In the desperate race to control COVID-19, vaccination against the SARS-CoV-2 virus will be the ultimate containment solution. But for those who have unfortunately fallen seriously ill with coronavirus symptoms, drug and supportive treatment is necessary. Since the novel coronavirus has been with us for a relatively short while, there hasn’t been enough time to develop new drugs. According to the US Food and Drug Administration (FDA)’s Coronavirus Treatment Acceleration Program (CTAP), based on data current as of 8/31/20, much work is being done to develop new drugs. However, there are still no drugs that have been officially approved for COVID-19 prevention or treatment. Research is being performed at breakneck speed all over the globe.

NOTE: After this article posted, the antiviral remdesivir was approved by the FDA on 10/22/20 as a treatment for patients 12 years of age and older hospitalized with COVID-19.

Treatments for COVID-19 focus on two areas: interrupting the virus’ life cycle and controlling symptoms, especially the “cytokine storm” that is responsible for the acute respiratory distress syndrome and other serious and potentially fatal consequences of infection. In the meantime, while vigorous research is being conducted on developing new drugs to kill the virus and control disease progression, scientists and clinicians have turned to currently available drugs using two well known practices: off-label use and repurposing. Emergency use is discussed briefly below as well.

Off-Label Drug Use

Off-label drug use occurs when a medication is prescribed by physicians for indications that have not been approved by the FDA (or a comparable regulatory agency in other countries) or the prescription is for a dose, dosage form, or population for which it has not been approved. “Off-label” means that the use does not appear in the FDA approved drug labeling information. It is rational for clinicians to try a drug for a disease or symptom that is not approved in a certain population, for example pediatrics, pregnancy, or geriatrics, as these populations are often excluded in the original clinical trials. Another reason is for a serious or life-threatening condition such as cancer, where a drug may not be approved specifically for that disease, but it makes pharmacologic sense to try it. COVID-19 falls into this second category. SARS-CoV-2 is a virus, so existing antiviral drugs are being pulled off the shelf and being studied in infected patients to try kill it. In addition, drugs that are not specifically antivirals but interfere with the virus’ life cycle through different mechanisms are being tested. To treat the wide array of life-threatening symptoms caused by cytokine and other inflammatory mediators precipitated by coronavirus infection, older drugs are rationally and sometimes irrationally being tried, gaining widespread media attention in the process.

Repurposing

Repurposing is similar to off-label use. Drugs that are already approved and on the market have been vetted for safety and efficacy, and there is already an available supply, so it makes sense to explore their usefulness during a pandemic caused by a new viral agent. The COVID-19 Early Treatment Fund (CETF), comprised of well known scientists and clinicians from Johns Hopkins, Harvard, Northwestern, University of California, and University of Virginia, was organized to conduct outpatient clinical trials of existing drugs to identify earlier treatments for the disease.

Doctors and researchers at Penn Medicine are also evaluating repurposing drugs for COVID-19 in a program called CORONA (COvid Registry of Off-label & New Agents). In a review of over 9000 patients who received some type of treatment for COVID-19 for the period December 1, 2019 through March 27, 2020, major categories of drugs (Figure a below) and specific drugs (Figure b below) that have been used for COVID-19 were identified. More information on this program can be found at penmedicine.org.

Emergency Use Authorization
Another way approved drugs can be used for unapproved indications in an emergency situation such as the current pandemic is Emergency Use Authorization (EUA).

With an EUA, “the FDA Commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN [Chemical, biological, radiological, nuclear] threat agents when there are no adequate, approved, and available alternatives.”

On February 4, 2020, the US Department of Health and Human Services “determined that there is a public health emergency that has a significant potential to affect national security or the health and security of United States citizens living abroad, and that involves the virus that causes COVID-19. On the basis of this determination, the Secretary then declared that circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID-19 pandemic.” The list of drugs and biological agents can be found here.

Old Drugs Being Used for COVID-19 of Interest in Wilderness, Travel, and Expedition Medicine
The sheer number of agents being studied for COVID-19 vaccination and treatment is quite staggering. This section will focus on those of interest to practitioners in wilderness, travel, and expedition medicine, reviewing their approved uses and how they are now being tested in this disease.

Lopinavir-ritonavir

• Use in wilderness/travel/expedition medicine: HIV-post-exposure prophylaxis

• Mechanism in COVID-19: viral protease inhibitor

• Results of clinical studies: lack of efficacy; may be more effective in combination with interferon beta (immune suppressant) and ribavirin (antiviral)

• Adverse reactions: nausea, diarrhea, liver toxicity

Hydroxychloroquine, Chloroquine

• Use in wilderness/travel/expedition medicine: prophylaxis and treatment of four species of malaria (P. vivax, P. malariae, P ovale, P. falciparum). Hydroxychloroquine is also approved for lupus and rheumatoid arthritis; chloroquine is also approved for extraintestinal amebiasis

• Mechanism in COVID-19: multiple antiviral mechanisms

• Results of clinical studies: Despite widespread media attention on the efficacy of the drugs in treatment and prevention of COVID-19, studies have demonstrated a lack of efficacy and more importantly, unacceptable toxicity

• Adverse reactions: Cardiac, blood/lymphatic, renal, liver toxicities

“On June 15, 2020…FDA has determined that CQ and HCQ are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other serious side effects, the known and potential benefits of CQ and HCQ no longer outweigh the known and potential risks for the authorized use. This warrants revocation of the EUA for HCQ and CQ for the treatment of COVID-19.”

Azithromycin

• Use in wilderness/travel/expedition medicine: indicated for a variety of respiratory, skin and genitourinary infections. Used off-label for the treatment of travelers’ diarrhea

• Mechanism in COVID-19: may have some antiviral and immunomodulating effects

• Results of clinical studies: lack of efficacy specifically against COVID-19; clinical utility in treating community-acquired pneumonia in COVID-19 patients

• Adverse reactions: dysrhythmias, QT prolongation especially in combination with hydroxychloroquine or chloroquine (the use of the combination has also been touted in the media)

Dexamethasone

-Use in wilderness/travel/expedition medicine: acute altitude sickness and HACE

-Mechanism in COVID-19: decreases inflammatory lung injury

-Results of clinical studies: there have been a number of recent studies demonstrating the efficacy of this corticosteroid; the RECOVERY trial showed a decrease in 28-day mortality (compared to usual care) in hospitalized patients on mechanical ventilation or oxygen therapy

-Adverse reactions: in the RECOVERY trial, no benefit (and possibly harm) in patients not ill enough to require oxygen therapy

Note: the corticosteroid methylprednisolone is being studied in clinical trials for its anti-inflammatory effect as well.

Famotidine

-Use in wilderness/travel/expedition medicine: dyspepsia/acid reflux; urticaria
-Mechanism in COVID-19: possible antihistamine effect
-Results of clinical studies: data is from observational studies only; one single-center retrospective study showed a lower risk of in-hospital mortality; this drug received much media attention as well even though studies were very small, and not randomized, controlled trials
-Adverse reactions: not reported in study

Other Drugs of Interest

Two antiparasitic agents, nitazoxanide (used for treatment of Giardia and Cryptosporidium) and ivermectin (used for treatment of nematode infections, lice, and scabies) are thought to have antiviral activity against SARS-CoV-2 and are being studied in clinical trials, some in combination with hydroxychloroquine. Melatonin, used for jet lag and insomnia, is currently being studied for its purported anti-inflammatory and antioxidant activity.

Drug Shortages in the Face of COVID-19

With the dramatically increased number of patients hospitalized for COVID-19, drug shortages are occurring. And when yet unproven treatments become a media sensation, they can cause drug shortages, denying a reliable supply of medication for those who need it for approved indications. Both the FDA and American Society of Health-System Pharmacists (ASHP) maintain Drug Shortages Pages. It is worthwhile to check both pages as the information may differ. On 9/15/20, both pages showed a shortage of dexamethasone injection, azithromycin tablets, famotidine injection and tablets; the ASHP site showed a shortage of azithromycin injection as well. The FDA site showed that shortages of hydroxychloroquine and chloroquine tablets have been resolved, but the ASHP site showed that these shortages continue.