FDA rescinds emergency authorizations for use of hydroxychloroquine and chloroquine as COVID-19 treatments.

By Claire Gillespie and Karen Pallarito
Updated June 15, 2020

An anti-malarial drug called hydroxchloroquine, commonly used to treat inflammatory conditions like lupus and rheumatoid arthritis, has received a lot of attention as a potential treatment for people with COVID-19. But is the excitement overblown?

So far, there's no evidence that either hydroxychloroquine or its cousin, chloroquine, is a panacea against COVID-19 infections or that either drug actually prevents the illness.

On Monday, the US Food and Drug Administration (FDA) withdrew its emergency approval for use of the drugs as coronavirus treatments. In short, FDA determined that the suggested dosing regimens "are unlikely to provide an antiviral effect" and that any potential benefits "outweigh their known and potential risks," according to a letter signed by FDA Chief Scientist Denise Hinton. Politico reported that clinical trials examining use of the drugs against COVID-19 may continue.

The FDA's decision follows a spate of disappointing clinical trial data. Earlier in the month, researchers reported results of a randomized controlled trial involving more than 800 people who had been exposed to someone with confirmed COVID-19. Hydroxychloroquine taken within four days of the exposure provided no better protection against the illness than taking a placebo, according to their report in the New England Journal of Medicine.

President Trump first touted chloroquine and its less-toxic derivative, hydroxychloroquine, during a March 19 White House Coronavirus Task Force briefing, claiming that these medicines could be "a game changer," although his own scientific advisers cited a lack of evidence from large clinical trials and potential adverse effects. In subsequent appearances, the President doubled down on his contention that hydroxychloroquine might be helpful. "There's a possibility," he said during an April 5 briefing. "What do you have to lose?"

Actually, scientists say, any potential benefits must be weighed against the risks—and the risks are not minor. When taken alone or in combination with other medications, chloroquine and hydroxychloroquine can pose severe complications and may, in some cases, prove deadly, they caution.

So, what is hydroxychloroquine, anyway, and how did it become a potential weapon in the fight against the new coronavirus?

The promise

Scientists around the world have been racing to find a treatment for the new coronavirus. ClinicalTrials.gov lists more than 1,700 COVID-19 trials, including nearly 300 in the US, of which dozens involve hydroxychloroquine. Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) were first prescribed for malaria in 1944. They can be given before exposure to malaria, which is caused by a parasite transmitted by infected mosquitos, to prevent infection. The drugs are also used as treatment after infection.

Antimalarial drugs are sometimes prescribed to people with lupus, per Johns Hopkins Lupus Center in Maryland. Hydroxychloroquine is more commonly prescribed because it is generally believed to cause fewer side effects, whereas chloroquine has a reputation for more serious side effects but may be prescribed in situations where hydroxychloroquine cannot be used.

A systematic review in the Journal of Critical Care concluded that there is “pre-clinical evidence of effectiveness and evidence of safety” from the long-time use of chloroquine for other health conditions to justify clinical research into its use in COVID-19 patients. Translation: it’s worth a closer look. Still, the review authors noted that data from high-quality clinical trials “are urgently needed.”

Lab studies (including research published in Virology Journal in 2005) show that chloroquine is effective at preventing as well as treating the virus that causes severe acute respiratory syndrome (SARS), which is caused by another strain of coronavirus.

And research from China found that the protein spikes on the surface of the COVID-19 virus are similar to the protein spikes found on the surface of the SARS virus. While the coronavirus uses lots of different proteins to replicate and invade cells, protein spikes are the main proteins it uses to bind to a receptor (another protein that creates an entryway to a human cell). When that happens, people become infected. Chloroquine works against SARS by acting as a barrier between those receptors, which then interferes with the ability of the virus to bind to human cells.

The risks

Trouble is, the body of evidence to support hydroxychloroquine and chloroquine treatment for COVID-19 is “limited and inconclusive.” That’s the conclusion of two US rheumatologists writing in the Annals of Internal Medicine. Studies assessing the virus-fighting capabilities of these drugs consist mostly of laboratory experiments and small, poorly controlled trials, they said.

An often-cited French study examining hydroxychloroquine plus azithromycin showed some benefit, but the study population was small and patients in the study were not randomized.

Separately, results of a randomized trial from China, released prior to peer review by researchers on the website medRxiv, found that hydroxychloroquine could help speed recovery in patients with mild illness. “Considering that there is no better option at present, it is a promising practice to apply HCQ [hydroxychloroquine] to COVID-19 under reasonable management,” the study authors concluded. Again, though, the study was small, and it excluded severely ill patients.

Michael J. Ackerman, MD, a genetic cardiologist and director of the Windland Smith Rice Sudden Death Genomics Laboratory at Mayo Clinic, says certain people taking these drugs may be at risk of sudden-induced cardiac death. In “Urgent Guidance” released pre-publication by Mayo Clinic Proceedings, Dr. Ackerman and colleagues warn about repurposing antimalarial drugs, such as chloroquine and hydroxychloroquine (as well as the HIV medicines lopinavir and ritonavir) for COVID-19 treatment without “QTc monitoring.”

QTc is an indicator of the health of the heart’s electrical recharging system, explains Mayo Clinic. People with a dangerously prolonged QTc may be at risk of potentially deadly heart-rhythm changes that can lead to sudden death—and some of the drugs being used to treat COVID-19 are known to cause prolonged QTc. "Correctly identifying which patients are most susceptible to this unwanted, tragic side effect and knowing how to safely use these medications is important in neutralizing this threat," states Dr. Ackerman in a news release.

Former FDA Commissioner Mark McClellan, MD, who addressed drug safety concerns during an Alliance for Health Reform webinar on April 6, acknowledged that people want access to treatments that "might work." At the same, clinical trials are necessary to provide real evidence on ones that actually "do work,” he said, “especially since it doesn't look like we've got a magic bullet yet."

Dr. McClellan pointed out that people with heart disease who take hydroxychloroquine along with the antibiotic azithromycin—a combo the President referenced during a recent media briefing—can experience irregular heart rhythms.

In late March, the FDA granted emergency use of chloroquine and hydroxychloroquine for people hospitalized with COVID-19 who don't have access to clinical trials or aren't eligible to participate. But, as the FDA pointed out at the time: "The safety of these drugs has only been studied for FDA approved indications, not COVID-19."

In the wake of reports of serious heart complications and death, the agency warned the public in April about using these drugs outside of a hospital setting to either treat or prevent the disease. Subsequently, Trump claimed that he was taking a course of hydroxychloroquine, a disclosure that followed news that two White House workers had tested positive for the virus.

Today's announcement means oral versions of chloroquine and hydroxychloroquine no longer are sanctioned by the FDA for use in treating hospitalized patients to treat COVID-19.

The fallout

Tragically, an Arizona man died and his wife required hospitalization after they consumed a chemical fish tank cleaner containing chloroquine, believing it would prevent COVID-19, NBC News reported. The woman said the drug name resonated with her when she heard the President mention it. But no drug has been proven to prevent COVID-19 infections, and the product they consumed, though useful for ridding fish tanks of parasites, is toxic to humans, noted The Washington Post. The active ingredient is not the same as the medication that is being administered in clinical trials to determine whether it might benefit people with coronavirus.

In recent months, reports that health professionals were hoarding antimalarial medications for themselves and their family members worried patient advocates and rheumatologists. A run on hydroxychloroquine could create shortages that lead to lapses in therapy and disease flares for people with lupus and other autoimmune conditions, per recent opinion pieces in the Annals of Internal Medicine.

Meantime, researchers continue to examine the drug's use in the coronavirus arena. The director-general of the World Health Organization recently announced that the WHO had resumed use of hydroxychloroquine in a clinical trial after the organization's Data Safety Monitoring Board determined it was safe to proceed with that arm of the trial.

The information in this story is accurate as of press time. However, as the situation surrounding COVID-19 continues to evolve, it's possible that some data have changed since publication. While Health is trying to keep our stories as up-to-date as possible, we also encourage readers to stay informed on news and recommendations for their own communities by using the CDCWHO, and their local public health department as resources.

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