Methotrexate

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/

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/