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March 1, 2024

Re: NADA 141-568
Senvelgo (velagliflozin oral solution)

CMS #: 674535

WARNING LETTER

Dear Mr. Legg:

The U.S. Food and Drug Administration (FDA) has reviewed your promotional communications for Senvelgo (velagliflozin oral solution), including your Vet Detailer, available on the Senvelgo website,¹ and found it makes false or misleading claims and representations about the safety and effectiveness of Senvelgo. This promotional communication misbrands Senvelgo within the meaning of the Federal Food, Drug and Cosmetic Act (FD&C Act), making its distribution violative. FD&C Act section 502(a) [21 U.S.C. 352(a)]; section 502(n) [21 U.S.C. 352(n)]; section 201(n) [21 U.S.C. 321(n)]; section 301(a) [21 U.S.C. 331(a)]; and 21 CFR 202.1(e)(5). This violation is especially concerning from a public health perspective because the misleading promotional communication contradicts the boxed warning, contraindications, and approved indication of your product’s labeling, creating a misleading impression regarding the safety and effectiveness of Senvelgo, which is a recently-approved veterinary drug in a novel therapeutic class.

Background

Senvelgo is indicated to “improve glycemic control in otherwise healthy cats with diabetes mellitus not previously treated with insulin.”²

Senvelgo’s FDA-approved PI contains a boxed warning due to increased risk of diabetic ketoacidosis (DKA) or euglycemic diabetic ketoacidosis (eDKA) in cats treated with Senvelgo, both of which “may result in death”. The boxed warning explains, “[d]ue to the risk of developing diabetic ketoacidosis or euglycemic ketoacidosis, do not use SENVELGO in cats with diabetes mellitus who have previously been treated with insulin […]” (emphasis added). Boxed warnings are the most significant type of warning in a product’s labeling and are used to emphasize serious or life-threatening risks.³ In accordance with the boxed warning, the “Contraindications” section of the PI also states, “Do not use SENVELGO in cats with diabetes mellitus who have previously been treated with insulin…” The PI contains additional adverse event, warning, precaution, and contraindication information unrelated to this letter.⁴

False or Misleading Claims

Prescription drug advertisements and labeling (promotional communications) misbrand a drug if they are false or misleading in any particular. See FD&C Act section 502(a),(n) (21 U.S.C 352(a),(n)). The determination of whether a promotional communication is misleading includes, among other things, not only representations made or suggested in the promotional communication, but also the extent to which the promotional communication fails to reveal facts material in the light of its representations or material with respect to consequences that may result from the use of the drug as recommended or suggested in the promotional communication FD&C Act section 201(n) (21 U.S.C 321(n)) and 21 CFR 202.1(e)(5).

Your promotional material, the Senvelgo Vet Detailer, includes the following statement:⁵

Demonstrated excellent efficacy and safety in multiple pivotal clinical field trials featuring over 300 insulin-naive, previously insulin-treated, and otherwise healthy diabetic cats

This statement is false and/or misleading because it indicates that Senvelgo was found to be safe and effective in previously insulin-treated cats based on multiple clinical field trials, including the “pivotal” trials (which are the trials that form the primary basis for FDA approval). This statement is in direct conflict with the product’s labeling and the results from the underlying trial(s). The PI’s Boxed Warning and Contraindications provide information about the severe health risks associated with using Senvelgo in cats that have previously been treated with insulin (namely, the development of DKA or eDKA, both of which can be fatal) and say, “do not use” Senvelgo in this population. The Indication section explicitly limits Senvelgo’s use to “otherwise healthy cats with diabetes mellitus not previously treated with insulin.” (emphasis added). We acknowledge that the multicenter field study performed for effectiveness did enroll 38 cats that had previously been treated with insulin. However, according to the Adverse Reactions section of the PI, twelve of the 38 cats (32%) developed ketonuria, DKA, or eDKA during the first week of treatment and were removed from the study. Due to these safety concerns, the approved labeling for Senvelgo explicitly excluded cats previously treated with insulin. The statement found in the Vet Detailer does not provide the context to explain that, although Senvelgo was tested in a small number of previously insulin treated cats, safety and effectiveness were not demonstrated for these cats, so they were intentionally and specifically excluded from the approved patient population and, instead, added to the Boxed Warning and Contraindication sections with a “do not use” statement.

The overall impression created by the statement is that Senvelgo is safe and effective for use in previously insulin-treated cats, in contradiction to the FDA-approved labeling and underlying trial data submitted to FDA. The statement in the Vet Detailer is especially concerning both because it could result in an adverse event that could be fatal and because it was made close to Senvelgo’s approval at a time when veterinarians are just learning its warnings, indications, and contraindications.⁶

We offer the following additional comment about the promotion of Senvelgo:

    - Your Vet Detailer (US-PET-0674-2023-V2) claims that cats on Senvelgo “had fewer monitoring requirements compared to cats receiving traditional insulin treatments” (page 2) and requires “less-intensive monitoring” (page 4). The majority of monitoring for cats on insulin treatment or Senvelgo occurs during the first several weeks of initiating treatment where nonroutine visits to the veterinarian occur because ketone testing, blood glucose curves, fructosamine testing, and numerous other tests/observations must be taken/made. These nonroutine, intense monitoring requirements do not substantially differ between Senvelgo and insulin and are of particular concern to caretakers and veterinarians because of the time and cost involved. We acknowledge that, once stabilized, there may be less monitoring compared with insulin; however, your Vet Detailer did not disclose that the “less-intensive monitoring” could only apply the post-stabilization monitoring that would occur at home and/or at routine visits.⁷

Conclusion and Requested Action

For the reasons discussed above, your website and Vet Detailer misbrand Senvelgo within the meaning of the FD&C Act and make its distribution violative. FD&C Act section 502(a), (21 U.S.C. 352(a)); section 502(n) [21 U.S.C. 352(n)]; section 201(n) (21 U.S.C. 321(n)); section 301(a) (21 U.S.C. 331(a)), and 21 CFR 202.1(e)(5).

This letter is not intended to be an all-inclusive statement of violations that may exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may lead to legal action, including without limitation, seizure, and injunction.

We request that you cease any violations of the FD&C Act. Within fifteen (15) working days of receipt of this letter, please submit a written response addressing the concerns described in this letter, listing all promotional communications for Senvelgo that contain representations like that described above, and explaining any plan for discontinuing use of such communications, or for ceasing distribution of Senvelgo. If you cannot complete the above requested actions within fifteen (15) working days, state the reason for the delay and the time within which you will complete them.

If you believe that your products are not in violation of the FD&C Act, please include in your submission to us your reasoning and any supporting information for our consideration within 15 working days from the date of receipt of this letter.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Veterinary Medicine, Division of Pharmacovigilance and Surveillance, 12225 Wilkins Ave, MPN II Room E474, Rockville, Maryland 20852. Please send a courtesy copy by email to CVMSurveillance@fda.hhs.gov. All correspondence should include a subject line that clearly identifies the submission as a Response to Warning Letter # 674535.

If you have any questions, please contact Dr. Christopher Loss by email at christopher.loss@fda.hhs.gov.

Sincerely,
/S/

Linda Walter-Grimm, DVM
Director, Division of Pharmacovigilance and
Surveillance
Office of Surveillance and Compliance
Center for Veterinary Medicine

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1 The Vet Detailer (US-PET-0674-2023-V2) and website (US-PET-0565-2023) were submitted by Boehringer Ingelheim under cover of Form FDA 2301. The Senvelgo website can be found at https://bianimalhealth.com/pets/feline/products/therapeutics/senvelgo (last accessed 3.1.2024).

2 FDA-approved package insert (PI) for Senvelgo

3 See, e.g., “Boxed Warning”, https://www.fda.gov/patients/clinical-trials-what-patients-needknow/glossary-terms

4 The risk information reproduced in this letter is only for background information related to the letter’s subject matter and does not necessarily represent the risk information that should be included in any promotional communications.

5 Vet Detailer, page 2, submitted by Boehringer Ingelheim under cover of Form FDA 2301 (US-PET-0674-2023-V2). Emphasis in original omitted.

6 Senvelgo (velagliflozin), NADA 141-568, was approved August 10, 2023.

7 In contrast to your Vet Detailer, your Patient Management Guide (US-PET-0676-2023, pdf page 2), also submitted to FDA, did properly make that distinction (“less monitoring and diagnostics are required for stabilized cats on SENVELGO oral solution”) (emphasis added)