Penicillin V with Methotrexate Interaction Details
Brand Names Associated with Methotrexate
- Amethopterin
- Methotrexate
- MTX
- Rheumatrex®
- Trexall®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Jan 04, 2024
Interaction Effect
Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Summary
Coadministration of methotrexate with penicillin antibiotics increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with penicillin antibiotics may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions. Methotrexate toxicity has been reported in several patients taking a variety of penicillins, including amoxicillin, mezlocillin, piperacillin, and oral penicillin . Methotrexate is eliminated by the kidney through both tubular secretion and glomerular filtration . It has been suggested that penicillins could interfere with the renal tubular secretion of methotrexate , since the antibiotic is structurally similar to methotrexate and both possess carboxylic acid containing an acetamide group .
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Coadministration of methotrexate with penicillin antibiotics increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with penicillin antibiotics may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions.
Mechanism Of Interaction
Decreased methotrexate renal clearance due to competition for tubular secretion
Literature Reports
A) A study described a 47-year old male who was receiving intravenous methotrexate 50 mg weekly for dermatomyositis whose white blood cell (WBC) count was stabilized in the 4000/cu mm-range. Furosemide 40 mg every other day and oral penicillin 250 mg every other day were added to his regimen for mild fluid retention and mild cellulitis, respectively. Within a week of the initiation of furosemide and penicillin, the patient experienced skin ulcerations, mouth ulcers, fatigue, cough, fever, and rigors. The patient's WBC count fell to 700/cu mm and he developed staphylococcal sepsis. The authors postulated that the renal clearance of the methotrexate dose was reduced by the presence of furosemide and penicillin competing for tubular secretion, thus producing low but toxic plasma concentrations of methotrexate .
B) A 16-year old male with malignant osteogenic sarcoma received ten cycles of high-dose methotrexate (8 grams per meter squared). During the tenth cycle, amoxicillin 1 gram every six hours was started six hours after the initiation of the methotrexate infusion, and was discontinued after six doses. When compared to the first nine cycles, significant differences for total plasma clearance, mean residence time, and distribution half-life of methotrexate were noted during the tenth cycle. High methotrexate plasma levels persisted for at least eight days, probably as a result of reduced renal excretion as a consequence of methotrexate-induced acute renal failure .
C) A 15-year old female with osteogenic sarcoma received two courses of high-dose methotrexate (12 grams per meter squared) 14 days apart. Leucovorin rescue at 15 mg per meter squared was administered during both methotrexate courses. During the first course, the patient also received empiric therapy with mezlocillin (330 mg/kg daily) and gentamicin (7.5 mg/kg daily). The patient experienced significantly more gastrointestinal toxicity, despite antiemetic therapy, during the first course of methotrexate. Methotrexate serum concentrations were monitored, and showed that terminal methotrexate elimination was 27.2 hours during the first course of treatment, when mezlocillin was also being administered, and only 10.1 hours during the second course. The authors suggested that if methotrexate elimination is indeed reduced by mezlocillin, then the concurrent use of these two drugs would require extensive monitoring of methotrexate concentrations and leucovorin doses may need to be increased and administered for longer periods of time .
D) In one study, four of five low-dose methotrexate patients received penicillins prior to or shortly after admission to the hospital. Methotrexate clearances were probably reduced sufficiently by concomitant therapy with the penicillins, resulting in neutropenia. Three of the reported patients died, while the other two experienced lengthy recovery periods. Penicillins that were administered to these five patients included amoxicillin, amoxicillin with clavulanic acid, piperacillin, piperacillin in combination with flucloxacillin, and flucloxacillin in combination with benzylpenicillin. It was proposed that the penicillins, which are weak organic acids, competitively inhibited active tubular secretion of methotrexate, resulting in toxic methotrexate serum concentrations .
Methotrexate Overview
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Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.