Methotrexate Blister Pack


You are correct that there is a significant interaction between some antibiotics and methotrexate. However, not all antibiotics share this interaction.

The most well-known is with penicillin (and its derivatives).

Penicillins reduce the elimination of methotrexate in the kidney, increasing concentrations which in turn could increase the risk of methotrexate-related side effects.

The prescribing information for methotrexate states the following regarding the interaction:

"Penicillins may reduce the renal [kidney] clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Use of methotrexate with penicillins should be carefully monitored."

It is important to note that the term 'penicillin', when used in regard to an interaction with methotrexate, refers to the entire family of penicillin antibiotics, which includes:

What Are The Side Effects From Too Much Methotrexate?

Potential side effects from high concentrations of methotrexate are numerous. If you are taking methotrexate, you should speak with your doctor immediately if you experience any of the following:

  • Fever
  • Chills
  • Bleeding or bruising that is unusual
  • Stomach pain/cramping
  • Mouth sores

The prescribing information for methotrexate notes two specific types of side effects from high doses, hematologic (relating to blood) and gastrointestinal. If they do occur, they typically manifest as stomach discomfort, unusual bleeding (including in the stool), a drop in white blood cell count and open sores (especially in the mouth).

Methotrexate has additional potential side effects, but the above are the most commonly seen from penicillin-related interactions.

Taking Penicillin-Family Antibiotics And Methotrexate Together

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Although the interaction between penicillin and methotrexate is concerning and always needs to be taken into account, the drugs are sometimes used together in the short-term. It is just important that doses are adjusted accordingly and the individual taking the medications are monitored for side effects.

The dose of methotrexate you are on plays an important role in the risk of an interaction with penicillin. When used for some indications, like rheumatoid arthritis, the risk of a severe interaction is lessened since the doses of methotrexate used are generally lower.

Separating Doses

If you have been instructed to separate doses of penicillin-type antibiotics from methotrexate to avoid the interaction, the time interval between dosing will depend on the specific antibiotic. I discuss the two most common oral penicillins below (penicillin and amoxicillin).

After Penicillin

Penicillin is metabolized and eliminated quickly from the body after dosing.

Peak concentrations in the blood are reached within 60 minutes after dosing and it has a reported half-life of only 30-60 minutes. This means that the majority of the drug will be completely eliminated within a few hours.

Therefore, the interaction with methotrexate would be minimal if methotrexate is given at least a few hours after penicillin.

After Amoxicillin

Amoxicillin has a longer half-life than penicillin and stays in the body for a longer period of time. The reported half-life 1 to 1.5 hours.

In general, it takes around 5-6 half-lives for a drug to be considered completely metabolized and eliminated in the body. Therefore, amoxicillin should be cleared by 6 to 10 hours after your last dose. Any interaction with methotrexate would be minimal after this amount of time.

After Methotrexate

Methotrexate has a fairly complex pharmacokinetic profile and elimination of the drug happens in multiple phases.

If you are looking to give a dose of a penicillin-type antibiotic after methotrexate, and want to avoid any chance of an interaction, you'll have to wait at least a few days as the reported half-life is at least 12 hours (meaning it will take a few days to be completely eliminated).

Nevertheless, the prescribing information states that the majority of methotrexate is eliminated via the kidneys during the first 12 hours after administration.

So, although the risk of an interaction with penicillin-type antibiotics exists 12 hours after dosing, it will likely be minimal.

Answer Summary

Penicillin and related antibiotics (e.g. amoxicillin) can increase methotrexate concentrations by decreasing elimination from the kidneys. This increases the risk of side effects. Nevertheless, they are sometimes used together in certain situations.

  • Methotrexate and penicillin interaction. PubMed
  • Effect of penicillin on the renal tubular secretion of methotrexate in the monkey. PubMed