METHOTREXATE AND RELATED AGENTS
- USES: Methotrexate is used alone or in combination with other agents to treat a variety of cancers (eg, breast cancer, leukemia, lymphoma, head and neck, lung, sarcomas). It is also used to treat patients with rheumatoid arthritis and severe psoriasis. PHARMACOLOGY: Methotrexate is a folate antimetabolite that reversibly inhibits dihydrofolate reductase. Dihydrofolates are reduced to tetrahydrofolates by this enzyme before they are used in the synthesis of purine nucleotides and thymidylate. Via this mechanism, methotrexate sodium interferes with DNA synthesis, repair, and cellular replication. The mechanism of action of methotrexate sodium in rheumatoid arthritis is unknown. TOXICOLOGY: After an overdose, the effects of decreased DNA synthesis and cell death are noticed primarily in organ systems with rapidly dividing cells (eg, bone marrow, gastrointestinal tract). EPIDEMIOLOGY: Acute methotrexate overdose is rare, but inadvertent intravenous and intrathecal overdoses have been reported. Inadvertent oral overdoses have been reported when methotrexate was administered as a daily dose rather than the recommended once a week dose. MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. SEVERE TOXICITY: Acute effects include acute renal failure, pancytopenia, nausea, vomiting, diarrhea, severe stomatitis, sepsis, acute lung injury, and respiratory failure. INTRATHECAL methotrexate overdose can cause headache, back pain, confusion, seizures, coma, respiratory failure, tachycardia, hypotension, and death. The onset of toxicity is generally rapid. ADVERSE EFFECTS: Adverse events may vary widely depending on the route of exposure and dose; hematologic and gastrointestinal side effects are common for those undergoing chemotherapy, but far less common in those taking methotrexate for rheumatoid arthritis. CNS: Headache, drowsiness, speech impairment including dysarthria and aphasia, hemiparesis, paresis, seizures, transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, and encephalopathy have been reported in patients receiving methotrexate. INTRATHECAL: CNS toxicity after the use of intrathecal methotrexate has been classified as: acute (within 24 hours of starting therapy) chemical arachnoiditis characterized by headache, back pain, nuchal rigidity, and fever; sub-acute (1 to 2 weeks after starting therapy) myelopathy or encephalopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots, ataxia, speech disorders, seizures, and affective disturbances; chronic leukoencephalopathy (months after exposure) characterized by confusion, irritability, somnolence, ataxia, dementia, seizures, coma, and death. This demyelinating encephalopathy is usually observed in association with cranial irradiation or other systemic chemotherapy. HIGH-DOSE REGIMENS: A transient acute neurologic syndrome has been reported in patients receiving high-dose methotrexate. Patients with this stroke-like encephalopathy may experience confusion, hemiparesis, transient blindness, seizures, and coma. DERMATOLOGIC: Reddening of the skin, alopecia, rash, photosensitivity, and depigmentation or hyperpigmentation of the skin. GASTROINTESTINAL: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting, diarrhea, anorexia, gastrointestinal ulceration and hemorrhage. These effects are very dose dependent and usually appear in a delayed fashion (3 to 7 days after therapy with resolution after 2 weeks). GENITOURINARY: Renal failure, azotemia, nephropathy, and cystitis. This is more common with higher doses and may be secondary to precipitation of the drug. HEMATOLOGIC: Anemia, leukopenia, and thrombocytopenia, which can lead to hemorrhage. These effects typically begin 6 to 9 days after exposure and last for approximately 2 weeks. HEPATIC: Cirrhosis and portal fibrosis have been reported with chronic methotrexate toxicity. In addition, acute elevation of liver enzymes is common after high-dose methotrexate, but usually resolves within 10 days. OCULAR: Blurred vision and transient blindness. RESPIRATORY: Pneumonitis and acute respiratory distress syndrome. OTHER RARE BUT POTENTIALLY LIFE-THREATENING REACTIONS: Anaphylactoid reaction, alveolitis, hepatic failure, lymphoproliferative disorders, osteonecrosis and soft tissue necrosis, pericarditis, erythema multiforme, Stevens-Johnson syndrome, and thromboembolism. Methotrexate administration appears to increase the risk of developing leukemias and lymphomas. REPRODUCTIVE: Methotrexate is teratogenic (FDA pregnancy category X). DRUG INTERACTIONS: Dantrolene, doxycycline, omeprazole, and trimethoprim/sulfamethoxazole may reduce methotrexate elimination and increase the risk of toxicity. Coadministration of NSAIDs or use of radiocontrast agents may increase toxicity, likely by reducing renal function.
Range of Toxicity:
METHOTREXATE AND RELATED AGENTS
- TOXICITY: Patients may experience toxicity following therapeutic dosing, though toxicity may be ameliorated or even prevented with prompt therapy (eg, leucovorin). In children, intrathecal overdoses of less than 100 mg (less than a 15-fold overdose) usually do not develop significant CNS toxicity. Doses greater than 100 mg can cause severe morbidity. Intrathecal overdoses of greater than 500 mg have caused severe toxicity and are often fatal. In adults, inadvertent daily dosing instead of weekly dosing (orally) has been fatal; doses ranged from 60 mg over 16 days to 230 mg over 23 days. Together two children (3 and 4 years of age, respectively) ingested 2,025 mg of methotrexate and were given leucovorin. Both recovered with minimal adverse effect. THERAPEUTIC DOSE: Doses in adults vary widely depending on the indication. Acute lymphoid leukemia (ALL): Adults and children: Induction, 3.3 mg/m(2)/day IV in combination with prednisone 60 mg/m(2)/day. Maintenance, 30 mg/m(2)/week administered in 2 divided ORAL or IM doses; 2.5 mg/kg IV every 14 days has also been used. Advanced non-Hodgkin’s lymphoma: Adults: (Burkitt’s lymphoma, stages I and II): 10 to 25 mg/day orally for 4 to 8 days for several courses with a 7 to 10 day rest period; (stage III) in combination with other antineoplastic agents. (lymphosarcoma, stage III): 0.625 to 2.5 mg/kg/day in combination with other antineoplastics. HIGH-DOSE THERAPY: High doses range from 2.7 g/m(2) to 5 g/m(2). Administration of intravenous high-dose methotrexate occurs at different intervals in treatment and depends on the regimen being used. Juvenile rheumatoid arthritis: Children: 10 mg/m(2) orally once weekly. Meningeal leukemia: Adults: 12 mg intrathecally in intervals of 2 to 5 days; intervals of less than one week may increase subacute toxicity; until the cell count of the CSF returns to normal, and then 1 additional dose. Children: Varies by age: ranges from 6 mg for children less than 1 year of age to 12 mg for children 3 years or older intrathecally in intervals of 2 to 5 days; intervals of less than 1 week may increase subacute toxicity; until the cell count of the CSF returns to normal, and then 1 additional dose. Osteosarcoma: Adults: initial, 12 g/m(2) IV over 4 hours in combination with other chemotherapy agents (bleomycin, cisplatin, cyclophosphamide, dactinomycin, doxorubicin); if a peak serum methotrexate concentration of 1,000 micromolar (10 x (-3) mol/L) is not obtained, the dose can be increased to 15 g/m(2). Psoriasis: Adults: initial 10 to 25 mg/week orally/IM/IV or 2.5 mg every 12 hour for 3 doses; not to exceed 30 mg/week. Rheumatoid arthritis: Adults: 7.5 mg orally once weekly or 2.5 mg ORALLY every 12 hours for 3 doses once weekly OR 10 to 15 mg orally once weekly, increase by 5 mg/wk every 2 to 3 weeks, MAX 20 to 30 mg/wk (consensus-based).
METHOTREXATE AND RELATED AGENTS
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Administer intravenous leucovorin as soon as possible. Administer intravenous fluids. Treat persistent nausea and vomiting with several antiemetics of different classes. Begin alkaline diuresis with a bicarbonate infusion to prevent renal precipitation of methotrexate. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. As toxicity is delayed for hours to days, the most critical intervention is to determine if the patient was exposed to a large enough dose to develop severe toxicity. MANAGEMENT OF SEVERE TOXICITY: Administer intravenous leucovorin as soon as possible. Administer intravenous fluids. Begin alkaline diuresis with a bicarbonate infusion to prevent renal precipitation of methotrexate. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Glucarpidase (formerly known as carboxypeptidase CPDG2) rapidly catabolizes methotrexate to an inactive metabolite. It is available in the United States as lyophilized powder 1000 Units per vial. To obtain glucarpidase (standard or expedited), contact ASD Healthcare Voraxaze(R) Customer Service at 1-855-7-VORAXAZE (1-855-786-7292) 24 hours/day, 365 days/year. Dosage is an IV bolus of 50 Units/kg over 5 minutes.
- Intrathecal injection: Inadvertent intrathecal overdose of methotrexate can cause severe toxicity. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. This is probably sufficient therapy in patients with less than 7-fold overdose or less than 100 mg of methotrexate. CSF exchange, ventriculolumbar perfusion, and intrathecal administration of glucarpidase should be performed after large overdoses (in children intrathecal overdoses greater than 120 mg or more than 15 times the intended dose). Glucarpidase rapidly catabolizes methotrexate to an inactive metabolite. It is available in the United States as lyophilized powder 1000 Units per vial. To obtain glucarpidase (standard or expedited), contact ASD Healthcare Voraxaze(R) Customer Service at 1-855-7-VORAXAZE (1-855-786-7292) 24 hours/day, 365 days/year. Glucarpidase 2000 Units over 5 minutes was administered to 7 patients who had inadvertent intrathecal methotrexate overdoses. Administration of corticosteroids (dexamethasone 4 mg IV every 6 hours for 4 doses) and leucovorin (100 mg IV every 6 hours for 4 doses) also may help. DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.
- Decontamination: PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway. For dermal and ocular exposures, standard decontamination procedures are reasonable. HOSPITAL: Activated charcoal binds to methotrexate and may be of use in patients without severe vomiting. There is some evidence that multiple-dose activated charcoal may be useful. Gastric lavage should be considered if a patient presents within an hour of overdose and has taken a life-threatening amount.
- Airway management: Endotracheal intubation and mechanical ventilation may rarely be required in patients with severe CNS and cardiac toxicity.
- Alkaline diuresis: Infuse a solution of 1 L of D5W with 44 mEq (1 ampule) of sodium bicarbonate at 3000 mL/m(2)/day. Monitor urine pH (goal is 7.0) and administer potassium as needed. Infusion may be changed to 1 L of D5W with 88 to 132 mEq (2 to 3 ampules) of sodium bicarbonate, infused at twice the maintenance rates, if necessary, to reach the target urine pH.
- Antidote: LEUCOVORIN: It is generally recommended that doses of leucovorin equal to or greater than the ingested/infused dose of methotrexate be given. Ideally, the dose should be given within one hour of exposure, or as soon as possible (do not wait for blood methotrexate concentrations) over 15 to 30 minutes. A dose of 100 mg/m(2) IV leucovorin infused over 15 to 30 minutes every 3 to 6 hours for several days (until methotrexate concentration is less than 0.01 mcmol/L (1 x 10(-8) M) in patients not receiving methotrexate OR less than 0.05 to 0.1 mcmol/L in patients receiving methotrexate as chemotherapy) should be effective in most cases. In adults, the infusion rate should not exceed 160 mg/minute. Because methotrexate half-life is variable (5 to 45 hours) and is dependent on the dose and the patient’s renal function, leucovorin therapy should be given for several days. If methotrexate levels are unavailable, leucovorin should be continued for 12 to 24 doses (3 days) or longer. NEVER administer leucovorin intrathecally. GLUCARPIDASE: Glucarpidase (formerly known as carboxypeptidase CPDG2) rapidly catabolizes methotrexate to an inactive metabolite. It is available in the United States as lyophilized powder 1000 Units per vial. To obtain glucarpidase (standard or expedited), contact ASD Healthcare Voraxaze(R) Customer Service at 1-855-7-VORAXAZE (1-855-786-7292) 24 hours/day, 365 days/year. Dosage is an IV bolus of 50 Units/kg over 5 minutes, or intrathecal administration of 2000 Units over 5 minutes. DEXTROMETHORPHAN: In studies, the oral administration of dextromethorphan was associated with complete resolution of neurologic deficits in patients with methotrexate-induced neurotoxicity.
- Myelosuppression: Administer colony stimulating factors as these patients are at significant risk for developing severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential for evidence of bone marrow suppression. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation.
- Neutropenia: Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
- Neutropenic sepsis: If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
- Nausea and vomiting: Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
- Stomatitis: Stomatitis usually begins 5 days after methotrexate administration and usually resolves by day 10. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a methotrexate overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
- Extravasation injury: Methotrexate is a non-irritant. Severe injury is not anticipated. If a reaction occurs, apply heat. There is no known antidote.
- Monitoring of patient: Anemia, leukopenia, and thrombocytopenia may occur. These effects typically begin 6 to 9 days after therapeutic use and last for approximately 2 weeks, may develop sooner and persist longer after overdose. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Monitor patient for signs of bleeding. Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Monitor serum electrolytes, renal function, and hepatic enzymes. Obtain a chest radiograph in patients with respiratory symptoms. Serum methotrexate concentrations are available and can be used to guide the length of leucovorin therapy, however, initial treatment should not be delayed while waiting for methotrexate concentrations.
- Enhanced elimination procedure: Methotrexate is approximately 50% protein bound in blood, but has a relatively low Vd (0.4 to 0.8 L/kg). High flux hemodialysis and charcoal hemoperfusion may enhance elimination of methotrexate, especially in patients with worsening renal function. Methotrexate plasma clearance is triphasic, with an initial plasma distribution half-life of 0.75 hour, the second phase (renal clearance) half-life of 2 to 3 hours, and the third phase half-life of 8 to 10 hours, indicating an extensive tissue redistribution. Persistent cytotoxic effects can occur when intracellular methotrexate is metabolized to polyglutamate derivatives that do not easily diffuse out of the cell. Hemodialysis is most effective if performed early after overdose. Because of significant rebound of serum concentrations (up to 221% reported) after dialysis, a prolonged course of recurrent intermittent hemodialysis with a high-flux membrane, or continuous venovenous hemodialysis may be required. In one case report, a patient developed acute renal failure and liver toxicity after receiving high-dose methotrexate therapy. Plasma exchange, hemodialysis, and hemofiltration were used successfully to reduce plasma methotrexate concentration. In another case, a patient with severe methotrexate toxicity recovered after continuous venovenous hemodialysis, single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration (CVVHDF), and glucarpidase therapy. CVVHDF achieved the highest clearance rate with an effluent rate of 4950 mL/hr. Glucarpidase therapy resulted in the most rapid percentage (86%) decline in methotrexate concentrations.
- Patient disposition: HOME CRITERIA: There is no data to support home management, as leucovorin rescue and activated charcoal are most effective when given early. All exposures should be evaluated in a health care facility. OBSERVATION CRITERIA: All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home. Since toxic effects may be delayed, patients should return to a healthcare provider for any symptoms. ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved. Patients with an intrathecal overdose or severe toxicity should be transferred to an intensive care setting. CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose. TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.