FDA Updates on Black Box Warnings

FDA Updates on Black Box Warnings
Sami Russo, PharmD., Goodrich Pharmacy

The FDA has updated black box warnings on several medications seen in primary care in recent months. Invokana®️ (canagliflozin) has had a warning removed, while there are new warnings to be aware of for benzodiazepines and non-steroidal inflammatory drug (NSAID) use in pregnancy.

The sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin (Invokana®️, Invokamet®️, and Invokamet XR®️) reduces renal glucose reabsorption through the blockage of SGLT2 receptors in the kidney, therefore lowering blood sugars through an increased excretion of glucose through the urine. In 2017, a black box warning was assigned to canagliflozin regarding increased risk of leg and foot amputations. The FDA has removed this boxed warning after new data has emerged. They found that while the risk of amputation remains with use of Invokana, the magnitude of the risk has been determined to be lower than previously described. Additionally, heart and kidney related benefits that have been studied since the introduction of Invokana are now thought to outweigh the relatively small risk of amputation. Specifically, 2018 the CANVAS study released data to show Invokana reduced the risk of heart attack, stroke, and death in patients with type 2 diabetes with concomitant heart disease. In 2019 the CREDENCE study showed additional benefit via a reduction in risk of end-stage kidney disease, worsening of kidney function, hospitalization for heart failure, and cardiovascular death. Continue to encourage preventative foot care and monitoring of instances of new pain, tenderness, soreness, or ulcers in the feet.

Benzodiazepines are a widely used class of medications used for generalized anxiety disorder, insomnia, seizures, social phobia, panic disorder, and other anxiolytic uses. Although commonly used, benzodiazepines are often abused and misused. This may be especially dangerous when combined with opioid pain relievers, alcohol, social drugs, or other prescribed medications, such as antihistamines and sleep medications. Additionally, physical dependence on benzodiazepines can occur after several days to weeks, leading to withdrawal symptoms if abruptly discontinued. Due to these concerns, the FDA has added a black box warning to include the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions to the labeling in order to help guide prescribers and patients to use the medications safely. This added labeling is a part of the FDA’s ongoing effort towards improving public health by minimizing risks of controlled substances. Prescribers should continue to use benzodiazepines with caution to minimize these risks.

New labeling has been added to NSAIDs regarding use in pregnancy. Medications classified as NSAIDs include ibuprofen, naproxen, diclofenac, meloxicam, and celecoxib. NSAIDs are used both over the counter (OTC) and as prescription medications to treat pain, fever, and inflammation. The FDA warns that using NSAIDs after 20 weeks of pregnancy may cause kidney problems in the fetus, which can lead to low levels of amniotic fluid. This condition has shown to be resolved after discontinuation of NSAID use. This has been a known risk, but is a risk that the FDA has decided should be more widely known to avoid complications in pregnancy. Warnings to avoid NSAIDs after 28 weeks are already established due to the risk of premature closing of the ductus arteriosus in the fetus. It is recommended that NSAID use be limited after 20 weeks gestation and if required, should be limited to the lowest dose and shortest duration possible. This updated warning will also be reflected in the Drug Facts labels on OTC NSAID products.


  1. U.S. Food & Drug Administration. Invokana, Invokamet, Invokamet XR (canagliflozin): MedWatch Safety Alert- Boxed Warning about Risk of Leg and Foot Amputations Removed. https://www.fda.gov/safety/medical-product-safety-information/invokana-invokamet-invokamet-xr-canagliflozin-medwatch-safety-alert-boxed-warning-about-risk-leg-and. Published August 26, 2020. Accessed November 9, 2020.
  2. U.S. Food & Drug Administration. FDA Requiring Labeling Changes for Benzodiazepines. https://www.fda.gov/news-events/press-announcements/fda-requiring-labeing-changes-benzodiazepines. Published September 23, 2020. Accessed November 9, 2020.
  3. U.S. Food & Drug Administration. FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications. https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications. Published October 15, 2020. Accessed November 9, 2020.