Can azithromycin (AZM) be given with antihistamines?

Can Azithromycin Be Given with Antihistamines?

Yes, azithromycin can generally be given with most modern antihistamines, but specific older antihistamines (terfenadine and astemizole) are absolutely contraindicated, and caution is warranted with certain second-generation antihistamines due to potential QTc prolongation.

Absolute Contraindications

Neither azithromycin nor any macrolide should be administered concomitantly with terfenadine or astemizole 1. These older non-sedating antihistamines are associated with:

• Acquired long QT syndrome when combined with macrolides 1
• Cardiac potassium channel blockade that prolongs repolarization 1
• Risk of torsades de pointes and fatal ventricular arrhythmias 1
• Pharmacokinetic interactions through CYP3A4 inhibition that elevate cardiotoxic drug levels 1

Note that terfenadine has been restricted or removed from most markets due to these risks 1.

Safe Combinations with Modern Antihistamines

Second-Generation Antihistamines

The FDA drug label indicates that azithromycin had only a modest effect on cetirizine pharmacokinetics, and no dosage adjustment is recommended when coadministered 2.

Desloratadine demonstrates excellent safety with azithromycin 3:

• Only small increases in pharmacokinetic parameters (Cmax ratio 115%, AUC ratio 105%) 3
• No statistically significant ECG changes including QTc interval 3
• Well tolerated with no cardiac adverse events 3

Fexofenadine shows significant pharmacokinetic interaction but remains clinically safe 3:

• Substantial increases in drug levels (Cmax increased 69%, AUC increased 67%) when combined with azithromycin 3
• Despite elevated levels, no ECG changes or cardiac adverse events occurred 3
• Greater pharmacokinetic variability compared to desloratadine 3

Cetirizine and loratadine have been used successfully in clinical practice 4:

• Combined treatment with azithromycin in elderly COVID-19 patients showed no adverse effects 4
• However, one study found significant QTc prolongation when cetirizine and azithromycin were used together for upper respiratory infections 5

QTc Prolongation Risk

Monitoring Considerations

Patients with baseline QTc >377.5 ms are at increased risk when prescribed azithromycin with cetirizine 5:

• 17.8% of patients developed QTc >430 ms after 3-4 days of combination therapy 5
• Significant QTc increase occurred in 95.6% of patients between day 1 and day 4 5

High-Risk Populations

The FDA has issued warnings about azithromycin and cardiovascular mortality, particularly in patients with 1:

• Baseline cardiovascular disease
• Pre-existing QTc prolongation
• Electrolyte abnormalities
• Concurrent use of other QT-prolonging medications

Practical Algorithm for Prescribing

Step 1: Screen for absolute contraindications

• Do not prescribe if patient is taking terfenadine or astemizole 1

Step 2: Assess cardiovascular risk

• Obtain baseline ECG if patient has cardiovascular disease, is elderly, or has risk factors for QTc prolongation 1
• Avoid combination if baseline QTc >377.5 ms when using cetirizine 5

Step 3: Choose antihistamine

• Preferred: Desloratadine (minimal interaction, excellent safety profile) 3
• Acceptable: Loratadine, levocetirizine (based on clinical experience) 6, 7, 4
• Use with caution: Cetirizine (monitor for QTc changes if risk factors present) 5
• Acceptable but monitor: Fexofenadine (significant drug level increase but clinically safe) 3

Step 4: Avoid first-generation antihistamines when possible

• These have anticholinergic and sedating effects that complicate clinical assessment 1
• No specific cardiac interaction data with azithromycin, but generally not preferred 1

Common Pitfalls to Avoid

• Do not assume all antihistamines are equivalent - terfenadine and astemizole remain absolutely contraindicated despite being older drugs that may still be available in some regions 1
• Do not ignore baseline cardiovascular status - the combination carries increased risk in patients with pre-existing heart disease or QTc prolongation 1, 5
• Do not forget about aluminum/magnesium antacids - these reduce azithromycin absorption and should not be taken simultaneously 1, 2
• Do not overlook drug-drug interactions - azithromycin requires monitoring when used with drugs metabolized by cytochrome P450, including digoxin and triazolam 1