Bottle of azithromycin with text overlay - with methotrexate


There is some concern with using methotrexate and azithromycin together, but overall, the combination is relatively safe to use in certain situations.

The two main concerns are:

  • Increases in liver enzymes
  • Increase in methotrexate concentrations

I discuss each of these in more detail below.

Liver Enzymes

Both azithromycin and methotrexate are metabolized through the liver and both have been reported to cause increases in certain liver enzymes.

The prescribing information for azithromycin states the following:[1]

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
Azithromycin Prescribing Information

Side effects involving the liver with azithromycin use are uncommon, however.

In clinical trials for the drug, elevated liver enzymes occurred in 4—6% of individuals receiving intravenous therapy. In those taking the drug orally, only 1—2% experienced an increase in liver enzymes. Severe side effects, like liver failure, are thought to be exceedingly uncommon and there are generally other predisposing factors in play.[2]

Methotrexate is more often associated with impaired liver function than azithromycin. Per the prescribing information:[3]

Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation.
Methotrexate Prescribing Information

In those taking methotrexate for extended periods of time, periodic liver function tests are recommended (about every one or two months).

Since both azithromycin and methotrexate could potentially cause liver dysfunction, caution is recommended when using them together.

Nevertheless, the concern here is generally in those who already have some sort of liver problem, or are taking additional drugs that may affect liver function.

Methotrexate Levels

Some sources state that azithromycin can increase concentrations of methotrexate in the body if taken together.

Our own interaction checker, which pulls data from DrugBank, reports the following:[4]

The serum concentration of Methotrexate can be increased when it is combined with Azithromycin.
DrugBank Interactions

This is based on the fact that both methotrexate and azithromycin are metabolized through the liver. Therefore, if used together, the liver may not be able to process them as efficiently. Additionally, if azithromycin alone causes liver dysfunction, methotrexate metabolism may be compromised.

Increases in methotrexate concentrations could theoretically increase the incidence of side effects.

Although azithromycin increasing methotrexate concentrations is possible, it hasn't been seen in clinical studies.

In fact, studies that specifically look into interactions concerning azithromycin and methotrexate don't list them as interacting agents.[5][6]

Final Words

While there is a concern with using azithromycin and methotrexate together, it is mostly based on whether or not either affects liver function.

Use of both in those with normal liver function generally shouldn't cause significant problems, but your liver function should be monitored periodically, especially if you are taking one or both on a long term basis.

Be sure to speak with your doctor regarding any concerns you have regarding the use of methotrexate and azithromycin together. You shouldn't alter your medication regimen at all without first talking with your doctor.


Azithromycin and methotrexate can cause increases in liver enzymes and potentially decrease overall liver function. Caution is recommended if using both together. In those with normal liver function, the combination has been used safely.

  1. ^ Azithromycin Prescribing Information. AccessFDA
  2. ^ Elsevier ClinicalKey: Azithromycin Monograph. ClinicalKey
  3. ^ Methotrexate Prescribing Information. AccessFDA
  4. ^ PharmacistAnswers Drug Interaction Checker. PharmacistAnswers
  5. ^ Drug interactions with azithromycin and the macrolides: an overview. PubMed
  6. ^ Pharmacokinetic drug-drug interactions with methotrexate in oncology. PubMed