Off-label prescribing in the era of COVID-19

Over a half a million documented cases of Coronavirus with over 20,000 dead in the United States without an end in sight. No preventative vaccine. No available cure. Emergency rooms and hospitals in some parts of the United States are overwhelmed with critically ill patients and discussions of potentially limiting care due to a critical shortage of ventilators are no longer a theoretical consideration. Numerous therapeutic approaches are being discussed in not only peer-reviewed journals but in newspapers, television news shows and social media. Despite no evidence-based literature supporting a standard-of-care for coronavirus infections, many providers are prophylactically prescribing medications like Hydroxychloroquine and Azithromycin in the hope that it will arrest the virus from causing a “cytokine storm.” In this potentially deadly development, uncontrolled levels of cytokines are released that eventually activate even more immune cells, attacking healthy tissue instead of just confining its response to the virus. An understandable bias toward action- “Don’t just stand there. Do something.” – has many providers thinking about the risk/benefit of prescribing drugs off-label to treat coronavirus. Even President Trump has been quoted as saying of the decision to use hydroxychloroquine and azithromycin, “What do you have to lose?” This article reviews some of the questions health care providers should consider when deciding whether to prescribe drugs off-label for Covid-19.

Legal

The Food and Drug Administration approves new medications that are safe and effective for specific indications but doesn’t limit how medications are prescribed once they are approved. However, some state boards of pharmacy and governors by executive order have restricted dispensing of hydroxychloroquine or chloroquine for FDA-approved indications or as part of a state-approved clinical trial for a patient who has tested positive for COVID-19 in the case of New York residents. Some states prohibit the use of hydroxychloroquine for experimental or prophylactic use and limit the duration of therapy for 14-days without any refills.  One of the common concerns from providers is whether there is legal risk for prescribing off-label medications. In general, courts have ruled that physicians do not explicitly need informed consent for off-label prescribing but discussing the risks and benefits of such an approach can foster shared decision-making.

Does it work? What are the potential risks?

To date, clinical trials are proceeding for multiple therapeutic agents against Covid-19 but notably the US Centers for Disease Control and Prevention on April 7^th updated its guidance for the use of hydroxychloroquine from providing references to anecdotal dosages to now highlighting there are no approved drugs for the treatment of Covid-19 infection. Many influential medical and science publications across the world have removed their paywalls and are providing Covid-19 related articles for anyone to access. Because of the pandemic’s global reach and significant morbidity and mortality, the rapid publication of potentially influential information to guide diagnosis and treatment has not illuminated a clear approach to direct evidence-based therapy. Many of the reports are descriptive and observational and are underpowered to detect a statistically significant effect and would otherwise not be published in such highly visible publications.

The expanded use of off-label drugs like hydroxychloroquine and azithromycin could potentially increase the number of clinically known side effects. In 2013, the FDA updated the Warnings and Precautions section of Azithromycin to include the potential development of a fatal heart rhythm in patients who might already be at risk for cardiovascular events. In initial reports, patients infected with Covid-19 have had cardiovascular involvement. Cardiovascular side effects have also been reported with the use of hydroxychloroquine in patients being treated for autoimmune diseases like systemic lupus erythematosus for which it does have FDA-approval. What is unknown is whether the potential side effects of these drug can further increase the risk of cardiac events in patients who have Covid-19 infection, especially if they already have cardiac involvement from the virus or a known cardiovascular disorder. To paraphrase Donald Rumsfeld, there are a lot of unknown unknowns about Covid-19 that makes off-label prescribing difficult.

Although off-label prescribing was found in approximately one out of every eight prescriptions by Eguale et al., in the January 2016 issue of JAMA Internal Medicine, there was a 54% increase in adverse drug events when there was not a strong scientific basis for its usage. Off-label prescribing is common in children and in psychiatric disorders for example, where there is not an FDA indication, and some drugs used for oncology treatment may have been approved for one type of cancer and are used successfully in another type.  Providers must decide whether Covid-19 treatments have a strong scientific basis for its use.

Ethics

Patients may not necessarily understand the term “off-label,” so it seems reasonable to discuss potential treatment options, including supportive care, especially if they believe that Covid-19 treatment will offer a definitive cure or their expectation is that the risk of side effects are so low that even unproven treatments are acceptable. Severity of the illness may also influence the decision-making discussion as critically ill patients may be more willing to tolerate the uncertainties around treatment compared to someone who is being offered prophylactic medication or is mildly ill. Because trust plays such a powerful role in the relationship between patients and their providers and for medicine in general, a practical framework proposed by Elwyn and colleagues surrounding shared-decision making can mitigate some of the uncertainties around treating Covid-19 patients. Writing in the October 2012 issue of the Journal of General Internal Medicine, the authors suggest that introducing choice, describing options and helping patients explore preferences can help promote these types of difficult decisions until more definitive answers become available. One could argue that only by having these types of poignant conversations with patients and their families that you really have nothing to lose.

Joseph M. Geskey, DO, MBA, MS-PopH is currently a Principal, Data Science & Member Insights for Vizient. He is currently writing a book about patients with challenging social determinants of health as they try to navigate the increasing technological era that medicine is embracing.