Indication(s):

Management of adults with severe, active rheumatoid arthritis (RA) or children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose NSAIDs. Symptomatic control of severe, recalcitrant, disabling psoriasis in adults with inadequate response to other forms of therapy, but only with an established diagnosis as by biopsy and/or dermatologic consultation. Limitation of use: not for treating neoplastic diseases.

Pharmacology:

Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.

Clinical Trials:

Clinical trials in patients with rheumatoid arthritis or polyarticular juvenile idiopathic arthritis (pJIA) were performed using other formulations of methotrexate.

In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3–6 weeks. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3–6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy.

In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with pJIA (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs and/or prednisone, methotrexate given weekly at an oral dose of 10mg/m² provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JIA, and the numerically greatest response was seen in this subgroup treated with 10mg/m²/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JIA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5mg/m² was not significantly more effective than placebo in this trial.

Legal Classification:

Rx

Adults:

Administer by SC inj in abdomen or thigh. RA: Initially 7.5mg once weekly using an oral formulation. Psoriasis: 10–25mg once weekly using an oral, IM, SC, or IV formulation; max 30mg/wk. Switching from oral to Otrexup SC inj: consider differences in bioavailability. Adjust dose gradually. Use alternative MTX form in patients requiring oral, IM, IV, intra-arterial, or intrathecal dosing, doses <10mg/wk or >25mg/wk, high-dose regimens, or dose adjustments <5mg increments.

Children:

Psoriasis: not established. pJIA: <2yrs: not established. Administer by SC inj in abdomen or thigh. ≥2yrs: initially 10mg/m² once weekly. Switching from oral to Otrexup SC inj: consider differences in bioavailability. Adjust dose gradually. Use alternative MTX form in patients requiring oral, IM, IV, intra-arterial, or intrathecal dosing, doses <10mg/wk or >25mg/wk, high-dose regimens, or dose adjustments <5mg increments.

Contraindication(s):

Alcoholism. Chronic liver disease. Immunodeficiency. Preexisting blood dyscrasias. Pregnancy (Category X). Nursing mothers.

Warnings/Precautions:

Be fully experienced in the use of antimetabolite therapy. Increased risk of severe toxic reactions. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function, every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Obtain liver biopsy prior to treatment if history of alcoholism, persistently abnormal LFTs, or chronic HBV/HCV infection; discontinue if persistently abnormal LFTs develop or liver biopsy shows moderate-to-severe changes. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Hepatic fibrosis. Steatohepatitis. Active infection. Renal impairment, ascites, pleural effusions: monitor for toxicity and reduce dose or discontinue if needed. Maintain adequate hydration. Elderly. Debilitated.

Interaction(s)

Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, low-dose steroids, PPIs (eg, omeprazole, esomeprazole, pantoprazole), phenylbutazone, phenytoin, sulfonamides, probenecid, penicillins (monitor), tetracycline, chloramphenicol, non-absorbable broad spectrum antibiotics, folic acid antagonists. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine); monitor. Impaired response to immunization. May potentiate theophylline, mercaptopurine. May be antagonized by folic acid. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Recall reactions after UV radiation.

Adverse Reaction(s)

Nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions”; myelosuppression, hepatotoxicity, nephrotoxicity, CNS toxicity, interstitial pneumonitis, tumor lysis syndrome, fatal skin reactions, fertility impairment.

How Supplied:

Single-dose auto-injector—1, 4

LAST UPDATED:

3/25/2014