methotrexate


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methotrexate

 [meth″o-trek´sāt]
an antimetaboliteantineoplastic agent that inhibits the conversion of folic acid to tetrahydrofolic acid by binding the enzyme dihydrofolate reductase, thus inhibiting DNA synthesis; it is specific for the S phase of the cell cycle. Used as the base and the sodium salt in the treatment of leukemias, lymphomas, sarcomas, and cancer of the head and neck, breast, colon, lung, testes, and other organs. Called also MTX. It is also used in the treatment of psoriasis and rheumatoid arthritis. Administered orally, intravenously, intramuscularly, intrathecally, or intra-arterially.

methotrexate (amethopterin, MTX)

Apo-Methotrexate (CA), Maxtrex (UK), Trexall

methotrexate sodium

Metoject (CA) (UK), Ratio-Methotrexate Sodium

Pharmacologic class: Antimetabolite, folic acid antagonist

Therapeutic class: Antineoplastic

Pregnancy risk category X

FDA Box Warning

• Give drug under supervision of physician experienced in antimetabolite use.

• Use drug only in life-threatening neoplastic diseases or in patients with severe, recalcitrant, disabling psoriasis that responds inadequately to other therapies.

• Deaths have occurred when drug was used to treat cancer and psoriasis.

• Monitor patient closely for bone marrow, liver, lung, and kidney toxicities. Explain risks involved, and stress importance of adequate follow-up.

• Use caution when giving high-dose regimen for osteosarcoma. (High-dose regimens for other cancers are investigational.)

• Don't use preserved forms and diluents containing preservatives for intrathecal or high-dose therapy.

• Don't give to pregnant women or women with childbearing potential unless medical evidence suggests benefits may outweigh risks. Drug has caused fetal death and congenital anomalies.

• Drug elimination is reduced in patients with renal impairment, ascites, or pleural effusions. Monitor them carefully for toxicity; dosage may need to be reduced or drug may need to be stopped.

• Unexpectedly severe (sometimes fatal) bone marrow suppression and GI toxicity have occurred in patients receiving drug (usually in high doses) concurrently with nonsteroidal anti-inflammatory drugs (NSAIDs).

• Drug causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acute liver enzyme elevations are common but usually transient and asymptomatic. Perform periodic liver biopsies in psoriasis patients receiving long-term therapy.

• Potentially dangerous lung disease may arise acutely at any time during therapy. Not always fully reversible, it has occurred at dosages as low as 7.5 mg/week.

• Interrupt therapy for diarrhea and ulcerative stomatitis; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.

• Malignant lymphomas may occur at low dosages and may not require cytotoxic treatment. Discontinue drug first; if lymphoma doesn't regress, begin appropriate treatment.

• Drug may induce tumor lysis syndrome in patients with rapidly growing tumors.

• Severe and occasionally fatal skin reactions have occurred within days of single or multiple P.O., I.M., I.V., or intrathecal doses. Drug withdrawal has led to recovery.

• Potentially fatal opportunistic infections may occur.

• When given concomitantly with radiation therapy, drug may increase risk of soft-tissue necrosis and osteonecrosis.

Action

Binds to dihydrofolate reductase, interfering with folic acid metabolism and inhibiting DNA synthesis and cellular replication

Availability

Injection: 20-mg, 25-mg, 50-mg, 100-mg, 250-mg, and 1,000-mg vials (lyophilized powder, preservative-free)

Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg

Indications and dosages

Acute lymphoblastic leukemia

Adults and children: 3.3 mg/m2 P.O. or I.M. daily for 4 to 6 weeks, then 20 to 30 mg/m2 P.O. or I.M. weekly in two divided doses; given with corticosteroid. Alternatively, 2.5 mg/kg I.V. q 14 days.

Meningeal leukemia

Adult and children: 12 mg/m2 (maximum of 15 mg) intrathecally at intervals of 2 to 5 days, repeated until cerebrospinal fluid cell count is normal

Burkitt's lymphoma

Adults: In stages I and II, 10 to 25 mg P.O. daily for 4 to 8 days; in stage III, combined with other neoplastic drugs. Patients in all stages usually require several courses of therapy, with 7- to 10-day rest periods between courses.

Mycosis fungoides

Adults: 2.5 to 10 mg/day P.O. or 50 mg I.M. q week or 25 mg I.M. twice weekly

Osteosarcoma

Adults: As part of adjunctive regimen with other antineoplastics, initially 12 g/m2 I.V. as 4-hour infusion, then 12 to 15 g/m2 I.V. in subsequent 4-hour infusions given at weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 until peak blood level reaches 1,000 micromoles. Leucovorin rescue must start 24 hours after methotrexate infusion begins; if patient can't tolerate oral leucovorin, dose must be given I.M. or I.V. on same schedule.

Trophoblastic tumors (choriocarcinoma, hydatidiform mole)

Adults: 15 to 30 mg P.O. or I.M. daily for 5 days. Repeat course three to five times as required, with rest periods of at least 1 week between courses, until toxic symptoms subside.

Lymphosarcoma (stage III)

Adults: 0.625 to 2.5 mg/kg/day P.O., I.M., or I.V.

Psoriasis

Adults: After test dose, 2.5 mg P.O. at 12-hour intervals for three doses weekly, to a maximum of 30 mg weekly. Alternatively, 10 to 25 mg P.O., I.M., or I.V. as a single weekly dose, to a maximum of 30 mg weekly; decrease dosage when adequate response occurs.

Rheumatoid arthritis

Adults: 7.5 mg P.O. weekly as a single dose or divided as 2.5 mg q 12 hours for three doses weekly. May gradually increase, if needed, up to 20 mg/week; decrease when adequate response occurs.

Dosage adjustment

• Renal or hepatic impairment

• Elderly patients

Off-label uses

• Relapsing-remitting multiple sclerosis

• Refractory Crohn's disease

Contraindications

• Hypersensitivity to drug

• Psoriasis or rheumatoid arthritis in pregnant patients

• Breastfeeding

Precautions

Use cautiously in:

• severe myocardial, hepatic, or renal disease; decreased bone marrow reserve; active infection; hypotension; coma

• elderly patients

• patients with childbearing potential

• young children.

Administration

Be aware that methotrexate is a high-alert drug when used orally for nonchemotherapeutic use.

Know that patient must be adequately hydrated before therapy and urine must be alkalized using sodium bicarbonate.

• Follow facility policy for handling, preparing, and administering carcinogenic, mutagenic, and teratogenic drugs.

• Be aware that oral administration is preferred. Give oral dose 1 hour before or 2 hours after meals. (Food decreases absorption of tablets and reduces peak blood level.)

• Reconstitute powder for injection with preservative-free solution, such as 5% dextrose solution or 0.9% sodium chloride injection. Reconstitute 20-mg and 50-mg vials to yield a concentration no greater than 25 mg/ml. Reconstitute 1-g vial with 19.4 ml to yield a concentration of 50 mg/ml.

• For high-dose I.V. infusion, dilute in 5% dextrose solution. Administer each 10 mg over 1 minute or by infusion over 30 minutes to 4 hours as directed.

• For intrathecal use, reconstitute immediately before administration, using preservative-free solution (such as 0.9% sodium chloride for injection), to a concentration of 1 mg/ml.

For intrathecal or high-dose therapy, use preservative-free injection form.

• Avoid I.M. injections if platelet count is below 50,000/mm3.

For osteosarcoma, make sure leucovorin rescue is used appropriately in patients receiving high methotrexate doses. Rescue usually starts 24 hours after methotrexate infusion begins.

Adverse reactions

CNS: malaise, fatigue, drowsiness, dizziness, headache, aphasia, hemiparesis, demyelination, seizures, leukoencephalopathy, chemical arachnoiditis (with intrathecal use)

EENT: blurred vision, pharyngitis

GI: nausea, vomiting, stomatitis, hematemesis, melena, GI ulcers, enteritis, gingivitis, pharyngitis, anorexia, GI bleeding

GU: hematuria, cystitis, infertility, menstrual dysfunction, defective spermatogenesis, abortion, tubular necrosis, severe nephropathy, renal failure

Hematologic: anemia, leukopenia, thrombocytopenia, severe bone marrow depression

Hepatic: hepatotoxicity

Metabolic: hyperuricemia, diabetes mellitus

Musculoskeletal: joint pain, myalgia, osteonecrosis, osteoporosis (with long-term use in children)

Respiratory: dry nonproductive cough, pneumonitis, pulmonary fibrosis, pulmonary interstitial infiltrates

Skin: pruritus, rash, urticaria, alopecia, painful plaque erosions, photosensitivity

Other: chills, fever, increased susceptibility to infection, septicemia, anaphylaxis, sudden death

Interactions

Drug-drug. Activated charcoal: decreased blood level of oral or I.V. methotrexate

Folic acid derivatives: antagonism of methotrexate effects

Fosphenytoin, phenytoin: decreased blood levels of these drugs

Hepatotoxic drugs: increased risk of hepatotoxicity

NSAIDs, phenylbutazone, probenecid, salicylates, sulfonamides: increased methotrexate toxicity

Oral antibiotics: decreased methotrexate absorption

Penicillin, sulfonamide: increased methotrexate blood level

Procarbazine: increased nephrotoxicity

Theophylline: increased theophylline level

Vaccines: vaccine inefficacy

Drug-diagnostic tests. Hemoglobin, platelets, red blood cells, white blood cells: decreased values

Pregnancy tests: false-positive result

Protein-bound iodine, transaminases, uric acid: increased levels

Drug-food. Any food: delayed methotrexate absorption and decreased peak blood level

Drug-herbs. Astragalus, echinacea, melatonin: interference with methotrexate-induced immunosuppression

Drug-behaviors. Alcohol use: increased hepatotoxicity

Sun exposure: photosensitivity

Patient monitoring

• Watch for vomiting, diarrhea, or stomatitis, which may cause dehydration.

Know that high-dose therapy may cause nephrotoxicity. Monitor renal function, hydration status, urine alkalization (for pH above 6.5), and methotrexate blood level.

Assess for fever, sore throat, bleeding, increased bruising, and other signs and symptoms of hematologic compromise or infection.

• With high-dose or intrathecal therapy, watch for CNS toxicity.

Monitor creatinine and methotrexate blood levels 24 hours after therapy starts and then daily. Adjust leucovorin dosage as prescribed.

• Check hematologic studies at least monthly; blood or platelet transfusions may be necessary.

• Monitor liver and kidney function studies every 1 to 3 months. Evaluate uric acid levels.

Watch for signs and symptoms of pulmonary toxicity, such as fever, dry nonproductive cough, dyspnea, hypoxemia, and infiltrates on chest X-ray.

• Know that methotrexate exits slowly from third-space compartments (ascites, pleural effusions). Before therapy starts, fluid should be evacuated; during therapy, monitor drug blood level.

Patient teaching

Review dosing instructions carefully with patient to avoid toxicity. Tell patient with rheumatoid arthritis or psoriasis to take doses weekly.

• Advise patient to take oral doses 1 hour before or 2 hours after meals.

• Instruct patient to report diarrhea, abdominal pain, clay-colored or black tarry stools, fever, chills, sore throat, unusual bleeding or bruising, sores in or around mouth, cough or shortness of breath, yellowing of skin or eyes, dark or bloody urine, swelling of feet or legs, or joint pain.

• Tell patient to take temperature daily and to report fever or other signs or symptoms of infection.

• Instruct patient to drink 2 to 3 L of fluid each day.

• Advise male patients to use reliable contraception during and for at least 3 months after therapy. Advise female patients to use reliable contraception during and for one ovulatory cycle after therapy; also caution them not to breastfeed.

• Advise patient to avoid sun exposure and to use sunscreen and protective clothing (especially if he has psoriasis).

• Instruct patient to avoid alcohol.

• Tell patient he'll need to undergo blood tests during therapy.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, herbs, and behaviors mentioned above.

meth·o·trex·ate

(meth'ō-trek'sāt),
A folic acid antagonist used as an antineoplastic agent; used to treat psoriasis and rheumatoid arthritis.
Synonym(s): amethopterin

methotrexate

/meth·o·trex·ate/ (-trek´sāt) a folic acid antagonist used as the base or the sodium salt as an antineoplastic, antipsoriatic, and antiarthritic.

methotrexate

(mĕth′ə-trĕk′sāt)
n.
A toxic antimetabolite, C20H22N8O5, that acts as a folic acid antagonist to interfere with cellular reproduction and is used to treat psoriasis, certain cancers, and some inflammatory diseases such as rheumatoid arthritis.

methotrexate

[meth′ōtrek′sāt]
an antineoplastic antimetabolite. Also called amethopterin.
indications It is prescribed in the treatment of a variety of malignant neoplastic diseases of the blood and organs and in the treatment of psoriasis, and it is widely used as an immunosuppressive agent for the treatment of autoimmune diseases such as rheumatoid arthritis.
contraindications Blood dyscrasias, severe renal or hepatic impairment, or known hypersensitivity to this drug prohibits its use.
adverse effects Among the more serious adverse effects are diarrhea, ulcerative stomatitis, bone marrow depression, hepatotoxicity, and skin rash.

methotrexate

A widely used, toxic antimetabolic agent. MTX is a potent folic acid antagonist (antifolate) and competes with dihydrofolate (the natural substrate) for binding sites on dihydrofolate reductase (DHFR), blocking production of tetrahydrofolate; folate is the vitamin co-factor in methyl group transport for purine and thymidilic acid synthesis and DNA synthesis.

Toxicity
Nausea, vomiting, anorexia, stomatitis, CNS changes, hypersensitivity, liver damage, ocular irritation, dose-limiting myelotoxicity may appear 4–7 days after beginning therapy, nephrotoxicity (crystallisation within renal tubules).

Lab
Transient increase of LFTs.
 
Gynaecology—Indications
May be used to manage tubal pregnancy; evokes resorption or tubal abortion by an unknown mechanism; failure of MTX is increased if hCG levels are increased.
 
Pronunciation
Medspeak-UK: pronounced MEE tho trex ate
Medspeak-US: pronounced MEH tho trex ate

Oncology
A widely used chemotherapeutic, which may be used alone to cure certain malignancies (e.g., choriocarcinoma) or with other agents for lymphoproliferations (ALL; ANLL; Hodgkin lymphoma; non-Hodgkin’s, Burkitt’s and histiocytic lymphomas; mycosis fungoides; myeloma; head and neck, ovarian and small-cell carcinomas; osteosarcoma; medulloblastoma) and nonmalignant conditions (e.g., recalcitrant psoriasis, rheumatoid arthritis, inflammatory bowel disease). Combined with cyclosporine and prednisone, MTX reduces the incidence of acute GVHD from 23% to 9%, without affecting disease-free survival.

methotrexate

Folex® PFS, Rheumatrex® Oncology A widely used but toxic antimetabolic chemotherapeutic which may be used alone to treat certain malignancies–eg, choriocarcinoma, and with other agents for lymphoproliferations–ALL, ANLL, Hodgkin's disease, non-Hodgkin's, Burkitt's and histiocytic lymphomas, mycosis fungoides, myeloma, head & neck, ovarian and small cell carcinomas, osteosarcoma, medulloblastoma; nonmalignant conditions–eg, recalcitrant psoriasis, rheumatoid arthritis; combined with cyclosporine and prednisone, MTX ↓ the incidence of acute GVHD from 23% to 9%, without affecting disease-free survival; MTX is a potent folic acid antagonist–antifolate and competes with dihydrofolate—the natural substrate, for binding sites on dihydrofolate reductase–DHFR, blocking production of tetrahydrofolate–folate is the vitamin co-factor in methyl group transport for purine and thymidilic acid synthesis and DNA synthesis. See Leucovorin rescue, MDR gene Toxicity N&V, anorexia, stomatitis, CNS changes, hypersensitivity, liver damage, ocular irritation, dose-limiting myelotoxicity may appear 4-7 days after beginning therapy, nephrotoxicity–crystallization within renal tubules Lab Transient ↑of LFTs.

meth·o·trex·ate

(meth'ō-trek'sāt)
A folic acid antagonist used as an antineoplastic agent and to treat psoriasis and rheumatoid arthritis.

methotrexate

An ANTIMETABOLITE and IMMUNOSUPPRESSIVE drug used to treat cancer and help in the treatment of RHEUMATOID ARTHRITIS. It acts by interfering with the metabolism of FOLIC ACID. The drug is on the WHO official list. A brand name is Maxtrex.

Methotrexate

A drug that interferes with cell growth and is used to treat rheumatoid arthritis as well as various types of cancer. Side-effects may include mouth sores, digestive upsets, skin rashes, and hair loss.

immunosuppressants

Drugs that prevent or reduce the immune response. They are used in the treatment of a variety of severe inflammations such as uveitis, scleritis, keratoconjunctivitis sicca, Behçet's syndrome, sympathetic ophthalmia, and to prevent corneal graft rejection. They include the corticosteroids (e.g. prednisolone), ciclosporin (cyclosporine), tacrolimus, and cytotoxic agents (e.g. azathioprine, chlorambucil, cyclophosphamide, methotrexate). It must be noted that immunosuppressants render the patient more susceptible to infection because immunity is reduced.

meth·o·trex·ate

(meth'ō-trek'sāt)
Folic acid antagonist used as an antineoplastic agent and to treat psoriasis and rheumatoid arthritis.

methotrexate

a folic acid antagonist used as an antineoplastic agent.

Patient discussion about methotrexate

Q. Is methotrexate available in the United States as a treatment for fibromyalgia? Last year I was diagnosed as fibromyalgia. I feel a lot of fatigue and stiffness. I came upon a website from where I read that rheumatoid arthritis causes those same symptoms and can be treated with methotrexate. After reading that, I purchased a half year supply of the drug over the counter in Mexico. It eliminated all of my symptoms. A month after my supply ran out, all the symptoms returned. Is methotrexate available in the United States as a treatment for fibromyalgia?

A. Yes fatigue and stiffness are some of the symptoms of fibromyalgia. Methotrexate is certainly available in the United States, but it is not approved for nor used as a treatment for fibromyalgia. It was originally developed to treat cancer and subsequently found to be very effective for a number of inflammatory disorders, such as RA and psoriasis. Because fibromyalgia is not an inflammatory disorder – that is, there is no identifiable inflammation in the muscles or joints in individuals with this condition – it is not clear why you responded to this drug. You should tell your physician about your response to methotrexate. It may be possible that you have an inflammatory disorder rather than – or in addition to – fibromyalgia.

More discussions about methotrexate
References in periodicals archive ?
They assigned 159 to continue weekly doses of methotrexate after flu vaccination and 161 to stop it for 2 weeks.
Patients with mild disease usually require only topical treatment however those with moderate to severe disease generally require phototherapy, ciclosporin, methotrexate and acitretin.
Four doses of methotrexate to be given until Serum BHCG level declines by 15%.
Within one month of methotrexate cessation, the lesion completely resolved, although clinically her peripheral arthritis worsened.
The patients' average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week.
We have not found any clinical or laboratory adverse events attributable to methotrexate therapy or to thalidomide therapy; however prednisolone induced cushingoid features, striae distansae, gastritis, and weight gain was present in all the cases.
Among the 1,083 women assigned to the watchful waiting protocol, 674 (62%) had spontaneous resolutions, while 409 (38%) had stable or increasing beta-hCG levels and received methotrexate, 50 mg/m2 IM, usually once, but sometimes twice.
In developing country like Pakistan methotrexate is an economical and effective antipsoriatic agent and is given for extensive plaque type psoriasis erythrodermic acute pustular and severe psoriatic arthropathy.
This was due to the increased risk of complications, including emergency surgery, repeated admission and subsequent doses of methotrexate.
Methotrexate itself is in fact almost undetectable in the serum 24 hours after administration.
To avoid adding staff and instrumentation for a new methotrexate assay, we developed a method to quantify methotrexate and other immunosuppressants in the same assay.