( Amethopterin ; MTX )

Pronunciation: meth-oh-TREK-sate
Class: Folic acid antagonist, Antirheumatic agent, Anti-psoriatic agent

Trade Names

Methotrexate LPF Sodium
- Injection 25 mg/mL

Methotrexate Sodium
- Injection 25 mg/mL

Methotrexate Sodium
- Powder for injection 20 mg
- Powder for injection 1 g

Rheumatrex Dose Pack
- Tablets 2.5 mg

Trexall
- Tablets 5 mg
- Tablets 7.5 mg
- Tablets 10 mg
- Tablets 15 mg

Apo-Methotrexate (Canada)
ratio-Methotrexate Sodium (Canada)

Pharmacology

Competitively inhibits dihydrofolic acid reductase and thereby inhibits DNA synthesis and cellular replication. In rheumatoid arthritis, believed to reduce immune function.

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Pharmacokinetics

Absorption

Oral absorption is dose dependent. T _max is 1 to 2 h (oral) and 30 to 60 min (IM). The mean bioavailability is 60%. Absorption of doses more than 80 mg/m ² is significantly less, possibly because of a saturation effect. Food delays absorption and reduces peak concentration.

Distribution

Initial Vd is 0.18 L/kg (18% of body weight); steady state Vd is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Approximately 50% is protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally, but it has been detected in breast milk.

Metabolism

Methotrexate undergoes hepatic and intracellular metabolism to active polyglutamated forms and is partially metabolized by intestinal flora after oral administration. Major metabolite is 7-hydroxymethotrexate.

Elimination

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% is excreted unchanged in urine within 24 h and less than 10% through biliary excretion. The t _½ for doses less than 30 mg/m ² is approximately 3 to 10 h; 8 to 15 h for high doses.

Special Populations

Renal Function Impairment

An increase in serum levels occurs because of decreased elimination in patients with renal function impairment.

Indications and Usage

Antineoplastic chemotherapy for treatment of gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole; treatment and prophylaxis of acute (meningeal) lymphocytic leukemia; treatment of breast cancer, epidermoid cancers of head and neck, advanced mycosis fungoides, and lung cancer; in combination therapy in advanced-stage non-Hodgkin lymphoma; as adjunct in high doses followed by leucovorin rescue in nonmetastatic osteosarcoma (postsurgically); symptomatic control of severe psoriasis and severe rheumatoid arthritis; polyarticular-course juvenile rheumatoid arthritis (JRA).

Contraindications

Use in nursing mothers. In patients with psoriasis or rheumatoid arthritis, methotrexate is contraindicated in pregnancy, alcoholism, alcoholic liver disease, chronic liver disease, overt or laboratory evidence of immunodeficiency syndrome, and preexisting blood dyscrasias (eg, leukopenia, thrombocytopenia); hypersensitivity to the drug.

Dosage and Administration

Choriocarcinoma and Thromboplastic Diseases
Adults

PO/IM 15 to 30 mg for 5 days. Repeat courses 3 to 5 times as required, with rest periods of more than 1 wk between courses.

Leukemia
Adults and Children Induction

PO/IM 3.3 mg/m ² /day in combination with prednisone 60 mg/m ² /day usually for 4 to 6 wk.

Postremission maintenance therapy (usually in combination with other drugs)

PO/IM 2 times/wk in total weekly doses of 30 mg/m ² or IV 2.5 mg/kg q 14 days.

Lymphoma (Burkitt Lymphoma, Stages 1 and 2)
Adults

PO 10 to 25 mg/day for 4 to 8 days. Provide 7- to 10-day rest period between courses.

Meningeal Leukemia
Adults

Intrathecal 12 mg/m ² (max, 15 mg). Administer q 2 to 5 days until cell count of CSF returns to normal, then give 1 additional dose. Dose reduction may be required in elderly patients because of differences in CSF volume.

Children at least 3 yr of age

Intrathecal 12 mg. Administer q 2 to 5 days until CSF cell count returns to normal.

Children 2 yr of age

Intrathecal 10 mg.

Children 1 yr of age

Intrathecal 8 mg.

Children younger than 1 yr of age

Intrathecal 6 mg.

Mycosis Fungoides
Adults

Dosage in early stages is usually 5 to 50 mg/wk. In patients responding poorly to weekly therapy, methotrexate has also been administered as 15 to 37.5 mg twice weekly. Combination chemotherapy regimens that include IV methotrexate at higher doses (with leucovorin rescue) have been used in advanced stages of the disease.

Osteosarcoma

Complex high dose with leucovorin rescue and other chemotherapeutic agents. Starting dose for high-dose methotrexate is 12 g/m ² .

Polyarticular-Course JRA

PO start with 10 mg/m ² /wk.

Psoriasis

Individualize dosage. Administer 5 to 10 mg parenteral test dose 1 wk prior to therapy.

Adults

IM/IV/PO 10 to 25 mg/wk (max, 30 mg/wk).

Adults

PO 2.5 mg q 12 h for 3 doses every wk (max, 30 mg/wk).

Rheumatoid Arthritis
Adults Initial therapy

PO 7.5 mg/wk in single dose or 2.5 mg q 12 h for 3 doses each wk. Gradually adjust dosage to max response; do not exceed 20 mg/wk.

Stage 3 Lymphosarcoma As Part of Combination Therapy
Adults

PO 0.625 to 2.5 mg/kg/day.

General Advice

• Injection
• Follow institutional procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.
• Ensure that leucovorin is available before beginning high-dose methotrexate therapy.
• Preservative-free methotrexate may be administered IM, IV, intra-arterially, or intrathecally.
• Reconstitute immediately prior to use.
• For intrathecal use, reconstitute immediately prior to administration using preservative-free diluent (eg, sodium chloride 0.9% injection).
• Follow manufacturer's guidelines for reconstitution and dilution of powder for injection and dilution of isotonic injection.
• Do not administer if solution is discolored or cloudy, or if particulate matter is noted.

Storage/Stability

Store tablets, injection, and powder for injection at controlled room temperature (59° to 86°F). Protect from light.

Drug Interactions

Acitretin, etretinate, NSAIDs, penicillins, probenecid, salicylates, sulfonamides, tetracyclines

May increase methotrexate blood levels and toxicity.

Antibiotics (oral) such as chloramphenicol, nonabsorbable broad spectrum antibiotics (eg, neomycin), and tetracycline

May decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation.

Charcoal

May reduce methotrexate efficacy.

Digoxin

May reduce serum digoxin levels and actions.

Folic acid

May decrease responses to systemically administered methotrexate.

Hydantoins

May reduce plasma levels.

Mercaptopurine

Plasma concentrations may be increased by methotrexate.

Theophylline

Methotrexate decreases Cl of theophylline.

Trimethoprim

May increase risk of methotrexate-induced bone marrow suppression and megaloblastic anemia.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Dizziness (1% to 3%); fatigue; headache; aphasia; hemiparesis; paresis; convulsions; leukoencephalopathy (IV after craniospinal irradiation); chemical arachnoiditis; transient paresis; neurotoxicity.

Dermatologic

Erythematous rashes, pruritus, alopecia (1% to 3%); urticaria; photosensitivity; pigmentary changes; ecchymosis; telangiectasia; acne; furunculosis; aggravation of psoriasis by ultraviolet light; Stevens-Johnson syndrome.

EENT

Blurred vision; ulcerative stomatitis; gingivitis; pharyngitis.

GI

Nausea, vomiting (10%); enteritis, stomatitis (3% to 10%); diarrhea (1% to 3%); abdominal distress (common); anorexia; hematemesis; melena; GI ulceration and bleeding.

Genitourinary

Renal failure; azotemia; cystitis; hematuria; severe nephropathy; reproductive disorders; infertility; abortion; fetal defects.

Hematologic

Thrombocytopenia (3% to 10%); leukopenia, pancytopenia (1% to 3%); bone marrow depression; anemia; hypogammaglobulinemia; hemorrhage; septicemia.

Hepatic

Elevated LFTs (15%); hepatotoxicity; hepatic cirrhosis and fibrosis.

Respiratory

Deaths from interstitial pneumonitis; chronic interstitial obstructive pulmonary disease.

Miscellaneous

Malaise; chills; fever; lower resistance to infections; arthralgia; myalgia; diabetes; osteoporosis; anaphylactoid reaction; sudden death.

Precautions

Warnings Deaths Deaths have occurred. Rheumatoid arthritis treatment Restrict use to patients with severe, recalcitrant, disabling disease not adequately responsive to other forms of therapy. Pregnancy Fetal death or congenital anomalies have occurred. Periodic monitoring Periodically monitor for toxicity, including CBC with differential and platelet counts and liver and renal function. Liver Methotrexate may cause hepatotoxicity, fibrosis, and cirrhosis. Lung disease Lung disease, a potentially dangerous lesion, may occur any time during therapy. Severe reactions Unexpectedly severe and sometimes fatal marrow suppression, aplastic anemia, and GI toxicity have been reported with coadministration of NSAIDs. Renal impairment Use with caution because methotrexate elimination will be prolonged. Skin reactions Severe and occasionally fatal skin reactions have been reported. Opportunistic infections Potentially fatal opportunistic infections may occur. Radiotherapy The risk of soft tissue necrosis and osteonecrosis may be increased by concurrent radiotherapy. GI Death from intestinal perforation may occur. Diarrhea and ulcerative stomatitis require interruption of therapy. Diluents Do not use methotrexate formulations and diluents containing preservatives for intrathecal or experimental high-dose methotrexate therapy. Malignant lymphomas Malignant lymphomas, which may regress following discontinuation of methotrexate, may occur. Tumor lysis syndrome May occur in patients with rapidly growing tumors.

Pregnancy

Category X (for rheumatoid arthritis and psoriasis); Category D (other uses).

Lactation

Contraindicated in nursing mothers.

Children

Safety and efficacy not established other than for cancer treatment and polyarticular-course JRA.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

Determine renal status before and during therapy.

Infection

Severe reactions may occur if live vaccines are administered.

Intrathecal therapy

Large doses may cause convulsions and systemic toxicity. Dosage regimens based on age may be more effective and associated with fewer neurotoxic side effects.

GI toxicity

Use with caution in presence of peptic ulcer disease or ulcerative colitis. Vomiting, diarrhea, or stomatitis may lead to dehydration.

Hematologic toxicity

Suppression of hematopoiesis, which may cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and thrombocytopenia, may occur.

Hepatic toxicity

Acute and chronic hepatotoxicity, which may be fatal, may occur.

Pulmonary symptoms

Pulmonary symptoms (eg, dry nonproductive cough) or a nonspecific pneumonitis may be indicative of a potentially dangerous lesion, requiring interruption of treatment.

Renal damage

Renal damage, leading to acute renal failure, may occur.

Severe effects

Potential toxicities include bone marrow depression, hepatotoxicity, lung disease (suggested by symptoms of dry, nonproductive cough), nephrotoxicity, and GI toxicity.

Overdosage

Symptoms

Hepatotoxicity, nephrotoxicity, GI toxicity, bone marrow toxicity, pulmonary toxicity

Intrathecal

Headache, nausea, vomiting, seizure or convulsion, acute toxic encephalopathy

Patient Information

• Advise patient, family, or caregiver of patient receiving parenteral or intrathecal methotrexate that medication will be prepared and administered by a health care provider in a medical setting.
• Review dose and appropriate dosing schedule, depending on condition being treated (eg, rheumatoid arthritis, psoriasis, neoplastic disease). Instruct patient to take medication exactly as prescribed and not to stop taking or change the dose unless advised by health care provider.
• Reinforce to patient taking methotrexate for rheumatoid arthritis or psoriasis that prescribed dose is taken once weekly, on the same day each week, and that taking more frequently can cause serious toxicity.
• Advise patient that medication can be taken without regard to meals but to take with food if stomach upset occurs.
• Caution patient to avoid using alcohol while taking methotrexate.
• Caution patient to avoid taking aspirin and other NSAIDs (eg, ibuprofen) while taking methotrexate unless advised by health care provider.
• Caution patient to avoid unnecessary exposure to UV light (sunlight, tanning booths) and to use sunscreen and wear protective clothing to avoid photosensitivity reaction.
• Advise patient that drug may cause drowsiness or dizziness and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
• Advise patient with rheumatoid arthritis that dose of medication may be changed based on tolerance and response and that therapy for up to at least 12 wk may be required before max benefit is noted.
• Advise patient with rheumatoid arthritis or psoriasis to continue to take other arthritis or psoriasis medications as prescribed by health care provider.
• Instruct patient to immediately report any of the following to health care provider: cough; difficulty breathing; diarrhea; stomach pain; sores in or around the mouth; fever, sore throat, or other signs of infection; rash or other skin reaction; bleeding or unusual bruising; yellow discoloration of skin or eyes; swelling of legs or feet.
• Advise patient to contact health care provider if medication does not control lesions and/or symptoms or if intolerable side effects develop.
• Advise women of childbearing potential to use effective contraception during and for at least 1 ovulatory cycle after therapy is completed.
• Advise female partner of male patient to use effective contraception during and for at least 3 mo after therapy has been completed by her partner.
• Instruct patient not to take any prescription or OTC medications, herbal preparations, or dietary supplements unless advised by health care provider. Folic acid, an ingredient in some OTC products, can reduce methotrexate efficacy.

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