Methotrexate Shortage: Why It’s Happening & Potential Solutions

In recent months, many rheumatologists and rheumatology professionals have noted issues related to obtaining supplies of injectable and oral methotrexate for their patients with rheumatoid arthritis (RA).

A conventional synthetic disease-modifying anti-rheumatic drug (csDMARD), methotrexate is available as both oral tablets and as a subcutaneous injection for the treatment of RA and other autoimmune diseases.¹ It is one of the oldest, most popular and effective agents used to treat RA.²

Methotrexate was first used in 1948 to treat childhood leukemia and is still used in treating breast and lung cancer, osteosarcoma and other cancers.³ It was first used clinically for the treatment of RA and other autoimmune diseases in 1962.

In the early 1960s, the National Institutes of Health reported positive results with methotrexate used to treat RA, psoriasis and psoriatic arthritis. Randomized, placebo-controlled studies with methotrexate in the early 1980s led to subsequent U.S. Food & Drug Administration (FDA) approval of methotrexate for the treatment of RA in 1988. It has been available as a generic medication for many years.

Short Supply

In March, the FDA first listed methotrexate injections on its drug shortage list. According to the American Society of Health-Systems Pharmacists (ASHP), injectable methotrexate availability has been hindered by issues related to high(er) demand, with pharmaceutical manufacturers unable to keep up.⁴ Currently, there is insufficient supply for what is considered the usual demand. This demand may have increased due to difficulties in obtaining oral methotrexate.

Some companies have resumed manufacturing, with supply release dates in late May and early June (Fresenius Kabi and Teva), or in late June (Hikma). A number of manufacturers cannot estimate a release date for injectable methotrexate. Making matters worse, methotrexate was one of several generic medications produced by Akorn Pharmaceuticals, which went bankrupt earlier this year.⁵

For methotrexate produced by other generic manufacturers, manufacturing delays and quality problems are blamed for the shortages. Because methotrexate is a hazardous generic product, when one manufacturer goes out of business, picking up the slack in manufacturing is often challenging.

In addition, with the Supreme Court overturning Roe v. Wade, some RA patients and others who receive methotrexate treatment may have had difficulty obtaining the agent due to its abortifacient properties.⁶ There has been speculation that the reported higher demand of methotrexate could be due in part to criminalization of abortions, with states specifically passing laws to ban certain medications as “abortion-inducing drugs,” which includes methotrexate, without distinguishing use by diagnosis.

Although an abortifacient, methotrexate is mostly used to treat autoimmune conditions and—at much higher doses—cancer. Methotrexate can also be used to manage ectopic pregnancies.

Recommendations

The injectable methotrexate shortage seems to be disappearing. However, patients currently receiving the injectable form could be switched to oral methotrexate or, potentially, leflunomide, which works similarly to methotrexate, or to another csDMARD they have not yet tried or that has not previously failed to work for them—if they have no contraindications for use.

Leflunomide is a dihydroorotate dehydrogenase inhibitor approved in September 1998.^7,8

These patients could also be switched to subcutaneous methotrexate, provided it is available.

To help patients get their methotrexate prescriptions filled, the Arthritis Foundation has set up a hotline: (800) 283-7800.⁶

And the FDA is working with manufacturers to identify temporary importation solutions to help meet patients’ needs until the approved manufacturers can meet the demand.

These next few months will most likely give us some insight into the future of methotrexate availability. The ACR is closely monitoring the drug shortage and working with the FDA and will continue to provide updates as they become available.

The FDA is seeking information about how rheumatology patients are being affected by the shortage. Share your experiences by sending an email to [email protected].

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Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Treatments: Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo) American College of Rheumatology. 2023.
2. Weinblatt ME. Methotrexate in rheumatoid arthritis: A quarter century of development. Trans Am Clin Climatol Asso. 2013;124:16–25.
3. Methotrexate sodium. National Cancer Institute. 2023 Mar 22.
4. Methotrexate injection. ASHP drug shortages list. American Society of Health-Systems Pharmacists. 2023 May 26.
5. Becker Z. After shutting down, Akorn recalls its 70-plus products nationwide. Fierce Pharma. 2023 Apr 26.
6. Arthritis Foundation statement on methotrexate access. Arthritis Foundation. 2022 Jun 24.
7. Leflunomide FDA approval letter. U.S. Food & Drug Administration. 1998 Sep 10.
8. Leflunomide FDA labeling. U.S. Food & Drug Administration. 1998 Sep 10.