PR Newswire
GREENFIELD, Ind.
, Feb. 13, 2025 /PRNewswire/ — Elanco Animal Health Incorporated issued the following statement regarding its commitment to clear veterinary and pet owner education following a promotional practices warning letter from U.S. Food and Drug Administration (FDA).
At Elanco, we are dedicated to helping veterinarians and pet owners help pets live longer, healthier, more active lives. Delivering new innovation to the marketplace and ensuring we clearly communicate with veterinarians and pet owners about how to safely and effectively use these products is a key part of that goal.
The U.S. FDA recently issued a Warning Letter to Elanco related to statements in Zenrelia™ (ilunocitinib tablets) promotional materials. The FDA uses these letters to notify companies of their positions and provide an opportunity to respond and make voluntary changes. We appreciate the FDA’s perspective and are working quickly to review and update Zenrelia promotional materials as appropriate.
Importantly, this letter is not related to the in-market product use experience; we are very pleased with Zenrelia’s real-world performance. We appreciate the opportunity to work closely with the FDA to resolve the issues as we continue to help veterinarians and pet owners understand how their patients and pets can benefit from this exciting new product.
Elanco does not expect the adjustments to the promotional materials to have a material impact on Zenrelia revenue. The company continues to expect accelerating organic constant currency revenue growth to mid-single digits in 2025.
The entire FDA letter follows. For full prescribing information for Zenrelia, including the boxed warning, speak with your veterinarian, call 1 888 545 5973 or visit www.elancolabels.com/us/zenrelia.
INDICATIONS
Zenrelia is a prescription medication used to control itching and inflammation associated with skin allergies for dogs over 12 months of age.
IMPORTANT SAFETY INFORMATION
See package insert including the Boxed Warning. For full prescribing information speak with your veterinarian, call 1 888 545 5973 or visit www.elancolabels.com/us/zenrelia.
WARNING: VACCINE-INDUCED DISEASE AND INADEQUATE IMMUNE RESPONSE TO VACCINES. Based on results of the vaccine response study, dogs receiving Zenrelia are at risk of fatal vaccine-induced disease from modified live virus vaccines and inadequate immune response to any vaccine. Discontinue Zenrelia for at least 28 days to 3 months prior to vaccination and withhold Zenrelia for at least 28 days after vaccination. Dogs should be up to date on vaccinations prior to starting Zenrelia. Do not use in dogs less than 12 months old or dogs with a serious infection. Dogs should be monitored for the development of infections because Zenrelia may increase the chances of developing an infection. Neoplastic conditions (benign and malignant) were observed during clinical studies. The most common side effects were vomiting, diarrhea and tiredness. Zenrelia has not been tested in dogs used for breeding, pregnant, or lactating dogs and has not been evaluated in combination with glucocorticoids, cyclosporine, or other immune suppressive drugs.
ABOUT ELANCO
Elanco Animal Health Incorporated (NYSE: ELAN) is a global leader in animal health dedicated to innovating and delivering products and services to prevent and treat disease in farm animals and pets, creating value for farmers, pet owners, veterinarians, stakeholders and society as a whole. With 70 years of animal health heritage, we are committed to breaking boundaries and going beyond to help our customers improve the health of animals in their care, while also making a meaningful impact on our local and global communities. At Elanco, we are driven by our vision of Food and Companionship Enriching Life and our Elanco Healthy Purpose™ sustainability pillars – all to advance the health of animals, people, the planet and our enterprise. Learn more at www.elanco.com.
The complete text of the letter from the U.S. Food & Drug Administration follows:
Elanco Animal Health
Attention: Jeffrey Simmons
President and CEO, Elanco Animal Health USA
2500 Innovation Way
Greenfield, Indiana 46140
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 Dermatitis4” 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. We are aware that Elanco submitted polymerase chain reaction (PCR) data to support this claim but, as discussed in a meeting with CVM on November 21, 2024, this data, in its current form, does not confirm that CAV-1, and not CAV-2, is present in the liver tissue from the dog in question. The PCR assay did not include CAV-2 primers and was not validated, and there were no results from PCR analysis of the pancreas. As suggested at the November 21, 2024 meeting, Elanco can submit any additional data it has to support this claim in a supplemental application. However, at this time, these claims are misleading because they contradict the conclusions of the Vaccine Response Study, which served as the basis of the boxed warning. If Elanco takes the position that the boxed warning on the currently approved product labeling is false and misleading, the appropriate approach is to submit a supplemental new animal drug application with supporting information to amend the product labeling.
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 success12 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 success13 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 Detailer14 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::Q.Q5. 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 [email protected]. 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 [email protected].
Sincerely,
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.
U.S. Food and Drug Administration MPN 2, Room E436
12225 Wilkins Avenue
Rockville, MD 20852
www.fda.gov
Zenrelia, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates. © 2025 Elanco or its affiliates.
PM-US-25-0265
Cautionary Statement Regarding Forward-Looking Statements
This statement contains forward-looking statements within the meaning of the federal securities laws, including, without limitation, statements concerning product launches and our 2025 full year organic constant currency revenue growth expectations.
These forward-looking statements are based on our current expectations and assumptions regarding our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, our actual results may differ materially from those contemplated by the forward-looking statements. Important risk factors that could cause actual results to differ materially from those in the forward-looking statements include regional, national or global political, economic, business, competitive, market and regulatory conditions, including but not limited to the following operating in a highly competitive industry; the success of our research and development (R&D) and licensing efforts; the impact of disruptive innovations and advances in veterinary medical practices, animal health technologies and alternatives to animal-derived protein; competition from generic products that may be viewed as more cost-effective; changes in regulatory restrictions on the use of antibiotics in farm animals; an outbreak of infectious disease carried by farm animals; risks related to the evaluation of animals; consolidation of our customers and distributors; the impact of increased or decreased sales into our distribution channels resulting in fluctuations in our revenues; our dependence on the success of our top products; our ability to complete acquisitions and divestitures and to successfully integrate the businesses we acquire; our ability to implement our business strategies or achieve targeted cost efficiencies and gross margin improvements; manufacturing problems and capacity imbalances, including at our contract manufacturers; fluctuations in inventory levels in our distribution channels; our dependence on sophisticated information technology systems and infrastructure, including the use of third-party, cloud-based technologies, and the impact of outages or breaches of the information technology systems and infrastructure we rely on; the impact of weather conditions, including those related to climate change, and the availability of natural resources; demand, supply and operational challenges associated with the effects of a human disease outbreak, epidemic, pandemic or other widespread public health concern; the loss of key personnel or highly skilled employees; adverse effects of labor disputes, strikes and/or work stoppages; the lack of availability or significant increases in the cost of raw materials; risks related to our presence in foreign markets; the potential impact that actions by activist shareholders could have on the pursuit of our business strategies; actions by regulatory bodies, including as a result of their interpretation of studies on product safety; the possible slowing or cessation of acceptance and/or adoption of our farm animal sustainability initiatives; the impact of increased regulation or decreased governmental financial support related to the raising, processing or consumption of farm animals; risks related to the modification of foreign trade policy; the impact of litigation, regulatory investigations, and other legal matters, including the risk to our reputation and the risk that our insurance policies may be insufficient to protect us from the impact of such matters; challenges to our intellectual property rights or our alleged violation of rights of others; misuse, off-label or counterfeiting use of our products; and unanticipated safety, quality or efficacy concerns and the impact of identified concerns associated with our products.
For additional information about the factors that could cause actual results to differ materially from forward-looking statements, please see the company’s latest Form 10-K and Form 10-Qs filed with the Securities and Exchange Commission. Although we have attempted to identify important risk factors, there may be other risk factors not presently known to us or that we presently believe are not material that could cause actual results and developments to differ materially from those made in or suggested by the forward-looking statements contained in this statement. Any forward-looking statement made by us in this statement speaks only as of the date thereof. Factors or events that could cause our actual results to differ may emerge from time to time, and it is not possible for us to predict all of them. We undertake no obligation to publicly update or to revise any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by law.
Investor Contact: Tiffany Kanaga (765) 740-0314 [email protected]
Media Contact: Colleen Parr Dekker (317) 989-7011 [email protected]
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