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The Unintended Consequences of Drugs That Go “Viral”

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I recently prescribed methotrexate, a reliable disease-modifying anti-rheumatic drug, to a 7-year-old girl with juvenile idiopathic arthritis (JIA) who had already tried anti-inflammatory medications and intra-articular steroid injections. I gave the mom my “methotrexate talk” that I have been giving for about two decades which include the benefits (significant control of arthritis), side effects (oral ulcers, nausea, etc.), and need for laboratory tests (to monitor for leukopenia or liver enzyme abnormalities). When I asked her if she had questions, she expressed that she had seen many reports about patients with rheumatoid arthritis (RA) having challenges in getting methotrexate filled for their arthritis. Since methotrexate can also be used to terminate ectopic pregnancy, the recent Supreme Court decision reversing Roe v. Wade has created considerable anxiety in the rheumatology community. She was worried that once started, if she could not get the medication filled regularly, her daughter’s care would be interrupted. This was a reminder to me that extraneous events can pose hurdles for patients and their clinicians, as illustrated by other examples from the recent past.

In spring and summer of 2020, as COVID-19 was causing significant infections and substantial anxiety, and prior to the availability of specific therapeutic agents and vaccines, a variety of remedies were being touted. While several drugs that are part of our armamentarium in rheumatology were tried in the treatment of COVID-19, two drugs exemplified this point — tocilizumab and hydroxychloroquine. Tocilizumab, a biological agent that blocks interleukin-6, was shown to be helpful in the hyperinflammation seen in many critically ill patients with COVID-19. This caused a shortage for patients with RA and juvenile arthritis for several months until the supply chain was streamlined, and other therapies for COVID-19 became available, easing the demand for tocilizumab. Each week, my partners and I had to review the list of patients due to get tocilizumab infusions and decide how to prioritize the limited supplies — who needed it now, who could wait another week, and who could we switch to subcutaneous injections? We all knew that for fragile patients, missing a dose could result in a disease flare. Each day, these decisions were fraught with trepidation.

However, the disruption to the supply of hydroxychloroquine during the COVID-19 pandemic was a different story altogether. Here was this drug which had been used to treat lupus, RA, and several other connective tissue diseases for decades. Hydroxychloroquine was generally considered safe so long as patients were getting regular retinal exams to detect toxicity. Suddenly, many prominent people were sharing their beliefs on the benefits of hydroxychloroquine in preventing and curing COVID-19. Thanks to social media, these claims spread far and wide. Almost overnight, it seemed that everyone was trying to take hydroxychloroquine or at least hoard it just in case. There were many reports of patients with lupus and RA facing challenges in obtaining a medicine that allowed them to function normally. A survey by the Lupus Research Alliance found that a third of patients were experiencing challenges in obtaining hydroxychloroquine. This phenomenon was not unique to the U.S., but also observed in other countries. A survey of clinicians in 42 countries across several continents also found that patients in many countries faced challenges accessing hydroxychloroquine.

It took several months, but finally things normalized. During this period, many pharmacies were only dispensing 30 days at a time and some only dispensed 14 days’ worth of doses. Pharmacies called our offices to confirm the indication for which hydroxychloroquine was being prescribed, even though some of these patients had been on the drug for years. Many patients reported rationing their pills by taking the dose every other day or only half of the dose to make sure they wouldn’t run out. Physician’s offices, including ours, had to obtain prior authorizations and write letters of medical necessity to make sure our patients got their medicine. All of this meant delays in patients being able to get a medicine as ordered by their doctor.

I observed another unintended consequence of the hydroxychloroquine story. In an effort to be critical of the unapproved use of hydroxychloroquine, different media reports surfaced, warning of the danger of such therapies, and patients who had been on this drug for many years safely started to develop anxiety about their medication. It took a lot of reassurance to keep some patients on this medicine for their rheumatic disease.

After my encounter with the mother of the child with JIA starting methotrexate, our office got a call from a pharmacist to confirm the diagnosis for a different 12-year-old girl with JIA who went to fill her methotrexate prescription. She had been on low dose methotrexate for a year and had filled the past prescriptions without any issues. After a couple of voicemails back and forth, our office was able to confirm she had JIA, then she was able to get her prescription filled. While she ultimately got the medicine, additional effort and time were involved.

I have now found several news reports about patients facing barriers to obtaining methotrexate for their rheumatic diseases. There is genuine fear and substantial anxiety among patients with rheumatic diseases who use methotrexate that they will face challenges in accessing the medication, at least in some states with restrictions on abortion. The concerns include that pharmacists or physicians may be subject to litigation if they dispense methotrexate. Some doctors may choose to avoid using methotrexate in favor of other, less controversial agents. Methotrexate is a safe, effective, inexpensive drug that has resulted in substantial improvement in outcomes of individuals with rheumatic diseases. While many of the newer biological agents are also effective, they are often expensive, and they are not without long-term safety concerns. The process to obtain these biological agents can be arduous.

To minimize disruptions, we now ensure that the indication and ICD code is included in all prescriptions for methotrexate and similar medications. Some families want a paper prescription, so they can go to a different pharmacy if they encounter issues at the first one. We also encourage families to contact advocacy organizations and share their stories. However, so long as major health care decisions are made by non-physician entities without considering every patient the choice may impact, physicians and patients are likely to be ensnared by unintended consequences.

How do you talk to your patients about drug shortages? Share your conversation tips in the comments.

Dr. Sampath Prahalad is a Professor of Pediatrics at Emory University and is the Chief of Pediatric Rheumatology at Children’s Healthcare of Atlanta. He is a physician, scientist, scholar, and mentor with a focus on juvenile arthritis, familial autoimmunity, and translational research. A devoted father and a husband, when he is not in the hospital, he loves to hike, travel, or try a new recipe on his instant pot. Dr. Prahalad is a 2021–2022 Doximity Op-Med Fellow.

All names and identifying information have been modified to protect patient privacy.

Image by Alphavector / Shutterstock

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