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
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,
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 tiffany.kanaga@elancoah.com
Media Contact: Colleen Parr Dekker
(317) 989-7011 colleen.dekker@elancoah.com
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SOURCE Elanco Animal Health
