Methotrexate Overdose Research Articles

Risk mitigations to prevent methotrexate dispensing errors in English hospitals: a mixed-methods exploratory study

Abstract Introduction Oral methotrexate is indicated for paediatric cancer indications and autoimmune diseases. Unfortunately, cases of inadvertent overdose due to confusion between 2.5mg and 10mg tablet strengths are widely documented. National guidance is available to prevent such errors; indeed, the overdose of methotrexate for non-cancer treatment is a Never Event.[1] At our organisation, the main mitigations to reduce the risk of dispensing errors were to segregate tablet strengths and restrict 10mg tablets to cancer indications.[2] Adherence had not been evaluated, and alternative risk mitigations had not been explored. Aim We aimed to 1) determine whether methotrexate 10mg tablets were restricted to cancer indications; and 2) explore strategies to prevent errors associated with methotrexate tablet strength at a sample of hospitals. Methods First, an audit approach was used to determine use of 10mg tablets; standards were derived from local policy.[2] The setting was a large teaching hospital providing acute, specialist, paediatric and cancer care. Dispensing transactions of 10mg tablets on the electronic pharmacy dispensing system between April 2022 and March 2023 were included. Details of prescription, dispensed quantity, dose instructions and speciality were recorded onto the data collection tool. Data were analysed descriptively. Second, a survey was conducted with a sample of twenty English hospitals (including the study site). These comprised ten large teaching hospitals and specialist paediatric cancer centres. A relevant pharmacist was contacted by email at each trust and asked a series of open questions about local risk strategies associated with methotrexate 10mg tablets. Notes were taken and data summarised descriptively. Results There were 79 dispensing issues for methotrexate 10mg tablets. Of those, 65 issues were for 13 cancer patients; the other 14 were erroneous issues where 10mg were dispensed instead of 2.5mg for non-cancer indications. Whilst most errors were rectified (n=13), one patient received a weekly dose of 40mg instead of 10mg, a four-times overdose. Nineteen (95%) trusts responded to our survey. There were three broad strategies reported: to only use 2.5mg tablets (n=9); isolate dispensing of 10mg tablets to dedicated cancer or paediatric dispensaries (n=5); or reliance on local protocol and physical segregation of 2.5mg and 10mg tablets within multi-service dispensaries (n=5). Conclusion It was encouraging that 10mg tablets were solely intended for cancer indications. However, the incidental discovery of errors highlighted the need for improvement. Findings suggest that eliminating 10mg tablets from practice was a feasible strategy, even for organisations providing cancer services. Findings have limited generalisability due to the small sample sizes, and detail provided in survey responses was variable. Nevertheless, the audit was effective in identifying a previously unknown Never Event. National Health Service organisations should acknowledge the risk associated with keeping 2.5mg and 10mg methotrexate tablets, particularly within dispensaries servicing multiple specialties. Dedicated cancer dispensaries are not commonplace, therefore eliminating 10mg tablets altogether should be considered. Indeed, the principle of limiting strengths is a well-established and effective medication risk management strategy. Further research should explore the potential negative implications for patients, such as increased tablet burden, if 2.5mg tablets are used exclusively for all indications. This may further inform national strategy to prevent Never Events.

Iatrogenic methotrexate overdose: a case series. Risks in the practice of a family doctor

Intoxication with methotrexate has been occasionally reported during the treatment of autoimmune diseases, and remains a significant problem. Intoxications are caused by incorrect prescriptions issued by physicians or misadventure. An overdose usually leads to the death of the patient, as it is usually apparent only after the symptoms of bone marrow aplasia develop. At this stage, only symptomatic treatment, which is known to have low efficacy, can be administered. Methotrexate overdose remains within the scope of interest of family doctors, perhaps not as prescribing physicians, but as medical professionals extending prescriptions for chronically taken medications ordered by specialists, mainly rheumatologists or dermatologists. In this paper, we describe a series of cases of methotrexate intoxication occurring in very different circumstances. In these cases, we were approached as experts to issue an opinion on the correctness of the medical procedure. Such cases should be consistently reported to enhance awareness not only within healthcare systems but also in society at large.

Methotrexate overdose induced acute kidney injury and pancytopenia: a case report

Methotrexate overdose induced acute kidney injury and pancytopenia: a case report

Clinical case of methotrexate overdose, the peculiarity of diagnostics in the conditions of the COVID-19 pandemic

The diversity and low specifi city of clinical manifestations of COVID-19, as well as its widespread prevalence, present diffi culties for diff erential diagnosis, including conditions caused by drug overdose. The challenging experience of providing medical care during the coronavirus pandemic draws attention to the importance and necessity of further improving its diagnosis, especially in comorbid conditions. A clinical case of diff erential diagnosis of non- iatrogenic overdose of methotrexate in a patient with a preliminary diagnosis (virus unknown) is described: U07.2 (ICD-10) COVID-19.

Implementation status of safety measures to prevent errors with non-oncologic methotrexate: surveys in community and hospital pharmacies

BackgroundAccidental overdose of low-dose methotrexate can lead to serious patient harm. Different safety measures are recommended to prevent errors, yet, as errors continue to happen, their implementation is questionable.AimTo evaluate the implementation status of safety measures for methotrexate in community and hospital pharmacies.MethodAn electronic questionnaire was sent to head pharmacists of 163 community and 94 hospital pharmacies in Switzerland. The implementation of recommended safety measures (general measures, safety working procedures, IT-based measures) was assessed and descriptive analysis performed. An analysis of sales data underlined the relevance of our results, i.e., the population under risk for overdose.ResultsA response was obtained from 53% (n = 87) of community and 50% (n = 47) of hospital pharmacists. Pharmacies had implemented a median of 6 (IQR 3, community) and 5 (IQR 5, hospital) safety measures overall. Most of these were defined safety procedures, instructing staff on how to handle methotrexate prescriptions. Across all safety measures, compliance with single procedures was perceived as “very likely” by 54% of community pharmacies. IT-based measures (e.g., alerts) were absent in 38% (n = 31) of community and 57% (n = 27) of hospital pharmacies. On average, every community pharmacy dispensed 22 packages annually.ConclusionSafety in relation to methotrexate in pharmacies relies mostly on staff instructions, which are considered weak measures. In light of the serious risk imposed on patients, pharmacies should set a focus on stronger IT-based measures that rely less on human performance.

Methotrexate induced erythema multiforme: a rare case report

Methotrexate is commonly used in the treatment of inflammatory disorders and malignancies. Although it is an effective therapeutic agent, it may have serious adverse effects in both therapeutic dose and overdose. Here, we report a case of a 54-year-old lady with polyarthritis, who was prescribed 2 tablets of methotrexate (10 mg) orally once a week. However, mistakenly the patient started taking the drug daily. After 12 days of starting methotrexate, she presented with widespread skin lesions, sore mouth and dysphagia. A diagnosis of methotrexate induced erythema multiforme was made. Laboratory investigations revealed pancytopenia. She was managed conservatively. Although rare, methotrexate overdose should be considered along with other possibilities in a patient with erythema multiforme. This case report also focuses on the rational use of drugs as well as the importance of good communication between health care professionals and patients.
 BIRDEM Med J 2023; 13(1): 52-55

Mucocutaneous Ulcerations Due to Methotrexate Toxicity Mimicking Vesiculobullous Disorder: A Diagnostic Challenge

Introduction: Methotrexate is an antifolate agent commonly used in various dermatological and rheumatological diseases such as psoriasis, systemic lupus erythematosus, and other connective tissue disorders. Acute toxicity manifesting as mucocutaneous ulcerations is a rare event in 3 - 10% of patients. Normal dosing commonly used for dermatologic and rheumatologic diseases is 15 - 25 mg/week. The main culprit leading to toxicity is the overdose of medication. Nausea, leukopenia, infections, gastrointestinal bleeding, renal impairment, etc. are the common manifestations of methotrexate toxicity. Mucocutaneous ulcerations, though infrequent, can appear as early as 3 - 7 days following methotrexate administration. Thus, it can be the imminent sign of methotrexate toxicity, providing a clue to its timely diagnosis. The crucial steps in the management of methotrexate toxicity are withdrawal of medication, immediate administration of leucovorin which is the biologically active form of folic acid, adequate hydration for increasing renal clearance, and urinary alkalinization with sodium bicarbonate, wherever necessary. Case Presentation: Here, we report an accidental methotrexate overdose in a patient with psoriasis, presenting with extensive mucocutaneous ulceration mimicking autoimmune vesiculobullous disorder and Stevens-Johnson syndrome- toxic epidermal necrolysis, leading to an extremely rare and challenging scenario. Conclusions: This case report emphasizes that careful history and evaluation of medical records facilitate early diagnosis and prompt management, which is critical to improving outcomes and patient’s survival.

National quality improvement intervention to reduce high risk oral methotrexate prescribing

BackgroundHarmful or fatal errors related to accidental overdose of methotrexate tablets are well documented. In England, the coprescription of 2.5 mg and 10 mg methotrexate tablets is not recommended, because...

Febuxostat ameliorates methotrexate-induced lung damage.

The intention of the present study was to assess the structural affection of the lung following methotrexate (MTX) overdose. The proposed underlying mechanisms involved in lung affection were studied. The possible modulation role of febuxostat over such affection was studied. Twenty-four rats were divided into three groups: control, MTX-treated, febuxostat-treated. The study was continued for 2 weeks. Lung was processed for histological and immunohistochemical (inducible nitric oxide synthase [iNOS] and cyclooxygenase [COX]-2) studies. Inflammatory markers (tumour necrosis factor alpha [TNF-a], interleukin 1 [IL-1]), Western blot evaluation of nuclear factor kappa B (NF-kB) and oxidative/antioxidative markers were done. Methotrexate-treated group exhibited inflammatory cellular infiltrations, thickened interalveolar septa, dilated congested blood vessels, extravasated blood, and apoptosis. The collagen fibres content increased 3-fold. MTX induced lung affection through oxidative stress (increase MDA/decrease GSH, SOD) and apoptosis. It induced sterile inflammation through an increase of NF-kB (2-fold), IL-1 (3-fold) and TNF-a (3-fold), COX-2 cells (2.5-fold) and iNOS (6-fold). With the use of febuxostat, the normal lung architecture was observed with a bit thickened interalveolar septum and extravasated blood. The collagen fibres content was minimal. Decrement of oxidative stress and sterile inflammation (COX-2 cells and iNOS were comparable to the control group. NF-kB, IL-1 and TNF-a became higher by 34%, 64% and 100%). The overdose of MTX displays inflammatory lung affection with residual fibrosis. It induces lung affection through oxidative stress, apoptosis and sterile inflammation. With the use of febuxostat, the normal lung architecture was preserved with a little structural affection or fibrotic residue. Febuxostat exerts its lung protection through its anti-inflammatory and antioxidant features.

A Case Report on Methotrexate Overdose Induced Pancytopenia and Mucocutaneous Ulcerations

A Case Report on Methotrexate Overdose Induced Pancytopenia and Mucocutaneous Ulcerations

Hemophagocytic Syndrome Caused by Methotrexate Overdose in a Total Knee Arthroplasty Patient: A Case Report.

We report a patient with rheumatoid arthritis (RA) who developed hemophagocytic syndrome (HPS). The HPS was attributed to sepsis, itself a consequence of methotrexate (MTX) overdose. The discovery of MTX overdose was facilitated by the presence of epidermolysis bullosa, multiple ulcers of the whole digestive tract, and additional history from the patient's family. For arthroplasty patients with underlying inflammatory disorders such as RA, drug history should be thoroughly inquired. Correct diagnosis results from careful history review, detailed physical examination, and necessary laboratory tests.

Methotrexate overdose in clinical practice

A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects including bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal failure that are difficult to manage. This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, that have important implications in current clinical practice. Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions of lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening. The management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase- G2) and plasma alkalization. In accordance with the dictum "prevention is better than cure", the author emphasizes on the role of patient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of methotrexate overdosing at the earliest stage.

Development of an algorithm to detect methotrexate wrong frequency error using computerized health care data.

We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system. We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors. The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%). Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.

Painful erosions on psoriatic plaques: cutaneous clue to life-threatening methotrexate overdose

A 50-year-old man presented for evaluation of painful, bleeding lesions on his body of 3 days’ duration. His medical history was significant for chronic plaque-type psoriasis of 15 years’ duration....

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose

Objective: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose.Case Report: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17.Discussion: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate’s pharmacokinetics and the patient’s normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

Abstract 3981: Enhancement of the anticancer activity of methylenetetrahydrofolate dehydrogenase knockdown by folate depletion with carboxypeptidase G2

Abstract The mitochondrial folate enzyme, methylene tetrahydrofolate dehydrogenase (MTHFD2), is a promising anticancer target because 1) it is required for the generation of one-carbon units required for purine synthesis and generation of NADH/NADPH necessary for protection from ROS in the mitochondria; 2) it is markedly distinct from the cytoplasmic MTHFD1 enzyme with respect to location, catalytic activity and cofactors; 3) it is expressed at low levels in proliferating normal cells; 4) in contrast, it is highly expressed in a variety of rapidly proliferating malignant tumors; 5) knockdown (KD) of MTHFD2 has been shown to inhibit proliferation in a subset of tumor cells in vitro; and 6) MTHFD2 KD is predicted to have metabolic consequences (glycine auxotrophy, folate deficiency) that could be exploited for combination therapy. In this study we tested the hypotheses that downregulation of MTHFD2 will result in relative folate deficiency, which can be exploited by using a folate-depleting enzyme, carboxypeptidase G2 (CPG2), to enhance tumor cell kill. CPG2 is approved by the FDA for the treatment of methotrexate overdose in patients. It acts to inactivate MTX or naturally occurring folates by hydrolyzing the terminal glutamate from folates and MTX, generating a pteroate and glutamate. As pteroates cannot be used to resynthesize folates, or MTX, this treatment depletes cells from MTX or folates. The combination of CPG2 in cell lines, MCF7 and T47D with MTHFD2 KD, was done and the actual increase in growth inhibition showed enhanced antitumor effects, indicating that when effective inhibitors of MTHFD2 are available, this combination may have widespread clinical usefulness, especially in rapidly proliferating tumors that express high levels of MTHFD2. Citation Format: Gulam M. Rather, John E. Kerrigan, Kathleen W. Scotto, Joseph R. Bertino. Enhancement of the anticancer activity of methylenetetrahydrofolate dehydrogenase knockdown by folate depletion with carboxypeptidase G2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3981.

Acute kidney injury secondary to the use of methotrexate

This article draws on the case of a 78-year-old man, Mr MC, who was diagnosed with drug-induced acute kidney injury (AKI) as a result of an overdose of methotrexate. Reflecting on this scenario, Adrian Coleman and Melissa Nankoo outline the indications for methotrexate, explore the drug's mechanism of action and discuss how excessive doses of methotrexate can lead to AKI.

Widespread skin necrosis due to methotrexate overdose in a patient with CKD

A 55-year-old man with psoriasis vulgaris presented with a progressive painful skin eruption over the body for 10 days. He also had fever, dysphagia, leg edema, and reduced urine output for 3 days. Physical examination showed diffuse ulceration of the oral mucosa, and widespread, coalescing ulcerative plaques with background erythema and sloughing epidermis in association with edema over the trunk and extremities (Figure 1, Supplementary Figures S1–S3 online). The eruption appeared to involve both psoriatic lesions and non-psoriatic skin. Laboratory data revealed serum creatinine of 11 mg/dl, impaired liver function, hyperbilirubinemia, and pancytopenia. Abdominal echo revealed parenchymal renal disease with decreased bilateral renal sizes. With a recent history of methotrexate treatment for psoriasis (2.5 mg per day for more than 6 days), methotrexate overdose was suspected. The diagnosis was further supported by a skin biopsy showing vacuolar interface dermatitis with parakeratosis with neutrophilic infiltrate in the horny layer and edema with necrosis of keratinocytes in the epidermis, and minimal inflammation without evidence of vasculitis in the dermis (Figure 2, Supplementary Figures S4–S6 online), and an elevated serum methotrexate (0.01 μmol/l, sampled after two sessions of hemodialysis). On tracing his history, his serum creatinine was about 2.0–2.2 mg/dl, and chronic kidney disease (CKD) was diagnosed by a local doctor about 2 years ago; however, he did not receive any follow-up renal function test during the past 2 years. His blood counts returned to normal and skin lesions resolved within 3 weeks after hemodialysis and supportive care. His serum creatinine levels returned to about 4 mg/dl. Methotrexate is mainly excreted in unchanged form by the kidney. Impaired kidney function delays methotrexate clearance and may lead to serious toxicity; thus, before the prescription of methotrexate, physicians should be cautious about patient’s history of renal diseases, and a renal function test is suggested for patients with risk(s) for CKD.

Intrathecal Methotrexate-Induced Posterior Reversible Encephalopathy Syndrome (PRES).

Posterior reversible encephalopathy syndrome (PRES) is an acute neuroradiological diagnosis presenting with headache, vomiting, seizure, abnormalities of the mental status, and visual disturbances associated with a breakdown in cerebral vasculature regulation. It has a unique neuroradiological pattern of symmetrical parietooccipital vasogenic edema [1]. The most common causes of this syndrome are sudden arterial hypertension, preeclampsia, eclampsia, uremia, immunosuppressive drugs, and cancer chemotherapies such as cyclosporine, tacrolimus, L-asparaginase, vincristine, gemcitabine, cytarabine, and cisplatin, typically used in cases of hematopoietic malignancies [2,3,4,5,6,7]. Intrathecal methotrexate-induced PRES in an adult is exceedingly rare [8]. A 43-year-old woman was admitted to gynecology with metrorrhagia. Cervical cancer was diagnosed and radical hysterectomy with lymph node dissection was performed. Final pathology and immunohistochemical analyses revealed B-cell phenotype malign lymphoma, which is consistent with Burkitt lymphoma. A chemotherapy treatment protocol with R-Hyper CVAD, consisting of rituximab, cyclophosphamide, vincristine, adriamycin, and dexamethasone plus 12 mg of intrathecal methotrexate without preservative, was then started. Twelve days after chemotherapy she had severe analgesic-irresponsive headache, nausea, motor agitation, and cooperation failure. Her vital signs and laboratory findings were normal. Cranial computed tomography revealed hypodense areas due to edema in the bilateral cerebral hemispheres, predominantly in the posterior regions. Magnetic resonance imaging (MRI) of the brain showed multiple confluent hyperintense lesions in T2-weighted and fluid-attenuated inverse recovery (FLAIR) sequences (Figure 1a), with no contrast enhancement in T1-weighted sequences. PRES was diagnosed and she was admitted to the intensive care unit (ICU) because of decreased alertness and agitation. Intrathecal methotrexate treatment was discontinued. On the second day in the ICU her blood pressure rose and was then normalized by diltiazem infusion. On the third day in the ICU, myoclonic jerks were seen in all extremities. Levetiracetam was started. Myoclonic symptoms were no longer observed. After treatment she had no neurological symptoms. Three weeks later, cranial MRI showed significantly improved brain lesions (Figure 1b). The 6-month follow-up was uneventful. Informed consent was obtained. Figure 1a MRI FLAIR images show bilateral multiple subcortical and cortical hyperintense lesions. Figure 1b MRI images 3 weeks after developing PRES revealed significant improvement. During chemotherapy for hematopoietic malignancies, possible causes of neurological symptoms (cerebrovascular disease, metabolic disturbances, neoplasia, and infections) must be excluded by clinical, biological, and imaging findings. During chemotherapy, various types of anticancer drugs are administered, and it is difficult to identify which drug induces PRES. In our case, intrathecal methotrexate treatment was stopped, and the patient’s symptoms were relieved and did not reoccur while her treatment was continued with other anticancer drugs. In treatment, the causal factor must be discontinued. The treatment of overdose of intrathecal methotrexate is dilution and removal from the cerebrospinal fluid with specific antidotal therapy. Leucovorin and anti-inflammatory agents are useful [9]. Although PRES is usually reversible with patient recovery and resolution of the imaging findings, it might be recurrent or result in permanent damage [10,11].

Oral mucositis in patients receiving low-dose methotrexate therapy for rheumatoid arthritis: report of 2 cases and literature review

The differential diagnosis of ulcerative oral lesions is diverse. This report discusses the rare causes of oral mucosal ulceration and suggests approaches for diagnosis and treatment. Two cases of methotrexate-induced stomatitis in patients receiving low dose methotrexate for rheumatoid arthritis are presented with a review of the current literature. In case 1, mucositis was caused by an unintended methotrexate overdose. In case 2, oral lesions were the result of chronic methotrexate toxicity. The treatment for methotrexate-induced mucositis required hospitalization in case 1, methotrexate discontinuation in both cases and oral folic acid supplementation in case 2. In both cases, the mucositis healed and no relapse was observed. Mucositis may be an early sign of systemic conditions, and dental providers are often the first doctors involved in the assessment of oral mucosal diseases. Meticulous questioning of the patient's history and the physical examination is important for elucidating the underlying cause.