FDA finalizes the gastrointestinal and aspiration labeling for Mounjaro

The Food and Drug Administration approved three supplemental new drug applications for Mounjaro (tirzepatide) on Nov. 1, 2024, folding a government-ordered warning about pulmonary aspiration during anesthesia into the prescribing information and adding two side effects — dysgeusia and dysesthesia — to the label's clinical trials section.^[1]

The approval letter, signed by Monika Houstoun, Pharm.D., M.P.H., deputy director for safety in FDA's Division of Diabetes, Lipid Disorders, and Obesity, went to Eli Lilly and Company and covers supplements S-010, S-015 and S-022 under NDA 215866.^[1] The three applications were dated and received Dec. 8, 2023, April 19, 2024, and Oct. 3, 2024.^[1]

What each supplement changed

S-010 provides for updates to the prescribing information regarding severe gastrointestinal adverse reactions. It also adds dysgeusia — a distortion of taste — to Section 6.1, Clinical Trials Experience, and revises the product description in Sections 11 and 12 of the label.^[1]

S-015 adds dysesthesia, an abnormal or unpleasant sensation, to Section 6.1, Clinical Trials Experience.^[1]

S-022 is the supplement that carries out an FDA safety directive. The agency referred Lilly back to its letter dated Sept. 6, 2024, which notified the company under Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act of new safety information that FDA determined should be included in the labeling for glucagon-like peptide-1 receptor agonist (GLP-1 RA) products.^[1] That information "pertains to the serious risk of pulmonary aspiration for patients undergoing elective surgeries or procedures requiring general anesthesia or deep sedation."^[1] S-022 revises the Mounjaro labeling to match that letter and follow-up email correspondence dated Oct. 11 and Oct. 16, 2024.^[1]

A Section 505(o)(4) notification is not a request. It is FDA's formal mechanism for requiring a labeling change based on new safety information, and the November approval is the step that puts the required language into the official Mounjaro label.^[1]

The approval letter does not spell out the exact wording added to the label, how often dysgeusia or dysesthesia occurred in trials, or how the aspiration language is phrased. The enclosed content of labeling — the prescribing information, Medication Guide and Instructions for Use — accompanies the letter but the specific text is not reproduced in it.^[1] FDA also noted it had previously granted a waiver of the half-page length limit for the label's Highlights section.^[1]

Why it matters for patients

Mounjaro is tirzepatide, the same molecule sold as Zepbound for weight management. The changes here apply to the Mounjaro label approved under NDA 215866.^[1]

The most practical change concerns surgery and procedures. FDA determined that the risk of pulmonary aspiration — stomach contents entering the lungs — during general anesthesia or deep sedation is serious enough to belong in the labeling of GLP-1 receptor agonists as a class.^[1] These drugs slow stomach emptying, which is the underlying reason the issue came up; that mechanism is part of how the class works, though the approval letter itself does not explain the mechanism. Patients scheduled for an elective procedure now have label language their surgical and anesthesia teams can point to when planning. The letter does not set out any specific pre-procedure instructions.^[1]

The gastrointestinal update in S-010 and the two added adverse reactions also change what shows up in the Medication Guide and in advertising. FDA told Lilly that all promotional materials making representations about the drug "must be promptly revised to be consistent with the labeling changes approved in this supplement, including any new safety-related information," and that revisions "should include prominent disclosure of the important new safety-related information."^[1] In practice, that means the updated risk language should begin appearing in ads and materials patients see.

What happens next

FDA set several deadlines running from the Nov. 1, 2024, letter date. Lilly had 7 days to submit a statement of intent to comply with the promotional materials rule at 21 CFR 314.70(a)(4).^[1] The company had no later than 14 days to submit the content of labeling in structured product labeling format through FDA's electronic listing system, after which the updated label becomes accessible through publicly available labeling repositories.^[1] Patent information required for Orange Book listing was due within 30 days of approval.^[1]

FDA also noted that because the supplements did not involve a new active ingredient, indication, dosage form, dosing regimen or route of administration, Lilly is exempt from the pediatric assessment requirement under the Pediatric Research Equity Act.^[1]