Nearly Pain-free Self-administration of Subcutaneous Methotrexate With an Autoinjector

Results of a Phase 2 Clinical Trial in Patients With Rheumatoid Arthritis Who Have Functional Limitations

Bruce Freundlich, MD; Alan Kivitz, MD; Jonathan S. Jaffe, MD

Disclosures

J Clin Rheumatol. 2014;20(5):256-260. 

In This Article

Abstract and Introduction

Abstract

Background. A methotrexate autoinjector (MTXAI) was developed for self-administration of subcutaneous (SC) methotrexate by patients with rheumatoid arthritis (RA). The MTXAI circumvents the need for vials, needles, and syringes and may therefore improve dosing accuracy, handling risks, and patient adherence.

Objectives. The objective of this study was to evaluate actual human use of the MTXAI in patients with RA and determine its reliability, robustness, safety, local tolerance, and ease of use.

Methods. In this phase 2, multicenter, open-label, single-dose, single-arm, in-clinic US study, adults (N = 101) treated with methotrexate for 3 months or longer were trained to use the MTXAI and assigned to 10, 15, 20, or 25 mg methotrexate based on previous treatment and disease status. Patients completed training confirmation and ease-of-use questionnaires. Pain was evaluated immediately after self-administration and at follow-up with a 100-mm visual analog scale (0 = no pain, 100 = worst possible pain).

Results. At screening, 90.1% of patients had moderate to severe functional limitations (class II–IV). All patients successfully completed the study. All devices functioned correctly and as intended. The device was rated easy to use by 98%, and instructions clear and easy to follow by 100% of patients. On the visual analog scale, mean and median pain scores were 3.6/100 and 1.0/100 mm, respectively, immediately after self-administration, and were lower at follow-up. Most patients (92.3%) had no administration-site erythema; 7.7% had minimal erythema.

Conclusions. The SC MTXAI was well tolerated and considered easy to use by patients with RA. Improving SC methotrexate delivery may increase patient tolerance of self-administration, possibly improving adherence.

Introduction

As supported by the European League Against Rheumatism and the American College of Rheumatology recommendations for the pharmacologic management of rheumatoid arthritis (RA), the cornerstone of therapy for RA is the disease-modifying antirheumatic drug methotrexate.[1,2] Multinational recommendations advocate the use of oral methotrexate, with the possibility for parenteral administration in cases of intolerance or inadequate clinical response to oral methotrexate, owing to enhanced bioavailability of parenteral administration, as an optimal, evidence-based approach.[3] Although it is recognized that oral methotrexate doses of 20 to 30 mg weekly are often administered for disease control,[1,4] the bioavailability of oral methotrexate has been found to plateau at doses 15 mg weekly or greater,[5–8] and the use of oral methotrexate is not infrequently limited by gastrointestinal adverse events (AEs).[4,9,10] Improved clinical outcomes, including improvements in tolerability, have been seen in several studies of patients who switched from oral methotrexate to parenteral methotrexate for inefficacy or intolerance.[10–13] Consequently, subcutaneous (SC) administration appears to have advantages over oral administration of methotrexate in patients with RA.

Oral administration of methotrexate is the most common route of administration in the United States, largely because of convenience.[4,10] It is estimated that the use of parenteral methotrexate is limited to less than 5% of patients with RA in the United States.[14] The drawbacks of SC methotrexate administration include its cytotoxicity and the need for patient or caregiver manipulation of vials, needles, and syringes. Methotrexate is classified as a hazardous drug by the US Department of Labor, Occupational Safety & Health Administration Hazard Communication Standard.[15] Therefore, all individuals who will be in contact with methotrexate require formal training, specific protocols are followed for cleanup of spills, and individuals exposed to methotrexate must be monitored to identify any biological effects.[16] The functional limitations imposed by RA may affect manual dexterity such that patients may have difficulty using vials, needles, and syringes, and caregivers who use these items are at risk for exposure and needlestick injuries. Patients may have anxiety over self-injection and may experience pain while caregivers may have anxiety about performing injections and causing the patient pain.

We have developed a prefilled, single-use, pressure-assisted methotrexate autoinjector (MTXAI) for the self-administration of SC methotrexate (Figure 1). The MTXAI (Otrexup™ [methotrexate], Antares Pharma, Ewing, NJ) was approved by the Food and Drug Administration for the management of patients with severe, active RA, who are intolerant of or had an inadequate response to first-line therapy.[17] This device enables SC administration without the need for opening a vial, handling a needle, or preparing and operating a syringe and can be stored conveniently at room temperature, protected from light. Self-administration involves only the removal of a cap, a safety, and 1-click autoinjection of methotrexate. In this phase 2 study, the actual human use of this autoinjector was evaluated in patients with RA with regard to safe usability, ease of use, and administration-site pain and appearance.

Figure 1.

Schematic diagram of the SC MTXAI.

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