Prescription drug overdoses in America have reached an all-time high, and put millions of patients at risk for death every year. After taking an in-depth look at how these drugs and other medications affect the body when taken at the same time, the Food and Drug Administration has issued a “black box warning” on nearly 400 products. The warning is the strongest the FDA can issue in order to alert doctors and potential patients that certain combinations put users at high risk for fatal overdoses.

Painkillers, such as oxycodone, hydrocodone, and morphine and cough treatments that contain opioids will carry the new warning. Benzodiazepines, including Xanax, Valium, and lorazepam, will also receive the overdose warning. According to the FDA, the life-threatening combination of anti-anxiety medications, like Xanax, with prescription painkillers has led to a significant increase in emergency room visits. Between 2004 and 2011, the number of deaths attributed to overdoses from taking the recommended dosage in combination with another drug has nearly tripled.

“It is nothing short of a public health crisis when you see a substantial increase of avoidable overdose and death related to two widely used drug classes being taken together,” said FDA Commissioner Dr. Robert Califf, in a statement. “We implore health care professionals to heed these new warnings and more carefully and thoroughly evaluate, on a patient-by-patient basis, whether the benefits of using opioids and benzodiazepines – or CNS depressants more generally – together outweigh these serious risks.”

People who mix opioids with the sedatives may experience breathing problems, comas, and eventually death. Painkiller overdoses alone were responsible for 47,000 deaths in 2014. Meanwhile, the Centers for Disease Control and Prevention notes that more than six out of 10 drug overdose deaths involve opioids. While doctors have tried to combat the problem by prescribing fewer painkillers, leading to a sudden decline in prescriptions for the first time in 20 years, the rate of fatal overdoses still continues to climb.

The FDA has issued the new warning, part of its Opioids Action Plan, in hopes of “reversing the prescription opioid abuse epidemic, while still providing patients in pain access to effective and appropriate pain management.”