levoleucovorin and Drug-Overdose

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.

Topics: Drug Interactions; Drug Overdose; Drug Prescriptions; Humans; Leucovorin; Methotrexate; Pharmacogenetics

A 7-y-old boy with acute lymphoblastic leukaemia (ALL) received 600 mg of i.v. methotrexate (MTX) over 2 h, followed by triple intrathecal therapy (TIT) with cytosine arabinoside 30 mg, methylprednisolone 10 mg and MTX 300 mg (instead of the prescribed 12 mg). Ninety minutes later the patient developed headache, loss of consciousness and generalized hypertonia. He was transferred to the Intensive Care Unit, intubated and treated with phenobarbital. Three hours after the TIT, the levogyrus form of folinic acid (equivalent to double doses of the racemic product) was started i.v. at a dose of 100 mg every 3 h for 24 h, and every 6 h in the following 24 h. Cerebrospinal fluid was examined and was found normal. The patient subsequently remained in normal neurological status. The favourable outcome in our case suggests that folinic acid rescue may be adequate to prevent sequelae in patients who undergo intrathecal MTX overdoses up to 300 mg.

Topics: Antidotes; Antimetabolites, Antineoplastic; Child; Drug Overdose; Humans; Injections, Spinal; Leucovorin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients' blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL.. Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m(2), in two doses 12 h apart, in place of methotrexate 100 mg/m(2) in four divided doses.. Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase.. Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.

Topics: Adolescent; Aminopterin; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Diseases; Child; Child, Preschool; Drug Overdose; Erythrocytes; Female; Fever; Folic Acid Antagonists; Gastrointestinal Diseases; Humans; Leucovorin; Male; Methotrexate; Neurotoxicity Syndromes; Pilot Projects; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Treatment Outcome

To describe the management and outcome of a dog following a 10-fold dosing error of vincristine.. A 2-year-old neutered female Toy Fox Terrier presenting for immune-mediated thrombocytopenia was administered an accidental overdose of vincristine (0.2 mg/kg [2.71 mg/m. This is the first report of the successful management of severe vincristine overdose in a dog. Therapy included the use of Tbo-filgrastim, folinic acid, and glutamic acid along with aggressive supportive care.

Topics: Animals; Dog Diseases; Dogs; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Female; Filgrastim; Glutamic Acid; Leucovorin; Thrombocytopenia; Vincristine

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.

Topics: Administration, Oral; Algorithms; Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; California; Clinical Coding; Delivery of Health Care, Integrated; Drug Administration Schedule; Drug Overdose; Electronic Health Records; Female; Humans; Incidence; International Classification of Diseases; Leucovorin; Male; Medication Errors; Methotrexate; Middle Aged; Product Surveillance, Postmarketing

Topics: Buffers; Dermatologic Agents; Drug Overdose; Fluid Therapy; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Psoriasis; Skin Ulcer; Sodium Bicarbonate; Treatment Outcome

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.. 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.. 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.

Topics: Anti-Bacterial Agents; Antirheumatic Agents; Azabicyclo Compounds; Blood Transfusion; Bone Marrow Diseases; Drug Overdose; Febrile Neutropenia; Female; Filgrastim; Gastrointestinal Diseases; Humans; Leucovorin; Methotrexate; Middle Aged; Mucositis; Piperazines; Suicide, Attempted; Tramadol

The use of uridine triacetate for the management of fluorouracil toxicity is reported.. A 55-year-old man with malignant neoplasm of the sigmoid colon (stage IIIC) was seen in an outpatient chemotherapy center for his first six-month regimen of leucovorin calcium, fluorouracil, and oxaliplatin. Fluorouracil 2400 mg/m(2) i.v. was prescribed to be given over the next 46 hours at a home infusion center. Due to a medication error, a home infusion pharmacist incorrectly programmed the 46-hour infusion of fluorouracil to be administered over 4 hours. To manage the fluorouracil overdose, the physician decided to start the patient on uridine triacetate. The patient received his first dose of uridine triacetate 18 hours after the fluorouracil overdose. He was admitted to the hospital for observation and daily laboratory tests during treatment with uridine triacetate. He received ondansetron (as the hydrochloride salt) 8 mg orally 20 minutes before each dose of uridine triacetate to prevent nausea and vomiting. Uridine triacetate 11 g every 6 hours was administered orally for a total of 20 doses. It was mixed with applesauce at the time of administration and followed with 8 oz of water. The patient's laboratory values remained stable. The patient did not experience any nausea or vomiting during treatment. He was discharged from the hospital on day 5, with no clinical complications and an Eastern Cooperative Oncology Group Performance score of 0.. A patient with colon cancer who had received an overdose of fluorouracil was successfully treated with a five-day course of oral uridine triacetate.

Topics: Antiemetics; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Overdose; Fluorouracil; Home Infusion Therapy; Humans; Leucovorin; Male; Medication Errors; Middle Aged; Ondansetron; Organoplatinum Compounds; Uridine

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.

Topics: Antidotes; Drug Overdose; Emergency Service, Hospital; Female; Humans; Infant; Leucovorin; Methotrexate

A male 34-year-old patient with aggressive diffuse malignant lymphoma was hospitalized for treatment. Because of high likelihood of CNS involvement, intrathecal methotrexate (MTX) 15 mg was administered with hydrocortisone 100mg. Shortly after the intrathecal injection the patient became agitated, and complained of severe low back pain and 2h later he became confused and developed generalized seizures. At this stage, it was realized that the dose contained 1200 mg of MTX (80-fold overdose). The patient developed ARDS and was comatose; he was intubated and transferred to ICU. The patient was immediately treated with intravenous leucovorin 1200 mg, and 15 mg every 6h, thereafter, for 72 h. In addition, CSF exchange with warm normal saline was initiated via intrathecal catheter, and a total of 200 ml of CSF were replaced during 48 h. Finally, at the end of the exchange 2 mg of leucovorin with 2 mg of dexamethasone were administered intrathecally. MTX levels in CSF 7h post-injection were 770 microM, and increased to 1250 microM 2h later. Thereafter, the levels in CSF declined, and 48 h post-injection were 47 microM. The plasma levels of MTX 7h post-injection were 10 microM, and declined to 0.7 microM at 68 h. The patient regained consciousness and underwent successful weaning from ventilator after tracheostomy. The highest reported intrathecal dose after which the patient survived was 625 mg. Due to the rarity of reported cases, there are no clear guidelines for treatment of massive intrathecal overdose. There is a controversy regarding the toxicity of intrathecal injection of leucovorin. We propose CSF exchange and intravenous leucovorin as the mainstay of treatment.

Topics: Adult; Antidotes; Dexamethasone; Drug Overdose; Emergency Treatment; Humans; Injections, Spinal; Leucovorin; Male; Methotrexate

Topics: Administration, Oral; Drug Labeling; Drug Overdose; Humans; Leucovorin; Methotrexate; Tablets

We report on a case of methotrexate (MTX) intoxication occurring in a 19-year-old man treated for a leukemia. Exchange-transfusion (ET) was performed in attempt to remove the MTX from the body. This exchange-transfusion was unable to decrease the MTX plasma concentration. This inefficacy of ET in MTX intoxication is in contradiction with previously reported recommendations. However, this result is easily explained by MTX pharmacokinetics parameters.

Topics: Acute Kidney Injury; Adult; Antidotes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Diuretics; Drug Overdose; Exchange Transfusion, Whole Blood; Furosemide; Humans; Leucovorin; Male; Methotrexate; Pancytopenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Failure

Intrathecal methotrexate is a standard and important therapy in acute leukemia. Unfortunately, overdose is a well reported complication of this therapy. We report a fatal event secondary to intrathecal leucovorin.. An 11-year-old boy with a 6-month history of treatment of acute lymphocytic leukemia received an "overdose" of 20 mg of intrathecal methotrexate. He was treated with intrathecal leucovorin and subsequently experienced severe neurotoxicity and died. This was attributed to the use of intrathecal leucovorin, the first such case reported in the medical literature.. A review of the literature indicates that a careful definition of overdose needs to be applied in cases of intrathecal methotrexate: those <100 mg need less intervention, >500 mg will not respond to any intervention, and the middle group, 100-500 mg, can be treated with a variety of approaches, which are outlined. The standard treatment includes the use of ventriculolumbar washout, CSF exchange, or intravenous pharmacotherapy with leucovorin. Recently, the use of carboxypeptidase has been under investigation. All clinicians who administer intrathecal medications should be aware of these complications and the appropriate treatments of them (including rescue). Leucovorin should not be given intrathecally.

Topics: Catheterization, Central Venous; Child; Cytarabine; Drug Overdose; Humans; Hydrocortisone; Injections, Spinal; Leucovorin; Male; Medication Errors; Methotrexate; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma