Recent FDA warnings that went under the radar

By Naveed Saleh, MD, MS
Published September 24, 2020

Key Takeaways

On June 15, 2020, the FDA revoked its emergency use authorization that permitted administration of hydroxychloroquine in hospitalized COVID-19 patients. This decision was based on results from a large randomized clinical trial on hydroxychloroquine and COVID-19 that showed that the drug failed to decrease the odds of death or speed recovery, as well as it being unlikely that the drug kills or inhibits coronavirus.

On July 1, 2020, after reviewing safety information, the FDA warned of reports of heart rhythm problems, blood/lymph disorders (ie, methemoglobinemia), kidney injury, and liver disease/failure in hospitalized COVID-19 patients receiving hydroxychloroquine or chloroquine.

Without delving into politics, hydroxychloroquine has been a hot-button healthcare issue that’s consumed much national attention. But it’s not the only drug that deserves attention these days. The FDA has issued other notable warnings or safety revisions in recent months that haven’t garnered the same amount of notoriety amid all the COVID-19 news.  

Boxed warning on benzodiazepines

This just in: The FDA announced on September 23 that it’s requiring all benzodiazepines to carry an updated Boxed Warning about the drugs’ serious risks of abuse, addiction, physical dependence, and withdrawal reactions. According to the agency, these drugs may be inappropriately prescribed and used because the current prescribing information doesn’t adequately warn of benzodiazepines’ significant risks and harms.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” said FDA Commissioner Stephen M. Hahn, MD. “We are taking measures and requiring new labeling information to help healthcare professionals and patients better understand that while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence.”

Benzodiazepines can cause physical dependence over a course of several days to weeks, even when taken as directed, the FDA warned. Abruptly stopping or reducing the dosage of benzodiazepines too quickly can result in withdrawal reactions, including potentially life-threatening seizures.

The FDA is also requiring drugmakers to update their existing medication guides to help educate patients and caregivers about these serious risks.

Montelukast and mental health

After reviewing case reports, conducting an observational study, and reviewing observational and preclinical studies, as well as re-assessing risks/benefits, the FDA issued a Boxed Warning for the asthma and allergy drug montelukast (SIngulair). 

Although the observational studies—including the FDA’s own—did not indicate any increased risk of adverse mental health effects compared with inhaled corticosteroids, various reports highlighted mental health risks of the drug, including contemplated suicide. Moreover, animal studies showed that the drug crosses into the brain.

“Due to the wide availability of alternative safe and effective allergy medicines with long histories of safety, we have reevaluated the risks and benefits of montelukast and have determined it should not be the first choice treatment particularly when allergic rhinitis symptoms are mild,” the FDA noted. “In addition, many health care professionals and patients/caregivers are not aware of the risk of mental health side effects despite the existing warnings in the prescribing information.” 

In the case of allergic rhinitis, montelukast should be prescribed only when patients are intolerant to other therapies or these therapies have failed.

The FDA advised healthcare providers to ask about a history of mental illness and monitor for emerging neuropsychiatric symptoms. Physicians should also advise patients of possible psychiatric side effects and have them report any disturbances as they arise. 

Although most neuropsychiatric events have occurred during treatment and symptoms often resolved after stopping treatment with montelukast, symptoms persisted in some patients even after discontinuing the drug. 

Naloxone prescription

Naloxone has turned out to be a wonder drug of sorts, and has saved countless lives by reversing respiratory depression caused by opioids. To further decrease risk of death due to opioid overdose, the FDA made three fresh recommendations.

First, for patients prescribed opioids, clinicians should discuss with them the availability of naloxone, as well as consider prescribing this drug to patients at increased risk of opioid overdose. Such patients include those taking benzodiazepines or other central nervous-system depressants, as well as those who have a history of opioid use disorder/previous overdose. Furthermore, naloxone should also be available to patients with associated contacts at risk of accidental overdose, including children or other household members.

Second, for patients prescribed medicines to treat opioid use disorder, such as methadone or buprenorphine, clinicians should discuss the availability of naloxone and strongly consider prescribing it. 

Third, clinicians should consider prescribing naloxone to those with a current or past diagnosis of opioid use disorder, as well as those who have overdosed, even if these patients are no longer taking opioids, methadone, or buprenorphine.

Canagliflozin and amputation

The drug canagliflozin (Invokana) is a sodium-glucose cotransporter-2 (SGLT2) inhibitor, which voids blood sugar via the kidney. In 2017, the FDA required a Boxed Warning for canagliflozin with regard to risk of amputation vs the drug’s benefits. However, after new clinical trial data came to light, the drug proved to decrease the risk of potentially deadly heart-related events, such as heart attack or stroke, in those with type 2 diabetes and heart disease. Furthermore, in those with diabetes and diabetic kidney disease, the drug decreased the risk of end-stage kidney disease, as well as decreasing the risk of heart failure and heart-related death.

“Collectively, “ the FDA stated, “these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine. Safety information from recent clinical trials also suggests that the risk of amputation, while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored. Based upon these considerations, we have concluded that the Boxed Warning should be removed. The amputation risk with canagliflozin remains and is still described in the Warnings and Precautions section of the prescribing information.”

The FDA emphasized that it’s important for physicians and patients to continue to perform preventative foot care and monitor the legs and feet for new pain, tenderness, sores, ulcers, and infections. “Risk factors that may predispose patients to the need for amputation should be considered when choosing antidiabetic medicines,” the agency advised. 

Duty to report

Because the FDA is continuously appraising the safety of approved drugs, including montelukast canagliflozin, it encourages both clinicians and patients to report any potential adverse effects.

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