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.