Acute versus chronic methotrexate poisoning; a cross-sectional study.

BACKGROUND: Data is limited on comparison of acute and chronic methotrexate (MTX) poisoning. Methotrexate is an anti-folate drug that may be prescribed in some malignant or chronic inflammatory conditions. The aim of the current study was to compare signs and symptoms, complications, treatment and final outcome of acute and chronic MTX toxicity. METHOD: In a retrospective study in a referral center between March 2010 and March 2018, all patients who had been referred with the history of MTX poisoning and hospitalized due to acute or chronic poisoning were evaluated and compared. RESULTS: Of the total 27 patients admitted during the study period, 13 had referred with acute (group 1; consumption of MTX for less than 7 days) and 14 had referred with chronic toxicity (group 2; consumption of MTX for more than 7 days). Mean age was significantly higher in the second group (P < 0.001). Median total dose of MTX was similar between the groups (P = 0.90). Mucosal ulcers and skin lesions (P < 0.001 and 0.02, respectively) were the only symptoms significantly different between the two groups. Leukopenia (P < 0.001), thrombocytopenia (P < 0.001), and anemia (P = 0.04) were significantly more common in the second group. Blood urea nitrogen and creatinine were also significantly higher in the second group of the patients (P < 0.001 and P = 0.048). Median leucovorin administered dose was 200 mg [14, 480] versus 150 mg [75, 187] (P = 0.69) in groups 1 and 2, respectively. CONCLUSIONS: Chronic MTX poisoning is more serious than acute toxicity and accompanies higher dermatologic, hematologic, and hepatic complications necessitating more aggressive treatments including administration of higher doses of leucovorin or bone marrow stimulants such as G-CSF. This may be attributable to the underlying diseases and features (including older ages) which predispose these patients to complications.

[Severe methotrexate toxicity in elderly: 7 years experience]. / Toxicidad grave por metotrexato en el anciano: nuestra experiencia en los últimos 7 años.

Methotrexate is one of the most widely used drugs in rheumatology due to its high efficacy-to-toxicity. However, patients treated with this drug are sometimes elderly, which increases toxicity risks, as well as mistakes in taking the medication. The case is presented of an 87 year-old patient, on multiple medications, with a history of cognitive impairment and low social support, who suffered acute methotrexate toxicity. A description is also presented on the characteristics of the toxicity cases due this drug admitted to this hospital in the last 7 years.

Methotrexate intoxication: Beyond the adverse events.

AIM: Methotrexate (MTX) is the first-line disease-modifying antirheumatic drug in rheumatoid arthritis (RA). However, this anchor may cause some side effects that may range from nausea to mortality. The clinical features of MTX toxicity are under-researched. In this study, we aimed to find out the potential predisposing factors and outcomes of the MTX toxicity (n = 31). METHODS: The data were collected from 31 patients whose ages ranged from 25 to 81 years, who were suffering from immune-mediated inflammatory diseases and major MTX-related toxicity. RESULTS: Out of 31 patients, six (19.4%) used MTX every day, and 13 (41.9%) patients had renal insufficiency who were admitted to the hospital because of mucositis (90.3%) and fever (71%). While using MTX, 27 patients (87.1%) were discharged after the treatment and four patients (12.9%) died. CONCLUSIONS: Although MTX has high efficacy for the toxicity ratio, wrong use and dosage of MTX may be harmful to patients. Thus, patients should be informed about the proper use of MTX.

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.

Evaluation of toxicity after acute accidental methotrexate ingestions in children under 6 years old: a 16-year multi-center review.

CONTEXT: There is little data on the frequency of adverse events following acute methotrexate ingestions in pediatric patients. Likewise, recommendations for observation length, site and management strategies in this population are not well established. Therefore, most recommendations are modeled after management of chronic overdose in patients with underlying medical conditions. OBJECTIVE: The primary objective of this study is to determine the frequency of acute toxicity after acute methotrexate accidental unsupervised ingestions in patients less than six years. In addition, we describe the frequency of late toxicity and characterize the management site and approaches. MATERIALS AND METHODS: This is a retrospective cohort study of pediatric accidental unsupervised methotrexate ingestions reported to six poison centers in the United States over a 16 year period. Demographic information, exposure details, signs, symptoms, treatments, length and location of observation and outcomes were collected. RESULTS: 103 patients met inclusion criteria. Methotrexate dose was reported in 86 patients (84%) and ranged from 1.3 mg-75 mg. The majority of cases (97%) ingested a dose ≤20 mg. The significant majority of cases experienced no clinical effects (99 of 103 cases; 96%). Three children experienced minor outcome (3%). There were no patients with a major outcome or death. CONCLUSIONS: The incidence of toxicity from pediatric single, acute ingestions of methotrexate is rare and when it occurs is generally limited to no or only minimally concerning effects. Because concentrations from single ingestions were consistent with low subtoxic exposures, we believe that home monitoring without hospital referral and without methotrexate specific therapy is reasonable in those with acute ingestions up to 20 mg.

What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning?

CONTEXT: Methotrexate (MTX) is an anti-folate drug that has been utilized in both malignant and chronic inflammatory conditions. Doctors are often concerned with a potential adverse outcome when managing patients with acute oral MTX poisoning given its potential for serious adverse reactions at therapeutic doses. However, there is surprisingly little data from acute poisoning cases and more data from the therapeutic use of high-dose MTX. OBJECTIVES: To review pharmacokinetic and pharmacological properties of MTX and systematically review series of acute MTX poisonings and therapeutic studies on high-dose MTX that provide pharmacokinetic or clinical data. METHODS: An Embase (1974-October 2016) and Medline (1946-October 2016) search was performed by combining "MTX" and "overdose/poison" or "MTX" and "toxicity" or "MTX" and "high-dose MTX" or "MTX" and "bioavailability" or "pharmacokinetics"; 25, 135, 109 and 365 articles were found, respectively, after duplicates were removed. There were 15 papers that provided clinical data on acute ingestion and toxicity that occurred with low-dose administration. Eighteen papers were on high-dose MTX (>1 g per m2 body surface area) used as a single chemotherapy agent which provided pharmacokinetic or clinical data on MTX toxicity. Thirty papers were reviewed to determine the toxic dose, pharmacokinetics, risk factors, clinical symptoms and management of acute MTX toxicity. Given the limited acute poisoning data, a retrospective audit was performed through the consultant records of the New South Wales Poisons Information Centre from April 2004 to July 2015 to examine the clinical syndrome and toxicity of acute oral MTX poisoning. Pharmacokinetics: Reduced MTX bioavailability is a result of saturable absorption. Although maximal bioavailable absorption occurs at a dose of ∼15 mg m-2, splitting the dose increases bioavailability. MTX clearance is proportional to renal function. Acute toxicity: Oncologists prescribe doses up to 12 g m-2 of MTX. Patients treated with an intravenous dose of MTX <1g m-2 do not require folinic acid rescue. MTX toxicity correlates better with duration and extent of exposure than peak serum concentration. Acute oral poisoning: Acute oral MTX poisoning in 177 patients did not report any severe toxicity. In the New South Wales Poisons Information Centre audit data (2004-2015), 51 cases of acute MTX poisoning were reported, of which 15 were accidental paediatric ingestions. The median reported paediatric ingestion was 50 mg (IQR: 10-100; range: 10-150) with a median age of 2 years (IQR: 2-2; range: 1-4). Of the 36 patients with acute deliberate MTX poisoning, median age and dose were 47 years (IQR: 31-62; range: 10-85) and 325 mg (IQR: 85-500; range: 40-1000), respectively. Of the 19 patients who had serum MTX concentrations measured, all were significantly below the concentrations used in oncology and the folinic acid rescue nomogram line and no patient reported adverse sequelae. Management of acute oral poisoning: Due to the low bioavailability of MTX, treatment is not necessary for single ingestions. Oral folinic acid may be used to lower the bioavailability further with large ingestions >1 g m-2. Oral followed by intravenous folinic acid may be used in patients with staggered ingestion >36 h or patients with acute overdose and renal impairment (eGFR <45 mL/min/1.73 m2). CONCLUSIONS: As a consequence of saturable absorption MTXs bioavailability is so low that neither accidental paediatric MTX ingestion nor acute deliberate MTX overdose causes toxicity. An acute oral overdose will not provide a bioavailable dose even close to 1 g m-2 of parenteral MTX. Hence, no treatment is required in acute ingestion unless the patient has renal failure or staggered ingestion. There is also no need to monitor MTX concentrations in acute oral MTX poisoning.

A Large Case Series of Acute Pediatric Methotrexate Ingestions: Significant Clinical Effects Are Rare.

OBJECTIVE: Significant adverse effects after acute pediatric methotrexate (MTX) exposures have been limited to parenteral exposures. Treatment recommendations for pediatric MTX exposures do not differentiate between routes of exposure. We report the incidence of significant clinical effects and drug-specific treatments reported in a large series of acute, pediatric MTX ingestions. METHODS: Poison center records of all MTX ingestions by patients younger than 17 years during 2000 to 2005 were collected from 6 poison centers. The cases included all MTX ingestions including those with additional substances. One trained reviewer, blinded to the study purpose, used a standardized data collection form to extract study data. Missing or conflicting data were reconciled with predetermined process. RESULTS: Forty-seven cases were documented for 6 years, 42 (89%) of which were unintentional. Thirty-six percent (17/47) were male. The mean age for the unintentional ingestions was 3.7 years (range, 20 days-17 y; median, 2 y). Five cases (11%) were intentional suicidal ingestions in teenagers. The mean dose in acute, unintentional ingestions (AUIs) in all children and in children younger than 6 years was the same, 8 mg (range, 2.5-17.5 mg). Eleven patients (23%) had follow-up greater than 12 hours. No patient with an AUI developed MTX-induced sedation, hepatotoxicity, renal insufficiency, seizures, or bone marrow suppression. Three patients with an AUI received folinic acid, but no patients in this group received sodium bicarbonate or hemodialysis. One patient with an intentional suicidal exposure developed hepatotoxicity, but the patient also ingested a toxic dose of acetaminophen and valproate. Hemodialysis was performed once on this patient. No patient died. CONCLUSIONS: Acute pediatric MTX ingestion is uncommon. Methotrexate-induced seizure, renal failure, hepatic injury, and sedation were not documented in our series. Supportive care and observation only should be considered the mainstay of treatment of pediatric AUIs. Prospective verification of our findings is warranted.

The utility of online haemodiafiltration in methotrexate poisoning.

Summary We report a case of a 56-year-old woman with a high-grade diffuse large B-cell lymphoma who unexpectedly developed toxic plasma levels of methotrexate (MTX) following the first cycle of rituximab-cyclophosphamide, hydroxydanorubicin, oncovin, prednisolone (R-CHOP) with a high-dose MTX chemotherapy protocol. She also developed non-oliguric acute kidney injury secondary to MTX nephrotoxicity. We elected to treat her with online-haemodiafiltration (HDF) and this proved to be efficient with a dramatic response. Rapid clearance of MTX to therapeutic levels was possible within three sessions. Prompt therapy with high-volume online-HDF is an effective choice for rapid MTX clearance and swift reversal of MTX nephrotoxicity.

Fatal methotrexate toxicity: could it have been avoided?

Methotrexate is used judiciously, only when specifically indicated. However, in this case the patient had a fatal outcome after only three doses. A young nulliparous woman diagnosed as having high-risk persistent trophoblastic disease was considered for multidrug chemotherapy. However, because of persistent low-grade fever it was decided to give only single agent, methotrexate. She developed severe toxicity which proved fatal, even before the first course could be completed. Analysing causes of this rare, unexpected outcome of methotrexate administration, suggested that estimation of serum levels can be a useful tool in monitoring patients showing hypersensitivity but this facility is rarely available especially in low-resource countries. Pharmacogenetical analysis of blood/tissue sample may be useful to help in identifying patients likely to show hypersensitivity reaction.

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

BACKGROUND: 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. METHODS: 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. RESULTS: In both cases, the mucositis healed and no relapse was observed. CONCLUSION: 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.

[Wrong administration of methotrexate can lead to fatal haematological complications in elderly patients]. / Methotrexat kan føre til fatale hæmatologiske komplikationer hos ældre.

We present four cases of life-threatening methotrexate intoxications of patients with rheumatological disease. In two of the cases, the direct cause of intoxication was accidentally daily administration of the drug instead of weekly. The patients presented with uncharacteristic symptoms, including nausea, mucositis and fever. All of them had pancytopenia, and despite therapy with broad spectrum antibiotics three patients died in a state of septic shock. These cases demonstrate the importance of adequate communication between health-care professionals, who are involved in the administration of methotrexate and in particular it emphazises that methotrexate should be administrated as weekly doses.

Continuous veno-venous hemodiafiltration in methotrexate intoxication.

UNLABELLED: Methotrexate is a highly nephro- and hepatotoxic drug used in osteosarcoma treatment protocols, in children and adults. High dose methotrexate therapy may lead to kidney injury and decrease of methotrexate clearance, followed by an increase of its serum concentration. As a result, systemic intoxication may develop. Prophylaxis based on intensive fluid therapy and urine alkalization may not be sufficient to prevent the formation of methotrexate crystals in kidney tubules. THE AIM of the study was to present three cases of methotrexate intoxication treated with continuous veno-venous hemodiafiltration. PATIENTS AND METHODS: Three children aged 9-16 years old with tibial or fibular osteosarcoma were admitted to the Nephrology Department due to severe methotrexate intoxication. All children presented with multiorgan injury, including liver, kidney, gastrointestinal tract and bone marrow impairment. Methotrexate concentration, 24 hours after drug administration, was 660-1238 µmol/L. Although intensive fluid therapy, urine alkalisation and administration of high doses of folinic acid (leucovorin), methotrexate serum concentration remained toxic. Effective reduction of methotrexate concentration (<1.5 µmol/L) was achieved 24-156 hours after CVVHDF initiation. Kidney and liver function recovered completely in all of the patients. CONCLUSION: Continuous veno-venous hemodiafiltration is an effective supportive method in methotrexate elimination in patients with severe intoxication.

Life-threatening complications following multidose methotrexate for medical management of ectopic pregnancy.

A 25-year-old primigravida was diagnosed to be suffering from unruptured ectopic pregnancy. The serum ß-human chorionic gonadotropin levels were 2851 mIU/l and the ectopic gestational sac was 2.7×2.7 cm without any fetal pole. It was decided to manage her by expectant therapy. But she received medical therapy with multidose methotrexate because of misinterpretation of expectant therapy as medical therapy. She suffered from methotrexate toxicity, which manifested as high-grade fever, vomiting, melena, oral ulcerations, pneumonitis, subconjunctival haemorrhages and skin pigmentation. She developed severe third space fluid collection and shock, which was mistaken for rupture ectopic gestation. Her haematological picture showed severe neutropaenia and thrombocytopaenia which confirmed the clinical picture to be due to methotrexate toxicity. She also developed septicaemia and candidal infection secondary to immunosuppression. She was managed in intensive care unit with ventilatory support, high-dose leucovorin and injection filgastrim. She responded well to the therapy with dramatic recovery in 4 days.

Accidental methotrexate ingestion in a 19-month-old child.

The authors present the youngest reported case of a single oral overdose of methotrexate in an otherwise well 19-month-old child who was treated with delayed folinic acid rescue. Initial history revealed possible ingestion of up to 10 tablets, each containing 2.5 mg of methotrexate. The peak methotrexate level was 0.67 µmol/l measured 8 h following ingestion. Depending on the protocol, methotrexate levels that remain greater than 0.05-0.1 µmol/l for 24-48 h are associated with risk of toxicity. No adverse sequelae were noted during hospital admission despite delayed folinic acid rescue and there was no evidence of myelosuppression for up to 3 weeks following the overdose.

Severe intoxication with methotrexate possibly associated with concomitant use of proton pump inhibitors.

BACKGROUND: Delayed elimination of methotrexate associated with serious side-effects has been attributed to the co-administration of benzimidazole proton pump inhibitors. PATIENTS AND METHODS: We have retrospectively analyzed the causes of delayed methotrexate elimination in patients who had received the rescue agent glucarpidase to evaluate the potential implication of benzimidazoles. RESULTS: Between 2002 and 2008, six patients (mean age: 30 years; range: 4-74 years) were treated with glucarpidase. Delayed elimination associated with impaired renal function occured after the first cycle except in 2 patients (2nd and 8th administration of high-dose methotrexate). The possible causes of delayed elimination identified were: insufficient hydration (n=1) and drug-drug interactions (n=5). The potential drug-drug interactions included the co-administration of piperacillin/tazobactam (n=1) and proton pump inhibitors (omeprazole, n=3; esomeprazole, n=2). Impaired elimination of methotrexate was not observed either in the 3 patients who were treated further or during the previous cycles of the 2 pretreated patients in relation to the absence of co-prescription of proton pump inhibitors. CONCLUSION: In line with the recent literature and given the prohibitive cost of glucarpidase, we have advocated the cessation of proton pump inhibitors administration during methotrexate treatment.