Medicines Q&As
Q&A 386.2
What is the clinical significance of the interaction between
methotrexate and penicillins?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 22nd October 2013
Background
Methotrexate is an immunomodulatory drug used for a number of conditions including rheumatoid
arthritis, cancer, and psoriasis. Its use may be associated with a number of serious side effects,
including blood dyscrasias, liver cirrhosis and pulmonary toxicity1.
Penicillins are a widely used group of broad spectrum antibiotics which may interact with
methotrexate1. The interaction does not, however, appear on the Summary of Product Characteristics
for methotrexate2. Many patients who are taking methotrexate will also require antibacterial therapy
with penicillins at some point in their lives 3.
Answer
Mechanism
Methotrexate is cleared by the kidneys, through tubular secretions and glomerular filtration4 .
Penicillins are weak acids which are capable of competing with methotrexate within the tubules of the
kidney, leading to reduced tubular secretion and therefore retention of methotrexate. Increased levels
can in turn predispose to toxicity4. Evidence for this mechanism is mostly limited to animal studies and
human case reports5,6,7 and its existence has also been disputed3,8. Penicillins do not appear to
interfere with the glomerular filtration aspect of methotrexate clearance.
Onset of methotrexate toxicity following initiation of a penicillin may be delayed 4.
Evidence
Amoxicillin
One case report describes a 16 year old given high dose methotrexate IV for osteogenic sarcoma.
Co-administration of amoxicillin resulted in a 56% reduction in excretion of methotrexate, leading to a
prolonged increase in methotrexate levels. The patient suffered from toxicity consisting of nausea,
vomiting, renal failure, myelosuppression, fever, and dermatologic abnormalities 8,9.
A case series reported by Lim et al looked at patients who had suffered from methotrexate-induced
pancytopenia. One of the patients included (who was taking a dose of 10mg weekly methotrexate)
had initiated a course of amoxicillin on the day of admission to hospital with symptoms of sepsis,
malaena, and mucositis. The patient died due to a colonic haemorrhage. The authors of the paper do
not attribute the development of pancytopenia to an interaction, but a follow-up letter to the authors
suggests this may be a cause6,10,11.
Oral amoxicillin for 7 days was given to a patient taking a 7.5mg weekly dose of methotrexate. The
patient developed neutropenia and thrombocytopenia, which was thought to be due to reduced
methotrexate clearance. The patient died despite folinic acid rescue therapy. The patient was also
given IV flucloxacillin, and IV benzylpenicillin8,12.
Neutropenia and thrombocytopenia were also observed in a patient who was prescribed co-amoxiclav
(amoxicillin and clavulanic acid) alongside methotrexate for psoriasis8,12.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Flucloxacillin
A patient receiving methotrexate 5mg weekly for rheumatoid arthritis suffered suspected
methotrexate-induced pneumonitis following a course of flucloxacillin. This prompted the authors to
conduct a study in 10 patients with RA who were given flucloxacillin, which suggested no clinically
significant pharmacokinetic effect on methotrexate levels. This small study is limited by the fact that it
looks only at pharmacokinetic factors, and the small number of patients recruited to the study, all of
whom were being treated for rheumatoid arthritis3.
A patient administered both flucloxacillin and piperacillin IV died as a result of neutropenia and
thrombocytopenia thought to be due to methotrexate toxicity. The patient’s dose of methotrexate was
2.5mg three times a week which was being given for psoriasis12.
Phenoxymethylpenicillin
A patient receiving 50mg IV methotrexate weekly for dermatomyositis experienced toxicity (including
leukopenia, thrombocytopenia, deranged LFTs, and skin ulcerations) within a week of initiation of
starting phenoxymethylpenicillin. The patient was treated with folinic acid and fluid replacement. This
patient had also been coprescribed furosemide. Attribution of the cause of toxicity is postulated to be
due to the interaction between both penicillin and furosemide, although it is acknowledged that the
patient had also received his dose of methotrexate two days earlier than scheduled, which could have
been a contributory factor8,13.
Antipseudomonal penicillins
A 50 year old female being treated with an intrathecal high dose methotrexate-containing regime for
Burkitt’s lymphoma experienced a prolonged increase in methotrexate levels which resolved only on
discontinuation of piperacillin/tazobactam. During a later cycle of the methotrexate-containing
chemotherapy regimen, Piperacillin/tazobactam was not administered, and methotrexate levels
reduced14.
A 67% reduction in methotrexate clearance was observed in a patient receiving a high dose IV course
of methotrexate for chronic myeloid leukaemia. The patient required prolonged folinic acid rescue 8.
Risk Factors:
Not all patients who use penicillins concurrently with methotrexate are affected by this interaction. So
far, there is no way of predicting who it may occur in, as current available evidence does not suggest
any strong risk factors for developing the interaction. Reports of symptomatic interactions are not
limited to high dose methotrexate therapy8. Theoretically, patients with a degree of existing renal
impairment may be more susceptible to the interaction 10.
Management
Patients who require a penicillin antibiotic whilst taking methotrexate therapy should be closely
monitored for the duration of the treatment. One resource suggests measuring platelets and white cell
counts twice weekly for two weeks. If methotrexate toxicity is suspected, methotrexate levels should
be performed, and folinic acid rescue should be available where required8. Another resource suggests
considering a dose reduction and monitoring serum methotrexate levels 4.
Patients should be counselled to look out for adverse effects of methotrexate such as sore throat,
infection, leukopenia, thrombocytopenia, and skin ulcerations1,4.
Summary
The evidence for an interaction between methotrexate and penicillins is limited to case reports and
animal studies. So far, there is no conclusive evidence that any particular patient group is more at risk
of an interaction occurring, and it does not appear to be dose related.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
If concurrent use of methotrexate and a penicillin is required, patients should be carefully monitored
during treatment. Monitoring may include measuring platelets and blood counts twice weekly for two
weeks, with methotrexate levels being taken if the patient becomes symptomatic.
Limitations
There have been no large, controlled studies in humans to determine the mechanism or clinical effect
of this potential interaction, so information is mainly limited to animal studies and case reports. This
makes it difficult to estimate incidence and likelihood of the interaction. Only evidence relating to UK
licensed penicillin antibiotics have been included in this Q&A.
Quality Assurance
Prepared by
Hayley Johnson, Regional Drug & Therapeutics Centre
Date Prepared
12th October 2011
Date of Update: 22nd October 2013
Checked by
Nancy Kane, Regional Drug & Therapeutics Centre
Date of check
23rd October 2013
Search strategy
Embase
METHOTREXATE/it [it=Drug Interaction]; AND [*AMOXICILLIN/ OR *AMOXICILLIN PLUS
CLAVULANIC ACID/ OR *AMPICILLIN/ OR *BENZATHINE PENICILLIN/ OR *BENZATHINE
PENICILLIN V/ OR *FLUCLOXACILLIN/ OR *PENICILLIN G/ OR *PENICILLIN V/ OR
*PIPERACILLIN/ OR *TICARCILLIN/]
Medline
*METHOTREXATE/ AND [*PENICILLIN G/ OR PENICILLIN V.af OR *FLOXACILLIN/ OR
TEMOCILLIN.af; OR *AMOXICILLIN/ OR *AMPICILLIN/ OR *AMOXICILLIN-POTASSIUM
CLAVULANATE COMBINATION/ OR CO-FLUAMPICIL.af OR *PIPERACILLIN/ OR *TICARCILLIN/
OR PIVMECILLINAM.af;]
.
In-house database/ resources
eBNF 66
Micromedex
Medicines Complete
References
1
Joint Formulary Committee. British National Formulary 66 ed. London : British Medical Association
and Royal Pharmaceutical Society of Great Britain; 2013 Accessed online via Medicines Complete
http://www.medicinescomplete.com/mc/bnf/current/index.htm on 22/10/2013
2 Summary of Product Characteristics – Maxtrex (methotrexate). Pharmacia Ltd. Accessed via
http://www.medicines.org.uk/EMC/medicine/6003/SPC/Maxtrex+Tablets+2.5+mg/ on 22/10/2013
[date of revision of the text Jun 2012, last updated on the eMC: 21/06/2012]
3 Herrick AL, Greenan DM, Griffen K et al. Lack of Interaction between flucloxacillin and methotrexate
in patients with rheumatoid arthritis. Br J Clin Pharmacol 1996; 41: 223-227
4 DRUGDEX®System: Methotrexate. In: Klasco RK (Ed): DRUGDEX® System (electronic version).
Truven Health Analytics Inc Micromedex, Greenwood Village, Colorado, USA. Available at:
http://www.micromedexsolutions.com/. Accessed on 2/10/2013
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
5
Williams WM, Chen TS and Huang KC. Effect of penicillin on the renal tubular secretion of
methotrexate in the monkey. Cancer Res 1984; 44: 1913-1917
6 Sathi N, Ackah J, and Dawson J. Methotrexate induced neutropenia associated with coprescription
of penicillins: serious and under-reported? Rheumatology 2006; 45: 362-363
7 Takeda M, Khamdang S, Narikawa S et al. Characterizastion of methotrexate transport and its drug
interactions with human organic anion transporters. Journal of Pharmacology and Experimental
Therapeutics 2002; 302(2): 666-671.
8 Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press. Accessed via
www.medcinescomplete.com on 22/10/2013
9 Ronchera CL, Hernandez T, Peris JE et al. Pharmacokinetic interaction between high dose
methotrexate and amoxicillin. Ther Drug Monit. 1993 Oct;15(5):375-9.
10 Lim AYN, Gaffney K, and Scott DGI. Methotrexate-induced pancytopenia: serious and underreported? Our experience of 25 cases in 5 years. Rheumatology 2005; 44: 1051-1055.
11 Lim, AYN, Gaffney K, Scott DGI. Methotrexate-induced pancytopenia: serious and under reported?
Our experience of 25 cases in 5 years: reply. Rheumatology 2006; 45: 363-364
12 Mayall B, Poggi G, and Parkin JD. Neutropenia due to low-dose methotrexate therapy for psoriasis
and rheumatoid arthritis may be fatal. Med J Aust. 1991 Oct 7;155(7):480-4.
13 Nierenberg DW and Mamelok RD. Toxic reaction to methotrexate in a patient receiving penicillin
and furoseide: A possible interaction. Arch Dermatol 1983; 119: 449-450
14 Zarychanski R, Wlodarczyk K, Ariano R et al. Pharmacokinetic interaction between methotrexate
and piperacillin/tazobactam resulting in prolonged toxic concentrations of methotrexate. Journal of
Antimicrobial Chemotherapy 2006. 58 (1): 228-230.
Available through NICE Evidence Search at www.evidence.nhs.uk
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