Methotrexate

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H301：Giftig bei Verschlucken.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H341：Kann vermutlich genetische Defekte verursachen.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

Methotrexate Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R61:Kann das Kind im Mutterleib schädigen.
  R25:Giftig beim Verschlucken.
  R36/38:Reizt die Augen und die Haut.
  R46:Kann vererbbare Schäden verursachen.

• S-Sätze Betriebsanweisung:

  S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
  S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.

• Beschreibung

  Methotrexate is an orange-brown crystalline powder. Molecular weight= 454.50; Freezing/Melting point=185204℃ (decomposes). Insoluble in water.

• Chemische Eigenschaften

  Methotrexate is an orange-brown crystalline powder.

• Chemische Eigenschaften

  Yellow Crystaline Powder

• Originator

  Methotrexate Lederle,Lederle,US,1955

• Verwenden

  Anti-cancer

• Verwenden

  dietary supplement, crosses the blood-brain barrier, potential activities as anxiolytic and vasodilator

• Verwenden

  A Folic acid antagonist. Used as a antineoplastic and antirheumatic.

• Verwenden

  A deuterated folic acid antagonist

• Verwenden

  Methotrexate is used to treat severe lymphatic leukemia, choriocarcinoma, non-Hodgkin’s lymphoma, bone carcinoma, as well as head, neck, breast, and lung tumors.

• Verwenden

  Used as a antineoplastic and antirheumatic. A folic Acid antagonist

• Definition

  ChEBI: Methotrexate is a member of pteridines, a monocarboxylic acid amide and a dicarboxylic acid. It has a role as an antineoplastic agent, an antirheumatic drug, an EC 1.5.1.3 (dihydrofolate reductase) inhibitor, a DNA synthesis inhibitor, an abortifacient, a dermatologic drug, an antimetabolite and an immunosuppressive agent. It is functionally related to a L-glutamic acid. It is a conjugate acid of a methotrexate(1-).

• Indications

  Of the DMARDs, methotrexate (Rheumatrex) is the most widely prescribed. It is indicated for the treatment of rheumatoid arthritis and psoriasis; it is also used for psoriatic arthritis, systemic lupus erythematosus, and sarcoidosis. It is generally as efficacious as the other agents, with a low incidence of serious side effects when prescribed on a low-dose weekly schedule.

• Indications

  Methotrexate is approved for use in severe disabling psoriasis recalcitrant to other less toxic treatments. The standard regimen is similar to low-dose therapy used for the treatment of rheumatoid arthritis . Although toxicities are similar to those described in the treatment of other diseases, hepatic cirrhosis and unexpected pancytopenia are of special concern given the chronicity of treatment.

• Indications

  Methotrexate, for example, is highly bound to serum albumin and can be displaced by salicylates, sulfonamides, phenothiazines, phenytoin, and other organic acids. The induction of hepatic drugmetabolizing enzymes by phenobarbital may alter the metabolism of cyclophosphamide to both active and inactive metabolites. Mercaptopurine metabolism is blocked by allopurinol, an occurrence that may result in lethal toxicity if the dosage of mercaptopurine is not reduced to one-fourth of the usual dosage. Methotrexate is secreted actively by the renal tubules, and its renal clearance may be delayed by salicylates.

• Indications

  Methotrexate competitively inhibits the binding of folic acid to the enzyme dihydrofolate reductase.
  Tetrahydrofolate is in turn converted to N⁵,N¹⁰- methylenetetrahydrofolate, which is an essential cofactor for the synthesis of thymidylate, purines, methionine, and glycine. The major mechanism by which methotrexate brings about cell death appears to be inhibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines.
  Cells in S-phase are most sensitive to the cytotoxic effects of methotrexate. RNA and protein synthesis also may be inhibited to some extent and may delay progression through the cell cycle, particularly from G1 to S.

• Manufacturing Process

  5 g (15 mmol) of diethyl-p-methylaminobenzoyl-L-glutamate and 8.0 g of aminomalononitrile tosylate (65% by NMR assay, 20 mmol) were dissolved in warm ethanol (65 ml, with 15% water by volume). To this solution, cooled to 0°C, was added all at once and with vigorous stirring, 3.6 g of βbromopyruvaldoxime (89% by NMR assay, 19 mmol). After 30 minutes the stirred mixture, which was allowed to warm slowly to room temperature, was neutralized with powdered NaHCO3 to pH 6, stirring continued for four additional hours, and the resulting mixture filtered through Celite. The filtrate was evaporated under reduced pressure to a glasslike substance, which was taken up in 500 ml of chloroform. The resulting suspension was then filtered using Celite, and the filtrate was washed with water, dried with anhydrous MgSO4, and evaporated to give an orange glasslike substance which was used directly in the next step.
  To a 20% solution of titanium trichloride in water (39 mmol), stirred under nitrogen, was added a solution of 18 g (230 mmol) of ammonium acetate in 55 ml of water. Then, to this mixture, cooled to 10°C and stirred with an airdriven stirrer, was added over a period of 5 minutes a solution of the orange glassy substance above distilled in 60 ml of tetrahydrofuran. The mixture was vigorously stirred for 15 minutes while a rapid stream of nitrogen was passed through. After this time, 15 g of powdered sodium sulfite (120 mmol) was added to the mixture, which after several minutes turned from green to yellowish white. This mixture was stirred into 1 liter of chloroform, and the heavy yellow layer separated by use of a separatory funnel. This chloroform layer was washed with water, dried using anhydrous MgSO4, and evaporated under reduced pressure to give a light orange glass, which was then chromatographed rapidly on a column made from 80 g of Baker silica gel, using 5% ethyl acetate in chloroform as the eluent.
  The product obtained by evaporation of the eluate was recrystallized from ethanol-ether (1:10) to give a light yellow powder, MP 85 to 88°C. The yield was 4.4 g (63%).
  A solution containing 4.8 g (10.2 mmol) of diethyl-N-[p-[[(2-amino-3-cyano5-pyrazinyl)methyl] methylamino]benzoyl]glutamate and 5 g (42 mmol) of guanidine acetate in 40 ml of dimethylformamide was stirred under nitrogen at 120°C for six hours. The resulting solution was cooled to room temperature, filtered and evaporated to a glassy product using a rotary evaporator and a mechanical vacuum pump to insure a better vacuum. The residual glass was taken up in 500 ml of chloroform, the resulting suspension filtered using Celite, and the filtrate washed with water, dried using anhydrous MgSO4, and evaporated to dryness. (The residual material was chromatographed rapidly on a column prepared from 250 g of Baker silica gel using, initially, 2% ethanol in chloroform, and then 5% ethanol in chloroform as eluents.) The material obtained by evaporation of the eluates was crystallized from ethanol-chloroform (4:1) to give small, pale yellow lustrous platelets, MP 142°C to 154°C; yield, 3.8 g (73%). Further crystallization of this material from ethanol-chloroform (4:1) raised the MP to 153°C to 155°C. The compound is completely racemic.
  A sample of this product was hydrolyzed in a mixture of water and methanol in the presence of potassium hydroxide. Essentially pure methotrexate was thus obtained.

• Trademarks

  Mexate (Bristol-Myers Oncology); Rheumatrex (Wyeth-Ayerst).

• Therapeutic Function

  Antineoplastic

• Biologische Funktion

  Although the mechanism of action of methotrexate in rheumatoid arthritis is unknown, recent studies have shown that methotrexate reversibly inhibits dihydrofolate reductase, blocking the proliferation of B cells by interfering with DNA synthesis, repair, and replication. Oral absorption is dose-dependent, being well-absorbed at doses of 7.5–25 mg once a week. At this dose, oral bioavailability is approximately 60%, and food can delay absorption and reduce peak concentration. The volume of distribution is 0.4 to 0.8 L/kg. Protein binding is approximately 50%. It is metabolized to active metabolites, methotrexate polyglutamates and 7-hydroxymethotrexate. Some metabolism occurs by intestinal flora after oral administration. Methotrexate is actively transported into the urine (80–90% unchanged in the urine within 24 hours) via the folate transporter, an organic anion transporter. Its elimination half-life is 3 to 10 hours.

• Acquired resistance

  Mammalian cells have several mechanisms of resistance to methotrexate. These include an increase in intracellular dihydrofolate reductase levels, appearance of altered forms of dihydrofolate reductase with decreased affinity for methotrexate, and a decrease in methotrexate transport into cells. The relative importance of each of these mechanisms of resistance in various human tumors is not known.
  Cellular uptake of the drug is by carrier-mediated active transport. Drug resistance due to decreased transport can be overcome by greatly increasing extracellular methotrexate concentration, which provides a rationale for high-dose methotrexate therapy. Since bone marrow and gastrointestinal cells do not have impaired folate methotrexate transport, these normal cells can be selectively rescued with reduced folate, bypassing the block of dihydrofolate reductase. Leucovorin (citrovorum factor, folinic acid, 5-formyltetrahydrofolate) is the agent commonly used for rescue.

• Allgemeine Beschreibung

  Methotrexate (MTX, Rheumatrex), an antifolate drug used in cancer treatment, has also been used in the disease management of RA since the 1950s. Because of its quicker therapeutic onset among all DMARDs and its demonstrated efficacy, tolerability, and low cost, MTX has been the firstline therapy for RA patients who are not responsive to NSAIDs alone.
  Recent findings have indicated that other DMARDs should only be used for patients who are refractory to MTX. At least four anti-inflammatory mechanisms of action have been suggested for MTX’s ability to slow down RA disease progression. First, MTX, being a folate antagonist, prevents antigen-dependent T-cell proliferation by blocking de novo pyrimidine biosynthesis, via a reversible inhibition of dihydrofolate reductase. It also inhibits folate-mediated production of spermine and spermidine in synovial tissue. These polyamines are believed to be the toxic compounds responsible for causing tissue injury in RA. MTX can also reduce intracellular glutathione concentration, thereby altering the cellular redox state that suppresses the formation of reactive oxygen radicals in synovial tissue. Lastly, MTX, similar to sulfasalazine, infliximab, and IL-4, can also inhibit osteoclastogenesis (i.e., bone erosion) in patients with RA, by modulating the interaction of the receptor activator of nuclear factor B, its ligand, and osteoprotegrin.

• Allgemeine Beschreibung

  Odorless yellow to orange-brown crystalline powder.

• Allgemeine Beschreibung

  The drug is available in 50-, 100-, 200-, and 1,000-mg vialsfor IV use. Methotrexate is used to treat several cancer typesincluding breast cancer, bladder cancer, colorectal cancer,and head and neck cancer. The mechanism of action ofmethotrexate involves inhibition of DHFR leading to a depletionof critical reduced folates. The reduced folates arenecessary for biosynthesis of several purines and pyrimidines.Resistance to methotrexate can occur because ofdecreased carrier-mediated transport of drug into cells orincreased expression of the target enzyme DHFR. Oralbioavailability varies with dose because of saturable uptakeprocesses, and high doses are required to reach therapeuticlevels in the CNS. The majority of drug dosage is excretedunchanged in the urine. The renal excretion of methotrexateis inhibited by several carboxylic acid drugs such as penicillins,probenecid, nonsteroidal anti-inflammatory agents,and aspirin. Methotrexate enhances 5-FU antitumor effectswhen given 24 hours prior to the fluoropyrimidine.Methotrexate toxicity includes myelosuppression, mucositis,nausea, vomiting, severe headaches, renal toxicity, acutecerebral dysfunction, skin rash, and hyperpigmentation.

• Air & Water Reaktionen

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

• Reaktivität anzeigen

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

• Hazard

  Very toxic. Questionable carcinogen.

• Brandgefahr

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

• Biologische Aktivität

  Cytotoxic agent. Inhibits thymidylate synthetase and de novo purine synthesis. Potent folic acid antagonist; inhibits dihydrofolate reductase. Also inhibits Ras carboxyl methylation in DKOB8 cells, leading to decreased p44 and Akt activation.

• Mechanism of action

  Methotrexate is a folic acid antagonist structurally designed to compete successfully with 7,8-DHF for the DHFR enzyme. The direct inhibition of DHFR causes cellular levels of 7,8-DHF to build up, which in turn results in feedback (indirect) inhibition of thymidylate synthase. Methotrexate also is effective in inhibiting glycine amide ribonucleotide (GAR) transformylase , a key enzyme in the synthesis of purine nucleotides. Take note of the structural differences between methotrexate and DHF, because these differences will be important to an understanding of the chemical mechanism of this anticancer agent.

• Pharmakologie

  Methotrexate is a folate antimetabolite that inhibits dihydrofolate reductase and other folate-dependent enzymes in cells. At the low doses used in the therapy of rheumatoid arthritis,methotrexate appears to be acting more as an antiinflammatory agent than as an immunosuppressant. Methotrexate inhibits folate-dependent enzymes involved in adenosine degradation, increasing concentrations of extracellular adenosine. Adenosine acts via cell surface receptors to inhibit the production of inflammatory cytokines such as TNF-α and IFN-γ.Methotrexate also decreases the production of inflammatory prostaglandins and proteases, though a direct action on the COX enzymes has not been noted.

• Pharmakologie

  Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. The major routes of drug excretion are glomerular filtration and active renal tubular secretion.
  The formation of polyglutamic acid conjugates of methotrexate has been observed in tumor cells and in the liver and may be an important determinant of cytotoxicity. These methotrexate polyglutamates are retained in the cell and are also potent inhibitors of dihydrofolate reductase.

• Clinical Use

  Methotrexate is part of curative combination chemotherapy for acute lymphoblastic leukemias, Burkitt’s lymphoma, and trophoblastic choriocarcinoma. It is also useful in adjuvant therapy of breast carcinoma; in the palliation of metastatic breast, head, neck, cervical, and lung carcinomas; and in mycosis fungoides.
  High-dose methotrexate administration with leucovorin rescue has produced remissions in 30% of patients with metastatic osteogenic sarcoma.
  Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis, and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis.

• Nebenwirkungen

  In the low-dose regimen used for rheumatoid arthritis, most side effects of methotrexate are mild and can be managed by temporarily stopping the drug or reducing the dose. These include nausea, stomatitis, GI discomfort, rash, diarrhea, and headaches. Changes in liver aminotransferases and mild to moderate immunosuppression have been reported in rheumatoid arthritis patients taking methotrexate. Severe toxicity is possible but rare and may be a function of drug accumulation. These effects include hepatotoxicity progressing to cirrhosis, pneumonitis progressing to pulmonary fibrosis, and bone marrow depression with anemia, leukopenia, and thrombocytopenia. Folic acid supplementation is often used to alleviate certain side effects of methotrexate therapy (stomatitis, GI irritation, hematopoietic effects) but may also contribute to resistance to this therapy.

• Nebenwirkungen

  Myelosuppression is the major dose-limiting toxicity associated with methotrexate therapy. Gastrointestinal toxicity may appear in the form of ulcerative mucositis and diarrhea. Nausea, alopecia, and dermatitis are common with high-dose methotrexate. The greatest danger of high-dose therapy is renal toxicity due to precipitation of the drug in the renal tubules, and the drug should not be used in patients with renal impairment. Intrathecal administration may produce neurological toxicity ranging from mild arachnoiditis to severe and progressive myelopathy or encephalopathy. Chronic lowdose methotrexate therapy, as used for psoriasis, may result in cirrhosis of the liver. Occasionally methotrexate produces an acute, potentially lethal lung toxicity that is thought to be allergic or hypersensitivity pneumonitis. Additionally, methotrexate is a potent teratogen and abortifacient.

• Synthese

  Methotrexate, N-[p-[[2,4-diamino-6-piperidinyl)methyl]methylamino]- benzoyl]-L-(
  )-glutamic acid (30.1.1.8), is made by reacting N-(4-methylaminobenzoyl)glutaminic acid (30.1.1.3) with 2-amino-4-hydroxyl-6-bromomethylpteridine(30.1.1.7). In order to do this, N-(4-methylaminobenzoyl)glutaminic acid (30.1.1.3) is synthesized from 4-nitrobenzoyl chloride, which is reacted with L-glutamic acid, forming N-(4-nitrobenzoyl)glutamic acid (30.1.1.1), the nitro group of which is reduced to an amino group using hydrogen over Raney nickel, which gives N-(4-aminobenzoyl)glutamic acid (30.1.1.2). This undergoes reductive methylation using formaldehyde and hydrogen, which forms N-(4-methylaminobenzoyl)glutamic acid (30.1.1.3).
  The second part of the methotrexate molecule, 2-amino-4-hydroxy-6-bromomethylpteridine (30.1.1.7), is made from 2,4,6-triaminopyrimidine (30.1.1.4), which is easily synthesized by reacting malonic acid dinitrile with guanidine. This is nitrosylated by anhydrous nitrous acid to 2,4,6-triamino-5-nitrosopyrimidine (30.1.1.5), and then it is reduced by sodium borohydride to 2,4,5,6-tetraaminopyrimidine (30.1.1.6). Upon reacting this with 1,2- dibromopropionic aldehyde, the product of attaching bromine to acrolein, 2-amino-4- hydroxy-6- bromomethyl-pteridine (30.1.1.7) is formed. Alkylating the amine nitrogen atom of N-(4-methylaminbenzoyl)glutamic acid (30.1.1.3) with resulting bromide (30.1.1.7) gives methotrexate (30.1.1.8).

  

• mögliche Exposition

  Methotrexate is an alkaloid anticancer drug available in tablet or injectable liquid form. A chemotherapy drug that interferes with DNA and RNA synthesis. It is also an insect chemosterilant.

• Veterinary Drugs and Treatments

  Indicated for lymphomas and some solid tumors in dogs and cats. In human medicine, methotrexate is also being used to treat refractory rheumatoid arthritis and severe psoriasis.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Anaesthetics: antifolate effect increased by nitrous oxide - avoid.
  Analgesics: increased risk of toxicity with NSAIDs - avoid.
  Antibacterials: absorption possibly reduced by neomycin; antifolate effect increased with co-trimoxazole and trimethoprim; penicillins and possibly ciprofloxacin reduce excretion of methotrexate (increased risk of toxicity); increased haematological toxicity with doxycycline, sulphonamides and tetracycline.
  Antiepileptics: concentration possibly increased by levetiracetam.
  Antimalarials: antifolate effect enhanced by pyrimethamine.
  Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
  Ciclosporin: methotrexate may inhibit the clearance of ciclosporin or its metabolites; ciclosporin may inhibit methotrexate elimination.
  Corticosteroids: increased risk of haematological toxicity.
  Cytotoxics: effects of methotrexate antagonised by asparaginase, crisantaspase and pegasparagase - give asparaginase, crisantaspase and pegasparagase 24 hours after methotrexate; increased pulmonary toxicity with cisplatin.
  Leflunomide: risk of toxicity.
  Probenecid: excretion of methotrexate reduced.
  Retinoids: concentration increased by acitretin, also increased hepatotoxicity - avoid.
  Ulcer-healing drugs: PPIs may reduce high dose methotrexate elimination; consider temporarily stopping PPI

• Erste Hilfe

  If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least 15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, remove contaminated clothing and wash immediately with soap and water. Seek medical attention immediately. If this chemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart action has stopped. Transfer promptly to a medical facility. When this chemical has been swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit.

• Stoffwechsel

  Methotrexate can be given orally in the treatment of breast, head and neck, and various lung cancers as well as in non-Hodgkin's lymphoma. The sodium salt form also is marketed for IV, intramuscular, intra-arterial, or intrathecal injection. Oral absorption is dose-dependent and peaks at 80 mg/m2 because of site saturation. The monoglutamate tail of methotrexate permits active transport into cells, with carrier-mediated transport predominating at serum concentration levels lower than 100 μM. Once inside the cell, methotrexate undergoes a polyglutamation reaction that adds several anionic carboxylate groups to trap the drug at the site of action. Polyglutamation is more efficient in tumor cells than in healthy cells and, therefore, may promote selective toxicity of this drug. Cancer cells can become resistant to methotrexate over time which may involve impaired transport across tumor cell membranes, enhanced efflux from the tumor cell, and attenuated polyglutamation rates. The polyglutamated drug will be hydrolyzed back to the parent structure before renal elimination. Up to 90% of an administered dose of methotrexate is excreted unchanged in the urine within 24 hours.

• Lager

  Store at RT

• Versand/Shipping

  UN1544 Alkaloids, solid, n.o.s. or Alkaloid salts, solid, n.o.s. poisonous, Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required.

• läuterung methode

  Most common impurities are 10-methylpteroylglutamic acid, aminopterin and pteroylglutamic acid. Purify it by chromatography on Dowex-1 acetate, followed by filtration through a mixture of cellulose and charcoal. It has been recrystallised from aqueous HCl or by dissolution in the minimum volume of N NaOH and acidified until precipitation is complete, filter or better collect by centrifugation, wash with H2O (also by centrifugation) and dry at 100o/3mm. It has UV: max at 244 and 307nm ( 17300 and 19700) in H2O at pH 1; 257, 302 and 370nm ( 23000, 22000 and 7100) in 2O at pH 13. [Momle Biochemical Preparations 8 20 1961, Seeger et al. J Am Chem Soc 71 1753 1949.] It is a potent inhibitor of dihydrofolate reductase and is used in cancer chemotherapy. [Blakley The Biochemistry of Folic Acid and Related Pteridines, North-Holland Publ Co., Amsterdam, NY, pp157-163 1969, Beilstein 26 IV 3833.] It is CARCINOGENIC; HANDLE WITH EXTREME CARE.

• Inkompatibilitäten

  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.

• Waste disposal

  It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

• Vorsichtsmaßnahmen

  Methotrexate is teratogenic and is contraindicated duringpregnancy and breast-feeding. Prior to attemptingpregnancy, women should wait at least one menstrualcycle and men at least 3 months after discontinuing thisdrug. Additional contraindications to methotrexate administrationinclude kidney, liver, and lung disease;moderate to high alcohol use; immunodeficiency; blooddyscrasias; and hypersensitivity. Elderly persons may be at increased risk for toxicity because of decreased renaland hepatic function.
  Methotrexate clearance can be decreased by thecoadministration of NSAIDs; however, this not usuallya problem with the low doses of methotrexate used totreat arthritis. Methotrexate can be displaced fromplasma protein binding sites by phenylbutazone, phenytoin,sulfonylureas, and sulfonamides and certain otherantibiotics. The antifolate effects of methotrexate areadditive with those of other folate-inhibitory drugs,such as trimethoprim.

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