FDA approves five Zepbound label updates, adding SURMOUNT-3 and SURMOUNT-4 trial data

Five changes to the prescribing information for Zepbound (tirzepatide) injection took effect on October 18, 2024, when the FDA approved them together in one action letter ^[1]. The updates add data from two phase 3 trials, retitle a gastrointestinal warning, list two additional side effects, remove a patient selection subsection, and address the risk of pulmonary aspiration during surgery ^[1].

Zepbound is Eli Lilly's tirzepatide product, a different molecule from semaglutide, the ingredient in Ozempic, Wegovy and Rybelsus. The supplements were submitted to the FDA between December 8, 2023 and October 3, 2024, according to the approval letter signed by John Sharretts, M.D., director of the agency's Division of Diabetes, Lipid Disorders, and Obesity ^[1].

What the five supplements cover

One supplement, S-006, adds data from nonclinical studies and two phase 3 trials ^[1]. The first, called SURMOUNT-3, tested tirzepatide once weekly against placebo after an intensive lifestyle program in people without type 2 diabetes who have obesity or are overweight with weight-related conditions ^[1]. The second, SURMOUNT-4, tested tirzepatide against placebo for maintenance of weight loss in the same population ^[1]. Both were randomized, double-blind trials ^[1]. The approval letter does not include the trial results or state how much weight participants lost, so those numbers are not yet known from this document ^[1].

Another supplement, S-005, retitled a section of the Warnings and Precautions to "Severe Gastrointestinal Adverse Reactions" and added dysgeusia, a distortion of taste, to the clinical trials experience section ^[1]. A third, S-011, added dysesthesia, an abnormal sensation such as burning or tingling, to the same clinical trials section ^[1].

A fourth supplement, S-015, made editorial revisions to the indication statement, removed Section 2.1, Patient Selection, and made matching revisions to the Medication Guide ^[1]. The letter does not describe what Patient Selection previously said or why it was removed ^[1].

The fifth, S-019, revised the label in response to an FDA safety labeling change notification dated September 6, 2024 ^[1]. That notification told Lilly about new safety information for GLP-1 receptor agonist products concerning the risk of pulmonary aspiration during elective surgeries or procedures requiring general anesthesia or deep sedation ^[1].

The FDA also wrote that Lilly is exempt from the Pediatric Research Equity Act requirement for these supplements because none of the criteria that trigger it apply ^[1].

Why it matters for patients

The prescribing information is the official document that describes what a drug is approved for, how it was studied, and what risks it carries. Patients and clinicians often meet it through the Medication Guide handed out at the pharmacy or quoted in clinical discussions. These five approvals change several of those passages at once ^[1].

Two newly listed side effects are now documented from the clinical trials experience section: taste distortion and abnormal skin or nerve sensations ^[1]. Both are described only by name in the approval letter, without frequency or severity, so how often they occurred has not been reported in this document ^[1].

The surgical warning is the change most likely to come up outside a weight-management visit. Zepbound's label now carries information about pulmonary aspiration risk for elective procedures using general anesthesia or deep sedation, following the FDA's September 2024 safety notification covering GLP-1 receptor agonist products ^[1]. Aspiration means stomach contents entering the airway during anesthesia. People scheduling such procedures have a concrete reason to mention their medication to the surgical team, though the letter does not say what the label instructs clinicians to do.

The removal of the Patient Selection subsection and the edits to the indication statement change how the label frames who the drug is intended for. The agency's letter does not explain the intent behind those edits ^[1].

What happens next

Lilly must submit the updated labeling in structured product labeling format within 14 days of the letter, and must file a statement of intent to comply with promotional material requirements within 7 days of receiving it ^[1]. Advertising and promotional materials that make claims about Zepbound must be revised to match the new label ^[1]. Patent information tied to the approved changes must be submitted on Form FDA 3542 within 30 days ^[1].