Methotrexate

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Especially tell your doctor if you take:

• nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, choline magnesium trisalicylate (Tricosal, Trilisate), ibuprofen (Advil, Motrin), magnesium salicylate (Doan's), naproxen (Aleve, Naprosyn) or salsalate.
• acitretin (Soriatane)
• azathioprine (Imuran)
• isotretinoin (Accutane)
• sulfasalazine (Azulfidine)
• tretinoin (Vesanoid)
• chloramphenicol (chloramycetin)
• penicillin
• tetracycline
• folic acid
• phenytoin (Dilantin)
• probenecid (Benemid)
• co-trimoxazole (Bactrim, Septra)
• sulfadiazine
• sulfamethizole (Urobiotic)
• sulfisoxazole (Gantrisin)
• and theophylline (Theocron, Theolair)

This is not a complete list of methotrexate drug interactions. Ask your doctor or pharmacist for more information.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of methotrexate there are no specific foods that you must exclude from your diet when receiving this medication.

WARNING:

• METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY. BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL):
• METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY.
• DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS. PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES.
• PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
• THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. HIGH DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED. METHOTREXATE FORMULATIONS AND DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR INTRATHECAL OR HIGH DOSE METHOTREXATE THERAPY
• Methotrexate has been reported to cause fetal death and/or congenital anomalies.Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate.
• Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration
• Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
• Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. 
• Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
• Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
• Like other cytotoxic drugs, methotrexate may induce“tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
• Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.
• Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.
• Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

You must use the correct dose of methotrexate for your condition. Methotrexate is usually taken once or twice per week and not every day. Follow the directions on your prescription label. Some people have died after taking methotrexate every day by accident. Ask your doctor if you have any questions about your dose of methotrexate or how often to take it.

Methotrexate can cause serious or life-threatening side effects on your liver, lungs, kidneys, and bone marrow (immune system). Do not take this medication in larger amounts, or take it for longer than prescribed. Follow the directions on your prescription label.

Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you have liver disease (especially if caused by alcoholism), a blood cell or bone marrow disorder, or if you are breast-feeding a baby.

This medication can cause birth defects in an unborn baby. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you are pregnant. Use an effective form of birth control, whether you are a man or a woman. Tell your doctor if you or your sexual partner become pregnant during treatment.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney or liver function may also need to be tested. Do not miss any scheduled appointments.

There are many other medicines that can interact with methotrexate. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

Antineoplastic agent and immunosuppressant; folic acid antagonist.a 262 265

• Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate reductase (enzyme that reduces folic acid to tetrahydrofolic acid); inhibition of tetrahydrofolate formation limits availability of one-carbon fragments necessary for synthesis of purines and conversion of deoxyuridylate to thymidylate in DNA synthesis and cell reproduction.a 262 265

• Also causes an increase in intracellular deoxyadenosine triphosphate, which is thought to inhibit ribonucleotide reduction, and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair.a

• Tissues with high rates of cellular proliferation (e.g., neoplasms, psoriatic epidermis, bone marrow, lining of GI tract, hair matrix, fetal cells, urinary bladder) are most sensitive.a

• Also has immunosuppressive activity, possibly because of lymphocyte multiplication inhibition.a

• Mechanism(s) of action in rheumatoid arthritis not known; suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects.113 116 127 128 138 141 142 144 145 262 265

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

In the U.S.

• Rheumatrex Dose Pack
• Trexall
• Xatmep

Available Dosage Forms:

• Solution
• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Antimetabolite

Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. Methotrexate irreversibly binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, thus interfering with DNA synthesis, repair, and cellular replication. Methotrexate is cell cycle specific for the S phase of the cycle. Actively proliferative tissues are more susceptible to the effects of methotrexate.

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

In Crohn disease, it may have immune modulator and anti-inflammatory activity.

Absorption

Oral: Highly variable; dose dependent; decreased absorption at higher doses (pediatric patients: >40 mg/m2; adult patients: >80 mg/m2); possibly due to saturation effect; IM injection: Complete

IM injection: Complete

Distribution

Penetrates slowly into 3rd space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); sustained concentrations retained in kidney and liver; Vd: IV: 0.18 L/kg (initial); 0.4 to 0.8 L/kg (steady state)

Metabolism

Partially metabolized by intestinal flora (after oral administration) to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-hydroxy 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. Polyglutamated forms can be converted back to methotrexate.

Excretion

Dose and route dependent; IV: Urine (80% to 90% as unchanged drug; 5% to 7% as 7-hydroxy methotrexate); feces (<10%)

Antirheumatic: 3 to 6 weeks; additional improvement may continue longer than 12 weeks

Time to Peak

Serum: Oral: Children: 0.7 to 4 hours (reported for a 15 mg/m2 dose); Adults: 1 to 2 hours; Children and Adults: IM: 30 to 60 minutes

Half-Life Elimination

Children: ALL: 0.7 to 5.8 hours (dose range: 6.3 to 30 mg/m2); pJIA: 0.9 to 2.3 hours (dose range: 3.75 to 26.2 mg/m2)

Adults: Low dose: 3 to 10 hours; High dose: 8 to 15 hours

Protein Binding

~50%

Known hypersensitivity to methotrexate or any component of the formulation; breast-feeding

Additional contraindications for patients with psoriasis, rheumatoid arthritis or polyarticular-course juvenile idiopathic arthritis: Pregnancy, alcoholism, alcoholic liver disease or other chronic liver disease, immunodeficiency syndromes (overt or laboratory evidence); preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)

Note: Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Doses >500 mg/m2 require leucovorin calcium rescue (refer to Dosing – Adjustment for Toxicity for leucovorin calcium dosing). Doses ≥250 mg/m2 (IV) are associated with moderate emetic potential. Antiemetics may be recommended to prevent nausea and vomiting.

Acute lymphoblastic leukemia (ALL):

Meningeal leukemia prophylaxis or treatment: Intrathecal: Manufacturer’s labeling: 12 mg (maximum 15 mg/dose) every 2 to 7 days; continue for 1 dose beyond CSF cell count normalization. Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer 1983; Kerr 2001).

CALGB 8811 regimen (Larson 1995; combination therapy):

Early intensification: Intrathecal: 15 mg day 1 of early intensification phase, repeat in 4 weeks

CNS prophylaxis/interim maintenance phase:

Intrathecal: 15 mg day 1, 8, 15, 22, and 29

Oral: 20 mg/m2 days 36, 43, 50, 57, and 64

Prolonged maintenance: Oral: 20 mg/m2 days 1, 8, 15, and 22 every 4 weeks for 24 months from diagnosis

Dose-intensive regimen (Kantarjian 2000; combination therapy):

IV: 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)

CNS prophylaxis: Intrathecal: 12 mg on day 2 of each cycle; duration depends on risk

Maintenance: IV: 10 mg/m2/day for 5 days every month for 2 years (in combination with prednisone, vincristine, and mercaptopurine)

Breast cancer: IV: CMF regimen: 40 mg/m2 days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil) for 6 to 12 cycles (Bonadonna 1995; Levine 1998)

Choriocarcinoma, chorioadenoma, gestational trophoblastic diseases: 15 to 30 mg oral or IM daily for a 5 day course; may repeat for 3 to 5 courses (manufacturer’s labeling) or 100 mg/m2 IV over 30 minutes followed by 200 mg/m2 IV over 12 hours (with leucovorin 24 hours after the start of methotrexate), administer a second course if hCG levels plateau for 3 consecutive weeks (Garrett 2002) or 100 mg/m2 IV push followed by 200 mg/m2 IV over 12 hours on day 1 (with leucovorin 24 hours after the start of methotrexate; in combination with dactinomycin, etoposide, vincristine, and cyclophosphamide) every 14 days and continuing for at least 2 cycles after hCG level is normal (Escobar 2003; Lurain 2006)

Head and neck cancer, advanced: IV: 40 mg/m2 once weekly until disease progression or unacceptable toxicity (Forastiere 1992; Guardiola 2004; Stewart 2009)

Lymphoma, non-Hodgkin: IV:

CODOX-M/IVAC regimen (Mead 2008): Cycles 1 and 3 of CODOX-M (CODOX-M alternates with IVAC)

Adults ≤65 years: IV: 300 mg/m2 over 1 hour (on day 10) followed by 2,700 mg/m2 over 23 hours (with leucovorin rescue)

Adults >65 years: IV: 100 mg/m2 over 1 hour (on day 10) followed by 900 mg/m2 over 23 hours (with leucovorin rescue)

Hyper-CVAD alternating with high-dose methotrexate/cytarabine regimen: IV: 1,000 mg/m2 over 24 hours on day 1 during even courses (2, 4, 6, and 8) of 21-day treatment cycles (Thomas 2006) or 200 mg/m2 bolus day 1 followed by 800 mg/m2 over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles (Khouri 1998) with leucovorin rescue

Mycosis fungoides (cutaneous T-cell lymphoma): 5 to 50 mg once weekly or 15 to 37.5 mg twice weekly orally or IM for early stages (manufacturer’s labeling) or 25 mg orally once weekly, may increase to 50 mg once weekly (Zackheim 2003)

Osteosarcoma: Adults ≤30 years: IV: MAP regimen: 12 g/m2 (maximum: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 4, 5, 9, and 10, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 24, 25, 28, and 29 (in combination with doxorubicin and cisplatin) (Bielack 2015; Whelan 2015); other combinations, intervals, age ranges, and doses (8 to 14 g/m2/dose) have been described (with leucovorin rescue), refer to specific reference for details (Bacci 2000; Bacci 2003; Goorin 2003; Le Deley 2007; Meyers 1992; Meyers 2005; Weiner 1986; Winkler 1988)

Psoriasis: Note: Some experts recommend concomitant folic acid 1 to 5 mg daily (except the day of methotrexate) to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.

Oral: Initial: 2.5 to 5 mg/dose every 12 hours for 3 doses per week or

Oral, IM, IV, SubQ: Initial: 10 to 25 mg given once weekly; adjust dose gradually to optimal response (doses above 20 mg once weekly are associated with an increased incidence of toxicity); doses >30 mg per week should not be exceeded.

Note: An initial test dose of 2.5 to 5 mg is recommended in patients with risk factors for hematologic toxicity or renal impairment. (Kalb 2009).

Rheumatoid arthritis: Note: Some experts recommend concomitant folic acid at a dose of least 5 mg per week (except the day of methotrexate) to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.

Oral (manufacturer labeling): Initial: 7.5 mg once weekly or 2.5 mg every 12 hours for 3 doses per week; adjust dose gradually to optimal response (dosage exceeding 20 mg once weekly are associated with an increased incidence of toxicity; alternatively, 10 to 15 mg once weekly, increased by 5 mg every 2 to 4 weeks to a maximum of 20 to 30 mg once weekly has been recommended by some experts. Consider parenteral therapy with inadequate response or intolerance to oral therapy (Visser 2009).

SubQ: Initial: 7.5 mg once weekly; adjust dose gradually to optimal response (doses above 20 mg once weekly are associated with an increased incidence of toxicity)

IM: 7.5 mg once weekly; adjust dose gradually to optimal response (doses above 20 mg once weekly are associated with an increased incidence of toxicity)

Off-label uses:

Acute promyelocytic leukemia (APL) maintenance phase:

Oral: 15 mg/m2 once weekly for 2 years (Ades 2008) or 20 mg/m2 once weekly for 1 year (Powell 2010)

IM: 15 mg/m2 once weekly for 2 years (Sanz 2004)

Bladder cancer (off-label use): IV:

Dose-dense MVAC regimen: 30 mg/m2 day 1 every 2 weeks (in combination with vinblastine, doxorubicin, and cisplatin) (Sternberg 2001)

CMV regimen: 30 mg/m2 days 1 and 8 every 3 weeks for 3 cycles (in combination with cisplatin, vinblastine and leucovorin rescue) (Griffiths 2011)

CNS lymphoma (off-label use): IV: 8,000 mg/m2 over 4 hours (followed by leucovorin rescue) every 14 days until complete response or a maximum of 8 cycles; if complete response, follow with 2 consolidation cycles at the same dose every 14 days (with leucovorin rescue), followed by 11 maintenance cycles of 8,000 mg/m2 every 28 days with leucovorin rescue (Batchelor 2003) or 2,500 mg/m2 over 2 to 3 hours every 14 days for 5 doses (in combination with vincristine, procarbazine, intrathecal methotrexate, leucovorin, dexamethasone, and cytarabine) (De Angelis 2002) or 3,500 mg/m2 over 2 hours on day 2 every 2 weeks (in combination with rituximab, vincristine, procarbazine, and leucovorin [with intra-omaya methotrexate 12 mg between days 5 and 12 of each cycle if positive CSF cytology]) for 5 to 7 induction cycles (Shah 2007)

Crohn disease, moderate/severe, corticosteroid-dependent or refractory (off-label use):

Remission induction or reduction of steroid use: IM, SubQ: 25 mg once weekly (Lichtenstein 2009)

Remission maintenance: IM: 15 mg once weekly (Feagan 2000; Lichtenstein 2009)

Dermatomyositis/polymyositis (off-label uses):

Oral: Initial: 7.5 to 15 mg per week, often adjunctively with high-dose corticosteroid therapy; may increase in weekly 2.5 mg increments to target dose of 10 to 25 mg per week (Note: Administration of folate 5 to 7 mg per week has been used to reduce side effects) (Briemberg 2003; Newman 1995; Wiendl 2008).

IV, IM: Doses of 20 to 60 mg/week have been employed if failure with oral therapy (doses >50 mg/week may require leucovorin calcium rescue) (Briemberg 2003)

Ectopic pregnancy (off-label use): IM:

Single-dose regimen: Methotrexate 50 mg/m2 on day 1; Measure serum hCG levels on days 4 and 7; if needed, repeat dose on day 7 (ACOG 2008; ASRM 2006; Barnhart 2009)

Two-dose regimen: Methotrexate 50 mg/m2 on day 1; Measure serum hCG levels on day 4 and administer a second dose of methotrexate 50 mg/m2; Measure serum hCG levels on day 7 and if needed, administer a third dose of 50 mg/m2 (ACOG 2008; Barnhart 2009)

Multidose regimen: Methotrexate 1 mg/kg on day 1; leucovorin calcium 0.1 mg/kg IM on day 2; measure serum hCG on day 2; methotrexate 1 mg/kg on day 3; leucovorin calcium 0.1 mg/kg on day 4; measure serum hCG on day 4; continue up to a total of 4 courses based on hCG concentrations (ACOG 2008; ASRM 2006; Barnhart 2009)

Graft-versus-host disease, acute (aGVHD), prophylaxis: IV: 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Chao 1993; Chao 2000; Ross 1999) or 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Chao 2000) or 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine, followed by leucovorin); may omit day 11 methotrexate for grade 2 or higher toxicity (Ruutu 2013)

Multiple sclerosis (off-label use): Oral: 7.5 or 20 mg once weekly either alone or as add-on therapy to interferon beta-1a (Calabresi 2002; Goodkin 1996; Lugaresi 2001)

Nonleukemic meningeal cancer (off-label uses): Intrathecal: 12 mg/dose twice weekly for 4 weeks, then weekly for 4 doses, then monthly for 4 doses (Glantz 1998) or 10 mg twice weekly for 4 weeks, then weekly for 1 month, then every 2 weeks for 2 months (Glantz 1999) or 10 to 15 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month (Chamberlain 2010)

Soft tissue sarcoma (desmoid tumors, aggressive fibromatosis), advanced (off-label use): IV: 30 mg/m2 every 7 to 10 days (dose usually rounded to 50 mg) in combination with vinblastine for 1 year (Azzarelli 2001)

Systemic lupus erythematosus, moderate-to-severe (off-label use): Oral: Initial: 7.5 mg once weekly; may increase by 2.5 mg increments weekly (maximum: 20 mg once weekly), in combination with prednisone (Fortin 2008)

Takayasu arteritis, refractory or relapsing disease (off-label use): Oral: Initial dose: 0.3 mg/kg/week (maximum: 15 mg per week), titrated by 2.5 mg increments every 1 to 2 weeks until reaching a maximum tolerated weekly dose of 25 mg (use in combination with a corticosteroid; Hoffman 1994)

Uveitis (off-label use): Oral: 7.5 to 20 mg once weekly either alone or in conjunction with other corticosteroids/immunosuppressants (Diaz-Llopis 2009; Galor 2008; Kaplan-Messas 2003; Munoz-Fernandez 2009)

Acitretin: May enhance the hepatotoxic effect of Methotrexate. Avoid combination

Alitretinoin (Systemic): May enhance the hepatotoxic effect of Methotrexate. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Methotrexate. Monitor therapy

Cephalothin: May diminish the therapeutic effect of Methotrexate. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Methotrexate. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexketoprofen: May increase the serum concentration of Methotrexate. Management: Concurrent use of dexketoprofen with methotrexate doses of 15 mg/week or more is inadvisable. Use with lower methotrexate doses should only be performed with caution and increased monitoring. Consider therapy modification

Diethylamine Salicylate: May increase the serum concentration of Methotrexate. Monitor therapy

Dipyrone: Methotrexate may enhance the adverse/toxic effect of Dipyrone. Specifically, the risk for agranulocytosis and pancytopenia may be increased. Dipyrone may enhance the adverse/toxic effect of Methotrexate. Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Foscarnet: May enhance the nephrotoxic effect of Methotrexate. Avoid combination

Fosphenytoin-Phenytoin: Methotrexate may decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug. Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Ibrutinib: May increase the serum concentration of Methotrexate. Monitor therapy

Leflunomide: Methotrexate may enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity. Monitor therapy

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

LevETIRAcetam: May increase the serum concentration of Methotrexate. Monitor therapy

Loop Diuretics: Methotrexate may diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics. Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic dose reductions may be necessary. Consider therapy modification

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Mipomersen: May enhance the hepatotoxic effect of Methotrexate. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Penicillins: May increase the serum concentration of Methotrexate. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Probenecid: May increase the serum concentration of Methotrexate. Management: Avoid concomitant use of probenecid and methotrexate if possible. If used together, consider lower methotrexate doses and monitor for evidence of methotrexate toxicity. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Proton Pump Inhibitors: May increase the serum concentration of Methotrexate. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

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

Sapropterin: Methotrexate may decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

SulfaSALAzine: May enhance the hepatotoxic effect of Methotrexate. Monitor therapy

Sulfonamide Derivatives: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (eg, bone marrow suppression). Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tegafur: Methotrexate may enhance the adverse/toxic effect of Tegafur. Monitor therapy

Teriflunomide: May increase the serum concentration of OAT3 Substrates. Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Theophylline Derivatives: Methotrexate may increase the serum concentration of Theophylline Derivatives. Monitor therapy

Tofacitinib: Methotrexate may enhance the immunosuppressive effect of Tofacitinib. Management: Avoid the use of tofacinib in combination with potent immunosuppressive methotrexate-containing regimens. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Trimethoprim: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression). Consider therapy modification

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Methotrexate may enhance the adverse/toxic effect of Vaccines (Live). Methotrexate may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose methotrexate (0.4 mg/kg/week or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses of methotrexate should be avoided. Consider therapy modification

Use only preservative-free methotrexate formulations and diluents for intrathecal and high-dose therapy. Do NOT use formulations or diluents containing preservatives for intrathecal and high-dose therapy because they contain benzyl alcohol.

Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.

The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care. High-dose regimens of methotrexate injection for other neoplastic diseases are investigational, and a therapeutic advantage has not been established.

Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate. Some products are contraindicated in pregnant women.

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).

Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.

Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.

Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.

Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.

Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.

Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Severe, occasionally fatal skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.

Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Methotrexate can cause the following severe or fatal adverse reactions. Monitor closely and modify dose or discontinue methotrexate as appropriate. Bone marrow suppression; serious infections; renal toxicity and increased toxicity with renal impairment; GI toxicity; hepatic toxicity; pulmonary toxicity; hypersensitivity and dermatologic; methotrexate can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of methotrexate oral solution and risks to the fetus when prescribing methotrexate oral solution to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with methotrexate oral solution.

Methotrexate should be used only by health care providers whose knowledge and experience include the use of antimetabolite therapy.

Do not receive a "live" vaccine while using methotrexate, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Methotrexate can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds), especially if you are being treated for psoriasis. Methotrexate can make your skin more sensitive to sunlight and your psoriasis may worsen.

Avoid drinking alcohol while taking methotrexate.

Get emergency medical help if you have any signs of an allergic reaction to methotrexate: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using methotrexate and call your doctor at once if you have:

• dry cough, shortness of breath;

• diarrhea, vomiting, white patches or sores inside your mouth or on your lips;

• blood in your urine or stools;

• swelling, rapid weight gain, little or no urinating;

• seizure (convulsions);

• fever, chills, body aches, flu symptoms;

• pale skin, easy bruising, unusual bleeding, weakness, feeling light-headed or short of breath;

• liver problems - nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common methotrexate side effects may include:

• changes in your menstrual periods;

• vomiting, upset stomach;

• headache, dizziness, tired feeling; or

• blurred vision.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to methotrexate: compounding powder, injectable powder for injection, injectable solution, oral solution, oral tablet, subcutaneous solution

Cardiovascular

Uncommon (0.1% to 1%): Vasculitis
Rare (less than 0.1%): Pericarditis, pericardial effusion, pericardial tamponade, hypotension, thromboembolic events (e.g., arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism), myocardial ischemia
Frequency not reported: Cerebral edema[Ref]

Dermatologic

Common (1% to 10%): Exanthema, erythema, itching
Uncommon (0.1% to 1%): Urticaria, photosensitivity, depigmentation or hyperpigmentation of the skin, alopecia, increase of rheumatic nodules, painful lesions of psoriatic plaque, herpetiform eruption of the skin, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)
Rare (0.01% to 0.1%): Increased pigmentary changes of nails, acne, petechiae, ecchymoses, erythema multiforme, cutaneous erythematous eruptions
Very rare (less than 0.01%): Furunculosis, telangiectasia
Frequency not reported: Exfoliative dermatitis, skin necrosis, skin ulceration, folliculitis, hidradenitis, allergic vasculitis[Ref]

Endocrine

Uncommon (0.1% to 1%): Inflammation and ulceration of the vagina
Very rare (less than 0.01%): Loss of libido (males and females), impotence, impaired menstruation, vaginal discharge, infertility, abortion, fetal death, fetal defects, gynecomastia, defective oogenesis or spermatogenesis, transient oligospermia, vaginal bleeding[Ref]

Gastrointestinal

Very common (10% or more): Anorexia, nausea, vomiting, abdominal pain, inflammation, ulcerations of the mucous membrane of mouth and throat (especially during the first 24 to 48 hours after administration), stomatitis, dyspepsia, dehydration
Common (1% to 10%): Diarrhea (especially during the first 24 to 48 hours after administration)
Uncommon (0.1% to 1%): GI bleeding and ulcers, pancreatitis
Rare (0.01% to 0.1%): Gingivitis, enteritis, melena, malabsorption
Very rare (less than 0.01%): Hematemesis, toxic megacolon
Frequency not reported: Glossitis[Ref]

General

Generally, the incidence and severity of acute side effects are related to dose and frequency of administration. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, undue fatigue, chills and fever, dizziness, and decreased resistance to infection.[Ref]

Genitourinary

Uncommon (0.1% to 1%): Dysuria
Rare (0.01% to 0.1%): Oliguria, anuria, azotemia
Very rare (less than 0.01%): Proteinuria
Frequency not reported: Cystitis, hematuria[Ref]

Hematologic

Common (1% to 10%): Leukocytopenia, thrombocytopenia, anemia
Uncommon (0.1% to 1%): Pancytopenia, agranulocytosis, hematopoietic disorders
Rare (0.01% to 0.1%): Megaloblastic anemia
Very rare (less than 0.01%): Severe bone marrow depression, aplastic anemia, lymphadenopathy, lymphoproliferative disorders (partly reversible), eosinophilia, neutropenia
Frequency not reported: Hemorrhage, hematoma, myelosuppression[Ref]

Hepatic

Very common (10% or more): Increase in liver related enzymes (ALAT, ASAT, alkaline phosphatase, bilirubin, and LDH levels) is commonly reported but usually resolves within one month after cessation of therapy
Uncommon (0.1% to 1%): Development of liver fattening, fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes), drop of serum albumin
Rare (0.01% to 0.1%): Acute hepatitis, hepatotoxicity
Very rare (less than 0.01%): Reactivation of chronic hepatitis, acute liver degeneration, liver insufficiency, liver failure, liver atrophy, necrosis[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Allergic vasculitis, severe allergic reactions progressing to anaphylactic shock[Ref]

Immunologic

Common (1% to 10%): Disseminated herpes zoster, pneumocystis carinii pneumonia
Very rare (less than 0.01%): Immunosuppression, hypogammaglobulinemia, sepsis, opportunistic infections (may be fatal in some cases), infections caused by the cytomegalic virus, acute paronychia
Frequency not reported: Nocardiosis, cryptococcus mycosis, disseminated herpes simplex, listeria meningitis, mycobacterium avium, intracellular pneumonia, systemic fungal infections (e.g., cryptococcosis, nocardiosis, aspergillosis, histoplasmosis), sepsis, decreased resistance to infection, pneumocystis jiroveci, pneumonia (most common infection), respiratory tract infection, cutaneous bacterial infections, pneumonia, reactivation of hepatitis B infection, worsening of hepatitis C infection[Ref]

Musculoskeletal

Uncommon (0.1% to 1%): Osteoporosis, arthralgia, myalgia
Rare (0.01% to 0.1%): Stress fracture, nodulosis
Very rare (less than 0.01%): Pain, muscular asthenia or paresthesia of the extremities
Frequency not reported: Osteoporosis, osteonecrosis (aseptic necrosis of the femoral head), soft tissue necrosis, abnormal tissue cell changes, arthralgia/myalgia, back pain[Ref]

Nervous system

Common (1% to 10%): Headache, fatigue, drowsiness
Uncommon (0.1% to 1%): Vertigo, confusion, seizures, convulsion, encephalopathy
Very rare (less than 0.01%): Paresis, effect on speech including dysarthria and aphasia, myelopathy, changes in sense of taste (metallic taste), meningism, acute aseptic meningitis[Ref]

Ocular

Rare (0.01% to 0.1%): Severely impaired vision, visual disturbances, blurred vision
Very rare (less than 0.01%): Conjunctivitis, retinopathy, transient blindness/loss of vision, periorbital edema, blepharitis, epiphora, photophobia, eye discomfort[Ref]

Oncologic

Frequency not reported: Lymphomas and leukemias have been associated with this drug[Ref]

Other

Very rare (less than 0.01%): Fever, impaired wound healing
Frequency not reported: Fetal death, fetal damage, abortion, tinnitus, chills, malaise, fatigue[Ref]

Renal

Uncommon (0.1% to 1%): Inflammation and ulceration of the urinary bladder (possibly with hematuria)
Rare (0.01% to 0.1%): Renal failure, elevated serum creatinine and urea level
Frequency not reported: Renal insufficiency (usually with high doses), severe nephropathy[Ref]

Respiratory

Common (1% to 10%): Pulmonary complications due to interstitial alveolitis pneumonitis (e.g., general illness, dry/nonproductive cough, shortness of breath progressing to rest dyspnea, chest pain, fever)
Uncommon (0.1% to 1%): Pulmonary fibrosis
Rare (0.01% to 0.1%): Pharyngitis, apnea, bronchial asthma
Very rare (less than 0.01%): Pneumocystis carinii pneumonia, chronic obstructive pulmonary disease, pleural effusion
Frequency not reported: Acute pulmonary edema, pleurisy, hypoxia, respiratory failure[Ref]

Metabolic

Rare (0.01% to 0.1%): Diabetes mellitus, hyperuricemia
Frequency not reported: Metabolic disorder, tumor lysis syndrome[Ref]

Psychiatric

Rare (0.01% to 0.1%): Mood alterations
Very rare (less than 0.01%): Insomnia, cognitive dysfunction
Frequency not reported: Psychosis, depression, confusion, irritability[Ref]

Some side effects of methotrexate may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Note: A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in anti-leukemic therapy.

-Induction: 3.3 mg/m2/day orally or parenterally (in combination with prednisone 60 mg/m2) daily for 4 to 6 weeks
-Maintenance dose during remission: 30 mg/m2 orally or IM 2 times a week
-Alternate maintenance dose during remission: 2.5 mg/kg IV every 14 days

Comments:
-When relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regimen.
-Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Use: Acute lymphoblastic leukemia (ALL)

-Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease: Use is not recommended.
-Severe liver disease (Child-Pugh C): Contraindicated

US BOXED WARNINGS:
-This drug should only be used by physicians whose knowledge and experience include the use of antimetabolite therapy.
-For intrathecal and high dose therapy, the preservative-free formulation of this drug should be used because it does not contain benzyl alcohol.
-Oral administration in tablet form is preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.
-The injectable form of this drug can be given by the IM, IV, or intraarterial route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
-This drug should be used only in life threatening neoplastic diseases, or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy.
-Deaths have been reported with the use of this drug in the treatment of malignancy, psoriasis, and rheumatoid arthritis.
-Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities.
-Patients should be informed by their physician of the risks involved and be under physician care throughout therapy.
-The use of high-dose regimens recommended for osteosarcoma requires meticulous care. High-dose regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established.
-This drug has been reported to cause fetal death and/or congenital anomalies; therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the risks.
-Pregnant women with psoriasis or rheumatoid arthritis should not receive this drug.
-Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of therapy.
-Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant administration of this drug (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
-This drug causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acute liver enzyme elevations are frequently seen; these are usually transient and asymptomatic and do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long term treatment. Persistent abnormalities in liver function tests may precede the appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
-MTX-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
-Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
-Malignant lymphomas, which may regress following withdrawal of therapy, may occur in patients receiving low-dose MTX and, thus, may not require cytotoxic treatment. Discontinue MTX first and, if the lymphoma does not regress, appropriate treatment should be instituted.
-Like other cytotoxic drugs, this drug may induce "tumor lysis syndrome" in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
-Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of this drug. Reactions have occurred within days of oral, IM, IV, or intrathecal administration. Recovery has been reported with discontinuation of therapy.
-Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with MTX therapy.
-When this drug is given concomitantly with radiotherapy, the risk of soft tissue necrosis and osteonecrosis may be increased.

-Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.
-Do not use the IV formulation in children less than one month old because there have been reports of fatal "gasping syndrome" in this population because the solution contains benzyl alcohol.

Consult WARNINGS section for additional precautions.

Administration advice:
-This drug should be used only by physicians who have knowledge and experience in the use of antimetabolite therapy because of the possibility of serious toxic reactions.
-Oral tablets are preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.
-The injectable form of this drug can be given by the IM, IV, subcutaneous, or intraarterial route. For intrathecal and high-dose therapy, the preservative-free formulation should be used (not the preserved formulation because it contains benzyl alcohol).

General:
-Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Monitoring:
-Patients should be closely monitored for toxic effects.
-Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray.
-During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy.
-During initial dosing, when changing doses, or during periods of increased risk of elevated MTX blood levels (e.g., dehydration), more frequent monitoring may be indicated.
-Transient liver function test abnormalities are observed frequently after administration and are usually not cause for modification of therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation.
-A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
-Pulmonary function tests may be useful if MTX-induced lung disease is suspected, especially if baseline measurements are available.