METHOTREXATE AND RELATED AGENTS

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 psoriasis (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate oral tablets, 2006; Prod Info methotrexate injection, 2005; Prod Info TREXALL(TM) oral tablets, 2005).
PIRITREXIM is not available in the United States. It has been used in limited clinical applications as a substitute for methotrexate in the treatment of metastatic melanoma, Kaposi's sarcoma, and certain carcinomas (bladder and head and neck) (Anon, 1997; Feun et al, 1994; Degardin et al, 1994; Uen et al, 1992).
TRIMETREXATE has been used in the management of Pneumocystis carinii pneumonia in patients with AIDS (Prod Info NEUTREXIN(R) IV injection, 2005). Trimetrexate is no longer available in the United States (MedImmune, 2007).

FORMS

METHOTREXATE is available in the United States as:

GENERIC: 1 g powder for solution for injection; 25 mg/mL solution for injection; 2.5 mg oral tablets (Prod Info methotrexate oral tablets, 2006; Prod Info methotrexate injection, 2005)
RHEUMATREX DOSE PACK: 2.5 mg tablets (Prod Info RHEUMATREX(R) oral tablets, 2009)
TREXALL: 5 mg, 7.5 mg, 10 mg, 15 mg tablets (Prod Info TREXALL(TM) oral tablets, 2005)

Piritrexim is not available in the United States.
Trimetrexate is no longer available in the United States (MedImmune, 2007).

-CLINICAL EFFECTS

GENERAL CLINICAL EFFECTS

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.

WITH POISONING/EXPOSURE

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.

WITH THERAPEUTIC USE

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.

Editor's Note: An ERG guide with information appropriate to this material does not exist.

ACUTE CLINICAL EFFECTS

SUMMARY

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.
OVERDOSE

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.

CARDIOVASCULAR

VASCULITIS: Vasculitis has been reported (Navarro et al, 1986).
HYPOTENSION: Hypotension has occurred with the use of methotrexate(Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007). In a series of 7 patients with inadvertent intrathecal methotrexate overdose, two patients developed severe cardiopulmonary compromise requiring aggressive support and vasopressors (Widemann et al, 2004).
PERICARDITIS: Pericarditis and pericardial effusion have been reported in patients taking methotrexate (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
CARDIOTOXICITY, CASE REPORT: A 36-year-old woman with osteosarcoma was treated with a single dose of cisplatin (200 mg) and doxorubicin (150 mg; 75 mg/m(2)). Three weeks later she developed chest pain and bradycardia 2 hours after receiving methotrexate (24 g [12 g/m(2)] over 6 hours) followed by intravenous leucovorin (200 mg over 1 hour). ECG abnormalities were reported in the patient, and although her symptoms resolved 48 hours after initial dosing and subsequent methotrexate doses were administered 2 weeks later, she died unexpectedly at home 2 days later (Perez-Verdia et al, 2005).

DERMATOLOGIC

Erythematous rashes, alopecia, pruritus, and urticaria have been reported in patients taking methotrexate (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme have rarely been reported in children and adults within days of oral, IM, IV, or intrathecal methotrexate (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
DERMATITIS: Total body erythema has been reported after methotrexate exposure. A high-dose of methotrexate has been reported to result in distal erythema and desquamation, which is responsive to dose reduction but not to leucovorin (Doyle et al, 1983).
PHOTOSENSITIVITY: Solar erythema or inflammation (sunburn) may be reactivated if methotrexate is administered 1 to 3 days after exposure to the sun (Mallory & Berry, 1986).
ALOPECIA: Alopecia may develop (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
SKIN NECROSIS: Rare reports of soft tissue necrosis and osteonecrosis have been reported after receiving radiation therapy and concomitant methotrexate treatment (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007; (Jones, 1999)).

GASTROINTESTINAL

NAUSEA AND VOMITING: Nausea and/or vomiting has been reported in patients receiving methotrexate therapy. It was reported in 10% of patients receiving low-dose oral methotrexate (7.5 to 15 mg per week) during clinical trials for rheumatoid arthritis (n=128) (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007). Nausea has been reported following methotrexate overdose (Yoon et al, 2008).
GASTROINTESTINAL HEMORRHAGE: Gastrointestinal ulceration and hemorrhage have been reported in patients taking methotrexate. (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
STOMATITIS: Ulcerative stomatitis, glossitis, and gingivitis have been reported. Stomatitis usually begins 5 days after methotrexate administration and usually resolves by day 10 (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007; Hansen et al, 1971).
DIARRHEA: Diarrhea and melena have been reported following methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
LARYNGOTRACHEITIS, CASE REPORT: A 65-year-old man with rheumatoid arthritis developed pseudomembranous laryngotracheitis after switching from oral methotrexate (20 mg/week for years) to intramuscular methotrexate (25 mg/week). Following the discontinuation of methotrexate, his symptoms resolved completely (Kroot et al, 2006).

GENITOURINARY

SERUM CREATININE RAISED: Elevations of BUN or serum creatinine have been reported with methotrexate and may indicate methotrexate renal effects or nephrotoxicity. Most adverse reactions, however, are reversible if detected early (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
TOXIC NEPHROPATHY: Severe nephropathy has been reported with methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007). Tubular precipitation (methotrexate and 7-hydroxymethotrexate) that produces obstructive renal failure is the most widely accepted mechanism implicated in methotrexate- induced nephrotoxicity (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
CYSTITIS: Cystitis has been reported with methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
AZOTEMIA: Azotemia has been reported with methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
BLOOD IN URINE: Hematuria has been reported with methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
ACUTE RENAL FAILURE: Acute renal failure has been reported after methotrexate overdose (Steger et al, 1993).

HEENT

BLURRED VISION: Blurred vision has been reported with methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
BLINDNESS: Transient blindness has been reported with methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).

HEMATOLOGIC

MYELOSUPPRESSION: Anemia, leukopenia, and thrombocytopenia may occur in patients receiving methotrexate therapy (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007; Esteve et al, 2007). These effects typically begin 6 to 9 days after exposure and last for approximately 2 weeks (Hansen et al, 1971).
PANCYTOPENIA: Pancytopenia occurs in an estimated 3% of rheumatoid arthritis patients receiving methotrexate therapy and occurs in approximately 1.4% of patients on weekly low-dose methotrexate therapy (Yoon & Ng, 2001).
LYMPHOPROLIFERATIVE DISORDER: Lymphadenopathy and lymphoproliferative disorders (including reversible) have been reported in patients receiving methotrexate (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).

HEPATIC

HEPATOTOXICITY: Hepatotoxicity, fibrosis, and cirrhosis may develop with methotrexate therapy, particularly after prolonged use. Hepatotoxicity appears to be dependent upon the total cumulative dose of methotrexate and seems to be enhanced by alcoholism, diabetes, obesity, and advanced age (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007). Elevations of SGOT, LDH, alkaline phosphatase, and/or bilirubin may also occur (Prod Info RHEUMATREX(R) oral tablets, 2009). Cases of hepatoxicity have been seen when patients mistakenly take methotrexate daily instead of the appropriate once weekly dose (Singh et al, 1999; Yoon et al, 2008).

IMMUNOLOGIC

ANAPHYLAXIS: Anaphylactoid reaction has been reported in patients receiving methotrexate (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).

NEUROLOGIC

Headache, drowsiness, speech impairment including dysarthria and aphasia, hemiparesis, paresis, seizures, transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy have been reported in patients receiving methotrexate (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
NEUROLOGIC SYNDROME, ACUTE: 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 (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
TOXIC ENCEPHALOPATHY: Leukoencephalopathy has been reported in patients receiving methotrexate therapy. It has been seen after intravenous administration in patients who were also receiving craniospinal irradiation, and manifestations included generalized or focal seizures (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007). The effect has also been observed months to years after the onset of therapy, and symptoms included dementia, ataxia, spasticity, seizures, and coma(Bleyer, 1978). In one case, a 59-year-old woman developed lupus-associated progressive multifocal leukoencephalopathy (PML) and myelosuppression after taking her oral methotrexate dose daily instead of weekly (Shprecher et al, 2008).
RADICULOPATHY: Polyradiculopathy and progressive paraparesis has bee noted in patients who received intrathecal methotrexate (Pascual et al, 2008; Koh et al, 1999). Progressive symptoms in these cases included severe motor deficit (unstable gait, severe flaccid paraparesis, neurogenic bladder dysfunction) (Pascual et al, 2008), leg weakness, areflexia with frequent falling, and flaccid paraplegia (Koh et al, 1999).
SEIZURE: Seizures have been reported in patients receiving methotrexate (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007). Some reported cases have included patients receiving intrathecal combination therapy comprised of methotrexate, cytarabine, and methylprednisolone. Therefore, the causal relationship to methotrexate is not clear (Kwong et al, 2009). Intrathecal overdoses of methotrexate can result in an extension of the neurotoxic adverse effects (eg, headache, altered level of consciousness and seizures) reported with therapeutic use, and appear dose-dependent (Finkelstein et al, 2004). In cases of severe overdose, seizure has occurred and can present shortly after administration (Ettinger, 1982; Finkelstein et al, 2004).
COMA: Coma can occur following methotrexate overdose (Widemann et al, 2004; Trinkle & Wu, 1996), and in such cases, death may result (Trinkle & Wu, 1996).
ASEPTIC MENINGITIS, CASE REPORT: A 62-year-old man with rheumatoid arthritis who was receiving 17.5 to 22.5 mg of intramuscular methotrexate once weekly, developed aseptic meningitis (headache, neck stiffness, and fever) one month after his dose was increased to 22.5 mg (Hawboldt & Bader, 2007).

RESPIRATORY

PULMONARY INFILTRATES: Pulmonary infiltrates, commonly called "methotrexate lung", have been noted following chronic therapy. Symptoms and signs include: dyspnea, tachypnea, cough, cyanosis, and crepitant rales (Leduc et al, 1992; Sostman et al, 1977).
ALVEOLITIS: Alveolitis has been reported in patients receiving methotrexate (Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).
ACUTE RESPIRATORY DISTRESS SYNDROME, CASE REPORT: Acute respiratory distress syndrome (fever, non-productive cough, and shortness of breath) developed in a 19-year-old man with acute lymphoblastic leukemia who received intrathecal methotrexate (15 mg) for CNS prophylaxis. His symptoms were relieved with corticosteroids, and pulmonary infiltrates resolved gradually (Dai et al, 2000).
DYSPNEA: Shortness of breath can occur in patients receiving methotrexate, and multiple case reports have identified this adverse effect (Dai et al, 2000; Kokelj et al, 1999; McKenna & Burrows, 2000).
PNEUMONITIS: Pneumonitis has resulted following methotrexate therapy. Concomitant symptoms in these cases included shortness of breath, cough, fever, hypoxemia, and tachypnea (Imokawa et al, 2000).

CHRONIC CLINICAL EFFECTS

The usual course of clinical treatment with methotrexate involves many doses of the drug; 2.5 to 50 mg/day may be given in prolonged continuous therapy (Dorr & Fritz, 1980). With an elimination half-life of 5 to 9 hours (Baselt, 1982), daily or weekly doses would not lead to methotrexate accumulation. Therefore the distinction between acute and chronic effects is not always clear.

All of the acute effects mentioned above can occur with repeated exposure. In addition, neurologic changes, including behavioral abnormalities, abnormal reflexes, abnormal sensorimotor signs, motor dysfunction, paralysis, palsies, and seizures may occur after two or three weekly doses (Walker et al, 1986).

A severe neurological complication, an irreversible encephalopathy, has developed in patients receiving methotrexate together with radiation therapy, or in some cases from high doses of methotrexate alone. This syndrome involves progressive dementia, dysarthria, ataxia, paralysis, seizures, coma, and death (Shapiro et al, 1980). Leukoencephalopathy was reported in one case after IV and intrathecal administration of methotrexate (Ilhan et al, 1995).

Acute interstitial pneumonitis is the most frequent pulmonary side effect of methotrexate therapy for rheumatoid arthritis; it could not be predicted by periodic pulmonary function tests (Cottin et al, 1996). Many patients receiving methotrexate develop a sustained cough, thought to be due to an irritant effect of methotrexate on the airways (Schnabel et al, 1996).

Other effects reported from chronic or repeated exposure to methotrexate include cirrhosis of the liver, hemolytic anemia, and urticaria (Zachariae et al, 1980; Woolley et al, 1983; Van Scott et al, 1964). The latter finding suggests that methotrexate is an allergen.

Methotrexate can induce hepatic cirrhosis in psoriasis patients. In a 10-year follow-up study of 25 patients with methotrexate-induced liver cirrhosis, 13 had no verifiable cirrhosis on biopsy, one had died from liver failure, and 5 autopsies in patients with non-methotrexate related deaths confirmed some degree of cirrhosis. Thus in most of these cases, methotrexate-induced liver cirrhosis was not aggressive (Zachariae et al, 1996).

Risk of developing hepatotoxicity from methotrexate in psoriasis patients was related to diabetes, but not to obesity or consumption of alcohol (Malatjalian et al, 1996). Development of hepatotoxicity can be predicted by monitoring serum albumin and AST at intervals of 4 to 8 weeks (Kremer, 1996).

Pancytopenia is an uncommon but severe side effect of methotrexate therapy; risk factors are age over 65 years, creatinine clearance lower than 50 mL/min, hypoalbuminemia, and combination therapy with antiinflammatory drugs or ranitidine (Laroche et al, 1996). Painful erosion of psoriatic plaques may precede bone marrow suppression (Pearce & Wilson, 1996).

The incidence of pancytopenia among patients receiving low-dose methotrexate therapy has been 1.4 percent; 17 percent of the cases have been fatal, and the minimum cumulative dose for inducing fatal pancytopenia was 10 mg (Gutierrez-Urena et al, 1996).

Methotrexate can adversely affect bone metabolism, causing a condition in children known as "methotrexate osteopathy" (Maenaut et al, 1996). Osteopathy has been seen in children receiving high-dose methotrexate therapy for leukemia and has rarely occurred in patients receiving low-dose therapy (Zonneveld et al, 1996).

Ventricular arrhythmias occurred in a man with history of myocardial infarction after several months of methotrexate therapy for psoriasis at weekly oral doses of up to 10 mg (Kettunen et al, 1995).

Three cases of gynecomastia (breast enlargement) have been reported with low-dose methotrexate treatment for rheumatoid arthritis (Thomas et al, 1995).

-FIRST AID

FIRST AID AND PREHOSPITAL TREATMENT

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.

ACTIVATED CHARCOAL

PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

CHARCOAL DOSE

Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

ADVERSE EFFECTS/CONTRAINDICATIONS

Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

-RANGE OF TOXICITY

MINIMUM LETHAL EXPOSURE

PEDIATRIC

INTRATHECAL

In a meta-analysis of pediatric intrathecal methotrexate overdoses (n=9; age range, 2 to 12 years), 2 fatal cases were reported (Trinkle & Wu, 1996).

CASE REPORT: A 9-year-old boy inadvertently received 650 mg (instead of 12 mg, a 54-fold overdose) of methotrexate intrathecally. Within moments, he developed leg numbness and then rapidly became unresponsive with agitation. Removal of 36 mL cerebrospinal fluid (CSF) was performed about 1 hour after the event, followed by CSF exchange in 30 to 40 mL aliquots for a total of 200 mL. He developed seizures and respiratory failure, and was treated with anticonvulsants, intubation and mechanical ventilation, sodium bicarbonate, mannitol and leucovorin. Decerebrate and decorticate posturing, flaccid paralysis, and areflexia also developed. The patient remained comatose until his death one month after the event (Ettinger, 1982). Of note, another 9-year-old child had severe neurological damage following a 650 mg overdose, but survived (Trinkle & Wu, 1996).
CASE REPORT: A second fatal case was reported in a 7-year-old after receiving 1000 mg of methotrexate with "widespread" brain damage reported. Death followed several days after the exposure (Trinkle & Wu, 1996).

Intrathecal overdoses of more than 500 mg are generally associated with severe morbidity or death (Jardine et al, 1996).

ADULTS

ORAL

CASE SERIES: A series of 5 adults with fatal, subacute methotrexate poisoning due to iatrogenic error has been reported. Doses ingested were: 10 mg/day for 23 days; 60 mg over 16 days; 100 mg over 8 days (as two 50 mg doses 8 days apart); 10 mg/day for 9 days; and 15 mg/day for 6 days. The intended doses were in the range of 10 to 20 mg per week (Sinicina et al, 2005).
CASE SERIES: Four adult patients with rheumatoid arthritis developed severe pancytopenia after taking methotrexate 10 to 20 mg/day (instead of weekly) for 7 to 9 days. Despite supportive therapy that included leucovorin (in 3 cases) and filgrastim (in 2 cases), all 4 patients died 2 to 2.5 weeks later (Moisa et al, 2006).

MAXIMUM TOLERATED EXPOSURE

PEDIATRIC

INTRATHECAL

In a meta-analysis of methotrexate intrathecal overdoses in children, 6 of the 7 nonfatal cases (age 2 to 12 years) occurred at doses ranging from 50 to 120 mg (less than a 15-fold overdose) (Trinkle & Wu, 1996).

Of the children who received overdoses under 15-fold, none had any symptoms of central nervous system toxicity, including 2 cases who did not receive corticosteroids. Most of these patients were treated with drug removal by CSF aspiration and/or CSF exchange. Of note, another 9-year-old child had "massive" neurological damage following a 650 mg overdose, but survived. All patients had received leucovorin either IV or IM as rescue therapy (Trinkle & Wu, 1996).

A 24-month-old girl received 85 mg of intrathecal methotrexate (intended dose 6 mg). She was treated with intravenous leucovorin and dexamethasone and developed only mild headaches (Ettinger et al, 1978).
Two children (4 and 11 years old) were given a 10-fold overdose of intrathecal methotrexate (120 mg and 100 mg, respectively). Both overdosages were discovered within several hours after administration. Neither patient developed neurotoxicity associated with the overdose. Both were treated successfully with cerebrospinal fluid exchange and no sequelae were observed after this procedure (Jakobson et al, 1992).
A 10-year-old girl with acute lymphoblastic leukemia did not experience any symptoms after receiving 120 mg of intrathecal methotrexate instead of 12 mg. She was treated with leucovorin and dexamethasone, and a cerebrospinal fluid exchange was performed (Malbora et al, 2009).
A 7-year-old boy received 300 mg intrathecal methotrexate (intended dose 12 mg). Within a few minutes, he had leg pain and diaphoresis, and 90 minutes later developed headache, lost consciousness and developed generalized hypertonia. He was intubated and received phenobarbital, intravenous leucovorin and dexamethasone, but no attempt was made to remove cerebrospinal fluid. The patient recovered over one week, but died of his primary malignancy after one year (Riva et al, 1999).
A 3-year-old girl and a 4-year-old boy each received 125 mg methotrexate intrathecally. Each of them developed generalized seizures within 3 hours of the event, but recovered completely. They were treated with intravenous leucovorin and dexamethasone, but no attempts were made to remove cerebrospinal fluid (Lee et al, 1997).

INTRAVENOUS

In studies, high doses (2.7 g/m(2) to 5 g/m(2)) of intravenous methotrexate in combination with other antineoplastic agents and leucovorin rescue have been used in children for treatment of non-Hodgkin's lymphoma (Reiter et al, 1995; Patte et al, 1992; Magrath et al, 1984).
In one study, methotrexate infusions (dose range 0.5 to 33.6 g/m(2)) were administered to 58 children with acute lymphoblastic leukemias. All children received leucovorin rescue, IV hydration, and urinary alkalinization. Relapsed children (n=25) had significantly higher systemic clearance of methotrexate (lower steady state methotrexate concentration) than those who remained in continuous complete remission (CCR) (n=33). No information on toxicity was provided (Borsi & Moe, 1987; Sterba et al, 2005).

ORAL

A 3-year-old and a 4-year-old, who together unintentionally ingested 2025 mg of methotrexate, were given leucovorin and recovered after transient elevation of SGOT and LDH (Pruitt et al, 1974).

ADULTS

INTRATHECAL

CASE REPORT: A 34-year-old man with a history of aggressive lymphoma developed confusion and generalized seizures within 2 hours of an inadvertent dose of 1200 mg methotrexate intrathecally instead of the prescribed 15 mg (an 80-fold overdose). The patient was immediately treated with intravenous leucovorin and CSF exchange was started within 6 hours post-exposure. The patient's course was complicated by ARDS and sepsis, along with residual cognitive and motor dysfunction (Finkelstein et al, 2004).
CASE REPORT: An overdose of methotrexate (625 mg) given intrathecally resulted in coma in a 26-year-old man who was successfully treated by CSF aspiration and subsequent ventriculolumbar perfusion, which removed 97% of the instilled dose. He was also treated with IV leucovorin, thymidine, urinary alkalinization, and aggressive hydration. He died of his underlying malignancy 6 months later (Spiegel et al, 1984).

INTRAVENOUS/INTRAMUSCULAR

Patients with renal failure may develop toxicity at lower doses of methotrexate. One study described 2 patients who developed bone marrow depression and granulocytopenia, one after receiving 5 mg of methotrexate intramuscular per week, and the other after receiving 2.5 mg IM one week and 5 mg IM the following week (Chatham et al, 2000).
In studies, 81% of adults treated with high-dose methotrexate (50 grams/course or 24 to 33 grams/m(2)) developed increased liver enzymes (Reggev & Djerassi, 1988).
When methotrexate was given to adults as a 1 hour infusion, the mean dose required to produce clinical toxicity was 200 mg/m(2) (approximately 5 mg/kilogram), with a range of 50 to 900 mg/m(2) (approximately 1.5 to 30 mg/kg) (Hansen et al, 1971).

ORAL

In a retrospective study of 13 patients (average age, 43 years; range, 20 months to 80 years) with either acute unintentional or suicidal oral ingestion of methotrexate (average dose, 13.03 mg), no significant toxicities were observed (LoVecchio et al, 2008).
CASE REPORT: A 32-year-old woman developed hemorrhagic mucositis and febrile neutropenia after inadvertently taking methotrexate 20 mg per day for 10 days instead of the prescribed dose of 20 mg per week. Laboratory results revealed profound pancytopenia. Following supportive care, including treatment with G-CSF, piperacillin/tazobactam, and an oral rinse containing 4 mL of lidocaine 2% and 120 mL of benzydamine hydrochloride 0.15%, she completely recovered in 10 days (Ozkol et al, 2015).
CASE REPORT: Severe mucositis with multiple hemorrhagic erosions over oral mucosa, gums, and tongue developed in a 56-year-old woman with rheumatoid arthritis after taking methotrexate 7.5 mg daily (instead of weekly) for 20 days. She recovered following transfusion support and leucovorin (Chakraborty & Achar, 2007).
CASE REPORT: A 67-year-old woman developed Koebner-like phenomenon (skin eruption), myelosuppression, nausea, anorexia, painful oral ulcerations, and elevated liver enzymes after ingesting methotrexate 15 mg/day (instead of weekly) for 7 days. She recovered following the discontinuation of methotrexate and supportive care, (Yoon et al, 2008).
CASE REPORT: Severe mucositis, myelosuppression, and hepatotoxicity developed in a 60-year-old woman with rheumatoid arthritis after taking methotrexate 7.5 mg daily (instead of weekly) for 7 days. She recovered following leucovorin therapy (Singh et al, 1999).

Carcinogenicity Ratings for CAS59-05-2 :

ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
EPA (U.S. Environmental Protection Agency, 2011): Not Listed
IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Methotrexate

3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
MAK (DFG, 2002): Not Listed
NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

TOXICITY AND RISK ASSESSMENT VALUES

EPA IRIS

EPA Risk Assessment Values for CAS59-05-2 (U.S. Environmental Protection Agency, 2011):

Not Listed

-STANDARDS AND LABELS

WORKPLACE STANDARDS

ACGIH TLV Values for CAS59-05-2 (American Conference of Governmental Industrial Hygienists, 2010):

Not Listed

AIHA WEEL Values for CAS59-05-2 (AIHA, 2006):

Not Listed

NIOSH REL and IDLH Values for CAS59-05-2 (National Institute for Occupational Safety and Health, 2007):

Not Listed

OSHA PEL Values for CAS59-05-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

Not Listed

OSHA List of Highly Hazardous Chemicals, Toxics, and Reactives for CAS59-05-2 (U.S. Occupational Safety and Health Administration, 2010):

Not Listed

ENVIRONMENTAL STANDARDS

EPA CERCLA, Hazardous Substances and Reportable Quantities for CAS59-05-2 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA CERCLA, Hazardous Substances and Reportable Quantities, Radionuclides for CAS59-05-2 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA RCRA Hazardous Waste Number for CAS59-05-2 (U.S. Environmental Protection Agency, 2010b):

Not Listed
Editor's Note: The D, F, and K series waste numbers and Appendix VIII to Part 261 -- Hazardous Constituents were not included. Please refer to 40 CFR Part 261.

EPA SARA Title III, Extremely Hazardous Substance List for CAS59-05-2 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA SARA Title III, Community Right-to-Know for CAS59-05-2 (40 CFR 372.65, 2006; 40 CFR 372.28, 2006):

Not Listed

DOT List of Marine Pollutants for CAS59-05-2 (49 CFR 172.101 - App. B, 2005):

Not Listed

EPA TSCA Inventory for CAS59-05-2 (EPA, 2005):

Listed as: L-Glutamic acid, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-

LABELS

NFPA

NFPA Hazard Ratings for CAS59-05-2 (NFPA, 2002):

Not Listed

-PERSONAL PROTECTION

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

PROTECTIVE CLOTHING

CHEMICAL PROTECTIVE CLOTHING. Search results for CAS 59-05-2.

Specific recommendations and test data for this chemical were not found in the available manufacturers' product literature. A complete list of consulted manufacturers and references is presented below.

-PHYSICAL HAZARDS

FIRE HAZARD

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

FLAMMABILITY CLASSIFICATION

NFPA Flammability Rating for CAS59-05-2 (NFPA, 2002):

Not Listed

FIRE CONTROL/EXTINGUISHING AGENTS

Editor's Note: An ERG guide with information appropriate to this material does not exist.

NFPA Extinguishing Methods for CAS59-05-2 (NFPA, 2002):

Not Listed

EVACUATION PROCEDURES

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

AIHA ERPG Values for CAS59-05-2 (AIHA, 2006):

Not Listed

DOE TEEL Values for CAS59-05-2 (U.S. Department of Energy, Office of Emergency Management, 2010):

Not Listed

AEGL Values for CAS59-05-2 (National Research Council, 2010; National Research Council, 2009; National Research Council, 2008; National Research Council, 2007; NRC, 2001; NRC, 2002; NRC, 2003; NRC, 2004; NRC, 2004; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; United States Environmental Protection Agency Office of Pollution Prevention and Toxics, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; 62 FR 58840, 1997; 65 FR 14186, 2000; 65 FR 39264, 2000; 65 FR 77866, 2000; 66 FR 21940, 2001; 67 FR 7164, 2002; 68 FR 42710, 2003; 69 FR 54144, 2004):

Not Listed

NIOSH IDLH Values for CAS59-05-2 (National Institute for Occupational Safety and Health, 2007):

Not Listed

CONTAINMENT/WASTE TREATMENT OPTIONS

SUMMARY

Editor's Note: An ERG guide with information appropriate to this material does not exist.

SMALL LEAK/SPILL

Editor's Note: An ERG guide with information appropriate to this material does not exist.

LARGE LEAK/SPILL

Editor's Note: An ERG guide with information appropriate to this material does not exist.

-PHYSICAL/CHEMICAL PROPERTIES

MOLECULAR WEIGHT

METHOTREXATE: 454.45 (Prod Info OTREXUP(TM) subcutaneous injection solution, 2013; Prod Info RASUVO(TM) subcutaneous injection, 2014)

DESCRIPTION/PHYSICAL STATE

METHOTREXATE occurs as yellow crystals (monohydrate) (Budavari, 1996) and is practically insoluble in water, in alcohol, in chloroform, and in ether; slightly soluble in 6N hydrochloric acid; and freely soluble in dilute solutions of alkali hydroxides and carbonates (Sweetman, 2004).

METHOTREXATE subQ solution is isotonic, clear, and yellow to brown in color (Prod Info RASUVO(TM) subcutaneous injection, 2014).

METHOTREXATE: 8 (Prod Info OTREXUP(TM) subcutaneous injection solution, 2013) to 8.5 (subQ solution) (Prod Info RASUVO(TM) subcutaneous injection, 2014)

METHOTREXATE SODIUM: 8.5 (IM, IV, intra-arterial solution) (Prod Info methotrexate intramuscular intravenous intra-arterial injection, 2011)

SOLUBILITY

IN WATER

METHOTREXATE: Practically insoluble (Sweetman, 2004)

IN ORGANIC SOLVENTS

METHOTREXATE: Practically insoluble in alcohol, in chloroform, and in ether (Sweetman, 2004)

OTHER

METHOTREXATE: Freely soluble in dilute solutions of alkali hydroxides and carbonates, and slightly soluble in 6N hydrochloric acid (Sweetman, 2004)

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66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.

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National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.

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Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.

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Product Information: OTREXUP(TM) subcutaneous injection solution, methotrexate subcutaneous injection solution. Antares Pharma, Inc. (per manufacturer), Ewing, NJ, 2013.

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METHOTREXATE AND RELATED AGENTS

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