FDA Pushes for New Buprenorphine Labeling

The US Food and Drug Administration (FDA) is urging manufacturers to revise labeling of transmucosal buprenorphine products to ease access to higher doses needed due to the rise of high-potency opioids like fentanyl.

The agency published its proposal in the Federal Register in late December. The move comes on the heels of increasing evidence that some clinicians, and many payers, are taking the current labeling too literally, and either not giving patients enough of the medications or denying payment for higher doses.

The labeling for Suboxone, a combination of buprenorphine and naloxone, and its generic equivalents currently states that for maintenance, “the target dosage” is “usually 16 mg/4 mg as a single daily dose,” and that “dosages > 24 mg/6 mg daily have not been demonstrated to provide a clinical advantage.”

For Zubsolv, a buprenorphine and naloxone sublingual tablet (Orexo), the label states that the “target” maintenance dose is 11.4 mg/2.9 mg and that no studies have shown an advantage for dosages > 17.2 mg/4.2 mg.

The instructions have “been misinterpreted by some as suggesting a maximum dosage of 16 or 24 mg daily although the labeling does not explicitly provide a maximum dosage,” said Marta Sokolowska, PhD, deputy center director for Substance Use and Behavioral Health at FDA’s Center for Drug Evaluation and Research, in a statement.

The agency said it is hoping to clarify “that daily maintenance dosages can be incrementally adjusted for each patient based upon their individual therapeutic need and that daily doses > 24 mg/d may be appropriate for some patients,” wrote Sokolowska.

“This is an important step forward because it’s recognizing that the drug supply has changed,” said Melissa Weimer, MD, associate professor of medicine and public health at Yale School of Medicine, New Haven, Connecticut. Clinicians need greater flexibility to individualize care, especially for individuals who are using high-potency opioids, Weimer, medical director of the Addiction Medicine Consult Service at Yale New Haven Hospital, New Haven, Connecticut, told Medscape Medical News.

“The science has evolved,” said Michelle Lofwall, MD, a professor of psychiatry and behavioral science at the University of Kentucky College of Medicine, Lexington, Kentucky. Data show that a higher dose of buprenorphine “is more protective than a lower dose,” said Lofwall, medical director of the university’s Robert Straus and First Bridge Clinics.

Lofwall and colleagues reported in the Journal of Addiction Medicine that individuals who received higher buprenorphine doses in the first 30 days of treatment had reduced opioid-involved overdose death and death from other causes.

As previously reported by Medscape Medical News, a study in JAMA Network Open showed that doses above 16 mg and 24 mg daily were associated with lower use of emergency department and other acute care services.

It is unclear whether manufacturers will apply to the FDA to change their products’ label.

“It’s hard for me to think of a reason why they wouldn’t,” Lofwall told Medscape Medical News.

Why the Change?

There are likely many factors that led the FDA to issue its call for action. The agency noted it had received a petition from the Colorado Society of Addiction Medicine in 2022 that said that label recommendations on initiation and maintenance for transmucosal buprenorphine products were perceived as dosage limits or maximums.

That was leading clinicians to not exceed 24 mg once daily, or even to stop at 16 mg, according to the petition. Payers, especially Medicaid programs, were denying coverage for higher doses, said the petition.

Weimer said the use of higher-dose buprenorphine has evolved quickly. As her practice began seeing more people using fentanyl, starting in 2019, higher doses of buprenorphine were needed to stabilize them “and to reduce their return to opioid use.” Most need 24 mg daily, and “some individuals were needing even higher doses,” Weimer noted.

In late 2023, Weimer and colleagues, through the American Society of Addiction Medicine, published a “Clinical Considerations” document to help guide clinicians treating individuals who use high-potency opioids like fentanyl. The paper concluded that buprenorphine doses > 16 mg, and often, > 24 mg, were necessary to achieve stabilization in opioid use disorder (OUD).

The FDA noted that a Reagan-Udall Foundation public meeting in the spring of 2023 — with FDA and the Substance Abuse and Mental Health Services Administration (SAMHSA) — and a December 2023 meeting with FDA, SAMHSA, and the National Institute on Drug Abuse helped shed more light on the ongoing barriers to the use of higher dosages. The FDA labeling was determined to be one of the biggest impediments.

Many speakers at the meetings discussed real-life harms due to misperceptions. Edwin Chapman, MD, a community physician in Washington, DC, said that a Medicare Advantage plan reduced a patient’s dose from 32 mg to 24 mg daily.

The patient was fine for a few months but began buying illicit buprenorphine, which contained fentanyl. He overdosed. The patient lived and Chapman was able to convince the plan to pay for the 32 mg dose.

Five states — Kentucky, Ohio, Tennessee, Virginia, and West Virginia — restrict buprenorphine initiation and maintenance doses, according to a database maintained by the Center for Public Health Law Research at Temple University Beasley School of Law, Philadelphia, and the public health organization Vital Strategies.

Many states have restrictions on buprenorphine prescribing, such as mandated counseling and drug testing for recipients, according to Vital Strategies. Some research indicates that mandated counseling may inhibit access to treatment access, but 14 states and the District of Columbia require counseling for some or all buprenorphine patients, the organization reported.

Fifteen states still have laws that incorporate outdated provisions of the federal X-waiver, which was discontinued in December 2022. The FDA’s efforts could help overturn some “out-of-date regulations,” said Lofwall.

Act Now, FDA Says

The agency is making it clear that it recommends that individuals with OUD should not be undertreated. “An adequate treatment dose, titrated to clinical effectiveness, [should] be achieved as rapidly as possible,” wrote Sokolowska in a letter to healthcare providers.

“OUD treatment is more likely to be successful when tailored to the needs of the individual patient, including consideration of the appropriate dose of buprenorphine,” she wrote.

Dosages of > 24 mg have not been evaluated in randomized trials, but that “does not mean that daily dosages > 24 mg have been shown to be ineffective,” or that it is a maximum dosage, wrote Sokolowska.

Clinicians don’t have to wait until a labeling change is made, she said.

Weimer said that she was pleasantly surprised at the FDA’s outreach. “The fact that it happened so quickly, I think, is wonderful,” she said.

Weimer reported no relevant financial relationships. Lofwall reported that she has been a research consultant for Braeburn Pharmaceuticals and has received honorarium from Camerus.

Alicia Ault is a Saint Petersburg, Florida–based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.