Methotrexate

Pronunciation

(meth oh TREKS ate)


U.S. Brand Names

Rheumatrex®; Trexall™



Synonyms

Amethopterin; Methotrexate Sodium; MTX; NSC-740



Generic Available

Yes



Canadian Brand Names

Apo-Methotrexate®; ratio-Methotrexate



Use

Treatment of trophoblastic neoplasms; leukemias; psoriasis; rheumatoid arthritis (RA), including polyarticular-course juvenile rheumatoid arthritis (JRA); breast, head and neck, and lung carcinomas; osteosarcoma; soft-tissue sarcomas; carcinoma of gastrointestinal tract, esophagus, testes; lymphomas



Pregnancy Risk Factor

X (psoriasis, rheumatoid arthritis)



Pregnancy Implications

Fetal death or teratogenic effects may occur. Use is contraindicated in pregnant women with psoriasis or rheumatoid arthritis. Use for the treatment of neoplastic diseases only when the potential benefit to the mother outweighs the possible risk to the fetus. Pregnancy should be excluded prior to therapy in women of childbearing potential. Pregnancy should be avoided for 3 months following treatment in male patients and 1 ovulatory cycle in female patients.



Lactation

Enters breast milk/contraindicated



Contraindications

Hypersensitivity to methotrexate or any component of the formulation; severe renal or hepatic impairment; pre-existing profound bone marrow suppression in patients with psoriasis or rheumatoid arthritis, alcoholic liver disease, AIDS, pre-existing blood dyscrasias; pregnancy (in patients with psoriasis or rheumatoid arthritis); breast-feeding



Warnings/Precautions

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered.

May cause potentially life-threatening pneumonitis (may occur at any time during therapy and at any dosage); monitor closely for pulmonary symptoms, particularly dry, nonproductive cough. Methotrexate may cause photosensitivity and/or severe dermatologic reactions which are not dose-related. Methotrexate has been associated with acute and chronic hepatotoxicity, fibrosis, and cirrhosis. Risk is related to cumulative dose and prolonged exposure. Ethanol abuse, obesity, advanced age, and diabetes may increase the risk of hepatotoxic reactions.

Methotrexate may cause renal failure, gastrointestinal toxicity, or bone marrow depression. Use with caution in patients with renal impairment, peptic ulcer disease, ulcerative colitis, or pre-existing bone marrow suppression. Gastrointestinal toxicity may be severe: diarrhea and ulcerative stomatitis may require interruption of therapy; death from hemorrhagic enteritis or intestinal perforation has been reported. Methotrexate penetrates slowly into 3rd space fluids, such as pleural effusions or ascites, and exits slowly from these compartments (slower than from plasma). The potential for toxicity may be increased under these conditions. Dosage reduction may be necessary in patients with renal or hepatic impairment, ascites, and pleural effusion. Toxicity from methotrexate or any immunosuppressive is increased in the elderly.

Severe bone marrow suppression, aplastic anemia, and GI toxicity have occurred during concomitant administration with NSAIDs. Use caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine). Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. Immune suppression may lead to opportunistic infections.

For rheumatoid arthritis and psoriasis, immunosuppressive therapy should only be used when disease is active and less toxic; traditional therapy is ineffective. Discontinue therapy in RA or psoriasis if a significant decrease in hematologic components is noted. Methotrexate formulations and/or diluents containing preservatives should not be used for intrathecal or high-dose therapy. Methotrexate injection may contain benzyl alcohol and should not be used in neonates.

Adverse Reactions

Adverse reactions vary by route and dosage. Hematologic and/or gastrointestinal toxicities may be common at dosages used in chemotherapy; these reactions are much less frequent when used at typical dosages for rheumatic diseases.

Note:

>10%:

Central nervous system (with I.T. administration or very high-dose therapy):

Arachnoiditis: Acute reaction manifested as severe headache, nuchal rigidity, vomiting, and fever; may be alleviated by reducing the dose

Subacute toxicity: 10% of patients treated with 12-15 mg/m2 of I.T. methotrexate may develop this in the second or third week of therapy; consists of motor paralysis of extremities, cranial nerve palsy, seizure, or coma. This has also been seen in pediatric cases receiving very high-dose I.V. methotrexate (when enough methotrexate can get across into the CSF).

Demyelinating encephalopathy: Seen months or years after receiving methotrexate; usually in association with cranial irradiation or other systemic chemotherapy

Dermatologic: Reddening of skin

Endocrine & metabolic: Hyperuricemia, defective oogenesis or spermatogenesis

Gastrointestinal: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting, diarrhea, anorexia, intestinal perforation, mucositis (dose dependent; appears in 3-7 days after therapy, resolving within 2 weeks)

Emetic potential:

<100 mg: Moderately low (10% to 30%)

100 mg or <250 mg: Moderate (30% to 60%)

250 mg: Moderately high (60% to 90%)

Hematologic: Leukopenia, thrombocytopenia

Renal: Renal failure, azotemia, nephropathy

Respiratory: Pharyngitis

1% to 10%:

Cardiovascular: Vasculitis

Central nervous system: Dizziness, malaise, encephalopathy, seizure, fever, chills

Dermatologic: Alopecia, rash, photosensitivity, depigmentation or hyperpigmentation of skin

Endocrine & metabolic: Diabetes

Genitourinary: Cystitis

Hematologic: Hemorrhage

Myelosuppressive: This is the primary dose-limiting factor (along with mucositis) of methotrexate; occurs about 5-7 days after methotrexate therapy, and should resolve within 2 weeks

WBC: Mild

Platelets: Moderate

Onset: 7 days

Nadir: 10 days

Recovery: 21 days

Hepatic: Cirrhosis and portal fibrosis have been associated with chronic methotrexate therapy; acute elevation of liver enzymes are common after high-dose methotrexate, and usually resolve within 10 days.

Neuromuscular & skeletal: Arthralgia

Ocular: Blurred vision

Renal: Renal dysfunction: Manifested by an abrupt rise in serum creatinine and BUN and a fall in urine output; more common with high-dose methotrexate, and may be due to precipitation of the drug. The best treatment is prevention: Aggressively hydrate with 3 L/m2/day starting 12 hours before therapy and continue for 24-36 hours; alkalinize the urine by adding 50 mEq of bicarbonate to each liter of fluid; keep urine flow over 100 mL/hour and urine pH >7.

Respiratory: Pneumonitis: Associated with fever, cough, and interstitial pulmonary infiltrates; treatment is to withhold methotrexate during the acute reaction; interstitial pneumonitis has been reported to occur with an incidence of 1% in patients with RA (dose 7.5-15 mg/week)

<1% (Limited to important or life-threatening): Acute neurologic syndrome (at high dosages - symptoms include confusion, hemiparesis, transient blindness, and coma); anaphylaxis, alveolitis, cognitive dysfunction (has been reported at low dosage), decreased resistance to infection, erythema multiforme, hepatic failure, leukoencephalopathy (especially following craniospinal irradiation or repeated high-dose therapy), lymphoproliferative disorders, osteonecrosis and soft tissue necrosis (with radiotherapy), pericarditis, plaque erosions (psoriasis), seizure (more frequent in pediatric patients with ALL), Stevens-Johnson syndrome, thromboembolism

Overdosage/Toxicology

Symptoms of overdose include nausea, vomiting, alopecia, melena, and renal failure.

Antidote: Leucovorin; administer as soon as toxicity is seen. Administer 10 mg/m2 orally or parenterally. Follow with 10 mg/m2 orally every 6 hours for 72 hours. After 24 hours following methotrexate administration, if the serum creatinine is

50% premethotrexate serum creatinine, increase leucovorin dose to 100 mg/m2 every 3 hours until serum methotrexate level is <5 x 10-8 M. Hydration and alkalinization may be used to prevent precipitation of methotrexate or methotrexate metabolites in the renal tubules. Toxicity in low dose range is negligible, but may present mucositis and mild bone marrow suppression; severe bone marrow toxicity can result from overdose. Generally, neither peritoneal nor hemodialysis have been shown to increase elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer. Leucovorin should be administered intravenously, never intrathecally, for overdoses of intrathecal methotrexate.

Drug Interactions

Acitretin: May enhance the hepatotoxic effect of methotrexate. Avoid concurrent use.

Cholestyramine: May decrease levels of methotrexate.

Corticosteroids: May decrease uptake of methotrexate into leukemia cells. Administration of these drugs should be separated by 12 hours. Dexamethasone has been reported to not affect methotrexate influx into cells.

Cyclosporine: Concomitant administration with methotrexate may increase levels and toxicity of each.

Cytarabine: Methotrexate, when administered prior to cytarabine, may enhance the efficacy and toxicity of cytarabine. Some combination treatment regimens (eg, hyper-CVAD) have been designed to take advantage of this interaction.

Hepatotoxic agents (azathioprine, retinoids, sulfasalazine) may increase the risk of hepatotoxic reactions

Mercaptopurine: Methotrexate may increase mercaptopurine levels. Dosage adjustment may be required.

NSAIDs: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant therapy. Should not be used during moderate or high-dose methotrexate due to increased and prolonged methotrexate levels (may increase toxicity); NSAID use during treatment of rheumatoid arthritis has not been fully explored, but continuation of prior regimen has been allowed in some circumstances, with cautious monitoring

Penicillins: May increase methotrexate concentrations (due to a reduction in renal tubular secretion). Primarily a concern with high doses of penicillins and higher dosages of methotrexate.

Probenecid: May increase methotrexate concentrations (due to a reduction in renal tubular secretion). Primarily a concern with higher dosages of methotrexate.

Salicylates: May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern.

Sulfonamides: May increase methotrexate concentrations (due to a reduction in renal tubular secretion). In addition, sulfonamides may reduce folate levels, increasing the risk/severity of bone marrow suppression. Particularly a concern with higher dosages of methotrexate.

Tetracyclines: May increase methotrexate toxicity; monitor

Theophylline: Methotrexate may increase theophylline levels.

Vaccines (live virus): Concurrent use with methotrexate may result in vaccinia infections.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may be associated with increased liver injury).

Food: Methotrexate peak serum levels may be decreased if taken with food. Milk-rich foods may decrease methotrexate absorption. Folate may decrease drug response.

Herb/Nutraceutical: Avoid echinacea (has immunostimulant properties).

Stability

Store tablets and intact vials at room temperature (15°C to 25°C); protect from light. Dilute powder with D5W or NS to a concentration of 25 mg/mL (20 mg and 50 mg vials) and 50 mg/mL (1 g vial). Intrathecal solutions may be reconstituted to 2.5-5 mg/mL with NS, D5W, lactated Ringer's, or Elliott's B solution. Further dilution in D5W or NS is stable for 24 hours at room temperature (21°C to 25°C). Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature. Intrathecal dilutions are stable at room temperature for 7 days, but it is generally recommended that they be used within 4-8 hours.

Use preservative free preparations for intrathecal or high-dose administration.

Compatibility

Stable in D5NS, D5W, NS

Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, asparaginase, aztreonam, bleomycin, cefepime, ceftriaxone, cimetidine, cisplatin, cyclophosphamide, cytarabine, daunorubicin, dexchlorpheniramine, diphenhydramine, doxorubicin, doxorubicin liposome, etoposide, etoposide phosphate, famotidine, filgrastim, fludarabine, fluorouracil, furosemide, ganciclovir, gatifloxacin, granisetron, heparin, hydromorphone, imipenem/cilastatin, leucovorin, linezolid, lorazepam, melphalan, mesna, methylprednisolone sodium succinate, metoclopramide, mitomycin, morphine, ondansetron, oxacillin, paclitaxel, piperacillin/tazobactam, prochlorperazine edisylate, ranitidine, sargramostim, teniposide, thiotepa, vinblastine, vincristine, vindesine, vinorelbine. Incompatible: Chlorpromazine, gemcitabine, idarubicin, ifosfamide, midazolam, nalbuphine, promethazine, propofol. Variable (consult detailed reference): Dexamethasone sodium phosphate, droperidol, vancomycin

Compatibility in syringe: Compatible: Bleomycin, cisplatin, cyclophosphamide, doxapram, doxorubicin, fluorouracil, furosemide, heparin, leucovorin, mitomycin, vinblastine, vincristine. Incompatible: Droperidol. Variable (consult detailed reference): Metoclopramide

Compatibility when admixed: Compatible: Cyclophosphamide, cyclophosphamide with fluorouracil, cytarabine, dacarbazine, fluorouracil, hydrocortisone, hydroxyzine, mercaptopurine, ondansetron, sodium bicarbonate, vincristine. Incompatible: Bleomycin

Mechanism of Action

Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis. Methotrexate is cell cycle specific for the S phase of the cycle.

The MOA in the treatment of rheumatoid arthritis is unknown, but may affect immune function. In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin.

Pharmacodynamics/Kinetics

Onset of action: Antirheumatic: 3-6 weeks; additional improvement may continue longer than 12 weeks

Absorption: Oral: Rapid; well absorbed at low doses (<30 mg/m2), incomplete after large doses; I.M.: Complete

Distribution: Penetrates slowly into 3rd space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); crosses placenta; small amounts enter breast milk; sustained concentrations retained in kidney and liver

Protein binding: 50%

Metabolism: <10%; degraded by intestinal flora to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-OH methotrexate; polyglutamates are produced intracellularly and are just as potent as methotrexate; their production is dose- and duration-dependent and they are slowly eliminated by the cell once formed

Half-life elimination: Low dose: 3-10 hours; High dose: 8-12 hours

Time to peak, serum: Oral: 1-2 hours; I.M.: 30-60 minutes

Excretion: Urine (44% to 100%); feces (small amounts)

Dosage

Refer to individual protocols.

Note: Doses between 100-500 mg/m2may require leucovorin rescue. Doses >500 mg/m2require leucovorin rescue.

Children:

Dermatomyositis: Oral: 15-20 mg/m2/week as a single dose once weekly or 0.3-1 mg/kg/dose once weekly

Juvenile rheumatoid arthritis: Oral, I.M.: 10 mg/m2 once weekly, then 5-15 mg/m2/week as a single dose or as 3 divided doses given 12 hours apart

Antineoplastic dosage range:

Oral, I.M.: 7.5-30 mg/m2/week or every 2 weeks

I.V.: 10-18,000 mg/m2 bolus dosing or continuous infusion over 6-42 hours

For dosing schedules, see table:

or

Methotrexate Dosing Schedules

Dose Route Frequency
Conventional &nbsp; &nbsp;
15-20 mg/m2 P.O. Twice weekly
30-50 mg/m2 P.O., I.V. Weekly
15 mg/day for 5 days P.O., I.M. Every 2-3 weeks
Intermediate &nbsp; &nbsp;
50-150 mg/m2* I.V. push Every 2-3 weeks
240 mg/m2* I.V. infusion Every 4-7 days
0.5-1 g/m2** I.V. infusion Every 2-3 weeks
High &nbsp; &nbsp;
1-25 g/m2* I.V. infusion Every 1-3 weeks
*Doses between 100-500 mg/m2 may require leucovorin rescue in some patients.
**Followed with leucovorin rescue - refer to Leucovorin monograph for details.

Pediatric solid tumors (high-dose): I.V.:

<12 years: 12-25 g/m2

12 years: 8 g/m2

Acute lymphocytic leukemia (intermediate-dose): I.V.: Loading: 100 mg/m2 bolus dose, followed by 900 mg/m2/day infusion over 23-41 hours.

Meningeal leukemia: I.T.: 10-15 mg/m2 (maximum dose: 15 mg) or an age-based dosing regimen; one possible system is:

3 months: 3 mg/dose

4-11 months: 6 mg/dose

1 year: 8 mg/dose

2 years: 10 mg/dose

3 years: 12 mg/dose

Adults: I.V.: Range is wide from 30-40 mg/m2/week to 100-12,000 mg/m2 with leucovorin rescue

Trophoblastic neoplasms:

Oral, I.M.: 15-30 mg/day for 5 days; repeat in 7 days for 3-5 courses

I.V.: 11 mg/m2 days 1 through 5 every 3 weeks

Head and neck cancer: Oral, I.M., I.V.: 25-50 mg/m2 once weekly

Mycosis fungoides (cutaneous T-cell lymphoma): Oral, I.M.: Initial (early stages):

5-50 mg once weekly or

15-37.5 mg twice weekly

Bladder cancer: I.V.:

30 mg/m2 day 1 and 8 every 3 weeks or

30 mg/m2 day 1, 15, and 22 every 4 weeks

Breast cancer: I.V.: 30-60 mg/m2 days 1 and 8 every 3-4 weeks

Gastric cancer: I.V.:1500 mg/m2 every 4 weeks

Lymphoma, non-Hodgkin's: I.V.:

30 mg/m2 days 3 and 10 every 3 weeks or

120 mg/m2 day 8 and 15 every 3-4 weeks or

200 mg/m2 day 8 and 15 every 3 weeks or

400 mg/m2 every 4 weeks for 3 cycles or

1 g/m2 every 3 weeks or

1.5 g/m2 every 4 weeks

Sarcoma: I.V.: 8-12 g/m2 weekly for 2-4 weeks

Rheumatoid arthritis: Oral: 7.5 mg once weekly or 2.5 mg every 12 hours for 3 doses/week, not to exceed 20 mg/week

Psoriasis:

Oral: 2.5-5 mg/dose every 12 hours for 3 doses given weekly or

Oral, I.M.: 10-25 mg/dose given once weekly

Ectopic pregnancy: I.M., I.V.: 50 mg/m2 as a single dose

Elderly: Rheumatoid arthritis/psoriasis: Oral: Initial: 5-7.5 mg/week, not to exceed 20 mg/week

Dosing adjustment in renal impairment:

Clcr 61-80 mL/minute: Reduce dose to 75% of usual dose

Clcr 51-60 mL/minute: Reduce dose to 70% of usual dose

Clcr 10-50 mL/minute: Reduce dose to 30% to 50% of usual dose

Clcr<10 mL/minute: Avoid use

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

Dosage adjustment in hepatic impairment:

Bilirubin 3.1-5 mg/dL or AST >180 units: Administer 75% of usual dose

Bilirubin >5 mg/dL: Do not use

Administration

Methotrexate may be administered I.M., I.V., or I.T.; I.V. administration may be as slow push, short bolus infusion, or 24- to 42-hour continuous infusion

Specific dosing schemes vary, but high dose should be followed by leucovorin calcium to prevent toxicity; refer to Leucovorin monograph

Monitoring Parameters

For prolonged use (especially rheumatoid arthritis, psoriasis) a baseline liver biopsy, repeated at each 1-1.5 g cumulative dose interval, should be performed; WBC and platelet counts every 4 weeks; CBC and creatinine, LFTs every 3-4 months; chest x-ray



Reference Range

Therapeutic levels: Variable; Toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach.

High-dose regimens produce drug levels that are between 10-6 Molar and 10-7 Molar 24-72 hours after drug infusion

10-6Molar unit = 1 microMolar unit

Toxic: Low-dose therapy: >9.1 ng/mL; high-dose therapy: >454 ng/mL

Dietary Considerations

Sodium content of 100 mg injection: 20 mg (0.86 mEq)

Sodium content of 100 mg (low sodium) injection: 15 mg (0.65 mEq)

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Report immediately any redness, swelling, pain, or burning at infusion/injection site. It is very important to maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and nutrition (small, frequent meals may help). Avoid alcohol to prevent serious side effects. You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause sensitivity to sunlight (use sunscreen, wear protective clothing, and eyewear); nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help - if unresolved, contact prescriber); drowsiness, dizziness, numbness, or blurred vision (use caution when driving or engaging in tasks that require alertness until response to drug is known); loss of hair (may be reversible); color change of skin; permanent sterility; or mouth sores (frequent mouth care with soft toothbrush or cotton swabs and frequent rinses may help). Report immediately any rash, excessive or unusual fatigue, or respiratory difficulty. Report rapid heartbeat or palpitations, black or tarry stools, fever, chills, unusual bleeding or bruising, shortness of breath, persistent GI disturbances, diarrhea, constipation, pain on urination or change in urinary patterns, or any other persistent adverse effects. Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. This drug may cause birth defects. Do not breast-feed.

Infusion/injection:Pregnancy/breast-feeding precautions:

Additional Information

50 mg/2 mL, 100 mg/4 mL, and 250 mg/10 mL vials with and without preservatives by Immunex

Latex-free products:

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Ulcerative stomatitis, gingivitis, glossitis, and mucositis (dose dependent; appears 3-7 days post-therapy and resolves within 2 weeks).



Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions



Mental Health: Effects on Mental Status

May cause drowsiness or dizziness



Mental Health: Effects on Psychiatric Treatment

Leukopenia is common; avoid clozapine and carbamazepine



Oncology: Emetic Potential

Very low (<10%):

50 mg/m2

Low (10% to 30%):

250 mg/m2

Moderate (30% to 60%):

1000 mg/m2

High (60% to 90%): >1000 mg/m2

Oncology: Vesicant

No



Dosage Forms

Injection, powder for reconstitution [preservative free]: 20 mg, 1 g

Injection, solution, as sodium: 25 mg/mL (2 mL, 10 mL) [contains benzyl alcohol]

Injection, solution, as sodium [preservative free]: 25 mg/mL (2 mL, 4 mL, 8 mL, 10 mL)

Tablet, as sodium: 2.5 mg

Rheumatrex®: 2.5 mg

Trexall™: 5 mg, 7.5 mg, 10 mg, 15 mg

Tablet, as sodium [dose pack] (Rheumatrex® Dose Pack): 2.5 mg (4 cards with 2, 3, 4, 5, or 6 tablets each)

References

Evans WE, Pratt CB, Taylor RH, et al, "Pharmacokinetic Monitoring of High-Dose Methotrexate: Early Recognition of High-Risk Patients,"Cancer Chemother Pharmacol, 1979, 3:161-6.

Furst DE, "Methotrexate: New Mechanisms and Old Toxicities,"Agents Actions Suppl, 1993, 44:131-7.

Grem JL, King SA, Wittes RE, et al, "The Role of Methotrexate in Osteosarcoma,"J Natl Cancer Inst, 1988, 80(9):626-55.

Jolivet J, Cowan KH, Curt GA, et al, "The Pharmacology and Clinical Use of Methotrexate,"N Engl J Med, 1983, 309(18):1094-104.

Treon SP and Chabner BA, "Concepts in Use of High-Dose Methotrexate Therapy,"Clin Chem, 1996, 42(8 Pt 2):1322-9.

International Brand Names

Abitrexate® (IL, RO, TH); Antifolan® [inj.] (RO); Antifolan® (RO); Apo-Methotrexate® (CA); Asta Medica Metotrexato® (BR); Biotrexate® (IN); Canceren® (RO); Cytosafe Methotrexate® (ID); Cytosafe Metotrexato® (BR); DBL Methotrexate® (TH); Emthexate® (BE, ES, HK, ID, NL, NZ, TH, TR); Emthexat® (FI, NO, SE); Ervemin® (AR); Farmitrexat® (DE, ID); Faulding-Metotrexato® (BR); Lantarel® (DE); Ledertrexate® (AU, BE, LU, MX, NL, NZ); Ledertrexato® (PT); Maxtrex® (GB); Metex® (DE); Methoblastin® (AU, NZ); Methotrexat Bigmar® (CH); Methotrexat biosyn® (DE); Methotrexate® (AR, AU, CL, CY, GB, HR, IE, IL, NO, NZ, PL, RO, RU, TR, YU); Méthotrexate Bellon® (FR); Methotrexat Ebewe® (AT, CH, CO, CZ, HU, ID, PL, RO, RU, TH, YU); Methotrexate Bigmar® (CH); Methotrexate DBL® (ID, SG); Methotrexate Ebewe® (DK); Methotrexate Farmos ® [inj.] (CH); Methotrexate Faulding® (FI); Methotrexate® [inj.] (BR, GB, IT, RO, TR); Methotrexate Injection BP® (AU, NZ); Methotrexate Lederle® (HR, ID, TH); Methotrexate Pharmacia® (DK, SE, SG); Methotrexate Pliva® (HR, SI); Methotrexate Remedica® (TH); Methotrexate Roger Bellon® (TR); Methotrexate Sodium® (GB); Methotrexate Teva® (CZ, HU, TR); Methotrexate Wyeth Lederle® (DK, FI, IE, SE); Methotrexate Wyeth® (SG); Methotrexat Farmos® (CH); Methotrexat GRY® (DE); Methotrexat® (HR, PL, RU, YU); Methotrexat Lachema® (CZ, HU); Methotrexat Lederle® (AT, CH, CZ, DE, RO); Methotrexat medac® (DE); Methotrexat Ridupharm® (CH); Methotrexatum Pharmacia & Upjohn® (BE); Metoject® (DK, SE); Metotressato Fidia® (IT); Metotressato Teva® (IT); Metotrexate® (AR); Metotrexato Almirall® (ES); Metotrexato® (AR, BR, CL, ES); Metotrexato Asofarma® (AR); Metotrexato Chiesi® (ES); Metotrexato DBL® (IT); Metotrexato Dosa® (AR); Metotrexato Faulding® (AR); Metotrexato Filaxis® (AR); Metotrexato Lederle® (ES); Metotrexato Martian® (AR); Metotrexato Pharmacia® (ES); Metotrex® (BR); MTX Hexal® (DE, LU); MTX® (SG); Natrijev Methotrexat Lederle® (SI); Neotrexate® (IN); Novatrex® (FR); O-trexat® (DE); ratio-Methotrexate (CA); Texate® (MX); Texorate® (ID); Trexan® (FI, HU, PL, RO, TR); Trixilem® (MX, RO, RU, TH); Xantromid® (AR)



Review Date: 1969-12-31 Reviewed By: Keywords: ,
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