Methotrexate

log Kow = -1.85

-2.2

less than 1 mg/mL at 66 °F (NTP, 1992)

Insoluble in water , alcohol, chloroform, ether; slightly soluble in dilute hydrochloric acid; soluble in dil solns of alkali hydroxides and carbonates.

Practically insoluble in water and in alcohol.

In water, 2.6X10+3 mg/L at 25 °C /Estimated/

1.71e-01 g/L

Breast Feeding; Lactation; Milk, Human; Abortifacient Agents, Nonsteroidal; Antimetabolites, Antineoplastic; Antirheumatic Agents; Folic Acid Antagonists; Immunosuppressive Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Pharmaceuticals

365 to 399 °F (decomposes) (NTP, 1992)

Melting point: 185-204 °C. /Methotrexate monohydrate/

195 °C

356-399 °F

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)

(c = 1, 0.05 M Na2CO3) [a]20 D = +17.0 - 19.5°

Methotrexate is an odorless yellow to orange-brown crystalline powder. (NTP, 1992) It is a chemotherapy drug that interferes with DNA and RNA synthesis.

Solid

Bright yellow-orange, odorless, crystalline powder.

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P264, P264+P265, P270, P280, P301+P316, P302+P352, P305+P351+P338, P318, P321, P330, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 132 reports by companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

Hazard Traits - Developmental Toxicity

L-Glutamic acid, N-4-(2,4-diamino-6-pteridinyl)methylmethylaminobenzoyl-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

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.

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.

Acute Tox. 3 (100%)

Acute Tox. 3 (100%)

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.

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.

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.

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)

Administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. Glucarpidase has been used intravenously in combination with thymidine and leucovorin to treat methotrexate toxicity. (T36)

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.

A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis where dry cough can be an important sign. The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed Leucovorin "rescue"- as this is the folic acid based drug used) (L1079).

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.

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).

Even a low dose of methotrexate is not free from adverse effects. The most common adverse effects are gastrointestinal (eg, nausea, vomiting, mucosal ulcers, and loss of appetite). These effects are noted in most patients and are easily managed. The most significant adverse effect of methotrexate is hepatotoxicity. These side effects are similar to folate deficiency and can be prevented by supplementing methotrexate with folic acid. A slightly elevated aminotransferase level is typical, but it is uncommon to have liver steatosis, fibrosis, and cirrhosis when taking a low dose of methotrexate. Over a long duration of treatment, ultrasound scanning and liver biopsy are required to ascertain the liver damage.

Inhalation (A314); dermal (A314); intravenous (A314) Oral absorption is dose dependent in adults and leukemic pediatric patients. In adults, peak serum levels are reached within one to two hours. At doses of 30 mg/m^2 or less, methotrexate is generally well absorbed with a mean bioavailability of 60%. At doses greater than 80 mg/m^2, the absorption of the doses is significantly less due to a saturation effect.

Signs and Symptoms of Overdose

Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=59-05-2]

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).

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/

L04AX03

L - Antineoplastic and immunomodulating agents

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

L01BA01; L04AX03

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.

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.

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 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.

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. Renal excretion is the primary route of elimination, and is dependent upon dosage and route of administration (A620). Route of Elimination: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Half Life: Low doses (less than 30 mg/m^2): 3 to 10 hours; High doses: 8 to 15 hours.

YL5FZ2Y5U1

METHOTREXATE

Established Pharmacologic Class [EPC] - Folate Analog Metabolic Inhibitor

Mechanisms of Action [MoA] - Folic Acid Metabolism Inhibitors

Methotrexate is a Folate Analog Metabolic Inhibitor. The mechanism of action of methotrexate is as a Folic Acid Metabolism Inhibitor.

METHOTREXATE

Non-steroidal chemical compounds with abortifacient activity.

Antimetabolites that are useful in cancer chemotherapy.

Drugs used to treat or prevent skin disorders or for the routine care of skin.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

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)

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.

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 Tmax 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).

MEDICATION: Methotrexate is a folic acid antagonist approved for the treatment of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy.

An insect chemosterilant

Use (kg) in Switzerland (2009): >10

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas. Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis. Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis.

Condensation of 2,3-dibromopropionaldehyde with 2,4,5,6-tetraaminopyrimidine to produce 6-bromomethyl-2,4-diaminopteridine and further condensation of this with N-(para-(methylamino)benzoyl)glutamic acid to yield methotrexate.

Preparation: J.M. Smith, D.B. Cosulich, US 2512572 (1959 to Cyanamid)

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/