose cap.

Symptoms

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

Management

The AEMPS label for erythromycin lists the combination with atorvastatin as contraindicated. The FDA label caps atorvastatin at 20 mg/day instead. Alternative antibiotic: azithromycin, which does not inhibit CYP3A4; otherwise pause the statin for the course.

Mechanism

Intravenous erythromycin is named outright in both SSRI labels, and its own SmPC forbids use in patients with a history of QT prolongation or with hypokalaemia and hypomagnesaemia. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions.

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. The SSRI labels name the intravenous form, but oral erythromycin works through the same hERG blockade, and the dronedarone label, for one, bans the oral macrolide. The antibiotic is picked outside this group.

Mechanism

Erythromycin inhibits CYP3A4 (disopyramide metabolism) and itself prolongs QT. Dual torsades risk.

Symptoms

QTc above 500 ms, syncope, torsades de pointes within 3-7 days.

Management

Combination contraindicated. Alternative – azithromycin (no CYP3A4 inhibition or QT effect).

Mechanism

Both drugs prolong the QT interval. The dronedarone label lists erythromycin among drugs that can induce torsade de pointes and contraindicates the combination because of the risk of proarrhythmia. Erythromycin also moderately inhibits the enzyme CYP3A4 and the transporter P-glycoprotein (erythromycin label). The liver breaks down dronedarone mainly through this enzyme. Erythromycin 500 mg three times a day for 10 days raised steady-state dronedarone levels 3.8-fold (dronedarone label, European Medicines Agency, EMA). The QT interval gets longer as dronedarone concentration rises (dronedarone label, US Food and Drug Administration, FDA). Dronedarone is a class III antiarrhythmic. The label of intravenous erythromycin contraindicates erythromycin with class Ia and III antiarrhythmics, which also prolong the QT interval.

Symptoms

The main risk is ventricular arrhythmia from a prolonged QT interval, up to torsade de pointes: palpitations, skipped beats, dizziness, fainting. Deaths from these arrhythmias have been reported during erythromycin treatment, and older people are more sensitive to its effect on the QT interval. A fast intravenous infusion of erythromycin can by itself prolong the QT interval and cause arrhythmia or low blood pressure. A slow pulse is common with dronedarone. As its concentration rises, the QT and PR intervals on the electrocardiogram (ECG) get longer.

Management

The combination is contraindicated (dronedarone labels, European Medicines Agency, EMA, and US Food and Drug Administration, FDA). Both labels name erythromycin. The contraindication also applies to intravenous erythromycin. The FDA dronedarone label does not limit it to any route of administration. The label of intravenous erythromycin contraindicates its use with class III antiarrhythmics (Spanish Agency of Medicines and Medical Devices, AEMPS), and dronedarone belongs to this class (dronedarone label, EMA). If erythromycin has been started during dronedarone treatment, stop dronedarone: the label requires stopping it whenever any contraindicated condition develops (dronedarone label, EMA). After stopping 400 mg twice daily, dronedarone and its metabolite are fully cleared from plasma within 2 weeks (dronedarone label, EMA). The documents set no specific interval before starting erythromycin. Correct potassium and magnesium before starting dronedarone and keep them in the normal range during treatment (dronedarone labels, EMA and FDA). Do not give erythromycin to patients with low potassium or magnesium (erythromycin label, AEMPS). Monitor the electrocardiogram (ECG) during dronedarone treatment and stop dronedarone if the QTc interval (QT corrected for heart rate) reaches 500 milliseconds or more (dronedarone label, EMA). Infuse intravenous erythromycin over 60 minutes, and over a longer time in patients with risk factors or a history of arrhythmia (intravenous erythromycin label, AEMPS).

Mechanism

Erythromycin is a CYP3A4 inhibitor. Ergotamine rises 5–10 fold, fatal ergotism. FDA Ergomar Section 4.

Symptoms

Digital ischaemia, MI within 1–5 days.

Management

Combination contraindicated.

Mechanism

Fluconazole prolongs the QT interval on its own by directly inhibiting the delayed rectifier potassium current (IKr) in heart cells. Erythromycin also prolongs the QT interval, and the enzyme CYP3A4 breaks it down. Fluconazole moderately inhibits this enzyme. Its prescribing information warns that this can increase QT prolongation caused by drugs broken down by CYP3A4. Because fluconazole has a long half-life, its effect on the enzyme lasts 4 to 5 days after the last dose. The documents give no figures for the rise in erythromycin levels.

Symptoms

The electrocardiogram (ECG) shows a prolonged QT interval and ventricular extrasystoles, and the person may notice palpitations or skipped beats. The most dangerous rhythm disorders, listed in the erythromycin documents, are torsade de pointes, ventricular fibrillation and cardiac arrest. The fluconazole documents name sudden cardiac death as the risk of this combination. The risk is higher with low potassium or magnesium, advanced heart failure, a slow heart rate and in older people.

Management

The combination is contraindicated (fluconazole prescribing information from the Spanish Agency of Medicines and Medical Devices, AEMPS, and the US Food and Drug Administration, FDA). Fluconazole keeps inhibiting the enzyme CYP3A4 for 4 to 5 days after the last dose (fluconazole documents, AEMPS and FDA). Take this time into account if erythromycin is needed right after a course of fluconazole. Do not give erythromycin to people with a history of QT interval prolongation or ventricular arrhythmias, including torsade de pointes, or with low potassium or magnesium (erythromycin prescribing information, AEMPS). Use fluconazole with caution in conditions that predispose to arrhythmias. The risk is higher with low potassium and advanced heart failure (fluconazole prescribing information, AEMPS). If something may disturb electrolytes, such as diuretics, laxatives, vomiting, diarrhoea or kidney disease, check electrolyte levels (erythromycin prescribing information, AEMPS).

Mechanism

CYP3A4 inhibition – lovastatin rises 5-fold. Rhabdomyolysis.

Symptoms

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

Management

Combination contraindicated.

Mechanism

Erythromycin is a moderate-to-strong CYP3A4 inhibitor. Pimozide concentration rises 3–5 fold, with additive QT prolongation (erythromycin itself is a QT prolonger). FDA Orap Section 4 contraindication.

Symptoms

QT prolongation, syncope, torsades de pointes within 3–10 days.

Management

Combination contraindicated. Alternative: azithromycin or another class. If erythromycin is needed, hold pimozide for the course.

Mechanism

Erythromycin inhibits CYP3A4. Simvastatin is a sensitive substrate; its concentration rises 6-fold. High rate of rhabdomyolysis with fatal cases reported. FDA Zocor Section 4.3 – strict contraindication.

Symptoms

Muscle pain, weakness, dark urine within 7 days. Labs show sharp rise in creatine kinase and creatinine.

Management

Combination contraindicated. Hold simvastatin during erythromycin therapy. Alternative: pravastatin or rosuvastatin – neither is metabolised via CYP3A4.

Mechanism

Bromocriptine is broken down in the liver by CYP3A4, and erythromycin inhibits this enzyme. With erythromycin, bromocriptine area under the curve (AUC) rose 2.8- to 3.7-fold and peak concentration 4.6-fold.

Symptoms

Bromocriptine side effects get stronger: nausea, vomiting, headache, dizziness, a drop in blood pressure on standing (rarely with fainting), drowsiness, confusion and hallucinations.

Management

Avoid the combination. The intravenous erythromycin label advises against using it with dopaminergic ergot alkaloids, the group that includes bromocriptine. It allows erythromycin with bromocriptine only if bromocriptine effects and side effects can be closely monitored; otherwise bromocriptine is stopped for the erythromycin course (erythromycin label). The bromocriptine dose may need to be lowered during co-administration (erythromycin label). The bromocriptine label advises caution with macrolides because they raise bromocriptine levels (bromocriptine label). For the bromocriptine formulation used in type 2 diabetes in the US, the US Food and Drug Administration (FDA) caps the dose at 1.6 mg a day with erythromycin (bromocriptine FDA label).

Mechanism

Erythromycin inhibits CYP3A4 and P-glycoprotein (erythromycin SmPC). CYP3A4 breaks down tacrolimus, and the tacrolimus SmPC places erythromycin in the same group as strong CYP3A4 inhibitors: tacrolimus levels can rise sharply within 1–3 days, and overall exposure can increase more than 5-fold. The effect can last several days after co-administration ends (tacrolimus SmPC). Both drugs can prolong the QT interval (both SmPCs).

Symptoms

Signs of tacrolimus excess: rising creatinine and worse kidney function, tremor, headache and other signs of neurotoxicity. QT prolongation on the ECG with a risk of torsades de pointes (both SmPCs).

Management

The erythromycin SmPC does not recommend giving it with tacrolimus, and the tacrolimus SmPC advises avoiding the combination. If erythromycin cannot be avoided, treatment is managed by a transplant specialist. Consider skipping the tacrolimus dose on the day erythromycin starts and restart the next day at a reduced dose guided by blood levels. Measure tacrolimus trough levels at baseline, check them often from the first days of co-treatment and reassess after erythromycin is stopped, adjusting the dose to these values. Monitor kidney and graft function, the QT interval on the ECG and signs of neurotoxicity closely (tacrolimus SmPC). Erythromycin is contraindicated with a history of QT prolongation or ventricular arrhythmia and with low potassium or magnesium (erythromycin SmPC). The tacrolimus SmPC classes azithromycin as a moderate or weak CYP3A4 inhibitor: it can also raise tacrolimus levels and needs the same monitoring.

Mechanism

An erythromycin metabolite inhibits the liver enzyme CYP3A (CYP3A3 in the label), so theophylline is cleared more slowly: according to the US Food and Drug Administration (FDA) theophylline label, theophylline levels rise by about 35%. At high theophylline doses this rise can reach toxic concentrations (erythromycin SmPC). The effect also runs the other way: with oral erythromycin, erythromycin levels fall by a similar amount and may become subtherapeutic (erythromycin SmPC and theophylline FDA label).

Symptoms

Early signs of excess theophylline: nausea, vomiting, especially repeated, headache, insomnia. At high levels: persistent vomiting, cardiac arrhythmias and intractable seizures that can be fatal. With oral erythromycin, erythromycin levels may fall below the therapeutic range and the infection may respond less well.

Management

The pair is not banned, but the theophylline dose is guided by blood levels. When erythromycin is added, theophylline levels are followed and the dose is reduced to avoid toxic concentrations (erythromycin SmPC). The US Food and Drug Administration (FDA) theophylline label warns that if the total daily dose is not reduced in time, severe and potentially fatal toxicity can occur; levels are measured both when an interacting drug is added and when it is stopped. In most patients steady state is reached after about 3 days of regular dosing (theophylline FDA label). If nausea or vomiting appear, the next theophylline dose is withheld and a level is measured at once (theophylline FDA label). After erythromycin is stopped, theophylline levels fall and the dose is increased back (theophylline FDA label).