Methotrexate is an antimetabolite chemotherapeutic agent that is also used for psoriasis, rheumatoid arthritis, systemic sclerosis, placenta accreta, and ectopic pregnancy. Most toxicity is caused by chronic oral overmedication. Inadvertent high-dose intrathecal, intravenous, and intramuscular methotrexate administration and acute intentional overdose have been reported.

1. Methotrexate is a folic acid antagonist that inhibits dihydrofolic acid reductase in the synthesis of purine nucleotide and thymidylate synthetase. It interferes with DNA synthesis and repair and with cellular replication. Tissues with active proliferation are more sensitive to this effect. It also affects immune function, likely through modulation of lymphocyte proliferation and migration.
2. Pharmacokinetics. Peak serum level occurs within 1-2 hours after ingestion. Bioavailability is 60% at a dose of 30 mg/m² but significantly decreases at doses greater than 80 mg/m². Peak serum concentration occurs 30-60 minutes after IM injection. The steady-state volume of distribution is 0.4-0.8 L/kg, with approximately 50% protein bound. Drugs such as trimethoprim-sulfamethoxazole (TMP/SMX), probenecid, and salicylates can compete with methotrexate for protein-binding sites, raising free levels. Methotrexate does not cross the blood-brain barrier in therapeutic doses given orally or parenterally. The terminal half-life is approximately 3-10 hours with low doses (<15 mg/m²) and 8-15 hours after higher doses. Methotrexate accumulates in third-space fluid, so a prolonged half-life and clinical effects can be observed in patients with ascites, pleural effusion, and pericardial effusion. Ninety percent of the absorbed dose is excreted unchanged in the urine within 48 hours.

1. Therapeutic doses vary widely, depending on the indication. Adults with rheumatoid arthritis often take 5-20 mg once a week. Ectopic pregnancy is treated with doses of 50 mg/m² IM, sometimes repeated 4 days later. Neoplastic disease is treated with much higher doses (eg, 8-12 g/m² IV for some sarcomas). Intrathecal doses of 0.2-0.5 mg/kg are given for some CNS neoplasms.
2. Toxic doses are variable, depending on the route and chronicity. Bone marrow suppression can occur in 25% of patients receiving therapeutic doses used for the treatment of cancers. Intrathecal injection of more than 500 mg is associated with severe morbidity or death. Toxicity often occurs after prolonged use (>2 years) or after a total oral dose of 1.5 g. Alcoholism, obesity, diabetes, advanced age, and decreased renal function are risk factors associated with chronic hepatic toxicity.

Acute unintentional ingestion is generally benign due to saturable bioavailability. Chronic oral overmedication may occur in patients who misunderstand and take their weekly doses daily for several days. Severe toxicity usually results from an inadvertent high dose of intrathecal or IV methotrexate. Causes of death in severe toxicity are sepsis and multiple-organ failure.

1. Gastrointestinal effects including nausea, vomiting, diarrhea, and ulcerative stomatitis are the most common reported adverse effects from oral methotrexate toxicity.
2. Hematologic effects such as leukopenia, anemia, thrombocytopenia, and pancytopenia occur within a week after exposure and resolve in 2 weeks. Bone marrow suppression can lead to fatal systemic infections.
3. Hepatic manifestations include acute elevated aminotransaminases and chronic fibrosis or cirrhosis after prolonged use.
4. Neurologic toxicity can be seen in patients with intrathecal or IV methotrexate overdose, or with chronic use. Serious neurotoxicity includes generalized or local seizures and coma. Acute chemical arachnoiditis following intrathecal dosing presents as headache, back pain, nuchal rigidity, and fever; paraparesis and paraplegia can occur. Chronic leukoencephalopathy may cause confusion, irritability, somnolence, ataxia, dementia, seizure, and coma, and may be mistaken for acute ischemic stroke with restricted diffusion seen on magnetic resonance imaging (MRI).
5. Interstitial pneumonitis manifests with a dry or nonproductive cough.
6. Renal damage from high-dose IV methotrexate results from deposition of methotrexate and its metabolite in the renal tubules.
7. Dermatologic reactions include toxic epidermal necrosis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme.
8. Teratogenic effects and fetal death are well documented. Methotrexate is categorized as Pregnancy Category X by the FDA.

Methotrexate intoxication should be suspected in any patient with nausea, vomiting, abdominal discomfort, elevated aminotransaminases, and/or bone marrow suppression.

1. Specific levels. A serum methotrexate level greater than 1 mcmol/L is potentially toxic. The level should be monitored every 24 hours after overdose.
2. Other useful laboratory studies include CBC with differential and platelet count, BUN, creatinine, electrolytes, liver function test, and chest radiography if indicated.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat coma, seizures, and infection if they occur.
   3. Treat nausea and vomiting with ondansetron or metoclopramide and fluid loss with IV crystalloid solutions.
   4. Bone marrow suppression should be treated with the assistance of an experienced hematologist or oncologist. Granulocyte colony-stimulating factor and transfusion of red cells or platelets may be considered if appropriate.
   5. Remove third-space fluid (eg, ascites, pleural effusion) in severe methotrexate overdose to prevent prolonged toxic effects.
   6. Intrathecal overdose. Intrathecal leucovorin administration may be fatal. Treatment strategies in reported cases include CSF drainage to remove methotrexate via lumbar puncture, CSF exchange, or ventriculolumbar perfusion. IV (not intrathecal) leucovorin (100 mg every 6 hours for 4 doses), IV dexamethasone (4 mg every 6 hours for 4 doses), and intrathecal glucarpidase (2,000 units over 5 minutes) have been used. Note: Adult patients who have received less than 100 mg of methotrexate intrathecally are unlikely to develop severe toxicity and probably do not require intervention.
2. Specific drugs and antidotes
   1. Leucovorin (folinic acid) should be administered as soon as possible to patients with significant risk for toxicity. Note: Do not wait for methotrexate levels to initiate therapy after acute poisoning. Leucovorin “rescue” is routinely used for patients receiving high-dose methotrexate (>500 mg/m²).
   2. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes methotrexate to the inactive metabolite 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid. It rapidly lowers serum methotrexate levels by IV and intrathecal administration. Glucarpidase does not counteract the intracellular effects of methotrexate; leucovorin rescue is still necessary.
   3. Administration of corticosteroids (dexamethasone 4 mg IV every 6 hours for 4 doses) may be of utility.
3. Decontamination measures are appropriate after acute ingestion but not chronic intoxication. Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination from the systemic circulation
   1. Effective clearance of methotrexate by means of acute intermittent hemodialysis (with a high-flux dialyzer) and by use of continuous venovenous hemodialysis have been reported. It is recommended for patients who have renal failure and are anticipated to have prolonged high serum methotrexate levels.
   2. Urine alkalinization is recommended to increase elimination and decrease precipitation of methotrexate and its metabolite in the renal tubules.
   3. Multiple-dose activated charcoal is reported to decrease the elimination half-life of methotrexate but has not been shown to affect outcomes.