Drug Update
Rasuvo (Methotrexate) Once-Weekly…Continued from page 27 Mechanism of Action Methotrexate works by inhibit ing dihydrofolic acid reductase.15 Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of one-carbon groups in synthesizing purine nucleotides and thymidylate. Methotrexate interferes with the synthesis and repair of DNA, as well as cellular replication. In gener al, actively proliferating tissues (eg, malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder) are more sensitive to this effect of methotrexate.15 The mechanism of action of methotrexate in patients with rheu matoid arthritis is unknown, but it may affect immune function. The production rate of epithelial cells in the skin is greatly increased in patients with psoriasis versus patients with normal skin. This dif ferential in proliferation rates serves as the basis for using methotrexate to control the process of psoriasis.15 Dosing and Administration Methotrexate injection is adminis tered once weekly subcutaneously in the abdomen or the thigh. A different formulation of methotrexate should be used instead of the subcutaneous form for patients requiring oral, intra muscular, intravenous, intra-arterial, or intrathecal dosing; doses of <7.5 mg weekly; doses >30 mg weekly; high-dose regimens; or dose adjust ments of <2.5-mg increments. The starting doses of methotrex ate are listed in the Table. The dose should be adjusted gradually in the individual patient to achieve an optimal response. Methotrexate injection is avail able as a single dose from a manu ally triggered autoinjector pen that delivers the drug. It is available in
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Table. Starting Doses for the Subcutaneous Injection of Methotrexate Indication
Starting dosea
Rheumatoid arthritis
7.5 mg once weeklyb
Polyarticular juvenile idiopathic arthritis
10 mg/m2 once weekly
Psoriasis
10-25 mg once weeklyc
The dose should be adjusted gradually to achieve an optimal response. Oral formulation is a potential alternative. c Oral, intramuscular, or intravenous formulation is a potential alternative. Source: Rasuvo (methotrexate) injection prescribing information; July 2014. a
b
10 different dosage strengths, rang ing from 7.5 mg to 30 mg, including 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg.14,15
Clinical Studies In patients with rheumatoid arthritis, clinical trials were per formed using other formulations of methotrexate. The effects of meth otrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks after the start of treat ment in patients with rheumatoid arthritis. Most studies of metho trexate in patients with rheuma toid arthritis have been of relatively short duration (3-6 months). Based on limited data from long-term stud ies, an initial clinical improvement should be maintained for at least 2 years with continuous therapy with subcutaneous methotrexate.15 Clinical trials in patients with pJIA were performed using for mulations other than subcutane ous methotrexate.15 Treatment with methotrexate was evaluated in a 6-month, double-blind, placebocontrolled study in 127 pediatric patients with pJIA (mean age, 10.1 years; mean duration of disease, 5.1 years).15,18 This study showed that in patients receiving background NSAIDs and/or prednisone, metho
RHEUMATOLOGY PRACTICE MANAGEMENT
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trexate given weekly at an oral dose of 10 mg/m2 resulted in significant clinical improvement compared with placebo as measured by the physician’s global assessment or by a patient composite (ie, 25% reduc tion in the articular severity score plus improvement based on parent and physician global assessments of disease activity).15,18 More than 66% of the patients in this study had pJIA; the numerically greatest response was seen in this subgroup of patients who received 10 mg/m2 per week of methotrex ate.15,18 The overwhelming major ity of the remaining patients had systemic-course juvenile idiopathic arthritis. All patients were unre sponsive to NSAIDs; approximately 33% were receiving low-dose cor ticosteroids.15,18 The 5-mg/m2 dose of weekly methotrexate was not significantly more effective than placebo.15,18
Safety The most common adverse reac tions associated with methotrex ate injection are nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diar rhea, liver function test abnormal ities, vomiting, headache, bronchi tis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness,