WARNING LETTER
Elanco Animal Health
MARCS-CMS 695170 —
January 28, 2025
Product:
Animal & Veterinary
Drugs
Recipient:
Recipient Name
Jeffrey Simmons
Recipient Title
President and CEO
Elanco Animal Health
2500 Innovation Way
Greenfield
,
IN
46140
United States
Issuing Office:
Center for Veterinary Medicine
United States
January 28, 2025
Re: NADA 141-585, Zenrelia™ (ilunocitinib tablets)
CMS #: 695170
WARNING LETTER
Dear Mr. Simmons:
The U.S. Food and Drug Administration (FDA) has reviewed your promotional communications for Zenrelia (ilunocitinib tablets) including your veterinarian product website,
1
the consumer directed website,
2
your Product Brochure and Itch Tracker,
3
which is linked on both websites, and a slide deck titled “Reach for Zen: New Relief for Dogs with Atopic Dermatitis
4
” and noted false or misleading claims and representations about the safety and effectiveness of Zenrelia. These promotional communications misbrand Zenrelia within the meaning of the Federal Food, Drug, and Cosmetic Act (FD&C Act). FD&C Act section 502(a) [21 U.S.C. 352(a)] and section 502(n) [21 U.S.C. 352(n)]; see also section 201(n) [21 USC 321(n)]. It is a prohibited act to distribute a misbranded product in interstate commerce. FD&C Act section 301(a) [21 U.S.C. 331(a)]. This violation is especially concerning from a public health perspective because the misleading promotional communications create a misleading impression regarding the safety and effectiveness of Zenrelia, which is a recently-approved veterinary drug in the Janus Kinase (JAK) inhibitor drug class.
Background
Zenrelia is indicated for “control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age.”
5
Zenrelia’s FDA-approved Prescribing Information (PI) contains a boxed and bolded warning of the risk of “fatal vaccine-induced disease from modified live virus vaccines and inadequate immune response to any vaccine” in dogs receiving Zenrelia. Therefore, the boxed warning states to discontinue Zenrelia for at least 28 days to 3 months prior to vaccination and withhold Zenrelia for at least 28 days after vaccination.
The PI contains additional warning language including:
“Dogs should be monitored for the development of infections because Zenrelia may increase susceptibility to opportunistic infections, including demodicosis, interdigital furunculosis, coccidiosis, and pneumonia, and exacerbation of subclinical or uncomplicated infections (see
Target Animal Safety
and
Adverse Reactions
).”
…
“Zenrelia may cause a progressive or persistently decreased hematocrit, hemoglobin, and/or red blood cell count without a corresponding increase in absolute reticulocyte count (see
Target Animal Safety
).”
“New neoplastic conditions (benign and malignant) were observed in dogs treated with Zenrelia during clinical studies (see
Adverse Reactions
).”
The PI contains additional adverse event, warning, precaution, and contraindication information.
6
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 sections 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. See FD&C Act section 201(n) (21 U.S.C 321(n)) and 21 CFR 202.1(e)(5).
Omitted Information
The websites mentioned above and the Product Brochure and Itch tracker omit the phrase “from modified live virus vaccines” from the boxed warning found in the Important Safety Information (ISI) sections. The Vaccine Response Study in the Target Animal Safety section of the PI describes a dog that was administered Zenrelia that developed lethargy, depression, poor body condition, and weakness after receiving a modified live virus (MLV) vaccination and was subsequently euthanized. This dog was later diagnosed with adenoviral hepatitis and pancreatitis that “were concluded to be vaccine-induced, secondary to Zenrelia-induced immunosuppression.” Omitting the phrase “from modified live virus vaccines” in promotional material is misleading because the fatal vaccine-induced disease occurred after administration of a MLV DHPP vaccination,
7
a core vaccination for all dogs.
8
Therefore, the phrase “from modified live virus vaccines” provides material facts that may be relevant to prescribing veterinarians and dog owners.
In the ISI section of the consumer-directed website and on page one of the Product Brochure and Itch Tracker, the specific time period to withhold Zenrelia before and after vaccination is omitted (i.e., at least 28 days to 3 months prior to vaccination and at least 28 days after vaccination) and replaced with the phrase “for a time period before and after vaccination.” The specific time frame is also omitted from a 30-second video found on the veterinarian product website.
9
The phrase “for a time period before and after vaccination” is misleading because it does not provide necessary information to the pet owner.
The Safety section of the Zenrelia veterinarian website contains only the statements “Read the entire package insert before using this drug, including the Boxed Warning” and “In clinical trials, the most observed adverse events were vomiting, diarrhea, and lethargy.” There is no mention of fatal vaccine-induced disease from MLV vaccines or inadequate immune response to any vaccines. We acknowledge that clicking on the box titled “Explore Zenrelia’s safety data” directs the reader to another webpage where more safety information is presented. However, this Safety section is also missing information about the risk of fatal vaccine-induced disease from MLV vaccines or inadequate immune response to any vaccines, as well as safety information from the Warnings section of the PI like monitoring for the development of infections, the risk of decreased hematocrit, hemoglobin, and/or red blood cell count, and the risk of new neoplastic conditions.
10
Misrepresented Study Results
The veterinarian product website makes misleading claims about the results of the Vaccine Response Study. In the “Vaccinations FAQs” section of the website, under the question “What is vaccine-induced disease?” the response in part states “After the label was finalized, PCR testing confirmed this dog had Infectious Canine Hepatitis due to infection with canine adenovirus type 1 (CAV-1), which is genetically distinct from the strain of CAV-2 used in the MLV. Furthermore, this dog developed clinical signs of hepatitis (hematemesis) prior to receiving its first MLV. CAV-1 is highly contagious and difficult to kill with routine disinfectants; it is unknown how this dog became exposed or if it was a carrier prior to entering the bio-secure facility used for this study.” This claim is repeated on page 33 of the “Reach for Zen” slide deck. This information is in direct conflict with the PI and Freedom of Information (FOI) summary for Zenrelia, which concluded that the dog in the study had vaccine-induced adenoviral hepatitis and pancreatitis secondary to Zenrelia-induced immunosuppression.
(b)(4)
The Safety section of the Zenrelia veterinarian website also contains information about adverse reactions seen in the field studies conducted for approval,
11
accessible by clicking on the boxes titled “US atopic dermatitis study vs placebo” and “US allergic dermatitis study vs placebo”. However, the adverse reaction data found on the website is not consistent with the information found in the Zenrelia PI. For example, for the Control of Pruritus Associated with Allergic Dermatitis study, the PI states that diarrhea was reported in 26 (12.2%) dogs and urinary tract infections were reported in 13 (6.3%) Zenrelia treated dogs, while the Zenrelia website reports these numbers as 19 (9.2%) and 3 (1.5%), respectively. The adverse reaction data was reviewed and verified by the FDA as part of the approval process. The statements on the Zenrelia website are therefore false and misleading because they misrepresent the safety profile of Zenrelia.
Additional Comments
We offer the following additional comments about the promotion of Zenrelia:
Your product websites and Product Brochure state that there are “visible improvements in allergic itch from day one.” Neither effectiveness study (i.e., Control of Atopic Dermatitis or Control of Pruritus Associated with Allergic Dermatitis) supporting FDA approval assessed the speed of action of Zenrelia. According to the FOI summary, in the Control of Atopic Dermatitis study, treatment success
12
on Day 28 was identified as the primary effectiveness endpoint. Pruritus Visual Analog Scale (PVAS) scores were also assessed at other time points, but they were considered secondary endpoints. This study did demonstrate that the estimated mean PVAS scores were lower in the Zenrelia group compared to placebo on Day 1, however, this difference was relatively small, and it is unknown if it represented a clinically identifiable difference in pruritus in the treatment group compared to the placebo group. Therefore, it cannot be concluded that the difference in PVAS scores indicates that Zenrelia improved pruritus compared to placebo on Day 1. In the Control of Pruritus Associated with Allergic Dermatitis study, the primary effectiveness endpoint was treatment success
13
on at least 5 of the first 7 days of treatment. In this study, PVAS scores were assessed on Days 1 through 7, but the estimated mean PVAS score in the Zenrelia group was not lower than the placebo group until after Day 1, beginning on Day 2.
Your product Detailer
14
makes the claim “77% of Zenrelia-treated dogs returned to normal versus 53% of Apoquel treated dogs.” The head-to-head study comparing treatment with Zenrelia to treatment with Apoquel showed that Zenrelia had similar efficacy as Apoquel on day 28, which was the primary effectiveness endpoint. The claim in the Detailer is based on PVAS scores on Day 112 of the study, which was a secondary endpoint. When multiple endpoints are tested statistically, the Type I error rate (the probability of erroneously concluding an effect when the truth is that there is no effect) may be inflated. Therefore, the p-values associated with the analyses of the multiple secondary endpoints should not be interpreted as evidence of statistically significant differences. We acknowledge you note with an asterisk that “PVAS <2; P
<
0.05. Secondary end point P values are not adjusted for multiple testing; therefore, caution should be exercised in interpretation.” However, this information is located in much smaller font at the bottom of the page and its inclusion in the Detailer does not mitigate the misleading impression made by the claim, which is presented prominently in large font in the center of the page. See 21 CFR 202.1(e)(7)(viii).
Your product Detailer claims that “Results of multiple other studies demonstrate very similar safety profiles between Zenrelia and Apoquel.” The Zenrelia PI has a boxed warning regarding the risk of fatal vaccine-induced disease from modified live vaccines and inadequate immune response to any vaccine as well as additional warning language regarding the risk of progressive or persistently decreased hematocrit, hemoglobin, and/or red blood cell count without a corresponding increase in absolute reticulocyte count, while the Apoquel PI does not. Therefore, the claim of “similar safety profiles between Zenrelia and Apoquel” may be misleading.
Conclusion and Requested Response
For the reasons discussed above, your websites, Product Brochure and Itch Tracker, and slide deck titled “Reach for Zen” misbrand Zenrelia within the meaning of the FD&C Act. 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));, and 21 CFR 202.1(e)(5). Introducing or delivering misbranded new animal drugs for introduction into interstate commerce violates section 301(a) of the FD&C Act [21 U.S.C. 331(a)].
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.
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 Zenrelia that contain representations like that described above, and explaining any plan for discontinuing use of such communications, or for ceasing distribution of Zenrelia. 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 E436, 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 # 695170.
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
_____________
1
https://my.elanco.com/us/campaign/zenrelia (last accessed on 1.27.25)
2
https://yourpetandyou.elanco.com/us/our-products/zenrelia (last accessed on 1.27.25)
3
Identified by Elanco as PM-US-24-0697
4
Identified by Elanco as PM-US-24-1330 and submitted to the Drug Experience Report (DER) portal under cover of form 2301 on October 2, 2024.
5
FDA-approved package insert (PI) for Zenrelia
6
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.
7
The DHPP vaccine contains canine distemper virus (CDV), canine adenovirus (CAV-2), canine parainfluenza (CPiV), and canine parvovirus (CPV).
8
A Core Vaccination is recommended for all dogs irrespective of lifestyle, unless there is a specific medical reason not to vaccinate according to the American Animal Hospital Association.
9
Identified by Elanco as PM-US-24-0930
10
We recognize some of this information is found in the ISI section at the bottom of the main veterinarian website and linked webpage. However, due to the location and small size of the text, this information is not comparably noticeable or conspicuous compared to the benefit information. See 21 CFR 202.1(e)(7)(viii).
11
The two field studies conducted for approval were the field study for Control of Atopic Dermatitis and the field study for Control of Pruritus Associated with Allergic Dermatitis.
12
Treatment success for each dog was defined as at least a 50% reduction from baseline (Day 0) in owner-assessed PVAS score for pruritus or at least a 50% reduction from baseline in investigator assessed CADESI-4 (Canine Atopic Dermatitis Extent and Severity Index version 4) score for skin lesions.
13
Treatment success for each dog was defined as at least a 50% reduction from baseline (Day 0) in owner-assessed PVAS score for pruritus on at least 5 out of the first 7 days of treatment
14
Identified by Elanco as PM-US-24-1164, submitted to the DER under cover of form 2301 on September 23, 2024.
Content current as of:
03/11/2025
Regulated Product(s)
Animal & Veterinary
Drugs