FDA Updates Safety Labels of Buprenorphine Products

The FDA has updated the safety labels of all products that contain buprenorphine to warn about the risks of dental disease and QT prolongation resulting from the use of these products. Buprenorphine is used to treat opioid use disorder and pain. These products are available as single-ingredient products and also in combination with naloxone.

The updates have been made to ensure all labels for buprenorphine products are consistent. This includes all generics as well as branded therapies, such as Belbuca, Buprenex, Suboxone, Zubsolv, and among others.

The QT interval is a measure made on an electrocardiogram and is used to assess the electrical properties of heart. Long QT can cause rapid heart rate and irregular rhythm and can be life-threatening.

The agency’s action for ensuring all labels warn of QT prolongation is supported by several studies, including a November 2020 study published in PLoS ONE. Previous studies with buprenorphine products have demonstrated a small QT prolongation effect. The label addition indicates that buprenorphine alone is unlikely to cause serious issues in patients without risk factors, such as low potassium, low heart rate, congestive heart failure, digitalis therapy, baseline QT prolongation, or severe low magnesium.

This new subsection reads:

“Thorough QT studies with buprenorphine products have demonstrated QT prolongation less than or equal to 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

“Consider these observations in clinical decisions when prescribing … to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.”

The FDA had also previously warned about the dental problems associated with buprenorphine products that dissolve in the mouth. These include tooth decay, cavities, oral infections, and loss of teeth and can be serious. These issues have been reported even in patients with no history of dental issues. The FDA has not identified a concern with buprenorphine products delivered by skin patch and injection.

Buprenorphine was approved in 2002 as a tablet to be administered under the tongue to treat opioid use disorder. In 2015, buprenorphine was approved as a film to be placed inside the cheek to treat pain.

The use of buprenorphine-containing medicines that are dissolved in the mouth has been growing. The estimated number of prescriptions dispensed from U.S. outpatient retail and mail-order pharmacies increased from 11 million in 2014 to 16 million in 2020, according to information provided by the FDA.

Regulators have identified 305 cases of dental problems (131 cases classified as serious) with buprenorphine medicines dissolved in the mouth. Most cases were in patients using the medicines for opioid use disorder; but 28 cases of dental problems occurred in patients using it to treat pain. In 26 cases, patients had no prior history of dental problems. Some cases reported dental problems occurring as soon as two weeks after treatment began, with the median time to diagnosis being about two years after starting treatment.

The most common treatment for these dental problems was tooth extraction/removal, which was reported in 71 cases. Other cases reported requiring root canals, dental surgery, and other procedures such as crowns and implants.

The new subsection on dental adverse events now reads:

“Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.”