Does Cipro (Ciprofloxacin) Interact With Methotrexate?

In our latest question and answer, the pharmacist discusses whether or not Cipro (ciprofloxacin) interacts with methotrexate.

Mar 15, 2018

Betsy asked

How soon after a 7 day course of ciprofloxacin can once weekly injectable methotrexate be restarted? My dose is 1 ml.


There is considered to be a moderate to major interaction between methotrexate and ciprofloxacin. Caution is advised when using both together. At the very least, individuals on both medications should be monitored for signs and symptoms of methotrexate toxicity.

Cipro (Ciprofloxacin) - Methotrexate Interaction

Methotrexate is primarily excreted via the kidneys with the majority of excretion happening in the first 12 hours after administration of the drug.

The prescribing information for methotrexate states the following in regard to potential drug interactions:

"Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity."

Ciprofloxacin is known to inhibit renal excretion of methotrexate. Co-administration of ciprofloxacin while also taking methotrexate can lead to increased methotrexate concentrations. Therefore, the risk of methotrexate side effects and toxic reactions increases as well.

Several case studies have discussed the interaction between methotrexate and ciprofloxacin and the potential for severe toxicity. Such cases can be found here and here.

While not an absolute contraindication, individuals on methotrexate therapy should be monitored carefully when using ciprofloxacin due to the potential for severe side effects.

Avoiding The Ciprofloxacin - Methotrexate Interaction

If you are looking to avoid the interaction, there are few studies discussing the best methods in doing so if both have been prescribed to you. Nevertheless, we can take into account what we know about the pharmacokinetic profile of ciprofloxacin to make a determination in regard to how long the drug lasts in the body.

After taking by mouth, peak concentration of ciprofloxacin is reached in about 1 to 2 hours. The half-life (i.e. time it takes for 50% of a drug to be metabolized in the body) of ciprofloxacin is reported to be around 4 hours according to the prescribing information for the drug.

It is generally assumed that it takes about 5 half-lives for drug to be considered metabolized and eliminated from the body and we can expect the vast majority of ciprofloxacin to be metabolized in about 20 hours. Therefore, it would be prudent to allow at least 20 hours to pass after ciprofloxacin dosing before initiating methotrexate dosing to avoid complications from taking both medications. 

It is important to note that every individual is different and there could be additional conflicting factors that need to be taken into considerations when dosing ciprofloxacin and methotrexate together. Therefore, you should speak with your doctor regarding how to best use both medication together safely for your particular situation.


  • Methotrexate is primarily metabolized via the kidney.
  • Ciprofloxacin can inhibit methotrexate excretion from the kidney, potentially increasing concentrations to toxic levels.
  • To avoid the interaction between ciprofloxacin and methotrexate, dose methotrexate at least 20 hours after the last ciprofloxacin dose.

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