Methotrexate

454.44

454.44

70669

200-413-8

YL5FZ2Y5U1

740

3249

TSCA listed

DTXSID4020822

C642

Light yellow to yellow

L04AX03|L01BA01|L - Antineoplastic and immunomodulating agents

29335995

211

-1.8

powder

1.4080 (rough estimate)

195°C

561.26°C (rough estimate)

11℃

1.6910 (estimate)

Insoluble. <0.1 g/100 mL at 19 ºC

−20°C

2.1X10-19 mm Hg at 25 deg C /Estimated/

LD50 oral in rat: 135mg/kg

Specific optical rotation: 20.4 + or - 0.6 deg at 21 °C/589 D (concentration by 0.1 N sodium hydroxide) maximum absorption: 243nm, A1= 388;307 nm, A1 = 475 (in 0.1 n hydrogen chloride). 258 nm, A1= 544; 303 nm, A1= 546; 372 nm, A1= 177 (in 0.1 N sodium hydroxide)

pKa 3.04/4.99(H2O,t =25,I=0.0025) (Uncertain)

Henry's Law constant = 1.5X10-31 atm-cu m/mol at 25 °C /Estimated/

4.7|pKa = 4.70 (carboxylic acid)|pKa = 3.5 carboxylic acid; pKa2 = 8.8, pKa3 = 9.2 (amines) /Estimated/

196.2 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|194.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Yellow crystals from dilute hydrogen chloride; decomp 185-204 °C (bath preheated to 160 °C). Max absorption (0.1 n hydrogen chloride): 244, 307 nm; max absorption (0.1 N sodium hydroxide): 257, 302, 370 nm; soluble in alkaline solns with decomposition /Methotrexate monohydrate/|Yellow powder; soluble in water. /Methotrexate sodium/|Hydroxyl radical reaction rate constant = 3.2X10-10 cu cm/molec-sec at 25 °C /Estimated/

Methotrexate is sensitive to hydrolysis, oxidation and light. Insoluble in water.

Acids, Carboxylic

Methotrexate decomposes in very acidic or alkaline conditions. Methotrexate is incompatible with strong oxidizing agents and strong acids.

Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

III

6.1(b)

UN 2811 6.1/PG 3

3

T,F

53-26-36/37-45-36/37/39-36-16

MA1225000

T,F

Store at RT

Stable, but light sensitive and hygroscopic. Incompatible with strong acids, strong oxidizing agents. Store at -15C or below.

P201-P280-P301 + P310 + P330-P305 + P351 + P338-P308 + P313-P337 + P313

Very toxic. Questionable carcinogen.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Combustible. Compounds of the carboxyl group react with all bases, both inorganic and organic (i.e., amines) releasing substantial heat, water and a salt that may be harmful. Incompatible with arsenic compounds (releases hydrogen cyanide gas), diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides (releasing heat, toxic, and possibly flammable gases), thiosulfates and dithionites (releasing hydrogen sulfate and oxides of sulfur). Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides, light, UV, moisture.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl methotrexate sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Methotrexate Sodium/

Tung JP, Maibach HI; Practical Use of Methotrexate in Psoriasis. Drugs 40: 697-712 (1990). A review of the use of methotrexate for the treatment of psoriasis is presented, including pathology, mechanism of action, pharmacokinetics, indications for use, pretreatment evaluations, monitoring parameters, dosage, overdose, drug interactions, adverse effects and the importance of patient information.

UN 2811 6.1/PG 3

Flash point data for Methotrexate are not available; however, Methotrexate is probably combustible.

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P264, P270, P280, P281, P301+P310, P302+P352, P305+P351+P338, P308+P313, P321, P330, P332+P313, P337+P313, P362, P405, and P501|Aggregated GHS information provided by 189 companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Aggregated GHS information provided by 39 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled using a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)

Excerpt from ERG Guide 151 [Substances - Toxic (Non-combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with 5% ammonium hydroxide, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% ammonium hydroxide to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% ammonium hydroxide followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store it in a freezer. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Approximately 1 ug/L methotrexate was reported in sewage effluent; location specifics were not indicated(1).

The oral LD50 in rats is 135mg/kg and in mice is 146mg/kg. Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding. In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase.

Methotrexate is well known to cause serum aminotransferase elevations and long term therapy has been linked to development of fatty liver disease, fibrosis and even cirrhosis. The literature on methotrexate is extensive, but with great variability in rates of liver test and biopsy abnormalities at different doses, dose regimens and durations of therapy.

Oral neomycin may decreases absorption of oral methotrexate.|Severe, sometimes fatal, toxicity (including hematologic and GI toxicity) has occurred following administration of a non-steroidal anti-inflammatory agent (eg, indomethacin, ketoprofen) concomitantly with methotrexate (particularly with high dose therapy) in patients with various malignant neoplasms, psoriasis, or rheumatoid arthritis.|Concomitant use of penicillins (e.g., amoxicillin, carbenicillin, mezlocillin) may decrease renal clearance of methotrexate, presumably by inhibiting renal tubular secretion of the drug. Increased serum concentrations of methotrexate, resulting in GI or hematologic toxicity, have been reported in patients receiving low- or high-dose methotrexate therapy concomitantly with penicillins, and patients receiving the drugs concomitantly should be carefully monitored.|Concurrent adminstration of intrathecal methotrexate and acyclovir may result in neurological abnormalities; use with caution.|For more Interactions (Complete) data for METHOTREXATE (16 total), please visit the HSDB record page.

LD50 Rat oral 180 +/- 45 mg/kg body weight|LD50 Rat ip 6-25 mg/kg body weight|LD50 Mice ip 94 +/- 9 mg/kg body weight

Methotrexate is 46.5-54% bound to plasma proteins.

Methotrexate's production and use as a chemosterilant(1), in the treatment of leukemia, cancer, arthritis(2), and in the treatment of severe psoriasis(3) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a log Kow of -1.85(2) and a regression-derived equation(3), indicates that methotrexate is expected to have very high mobility in soil(SRC). The pKa of methotrexate is 4.70(4), indicating that this compound will primarily exist as an anion in the environment and anions do not volatilize and tend to have high mobility in soils. Methotrexate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-19 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation may be an important fate process in the soil environment as indicated by a 95% biodegradation rate using the OECD Confirmatory test and a sewage inoculum; however, the degradation product 7-hydroxymethotrexate is toxic and persistent(6).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a log Kow of -1.85(2) and a regression-derived equation(3), indicates that methotrexate is not expected to adsorb to suspended solids and sediment(SRC). The pKa of the carboxylic acid moiety of methotrexate is 4.70(4), indicating that this compound will primarily exist as an anion in the environment and anions do not volatilize(5). According to a classification scheme(6), an estimated BCF of 3.2(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Methotrexate absorbs light at wavelengths >290 nm(8) and may be susceptible to photlysis in sunlit surface water but the rate of this reaction is not known. Biodegradation may be an important fate process in the aquatic environment as indicated by a 95% biodegradation rate using the OECD Confirmatory test and a sewage inoculum; however, the degradation product 7-hydroxymethotrexate is toxic and persistent(9).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methotrexate, which has an estimated vapor pressure of 2.1X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase methotrexate may be removed from the air by wet and dry deposition(SRC). Methotrexate absorbs UV light at wavelengths >290 nm(3); therefore, methotrexate may be susceptible to photolysis however the rate of this reaction is not known(SRC).

Methotrexate absorbs UV light at wavelengths >290 nm(1); therefore, methotrexate may be susceptible to photolysis however the rate of this reaction is not known(SRC). The pKa of methotrexate is 4.7(2), indicating that this compound will exist primarily as an anion in the environment.

An estimated BCF of 3.2 was calculated for methotrexate(SRC), using a log Kow of -1.85(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC), provided the compound is not altered physically or chemically once released into the environment(SRP).

The Koc of methotrexate is estimated as 1(SRC), using a log Kow of -1.85(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that methotrexate is expected to have very high mobility in soil. The pKa of the carboxylic acid moiety of methotrexate is 4.70(4), indicating that this compound will primarily exist in anion form in the environment and anions generally do not adsorb more strongly to organic carbon and clay than their neutral counterparts(5). However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(6,7), suggesting that mobility may be much lower in some soils(SRC).

With a pKa of 4.7(1), methotrexate will exist predominantly as an anion in the environment and anions do not volatilize from water or moist soil surfaces. Methotrexate is not expected to volatilize from dry soil based on its estimated vapor pressure of 2.1X10-19(SRC), determined from a fragment constant method(2).

SURFACE WATER: Less than 6.25 ng/L methotrexate was reported in river water; location specifics were not indicated(1).

Occupational exposure to methotrexate may occur through inhalation and dermal contact with this compound at workplaces where methotrexate is produced or used(SRC). The general population exposure will be limited to those being administered medications containing methotrexate(SRC). A monitoring study of 25 pharmacy technicians and nurses from 4 departments in a hospital revealed that methotrexate was found on the gloves of the clinical pharmacy staff (2 of 9 pairs contaminated, range of <6-49 ug/glove), and gloves used for hood cleaning (2 of 6 pairs contaminated, range of <6-49 ug/glove). It was detected not quantified on the drug administration room floor(1). The compound was not detected in urine samples of the health care providers(1). Exposure to the drug among the general population may be limited to those administered methotrexate (a chemosterilant)(SRC).

Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis. Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis. Other formulations are indicated to treat gestational choriocarcinoma, chorioadenoma destruens, hydatiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin's lymphoma. It is also used in the maintenance of acute lymphocytic leukemia. Methotrexate is also given before treatment with leucovorin to prolong relapse-free survival following surgical removal of a tumour in non-metastatic osteosarcoma.|FDA Label|Nordimet is indicated for the treatment of:active rheumatoid arthritis in adult patients,polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA), when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, psoralens and ultraviolet A (PUVA), and retinoids, and severe psoriatic arthritis in adult patients,induction of remission in moderate steroid-dependent Crohn's disease in adult patients, in combination with corticosteroids and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate.|In rheumatological and dermatological diseasesActive rheumatoid arthritis in adult patients.Polyarthritic forms of active, severe juvenile idiopathic arthritis (JIA) in adolescents and children aged 3 years and over when the response to non-steroidal anti-inflammatory drugs (NSAIDs) has been inadequate.Severe, treatment-refractory, disabling psoriasis which does not respond sufficiently to other forms of treatment such as phototherapy, psoralen and ultraviolet A radiation (PUVA) therapy and retinoids, and severe psoriatic arthritis in adult patients.In oncologyMaintenance treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children aged 3 years and over.|Drug: Cmf|Drug: Methotrexate|Drug: Mvac|Drug: Vamp

Methotrexate is an antineoplastic and immunosuppressive agent widely used in the therapy of leukemia, lymphoma, solid tumors, psoriasis and rheumatoid arthritis. When given in high intravenous doses, methotrexate can cause acute elevations in serum enzymes, and long term methotrexate therapy has been associated with frequent but mild elevations in serum liver enzymes and, more importantly, with development of chronic liver injury, progressive fibrosis, cirrhosis and portal hypertension.

Antineoplastic Agents

Abortifacient Agents, Nonsteroidal; Antimetabolites, Antineoplastic; Antirheumatic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Nucleic Acid Synthesis Inhibitors|Methotrexate is indicated for treatment of breast carcinoma, head and neck cancers (epidermoid), non-small cell lung carcinoma (especially squamous cell types), small cell lung carcinoma, and gestational trophoblastic tumors (gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole). /Included in US product labeling/|Methotrexate is indicated for treatment of cervical carcinoma, ovarian carcinoma, bladder carcinoma, colorectal carcinoma, esophageal carcinoma, gastric carcinoma, pancreatic carcinoma, and penile carcinoma. /NOT included in US product labeling/|Methotrexate is indicated for treatment of acute lymphocytic leukemia and prophylaxis and treatment of meningeal leukemia. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for METHOTREXATE (17 total), please visit the HSDB record page.

Methotrexate is a highly toxic drug with a very low therapeutic index and a therapeutic response is not likely to occur without some evidence of toxicity. ... When methotrexate is used in combination with other antineoplastic agents and/or radiation therapy, toxic reactions may be more severe than would occur with methotrexate therapy alone. Although doses of methotrexate used in the management of psoriasis and rheumatoid arthritis are usually lower than those used in antineoplastic chemotherapy, severe toxicity may occur in any patient receiving the drug and deaths have been reported with the use of methotrexate in the management of psoriasis and rheumatoid arthritis.|Methotrexate should be used with extreme caution in patients with infection, peptic ulcer, ulcerative colitis, or debility, and in very young or geriatric patients. Methotrexate should be used with extreme caution, if at all, in patients with malignant disease who have preexisting liver damage or impaired hepatic function, preexisting bone marrow depression, aplasia, leukopenia, thrombocytopenia, or anemia; the drug is usually contraindicated in patients with impaired renal function. In the management of psoriasis, methotrexate is contraindicated in patients with poor nutritional status or severe renal or hepatic disorders, those with overt or laboratory evidence of an immunodeficiency syndrome, and in those with preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or clinically important anemia; relative contraindications also include cirrhosis, active or recent hepatitis, or excessive alcohol consumption. In the management of rheumatoid arthritis, methotrexate is contraindicated in patients with preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or clinically important anemia; those with overt or laboratory evidence of immunodeficiency syndromes; and those with excessive alcohol consumption, alcoholic liver disease, or chronic liver disease.|Elevations in serum uric acid concentrations may occur in patients receiving methotrexate as a result of cell destruction and hepatic and renal damage. In some patients, uric acid nephropathy and acute renal failure may result. Tumor lysis syndrome associated with other cytotoxic drugs (e.g., fludarabine, cladribine), also has been reported in patients with rapidly growing tumors who were receiving methotrexate. Pharmacologic and appropriate supportive treatment may prevent or alleviate this complication. Methotrexate also was reported to precipitate acute gouty arthritis in two patients being treated for psoriasis. Administration of large volumes of fluids, alkalinization of the urine, and/or administration of allopurinol may be useful in preventing acute attacks of hyperuricemia and uric acid nephropathy.|Severe nephropathy manifested by azotemia, hematuria, and renal failure may occur in patients receiving methotrexate; fatalities have been reported. In one study, postmortem examination revealed extensive necrosis of the epithelium of the convoluted tubules. In patients with renal impairment, methotrexate accumulation and increased toxicity or additional renal damage may occur.|For more Drug Warnings (Complete) data for METHOTREXATE (22 total), please visit the HSDB record page.

Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions. It has a long duration of action and is generally given to patients once weekly. Methotrexate has a narrow therapeutic index. Do not take methotrexate daily.

Drugs used to treat or prevent skin disorders or for the routine care of skin. (See all compounds classified as Dermatologic Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)|Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Folic Acid Antagonists.)|Compounds that inhibit cell production of DNA or RNA. (See all compounds classified as Nucleic Acid Synthesis Inhibitors.)|Antimetabolites that are useful in cancer chemotherapy. (See all compounds classified as Antimetabolites, Antineoplastic.)|Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)|Non-steroidal chemical compounds with abortifacient activity. (See all compounds classified as Abortifacient Agents, Nonsteroidal.)|Drugs that are used to treat RHEUMATOID ARTHRITIS. (See all compounds classified as Antirheumatic Agents.)

Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate.. Methotrexate has a T_max of 1 to 2 hours. oral doses of 10-15µg reach serum levels of 0.01-0.1µM.|Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite. Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile.|The volume of distribution of methotrexate at steady state is approximately 1L/kg.|Methotrexate clearance varies widely between patients and decreases with increasing doses. Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken.|In adults, oral absorption of methotrexate appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/sq m or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/sq m is significantly less, possibly due to a saturation effect.|After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight).|Protein binding: Moderate (approximately 50%), primarily to albumin.|At serum methotrexate concentrations exceeding 0.1 umol/mL passive diffusion becomes a major means of intracellular transport of the drug. The drug is widely distributed into body tissues with highest concn in the kidneys, gallbladder, spleen, liver, and skin.|For more Absorption, Distribution and Excretion (Complete) data for METHOTREXATE (10 total), please visit the HSDB record page.

Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues. Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate. A small amount of methotrexate is also converted to 7-hydroxymethotrexate.|After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamate, metabolites which by hydrolysis may be converted back to methotrexate. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors. In addition, small amounts of methotrexate polyglutamate may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora.

The half life of low dose methotrexate is 3 to 10 hours in adults. The half life for high dose methotrexate is 8 to 15 hours. Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0.7 to 5.8 hours. Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0.9 to 2.3 hours.|Terminal: Low doses: 3 to 10 hours. High doses: 8 to 15 hours. Note: There is wide interindividual variation in clearance rates. Small amounts of methotrexate and its metabolites are protein-bound and may remain in tissues (kidneys, liver) for weeks to months; the presence of fluid loads, such as ascites or pleural effusion, and renal function impairment will also delay clearance.

Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate. Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase. Inhibtion of nucleotide synthesis prevents cell division. In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate. This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action.|Methotrexate and its polyglutanate metabolites reversibly inhibits dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one-carbon fragments necessary for synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The affinity of dihydrofolate reductase for methotrexate is far greater than its affinity for folic acid or dihydrofolic acid. and, therefore, even very large doses of folic acid given simultaneously will not reverse the effects of methotrexate. Leucovorin calcium, a derivative of tetrahydrofolic acid, may block the effects of methotrexate if given shortly after the antineoplastic agent. Results of one study indicate that methotrexate also causes an increase in intracellular deoxyadenosine triphosphate, which is thought to inhibit ribonucleotide reduction, and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair. Tissues with high rates of cellular proliferation such as neoplasms, psoriatic epidermis, bone marrow, the lining of the GI tract, hair matrix, and fetal cells are most sensitive to the effects of methotrexate.|Methotrexate ... has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or antiinflammatory effects.

SYMPTOMS: Symptoms of exposure to this compound include renal damage, leukopenia, headache, drowsiness, blurred vision, aphasia and hemiparesis. In addition, it causes developmental abnormalities of the craniofacial area and the musculoskeletal system, carcinogenic effects, leukemia, lymphoma effects including Hodgkin's disease, thrombocytopenia, bone marrow changes, other blood changes, cerebral spinal fluid effects, eye effects, blood pressure lowering, cough, dyspnea, fibrosis (pneumoconiosis), cyanosis, gastrointestinal effects, fatty liver degeneration and other liver changes, hepatitis, impaired liver function tests, skin tumors, fever, effects on inflammation or mediation of inflammation. Other symptoms include hemorrhagic enteritis, dermatitis, interstitial pneumonitis, neurotoxicity, nephrotoxicity, defective oogenesis o spermatogenesis, teratogenesis, hepatic dysfunction, progressive weight loss, depression, swelling and cytoplasmic vacuolization of the mucosal cells of the intestinal epithelium, desquamation of epithelial cells, extrusion of plasma into the lumen of the bowel, leukocytic infiltration of the submucosa, disturbance in the maturation of erythrocytes, rapid pathological alteration in myelopoiesis, diminution in content of lymphoid cells in lymphatic tissue and interference with embryogenesis. Interference with cellular reproduction, embryotoxicity, abortion, fetal defects, fertility impairment, menstrual dysfunction, hematopoiesis suppression, acute and chronic hepatotoxicity, nonspecific pneumonitis, chemical arachnoiditis manifested by headache, back pain and nuchal rigidity, paresis manifested by paraplegia, leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia and convulsions, ulcerative stomatitis, nausea, alopecia, ecchymosis, telangiectasia, acne, furunculosis, vomiting, diarrhea, gastrointestinal ulceration and bleeding, azotemia, cystitis, hematuria, vaginal discharge, arthralgia, myalgia, metabolic changes, precipitating diabetes, osteoporotic effects, abdominal distress, malaise, undue fatigue, chills, dizziness, reduce resistance to infection, erythematous rash, pruritus, urticaria, gingivitis, photosensitivity, pigmentary changes, pharyngitis, anorexia, hematemesis, melena, transient oligospermia and sudden death may also result. In children it can cause pulmonary tract damage by ingestion, and blood dyscrasia intravenously. It may also cause lung changes, uro-genital toxicity and conjunctivitis. It may also cause septicemia and bleeding from various sites, mucositis, cerebral and cerebellar calcification, bone pain, fractures, aseptic necrosis of the head of the femur and shortness of breath. Granulocytopenia, hypoplasia of all elements of bone marrow and anemia may also occur. It may cause congenital malformation in the fetus and alter genetic material. Ulceration of the mouth, megaloblastic anemia, hypogammaglobulinemia, kidney damage, pulmonary reactions, progressive intellectual impairment, coma and pyrexia may also occur. ACUTE/CHRONIC HAZARDS: This compound can cause eye irritation. It may be absorbed through the skin and may be fatal if inhaled, swallowed or absorbed through the skin. It is readily absorbed through the gastrointestinal tract. When heated to decomposition it emits toxic fumes of carbon monoxide, carbon dioxide and nitrogen oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.|In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a highflux dialyzer.|Inadvertent intrathecal overdosage of methotrexate constitutes a medical emergency, requiring prompt treatment and management. Although data are limited, management may be guided by the dose administered, time elapsed since administration, and anticipated severity of neurotoxicity. Regardless of the dose administered, as soon as the overdose is recognized, a repeat lumbar puncture should be performed immediately and CSF allowed to drain to gravity. The efficacy of CSF drainage alone as a means for removing the drug is a function of the dose administered and time elapsed since administration, and decreases as these factors increase. If the dose exceeds 100 mg, prompt neurosurgical intervention with ventriculolumbar perfusion following immediate CSF drainage should be considered; continuous CSF drainage or multiple CSF exchanges may also be considered but are not likely to be as effective. Other treatment measures may include high-dose parenteral leucovorin calcium therapy to minimize systemic toxicity, corticosteroids to minimize CNS inflammatory reactions, and other supportive therapy as necessary.|/EXPTL/ Carboxypeptidase G2 (CPDG2), an enzyme that rapidly hydrolyzes and inactivates methotrexate, is an experimental agent that has shown promise in the management of severe overdoses of intrathecal methotrexate.|For more Antidote and Emergency Treatment (Complete) data for METHOTREXATE (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea and vomiting, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported.|/SIGNS AND SYMPTOMS/ In cases /of inadvertent intrathecal overdosage with methotrexate/ in which the dose exceeded 100 mg, severe neurotoxicity occurred, manifested as prompt burning or numbness in the lower extremities, stupor, agitation, seizures, and/or respiratory insufficiency; in some cases, brain damage or fatal necrotizing leukoencephalopathy resulted despite prompt treatment, but complete recovery following prompt and aggressive therapy has been reported.|/SIGNS AND SYMPTOMS/ Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported.

Amethopterin

Grade: United States Pharmacopeia|Oral Tablets: 2.5 mg (of methotrexate) Rheumatrex Dose Pack (scored), (Wyeth). Tablets, film coated: 5 mg (of methotrexate) Trexail (scored), (Barr); 7.5 mg (of methotrexate) Trexail (scored), (Barr); 10 mg (of methotrexate) Trexail (scored), (Barr); 15 mg (of methotrexate) Trexail (scored), (Barr). /Methotrexate sodium/|Parenteral Injection: 25 mg (of methotrexate) per ml, Methotrexate Sodium Injection Isotonic (with benzyl alcohol 0.9%), (American Pharmaceutical Partners, Baxter). /Methotrexate sodium/|Parenteral For Injection: 1 g (of methotrexate) Methotrexate Sodium for Injection, (American Pharmaceutical Partners). Injection: 25 mg (of methotrexate) per mL Methotrexate Sodium Injection Isotonic, (American Pharmaceutical Partners, Baxter, Bedford). /Methotrexate sodium (preservative-free)/

L-Glutamic acid, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-: ACTIVE|A folic acid antagonist|Methotrexate is a mixture containing at least 85% 4-amino-10-methylfolic acid, calculated on the anhydrous basis, and small amounts of related compounds.|Information available in 2005 indicated that Methotrexate was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Croatia, Cyprus, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Russian Federation, Singapore, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Kingdom, Yugoslavia (1,2)|Information available in 2005 indicated that Methotrexate sodium was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, France, Germany, Indonesia, Israel, Italy, Malaysia, Mexico, Netherlands, New Zealand, Poland, Romania, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Kingdom, United States (1,2) /Methotrexate Sodium/

Analyte: methotrexate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: methotrexate; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: methotrexate; matrix: chemical purity; procedure: liquid chromatography with detection at 302 nm and comparison to standards|Analyte: methotrexate; matrix: pharmaceutical preparation (injection solution); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|For more Analytic Laboratory Methods (Complete) data for METHOTREXATE (9 total), please visit the HSDB record page.

TISSUES; FLUORESCENCE SPECTROPHOTOMETRY.|A RADIOIMMUNOASSAY PROCEDURE WAS DEVELOPED FOR DIRECT MEASUREMENT OF METHOTREXATE IN PLASMA, SERUM, CSF OR URINE SAMPLES. ASSAY IS SENSITIVE TO 100 PICOGRAMS; IS HIGHLY SPECIFIC FOR METHOTREXATE IN PRESENCE OF LEUCOVORIN, FOLIC & TETRAHYDROFOLIC ACID & OTHER FOLATE ANALOGS.|Sample matrix: Blood plasma. Sample preparation: Add trichloroacetic acid and centrifuge; add acetic acid-sodium acetate buffer; oxidize with aqueous potassium permanganate solution; add hydrogen peroxide. Assay procedure: HPLC with fluoroescence detection. Limit of detection: 0.01 ug/ml. /From table/|Sample matrix: Blood serum and urine. Sample preparation: Add sample to H-methotrexate; add yeast lysate mix; incubate; centrifuge. Assay procedure: Radiobinding assay. Limit of detection: 450 ng. /From table/|For more Clinical Laboratory Methods (Complete) data for METHOTREXATE (6 total), please visit the HSDB record page.

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