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Pfizer Animal Health
Technical Bulletin
December 2011
Value of CERENIA® (maropitant citrate) in the
Treatment of Acute Vomiting in Dogs
Matthew Krecic, DVM, MS, MBA,
Diplomate ACVIM
Robert Lavan, DVM, MS, MPVM,
Diplomate ACVPM
KEY POINTS
• Vomiting is a complex physiological process that is regulated by several brainstem nuclei that comprise
the emetic center and chemoreceptor trigger zone (CRTZ) in the central nervous system (CNS). There
are multiple causes of vomiting that act via central direct (higher brain), peripheral direct (GI tract), or
peripheral indirect (blood borne toxins such as in kidney failure) pathways. Some serious diseases can
stimulate the vomiting reflex through both peripheral pathways. Causes of vomiting include diseases of the
gastrointestinal (GI) tract, non-GI tract diseases, exposure to toxins, and motion sickness.
• CERENIA (maropitant citrate) is an FDA-approved drug for the prevention of acute vomiting and the
prevention of vomiting due to motion sickness in dogs 16 weeks and older. Maropitant is a neurokinin
receptor (NK1) antagonist that blocks the binding of the endogenous ligand substance P in the CNS.
Substance P is the main CNS neurotransmitter that mediates emesis. Because of its pharmacodynamic
action at the central NK1 receptor, CERENIA is broadly effective against vomiting caused by central and
peripheral signals.
• CERENIA (maropitant citrate) Tablets are indicated for the prevention of acute vomiting and the prevention
of vomiting due to motion sickness in dogs. CERENIA Injectable Solution is indicated for the prevention
and treatment of acute vomiting in dogs. CERENIA is available as an oral tablet (multiple strengths) and as
a solution for subcutaneous (SC) injection. The recommended dosing schedules for CERENIA Tablets are 2
mg/kg body weight once daily for up to five consecutive days for the prevention of acute vomiting, and 8 mg/
kg body weight once daily for up to two consecutive days for prevention of vomiting due to motion sickness.
The recommended dosing schedule for CERENIA Injectable Solution is 1 mg/kg body weight once daily
subcutaneous for up to five consecutive days for the prevention and treatment of acute vomiting.
• A retrospective analysis of the US pivotal efficacy study showed that CERENIA added to supportive
care was effective in stopping vomiting in dogs with the specific diagnoses of vomiting due to
parvovirus, pancreatitis, and gastroenteritis.1
All brands are the property of Pfizer Inc, its affiliates, and/or its licensors. © 2011 Pfizer Inc. All rights reserved.
• The dual routes of administration of CERENIA create an opportunity for the veterinarian to continue
antiemetic therapy with an oral option (CERENIA Tablets) and/or to allow the pet owner to treat the pet
at home.
• The once daily administration of CERENIA may be less stressful for the pet and pet owner compared to
other medications that must be dosed multiple times a day.
• In a recent Veterinary Online Interactive Community Exchange (VOICE) Pfizer market research survey,
86.5% (n=122/147) of responding veterinarians identified CERENIA as the antiemetic treatment that they
were most confident would stop vomiting in dogs.2
• In the same survey, 92% (n=132/143) of responding veterinarians indicated that adding an antiemetic to
supportive care shortens recovery time for a vomiting dog, and 99% (n=140/141) of respondents indicated
that a medication that shortens the duration of hospitalization and speeds recovery was valuable to their practice.2
• In the same survey, 84% (n=119/141) of responding veterinarians noted that rapid resolution of emesis has a
beneficial effect on a dog’s quality of life, and that of the dog owner.2
INTRODUCTION
substance P to NK1 receptors. NK1 receptors are
densely distributed within the emetic center and
maropitant acts to directly inhibit vomiting by
blocking substance P binding at these NK1 receptors
in the CNS.
Vomiting equals suffering. Identifying and
countering a specific cause of vomiting is of
primary importance, yet stopping the vomiting
is also important to address the patient’s
immediate physical needs while investigating or
treating for the specific cause.
The predominant peripheral direct and indirect
pathways carry stimuli to induce vomiting through
the emetic center and CRTZ, respectively. All
stimuli that cause vomiting converge within the
emetic center; therefore, stimuli, such as toxins
retained by diseased kidneys, within the circulation
initially carried to the CRTZ via the peripheral
indirect pathway ultimately end within the emetic
center. Alternatively, the peripheral direct pathway
carries stimuli from diseased abdominal organs right
to the emetic center. The emetic center also directly
receives stimuli that induce vomiting from the
higher brain (ie, cerebrum) via the central pathway.
The CRTZ likewise also receives stimuli from the
vestibular apparatus, which underlies vomiting
due to motion sickness. Some diseases can cause
vomiting due to multiple pathways. Once the emetic
center and CRTZ receive these stimuli, substance
P is released and binds to NK1 receptors within the
emetic center and CRTZ. This interaction induces
efferent nerve impulses to the abdominal muscles and
diaphragm to start the vomiting reflex.
Vomiting is a nonspecific clinical sign; it is similar
to other vague clinical signs such as lethargy and
depression. Common GI diseases include foreign
bodies, gastroenteritis, inflammatory bowel disease,
neoplasia (eg, lymphosarcoma), parasitism, and
canine parvovirus. Common non-GI diseases include
hypoadrenocorticism, hyperthyroidism, kidney
disease (uremia), liver disease, and pancreatitis.
Additionally, toxins (eg, lead) and medications (eg,
digoxin, chemotherapies) may also cause vomiting.
Identifying and countering a specific cause of vomiting
is of primary importance, yet stopping the vomiting is
an important component of addressing the patient’s
immediate physical needs while investigating or
treating for the specific cause. Despite the many causes
of vomiting, effectively stopping the vomiting while
allowing for further examination is possible with the
antiemetic CERENIA (maropitant citrate).
Maropitant is a neurokinin (NK1) receptor antagonist
that blocks the binding of the endogenous ligand
The injectable form (10 mg/ml) of CERENIA, dosed
2
at 1 mg/kg SC once daily for up to five consecutive
days, is labeled for prevention and treatment of acute
vomiting in dogs. The tablet form (16, 24, 60, and 160
mg) of CERENIA is labeled for prevention of acute
vomiting and prevention of vomiting due to motion
sickness in dogs. The oral dose for preventing and
treating acute vomiting is 2 mg/kg once daily for up to
five consecutive days, and the oral dose for preventing
motion sickness is 8 mg/kg once daily for up to two
consecutive days. However, a combination of injectable
and oral CERENIA not to exceed five consecutive
days may be prescribed to dogs with acute vomiting.
CERENIA does not have any known contraindications.
CERENIA was the only agent that effectively
prevented vomiting regardless of the emetic stimuli.
Additionally in laboratory studies, researchers have
demonstrated the effectiveness of CERENIA in
controlling emesis from challenges with two emetics,
syrup of ipecac and apomorphine.5 When a dog
ingests syrup of ipecac, it irritates the stomach,
stimulating vomiting via the peripheral direct pathway.
Apomorphine administered intravenously (IV)
travels to the CRTZ where it stimulates dopamine
receptors, leading to vomiting; this is via the peripheral
indirect pathway. Compared to the antiemetics
metoclopramide, chlorpromazine, and ondansetron,
CERENIA effectively prevented vomiting regardless of
the emetic stimuli. Researchers showed metoclopramide
and chlorpromazine to be effective at preventing
vomiting induced by apomorphine but not by syrup of
ipecac. Similarly, researchers showed ondansetron to
be effective at preventing vomiting induced by syrup
of ipecac but not by apomorphine. CERENIA was
the only agent that effectively prevented vomiting
in the vast majority of cases regardless of the emetic
stimuli. Since the introduction of CERENIA to the
marketplace, other CERENIA-related studies have been
published.6-9
Since 2007, Cerenia has become the most
prescribed antiemetic, with 74% of all practice
veterinarians prescribing it.3
CERENIA became commercially available in the US
in 2007. Since then, it has become the most prescribed
antiemetic, with 74% of all practice veterinarians
prescribing it.3 Since launch, the recommended length of
time the injectable form can be stored once opened has
been increased. An opened vial of CERENIA now has a
90-day shelf life, increased from the previously approved
28 days.
DESCRIPTION OF THE CERENIA
US PIVOTAL EFFICACY STUDY
A RETROSPECTIVE EXAMINATION
OF THE CERENIA US PIVOTAL
EFFICACY STUDY10
A summary of the results from the CERENIA US
pivotal efficacy study were published in 2008.4 This
study supported the New Animal Drug Application
and the approval of CERENIA for use in the treatment
and prevention of acute emesis in dogs. The study
was started in August 2003 and the last patient was
enrolled in June 2004. All dogs had been vomiting at
enrollment and all were treated for three to five days.
Data were pooled across several vomiting etiologies.
The study concluded “in spite of the diverse and
often severe nature of acute or chronic disease in the
diverse population (various ages and breeds) of enrolled
dogs, CERENIA demonstrated broad-spectrum
utility in treatment and prevention of acute emesis
by significantly (p < 0.0012) reducing the percentage
of dogs exhibiting vomiting following treatment from
50% in placebo-treated dogs to 21.8% in dogs given
CERENIA.”
Data from the CERENIA pivotal efficacy study
was retrospectively examined to determine if the
performance of CERENIA could be described in
several subpopulations of dogs sharing common
diagnoses that could be driving the vomiting
(See Appendix). Approximately 70% (n = 183) of
the dogs in the pivotal efficacy study were diagnosed
with a specific cause of vomiting that included dogs
diagnosed with parvovirus (n = 48), pancreatitis
(n = 26), gastroenteritis (n = 67), gastritis (n = 27),
or dietary indiscretion (n = 15). In this retrospective
analysis, 137 dogs received CERENIA plus supportive
care and 46 received supportive care alone. The
diagnosis of parvovirus was usually made from a
confirmatory fecal enzyme-linked immunosorbent
assay (ELISA) test. The diagnosis of other vomiting
causes was made through a combination of clinical
3
signs, vomiting history, physical examination findings
and laboratory tests. Veterinarians could only assign a
single diagnosis for each vomiting dog and could treat
dogs with supportive care, which usually consisted
of intravenous (IV) fluids and injectable antibiotics.
Dogs were blocked and randomly assigned to groups
in a 3:1 ratio (CERENIA:placebo), receiving either a
once daily dose of CERENIA or placebo, in addition to
supportive care. All dogs were hospitalized for three to
five days.
When veterinarians prescribe CERENIA for
vomiting or motion sickness, they dispense a
medication only available through licensed
veterinarians. Pfizer Animal Health does not sell
this medication “over-the-counter” or to retail
pharmacies.
In the licensing study for CERENIA, dogs were
recruited into the study when their owners took them
to the clinic for treatment of vomiting.4 All dogs were
treated for three to five days and monitored twice a day
for ongoing emesis. Treatment consisted of supportive
care with or without CERENIA. In a recent Veterinary
Online Interactive Community Exchange (VOICE)
Pfizer market research survey of veterinarians on their
practice approach to canine vomiting, 67% (n=96/143)
indicated that they had prescribed supportive care
alone without an antiemetic for dogs that presented
for vomiting.2 This approach is equivalent to the
control group of dogs in the CERENIA pivotal study
that were treated with supportive care but without
an antiemetic. While the initial dose of CERENIA
or placebo in the pivotal study was given as a SC
injection, the veterinarian had the option of treating
the dog for additional days with CERENIA Tablets
or Injection (or identical placebo). The dual routes of
administration of CERENIA create an opportunity for
the veterinarian to continue antiemetic therapy with
an oral medication option (CERENIA Tablets) and/
or to allow the pet owner to be part of the treatment
team and treat the pet at home for up to 5 days.
The initial dose of CERENIA was given as an
injection, dosed at 1 mg/kg SC, at the start of the
study (Day 0). Subsequent doses of CERENIA
could be given as either an injection or tablet, per
the label dosing. All dogs in the CERENIA group
received three to five days of treatment.
There was a statistically significant cessation of
vomiting associated with CERENIA plus supportive
care versus supportive care alone detected on the
first day of the three to five day treatment period
(Appendix Table A1). A statistically significant
effect of CERENIA was seen in the all causes group
(p=0.0001), as well as in the parvovirus (p=0.01),
pancreatitis (p=0.0001), and gastroenteritis (p=0.0001)
subgroups. This action of CERENIA was not
statistically significant in dogs that were vomiting
due to gastritis, but there were only three dogs in the
analysis with this diagnosis who received supportive
care only. The subgroup of dogs with a diagnosis of dietary
indiscretion was too small to allow for a valid statistical
analysis.
The once daily administration of CERENIA may
be less stressful for the pet and pet owner compared
to other medications that must be dosed multiple
times a day.
THE RESOLUTION OF EMESIS AND
ITS IMPLICATIONS
Many dogs receiving CERENIA benefit from the arrest
of vomiting within the first 24-48 hours. As seen in
the pivotal study, the cumulative proportion of dogs
in the placebo control group needed approximately
three days of supportive care to match the proportion
of dogs whose emesis had stopped on the first day of
CERENIA therapy (84%, n=115/137). Prior to sending
a vomiting dog home, many veterinarians want to
monitor a dog for at least 24 hours after the last
vomiting episode in order to be sure that emesis has
stopped. In the VOICE survey, 67% (n = 99/147) of
respondents indicated that they keep a dog hospitalized
for up to 24 hours of monitoring after the last
observed vomiting episode.2 With CERENIA added to
supportive care, veterinarians have the opportunity to
send a larger percentage of vomiting dogs home sooner.
As is seen in the pivotal study, supportive care and
an antiemetic given to the appropriate patient can
reduce the number of days of clinical illness and speed
recovery. Identifying and treating the underlying
cause of vomiting is equally important in reducing the
number of days of illness and at speeding recovery.
This effective way of symptomatically treating a
disease validates the pet owners’ reasons for seeking
care with particular veterinarians and veterinary
hospitals.
Effective treatment builds trust and confidence
with veterinarians and their staff, validates clients’
selection of veterinary hospitals, and reinforces the
veterinarian-client-patient relationship.
4
Medical charges (in 2003 dollars) were calculated for
the treatment given to vomiting dogs in the CERENIA
pivotal study.4 The actual charges were identified
in the medical records for some patients. Often, an
itemized list of services and medications was created
from notes in the medical record. The Veterinary
Fee Reference (2009), or other source, was used to
find nationalized average charges for each item.11 The
consumer price index calculator (www.bls.gov/cpi/)12
was used to correct clinic charges back to 2003 dollar
values, which would have been in effect at the time
that the CERENIA pivotal study was performed. On
average, veterinarians charged $350 for the first day of
care of a vomiting dog and approximately $160 for each
day after that (Table 2). The higher charge for the first
day of care was associated with the singular costs of
running the initial diagnostic tests, the IV catheter set
up, and other first-day procedures.
Dogs that stopped vomiting at the start of therapy (Day
0) could be observed for 24 hours (Day 1) and sent home
the morning of Day 2. This occurred in the pivotal
study for about 84% (n=115/137) of the dogs receiving
CERENIA plus supportive care versus about 57%
(n=26/46) of dogs receiving placebo plus supportive care.
Veterinarians were also asked whether rapid
control of a patient’s vomiting impacts client
confidence. Ninety-one percent responded
that this would somewhat increase or strongly
increase client confidence.2
In the VOICE survey, veterinarians were asked how
confident they are in the ability of various antiemetics
to stop vomiting.10 CERENIA received the highest
confidence scores from 87% of respondents, compared
with metoclopramide, ondansetron and phenothiazines
(Table 1). The respondents’ confidence with
CERENIA is the likely reason they most frequently
prescribed it over the past year. Veterinarians were also
asked whether rapid control of a patient’s vomiting
impacts client confidence. Ninety-one percent
(n=128/141) responded that this would somewhat
increase or strongly increase client confidence.2
Any therapy that shortens the length of time that
a pet is hospitalized saves money for the pet owner.
Veterinarians may be concerned about the fees that
are charged to pet owners and may make decisions
about what services to offer based on their perception
of what pet owners can afford.13 In the CERENIA
pivotal study, the average daily charge for hospitalized
care became smaller the longer that the pet was
hospitalized (See Table 2). Veterinarians repeated the
treatment program each day during hospitalization
until the dog was discharged. Because of the
decreasing average daily charge, longer hospitalizations
may be less profitable for the hospital.
The presentation of population data from the pivotal
efficacy study allows the veterinarian to see the
positive effect of CERENIA on emesis in a group of
dogs. While not predictive of how a specific dog may
respond, it allows veterinarians to see the variability
that exists for responses to the medication. While
many dogs in the pivotal study received an immediate
antiemetic benefit, some dogs, especially those
diagnosed with parvovirus or gastroenteritis, continued
to vomit for several days.
Ongoing vomiting in a hospitalized patient often
means that the cage or pet needs to be cleaned
repeatedly. In the VOICE survey, 76% of responding
Table 1
VOICE Market Research Survey of Veterinarians Asked How Confident They Were That Dogs Will Stop Vomiting When Using a
Named Medication. Confidence Was Assessed Using a Whole Number Scale of 1 (Most Confident) to 5 (Least Confident). Data
Are Percent and Number of Survey Respondents (N= 147).2
Confidence Score
1
2
3
4
5
86.5% (n=122)
8.5% (n=12)
2.1% (n=3)
-
2.1% (n=3)
Metoclopramide
2.1% (n=3)
47.5% (n=67)
36.9% (n=52)
9.9% (n=14)
-
Ondansetron
6.4% (n=9)
33.3% (n=47)
9.9% (n=14)
5.0% (n=7)
1.4% (n=2)
-
3.5% (n=5)
12.8% (n=18)
24.8% (n=35)
0.7% (n=1)
Maropitant
Phenothiazines
5
increased” to “strongly increased.”2 Veterinarians
commented that the increased stress was derived from
a shared concern for the patient’s well-being, and the
fact that these patients take more time for care and
leave fewer personnel available for other routine daily
duties.
veterinarians indicated that the charge for a day of
hospitalization is often the same, regardless of how
many times a cage or pet needs to be cleaned.2
Reducing emesis early in the treatment program
should decrease staff time and reduce the costs
associated with humane cage care.
Eighty-four percent of veterinarians said rapid
resolution of emesis has a significant beneficial
effect on a dog’s quality of life, with a slightly
lower benefit for the pet owner.
When a dog is admitted to the hospital with vomiting
and/or diarrhea, veterinarians use various diagnostic
means to determine whether the dog presents an
infectious risk to other animals or humans. A diagnosis
of parvovirus or infectious gastroenteritis, for example,
may require partial isolation or quarantine, which
increases the work load for the hospital staff.14 In the
VOICE survey, approximately 70% of veterinarians
indicated that they were somewhat concerned or
extremely concerned about the spread of infectious
disease between dogs with vomiting and/or diarrhea
and other animals in the hospital.2 A medication that
shortens the vomiting interval provides veterinarians
with the option of shortening the hospitalized
period of the affected dog. Discharging the affected
dog from the hospital sooner can reduce the risk of
disease transmission to other pets that are in the
hospital for boarding, office visits, or elective surgery.
Earlier discharge can also reduce hospital staff time
required to practice heightened hygiene and the use of
monitoring equipment, cages, and extra supplies (eg,
disposable overalls and gloves, and cleaning supplies).
Reducing the use of supplies is another way for a
hospital to improve profitability; studies have reported
that the actual costs of goods and services have risen
about twice as fast as total revenue for small animal and
mixed animal practices.15
Based on this discussion, patients, pet owners,
veterinarians, and hospital staff all clearly benefit
when a vomiting dog is returned to health sooner.
Adding CERENIA to your current course of therapy
can have a positive impact on the outcome for the
patient. In the VOICE survey, veterinarians were
asked to rate how the rapid resolution of a dog’s emesis
affects the quality of life of the dog, the dog’s owner,
and the hospital staff (See Table 3).2 Eighty-four percent
of veterinarians said rapid resolution of emesis has a
significant beneficial effect on a dog’s quality of life, with
a slightly lower benefit for the pet owner. Discussions
about the impact on the quality of life for the pet and
the pet owner revolve around the perceived strength
of the human-animal bond. The beneficial impact on
the hospital staff’s quality of life was variable but more
evenly distributed between moderate and significant.
The results may have to do with concern for the
animal’s welfare as well as managing the increased
workload associated with the humane treatment of
hospitalized animals.
CONCLUSION
CERENIA is an effective and important antiemetic for
the prevention and treatment of acute vomiting of dogs.
Based on review of the data from the pivotal efficacy
When asked in the VOICE survey how a hospitalized
vomiting dog affects their staff, 72% of responding
veterinarians indicated that stress is “somewhat
Table 2
Average Daily Retail Charge for Hospitalized Care Versus the Number of Days Hospitalized. Data Obtained from the CERENIA®
Pivotal Efficacy Study.10
Day of Hospitalization
1
2
3
4
Average Daily Retail Charge ($)
350.00
160.00
160.00
160.00
Average Daily Retail Charge for Hospitalized Care
over Entire Course of Hospitalization ($)
350.00
255.00
223.00
208. 00
6
study, CERENIA in addition to supportive care greatly
reduced the number of days of vomiting for several
conditions; supportive care alone is not as effective.
receiving supportive care had no additional vomiting
compared with 84% (n=115/137) of dogs receiving
supportive care plus CERENIA. The difference in
proportional cessation of vomiting between treatment
groups on Day 0 was statistically significant (p = 0.0001).
CERENIA-treated dogs not only received a
single injection at the time of hospitalization
but also received three to five more days of
CERENIA therapy, either as injection or tablets
per label instructions, in order to prevent
recurrence of vomiting. Therefore, up to five
days of CERENIA along with supportive care
compared to supportive care alone significantly
contributed to these ill dogs’ return to health
and discharge from the hospital.
If we look at the entire population of dogs over the five-day
study period, we can see the benefit that CERENIA
brings to the resolution of vomiting in Diagram 1
(Kaplan-Meier Plot), comparing the cessation in
vomiting between treatment groups. Supportive
care, which includes intraveous fluid therapy, is an
appropriate way to treat vomiting. The addition of
Cerenia provides an important population benefit
associated with cessation of vomiting.
Rapid resolution of vomiting not only positively
impacts dogs but also their veterinarians, hospital staff,
and owners.
A cumulative analysis showed that dogs needed three
days of supportive care without an antiemetic to
provide the same population benefit realized by the
group that had CERENIA added to supportive care
on Day 0 (Table A-2). Only the first four days of data
are included in Table A-2 because we do not know if
vomiting seen on Day 5 was the last bout of vomiting
for that dog. Veterinarians were not required to
continue vomiting observations beyond day 5.
APPENDIX: RETROSPECTIVE
EVALUATION OF CERENIA
EFFICACY BY CAUSE OF VOMITING
(DIAGNOSIS)1
For all causes of vomiting combined, dogs were 50%
more likely to stop vomiting if CERENIA was added
to supportive care for the next three to five days
(Risk Rate [RR] = 1.5).
All Vomiting Causes Combined
Data for this analysis were obtained from the pivotal
efficacy study10 and included pooled data from 183 dogs
diagnosed with parvovirus, pancreatitis, gastroenteritis,
gastritis, and dietary indiscretion. Forty-six dogs
received supportive care alone and 137 received
CERENIA plus supportive care (See Table A-1). At the
initiation of therapy on Day 0, 57% (n=26/46) of dogs
Clearly, supportive care, which includes IV fluids, is
appropriate for a debilitating process that dehydrates
the animal and causes electrolyte disturbances. The
addition of a once daily dose of CERENIA provides a
significant advantage towards stabilizing the patient.
Table 3
VOICE Market Research Survey Assessment of the Impact of Stopping Vomiting Sooner on the Quality of Life of Patients, Pet
Owners and Hospital Staff. Impact of Effect Was Assessed Using a Whole Number Scale of 1 (No Effect) to 5 (Significant Effect).
Data Are Percent and Number of Survey Respondents.2
Effect on Quality of Life
5
4
3
Patient Quality of Life
84.4% (n=119)
12.8% (n=18)
2.8% (n=4)
Pet Owner Quality of Life
62.4% (n=88)
29.8% (n=42)
7.1% (n=10)
0.7% (n=1)
Veterinary Staff Quality of Life
35.5% (n=50)
29.1 % (n=41)
25.5% (n=36)
7.1% (n=10)
7
2
1
2.8% (n=4)
respectively, of treatment.
For many veterinarians, once emesis stops, they
can switch their patients to oral CERENIA tablets
for continued in-hospital or at-home treatment.
Parvovirus infection is characterized by profuse
emesis and diarrhea, with or without blood.17 Rapid
dehydration and electrolyte imbalance are often
associated with death, particularly in young dogs.
In this study, parvovirus infection was a powerful
driver of emesis and provided a strong challenge
to CERENIA efficacy. On a population basis, the
addition of CERENIA to supportive care significantly
shortened the period of emesis and fluid loss in dogs.
Parvovirus
Parvovirus infection is a powerful driver of emesis in
dogs. Forty-eight dogs were diagnosed with vomiting
from parvovirus infection and subsequently included
in this analysis, with 14 dogs (mean age 25 weeks)
allocated to receive supportive care alone and
34 dogs (mean age 27 weeks) allocated to receive
supportive care plus once daily CERENIA (See
Table A-1). Forty-three percent (n = 6/14) of dogs
had no further vomiting after initiating supportive
care. Fifty-nine percent (n=20/34) of vomiting dogs
diagnosed with parvovirus had no further vomiting
once initiating supportive care plus CERENIA. The
differential population response between these two
treatment groups at the start of treatment (Day 0) was
statistically significant (p = 0.0135). 83% and 97% of
the dogs receiving CERENIA with supportive care
stopped vomiting within the first 48 hours and by Day 4,
Dogs diagnosed with parvovirus were 37% more
likely to stop vomiting if CERENIA was added to
supportive care (Day 0) and continued for the next
three to five days (RR = 1.37).
Pancreatitis
Twenty-six dogs were diagnosed with vomiting from
pancreatitis and included in this analysis (supportive
care, n = 8; supportive care plus CERENIA, n
= 18; See Table A-1). While 63% of dogs had no
additional vomiting once beginning supportive care
Diagram 1 - Response to therapy in a population of vomiting dogs (all vomiting causes combined).
Cumulative Proportion of Dogs that Continued Vomiting Each Study Day
Proportion of Population that Continues Vomiting
With 95% Confidence Limits
Cumulative Proportion of Dogs that Continued to Vomit Each Study Day. The study days are labeled on the x-axis
and the proportion of dogs that continued to vomit is labeled on the y-axis. Treatment began on day 0. Treatment
groups are Cerenia + supportive care and supportive care alone; dogs in the Cerenia + supportive care group minimally
received 3 consecutive days of Cerenia despite cessation of vomiting. The mean proportion of dogs that continued
to vomit is less for dogs treated with Cerenia + supportive care (solid blue line) vs. dogs treated with supportive care
alone (red dashed line). Ninety-five percent confidence intervals (CI) are noted for each group by blue (Cerenia +
supportive care) and pink (supportive care alone) boxes. Confidence intervals overlap between groups after day 2 of
treatment. The difference in the proportion of dogs that continued to vomit between treatment groups on day 0 was
statistically significant (p = 0.0001).
8
Table A-1
The Performance of CERENIA® in Stopping Vomiting in Dogs in the Pivotal Efficacy Study by Cause of Vomiting (Diagnosis).
Data Are Percent and Number of Dogs.1
Last Day of Vomiting
Treatment Start
Day 1
Day 2
Day 3
Day 4
Day 5
Supportive Careb (n=46)
57%
(n=26)
7%
(n=3)
15%
(n=7)
9%
(n=4)
4%
(n=2)
9%
(n=4)
CERENIA + Supportive Care
(n=137)
84%
(n=115)
4%
(n=5)
4%
(n=6)
2%
(n=3)
4%
(n=5)
2%
(n=3)
Supportive Careb (n=14)
43%
(n=6)
7%
(n=1)
14%
(n=2)
21%
(n=3)
0
14%
(n=2)
CERENIA + Supportive Care
(n=34)
59%
(n=20)
6%
(n=2)
18%
(n=6)
6%
(n=2)
8%
(n=3)
3%
(n=1)
Supportive Careb (n=8)
63%
(n=5)
12%
(n=1)
12%
(n=1)
0
12%
(n=1)
0
CERENIA + Supportive Care
(n=18)
94%
(n=17)
0
0
0
6%
(n=1)
0
Supportive Careb (n=15)
67%
(n=10)
7%
(n=1)
13%
(n=2)
0
0
13%
(n=2)
CERENIA + Supportive Care
(n=52)
90%
(n=47)
2%
(n=1)
0
2%
(n=1)
2%
(n=1)
4%
(n=2)
Supportive Careb (n=3)
100%
(n=3)
0
0
0
0
0
CERENIA + Supportive Care
(n=24)
92%
(n=22)
8%
(n=2)
0
0
0
0
Supportive Careb (n=6)
33%
(n=2)
0
33%
(n=2)
17%
(n=1)
17%
(n=1)
0
CERENIA + Supportive Care
(n=9)
100%
(n=9)
0
0
0
0
0
a
Parvovirus
Pancreatitis
Gastroenteritis
Gastritis
Dietary Indiscretion
All dogs received three to five days of therapy
All Vomiting Causes Combined
Students T-Test for cessation of vomiting at the initiation of therapy. All vomiting causes combined (p=0.0001); parvovirus (p=0.01); pancreatitis (p=0.0001);
gastroenteritis (p=0.0001).
b.
Supportive care included IV fluids and any other therapy determined by the veterinarian. No anti-emetic medication was provided.
a.
alone (Day 0), 94% of the group that had CERENIA
added to supportive care demonstrated no additional
vomiting. This difference at the start of therapy was
statistically significant (p = 0.0001). The proportion of
dogs with pancreatitis receiving supportive care alone
needed four days of treatment (Day 4) to match the
proportional degree of emesis control seen in the group
that started therapy (Day 0) with CERENIA and
supportive care.
Dogs diagnosed with pancreatitis were 50% more
likely to stop vomiting if CERENIA was added to
supportive care on Day 0 and continued for the next
three to five days (RR = 1.5).
9
Gastroenteritis
care provided a high degree of emesis control as soon
as treatment was started (92%) but emesis control with
CERENIA and supportive care was not statistically
different from emesis control with supportive care alone.
One conclusion from this data is gastritis is a mild driver
of emesis, for which an antiemetic may or may not be
needed.
We analyzed 67 dogs diagnosed with vomiting from
gastroenteritis (supportive care, n=15; supportive
care plus CERENIA, n = 52; See Table A-1). Not
surprisingly, the dogs tended to be young adult
to middle-aged dogs. Immediately following the
initiation of treatment (Day 0), 67% of dogs receiving
supportive care demonstrated no additional vomiting.
When CERENIA was added to supportive care, this
population response increased to 90%. This response
to therapy on Day 0 was significantly different (p =
0.0001) between groups. In the five-day study period,
approximately 87% of the dogs receiving supportive
care alone had stopped vomiting. We do not know if
those dogs that vomited on Day 5 actually stopped
vomiting that day or may have vomited after the end
of the study. Compare this with the proportion of
dogs (90%) that stopped vomiting as soon as initiating
CERENIA and supportive care (Day 0).
Dietary Indiscretion
A diagnosis of dietary indiscretion is often made
by questioning the pet owner as to the dog’s recent
history. Owners observing their dogs chewing on
foreign objects or getting into the trash, coupled
with physical examinations of fairly healthy dogs,
often lead to this diagnosis. In this study, the small
number of dogs diagnosed with dietary indiscretion
precludes statistical analysis but allows the observation
that CERENIA was effective in arresting additional
vomiting (See Table A-1).
Important Safety Information
Dogs diagnosed with gastroenteritis were 40% more
likely to stop vomiting at the start of therapy if
CERENIA was added to supportive care for the next
three to five days (RR = 1.4).
The safe use of CERENIA has not been evaluated in
dogs used for breeding, pregnant or lactating bitches,
dogs with gastrointestinal obstruction, or dogs that
have ingested toxins. Use with caution in dogs with
hepatic dysfunction. CERENIA is recommended for
dogs 16 weeks and older. The most common adverse
reactions reported are hypersalivation (5-13%), lethargy
(9%) and post-dose emesis not due to motion sickness
(5-9%). For more information, read the full prescribing
information at the end of this Tech Bulletin or visit
www.CERENIA.com.
Gastritis
Compared to the number of dogs diagnosed with
parvovirus or gastroenteritis, the pivotal efficacy study
only included a few dogs diagnosed with gastritis or
dietary indiscretion (See Table A-1). For dogs diagnosed
with gastritis, the addition of CERENIA to supportive
Table A-2
The Cumulative Performance of CERENIA® in Stopping Vomiting (All Causes Combined) in Dogs in the Pivotal Efficacy
Study. Data Are the Cumulative Percent and Number of Dogs That Had Stopped Vomiting.1
Study Days
Supportive Care (n=46)
CERENIA + Supportive Care (n=137)
0
1
2
3
4
57%
(n=26/46)
64%
(n=29/46)
79%
(n=36/46)
88%
(n=40/46)
92%
(n=42/46)
84%
(n=115/137)
88%
(n=120/137)
92%
(n=126/137)
94%
(n=129/137)
98%
(n=134/137)
10
REFERENCES
11. Veterinary Fee Reference. Vital statistics for your
veterinary practice. 6th ed. American Animal
Hospital Association; 2009.
1. Data on file. Outcomes Research and Key Brand
Clinical Support, Pfizer Animal Health, 2009.
12. Cron WL, Slocum JV, Goodnight DB, et al.
Executive summary of the Brakke management
and behavior study. J Am Vet Med Assoc.
2000;217(3):332-338.
2. Pfizer Animal Health Global Market Research,
VOICE Survey. Caring for vomiting dogs. April,
2011. Data on file.
13. Portner J, Johnson J. Guidelines for reducing
pathogens in veterinary hospitals: disinfection
selection, cleaning protocols, and hand hygiene.
Compend Contin Educ Vet. 2010;32(5):E1-E12.
3. GMR Purchased, Dispensed, and Inventory Report
for US CERENIA for 4Q 2010.
4. Ramsey DS, Kincaid K, Watkins JA, et al. Safety
and efficacy of injectable and oral maropitant, a
selective neurokinin 1 receptor antagonist, in a
randomized clinical trial for treatment of vomiting
in dogs. J Vet Pharmacol Therap. 2008;31:538-543.
14. Brown JP, Silverman JD. The current and future
market for veterinarians and veterinary medical
services in the United States. J Am Vet Med Assoc.
1999;215(2):161-183.
5. Sedlacek HS, Ramsey DS, Boucher JF, et al.
Comparative efficacy of maropitant and selected
drugs in preventing emesis induced by centrally
or peripherally acting emetogens in dogs. J Vet
Pharmacol Therap. 2008;31(6):533-537.
15. McCaw DL, Hoskins JD. Canine Viral Enteritis.
In: Greene CE, ed. Infectious Diseases of the Dog
and Cat. 3rd ed. St Louis, Missouri: SaundersElsevier; 2006; Chapter 8:63-73.
6. Conder GA, Sedlacek HS, Boucher JF, et al.
Efficacy and safety of maropitant, a selective
neurokinin-1 receptor antagonist, in two
randomized clinical trials for prevention of
vomiting due to motion sickness in dogs. J Vet
Pharmacol Therap. 2008;31:528-532.
7. Hickman MA, Cox SR, Mahabir S, et al. Safety,
pharmacokinetics and use of the novel NK-1
receptor antagonist maropitant (CERENIA) for
the prevention of emesis and motion sickness in
cats. J Vet Pharmacol Therap. 2008;31:220-229.
8. Rau SE, Barber LG, Burgess KE. Efficacy of
maropitant in the prevention of delayed vomiting
associated with administration of doxorubicin to
dogs. J Vet Intern Med. 2010;24(6):1452-1457.
9. Vail DM, Rodabaugh HS, Conder GA, et al.
Efficacy of injectable maropitant (CERENIA)
in a randomized clinical trial for prevention and
treatment of cisplatin-induced emesis in dogs
presented as veterinary patients. Vet Comp Oncol.
2007;5:38-46.
10. Data on file Pfizer Inc. Study No. 1467C-60-01-597,
Field Safety and Effectiveness of Subcutaneous and
Oral Maropitant Administered for Emesis in Dogs
Presented as Veterinary Patients. 2004.
11
ADVERSE REACTIONS:
DOGS:
In a US field study for the prevention and treatment of vomiting associated with administration of cisplatin for cancer chemotherapy, the
following adverse reactions were reported in 77 dogs treated with CERENIA Injectable Solution at 1 mg/kg subcutaneously or 41 dogs treated
with placebo:
Frequency of Adverse Reactions by Treatment
Tablets and Injectable Solution
Antiemetic
Adverse Reaction
CERENIA Tablets
For oral use in dogs only
CERENIA Injectable
For subcutaneous injection in dogs and cats
CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.
Placebo (n=41)
CERENIA (n=77)
# dogs
% occur
# dogs
% occur
Diarrhea
1
2.4
6
7.8
Anorexia
0
0
4
5.2
Injection site reaction (swelling, pain upon injection)
0
0
3
4
Lethargy
1
2.4
2
2.6
Adverse reactions seen in a European field study included ataxia, lethargy and injection site soreness in one dog treated with CERENIA
Injectable Solution.
DESCRIPTION:
Maropitant is a neurokinin (NK1) receptor antagonist that blocks the pharmacological action of substance P in the central nervous system
(CNS). Maropitant is the non-proprietary designation for a substituted quinuclidine. The empirical formula is C32H40N2O C6H8O7 H2O and
the molecular weight 678.81. The chemical name is (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine citrate
monohydrate. Each mL of CERENIA Injectable Solution contains 10 mg maropitant, 63 mg sulphobutylether-beta-cyclodextrin, 3.3 mg
meta-cresol and water for injection.
The following adverse reactions were reported during the course of a US field study for the prevention and treatment of acute vomiting in dogs
treated with 1 mg/kg CERENIA Injectable Solution subcutaneously and/or CERENIA Tablets at a minimum of 2 mg/kg orally once daily for up
to 5 consecutive days:
Frequency of Adverse Reactions by Treatment
The chemical structure of maropitant citrate is:
Adverse Reaction
Placebo (n=69)
CERENIA (n=206)
# dogs
% occur
# dogs
% occur
Death during study
4
5.8
10
4.9
Euthanized during study
0
0
2
1
Diarrhea
6
8.7
8
3.9
Hematochezia/bloody stool
5
7.2
4
1.9
Anorexia
2
2.9
3
1.5
Otitis/Otorrhea
0
0
3
1.5
Endotoxic Shock
1
1.4
2
1
INDICATIONS:
Hematuria
0
0
2
1
CERENIA (maropitant citrate) Tablets are indicated for the prevention of acute vomiting and the prevention of vomiting due to motion
sickness in dogs. CERENIA (maropitant citrate) Injectable Solution is indicated for the prevention and treatment of acute vomiting in dogs
and for the treatment of vomiting in cats.
Excoriation
0
0
2
1
DOSAGE AND ADMINISTRATION:
TABLETS (dogs only)
Other clinical signs were reported but were <0.5% of dogs.
The following adverse reactions were reported during US studies for the prevention of vomiting due to motion ­sickness in dogs treated with
CERENIA Tablets at a minimum of 8 mg/kg orally one time. Dogs may have experienced more than one of the observed adverse reactions.
Frequency of Adverse Reactions by Treatment
For Prevention of Acute Vomiting in dogs 8 weeks and older
Administer CERENIA Tablets orally at a minimum dose of 2 mg/kg (0.9 mg/lb) body weight once daily for up to 5 consecutive days.
Adverse Reaction
Kilograms
2.2 – 8.8
1.0 – 4
8.9 – 17.6
4.1 – 8
# dogs
% occurrence
Hypersalivation
19
9.7
26
12.5
Vomiting1
0
0
11
5.3
Muscle Tremors
1
0.5
2
1
/2
Sedation/Depression
3
1.5
2
1
1
Retching
3
1.5
1
0.5
Flatulence
0
0
1
0.5
Number of Tablets
24 mg
16 mg
1
60 mg
17.7 – 26.4
8.1 – 12
1
26.5 – 52.8
12.1 – 24
2
52.9 – 66
24.1 – 30
1
66.1 – 132
30.1 – 60
2
1
CERENIA Tablets may be used interchangeably with CERENIA Injectable Solution for once daily dosing for the prevention of acute vomiting.
For Prevention of Vomiting Due to Motion Sickness in dogs 16 weeks and older
Administer CERENIA Tablets orally at a minimum dose of 8 mg/kg (3.6 mg/lb) body weight once daily for up to 2 consecutive days.
Dogs should be fasted 1 hour prior to administration of CERENIA Tablets. Administer CERENIA Tablets 2 hours prior to travel.
Dog body weight
Frequency of Adverse Reactions by Treatment
Adverse Reaction
Number of Tablets
Kilograms
16 mg
24 mg
60 mg
Not associated with motion sickness
The following adverse reactions were reported during a European field study for the prevention of vomiting due to motion ­sickness in dogs
treated with CERENIA Tablets at a minimum of 8 mg/kg orally once daily for 2 consecutive days. Dogs may have ­experienced more than one of
the observed adverse reactions.
Prevention of Vomiting Due to Motion Sickness
Minimum of 8 mg/kg BW Dosing
Pounds
CERENIA (n=208)
% occurrence
Dog body weight
Pounds
Placebo (n=195)
# dogs
Prevention of Acute Vomiting
Minimum of 2 mg/kg BW Dosing
160 mg
2.2
1
2.3 – 3.3
1.1 – 1.5
/2
3.4 – 4.4
1.6 – 2
4.5 – 6.6
2.1 – 3
6.7 – 8.8
3.1 – 4
8.9 – 13.2
4.1 – 6
13.3 – 16.5
6.1 – 7.5
16.6 – 22
7.6 – 10
22.1 – 33
10.1 – 15
33.1 – 44
15.1 – 20
1
44.1 – 66
20.1 – 30
1 /2
66.1 – 88
30.1 – 40
2
88.1 – 132
40.1 – 60
3
1
/2
1
1
1
2
2
1
1
/2
Placebo (n=106)
CERENIA (n=107)
# dogs
% occurrence
# dogs
% occurrence
Vomiting
4
4
10
9
Drowsiness/Lethargy/Apathy
1
1
8
8
Hypersalivation
2
2
5
5
2
Anxiety
0
0
2
Trembling/Tremors
0
0
2
2
Inappetence
0
0
2
2
Mucus in stool
0
0
1
1
CATS:
The following adverse reactions were reported during the course of a US field study for the treatment of vomiting in cats treated with 1 mg/kg
CERENIA Injectable Solution subcutaneously once daily for up to five consecutive days:
Frequency of Adverse Reactions by Treatment
2
Adverse Reaction
1
Placebo (n=62)
CERENIA (n=133)
# cats
% occur
# cats
% occur
Moderate Response to Injection1,2
1
1.6
30
22.6
Significant Response to Injection1,3
1
1.6
15
11.3
INJECTABLE (dogs and cats)
Fever/Pyrexia
2
3.2
2
1.5
For Prevention of Acute Vomiting in dogs 8 weeks and older and for the Treatment of Vomiting in cats 16 weeks and older
Administer CERENIA Injectable Solution subcutaneously at 1 mg/kg (0.45 mg/lb) equal to 1 mL/10kg (1 mL/22 lb) of body weight once daily
for up to 5 consecutive days. Use of refrigerated product may reduce the pain response associated with the injection.
Dehydration
0
0
3
2.3
Lethargy
0
0
2
1.5
Anorexia
0
0
1
0.8
Hematuria
0
0
1
0.8
Hypersalivation
0
0
1
0.8
Injection site swelling
1
1.6
0
0
For dogs, CERENIA Injectable Solution may be used interchangeably with CERENIA Tablets for once daily dosing for the prevention of acute vomiting.
INFORMATION FOR USE:
CERENIA Tablets have been shown to be effective for the prevention of vomiting (see EFFECTIVENESS), however where the frequency of
vomiting is high, orally administered CERENIA may not be absorbed before the next vomiting event occurs. Therefore, initiation of therapy
with CERENIA Injectable Solution is recommended. If vomiting persists despite treatment, the case should be re-evaluated. CERENIA is most
effective in preventing vomiting associated with chemotherapy if administered prior to the chemotherapeutic agent.
WARNINGS:
Not for use in humans. Keep out of reach of children. In case of accidental ingestion, injection or exposure, seek medical advice. Topical
exposure may elicit localized allergic skin reactions in some individuals. Repeated or prolonged ­exposure may lead to skin sensitization. In
case of accidental skin exposure, wash with soap and water. CERENIA is also an ocular irritant. In case of accidental eye exposure, flush with
water for 15 minutes and seek medical attention.
In puppies younger than 11 weeks of age, histological evidence of bone marrow hypocellularity was observed at higher frequency and greater
severity in puppies treated with CERENIA compared to control puppies. In puppies 16 weeks and older, bone marrow hypocellularity was not
observed (see Animal Safety).
The clinician observed and graded each cat’s response to injection.
Cat objected to the injection by retreating and vocalizing
3
Cat objected to the injection by retreating, hissing, scratching, and vocalization
1
2
Post-Approval Experience
The following adverse events are based on post-approval adverse drug experience reporting. Not all adverse events are reported to FDA CVM. It is
not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data.
The following adverse events for CERENIA Tablets are listed in decreasing order of reporting frequency in dogs: depression/lethargy, anorexia,
hypersalivation, vomiting, diarrhea, ataxia, and trembling.
Cases of ineffectiveness have been reported
PRECAUTIONS:
The safe use of CERENIA has not been evaluated in dogs or cats used for breeding, or in pregnant or lactating bitches or queens. The safe use
of CERENIA has not been evaluated in dogs or cats with gastrointestinal obstruction, or dogs or cats that have ingested toxins.
The following adverse events for CERENIA Injectable use in dogs are listed in decreasing order of reporting frequency in dogs: Pain/
vocalization upon injection, depression/lethargy, anorexia, anaphylaxis/anaphylactoid reactions (including swelling of the head/face), ataxia,
convulsions, and hypersalivation.
Use with caution in patients with hepatic dysfunction because CERENIA is metabolized by CYP3A enzymes (see Pharmacokinetics). Use
with caution with other medications that are highly protein bound. The concomitant use of CERENIA with other protein bound drugs has not
been studied in dogs or cats. Commonly used protein bound drugs include NSAIDs, cardiac, anticonvulsant, and behavioral medications. The
influence of concomitant drugs that may inhibit the metabolism of CERENIA has not been evaluated. Drug compatibility should be monitored
in patients requiring adjunctive therapy.
Cases of death (including euthanasia) have been reported.
CERENIA causes dose related decreases in appetite and body weight (see ANIMAL SAFETY). To maximize therapeutic potential of CERENIA,
the underlying cause of vomiting should be identified and addressed in dogs receiving CERENIA.
The following adverse events for CERENIA Injectable use in cats, reported since 2007, are listed in decreasing order of reporting frequency in
cats: depression/lethargy, anorexia, injection site pain, and hypersalivation.
For a complete listing of adverse reactions for CERENIA Tablets reported to CVM see:
http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055369.htm
For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions call Pfizer Animal Health at 1-800-366-5288.
CLINICAL EXPERIENCE:
CERENIA Tablets
For motion sickness, prolonged fasting before administration should be avoided. Feeding dogs a small amount of food one hour prior to
the administration of 8 mg/kg of CERENIA Tablets may mitigate vomiting that may occur within two hours post-dosing and prior to travel.
CERENIA Injectable Solution
The pain or vocalization upon injection resolves within minutes without treatment. Administration of CERENIA Injectable Solution at refrigerated
temperature may mitigate this response (see DOSAGE AND ADMINISTRATION). Allergic reactions typically resolve with treatment within 48 hours
after discontinuing CERENIA administration.
CLINICAL PHARMACOLOGY:
Pharmacodynamics:
Vomiting is a complex process coordinated centrally by the emetic center which consists of several brainstem nuclei (area postrema,
nucleus tractus solitarius, dorsal motor nucleus of the vagus) that receive and integrate sensory stimuli from central and peripheral sources
and chemical stimuli from the circulation and the cerebrospinal fluid. Maropitant is a neurokinin 1 (NK1) receptor antagonist which acts by
inhibiting the binding of substance P, a neuropeptide of the tachykinin family. Substance P is found in significant concentrations in the nuclei
comprising the emetic center and is considered the key neurotransmitter involved in emesis.1 By inhibiting the binding of substance P within
the emetic center, maropitant provides broad-spectrum effectiveness against neural (central) and humoral (peripheral) causes of vomiting.
In vivo model studies in dogs have shown that maropitant has antiemetic effectiveness against both central and peripheral emetogens
including apomorphine, cisplatin, and syrup of ipecac.
Diemunsch P, Grelot L. Potential of substance P antagonists as antiemetics. [Review] [60 refs]. Drugs. 2000;60:533-46.
1
Pharmacokinetics
CERENIA is formulated using sulphobutylether-β-cyclodextrin (SBECD), which exhibits enhanced binding to maropitant at refrigerated
temperatures. The enhanced binding affinity reverses rapidly upon warming.
DOGS:
The pharmacokinetic characterization associated with maropitant after oral (PO) or subcutaneous (SC) administration in adult Beagle dogs
is provided in the table below.
In US field studies in veterinary patients, CERENIA Injectable Solution and Tablets were well tolerated in dogs presenting with various clinical
conditions including parvovirus, gastroenteritis, and renal disease. There were no notable differences in mean laboratory values between
CERENIA-treated and placebo-treated patients.
CERENIA Injectable Solution was used safely in dogs receiving other frequently used veterinary products such as fluid and electrolyte
replacement solutions, antimicrobial agents, vaccines, antacids, and antiparasitic agents.
Prevention of Vomiting due to Motion Sickness
In a study of canine veterinary patients taken on a one-hour car journey and treated with either CERENIA Tablets at a minimum dose of
8 mg/kg BW or placebo tablets 2 hours prior to the journey, 67 of 122 (55%) of dogs vomited during the journey when treated with placebo
while 8 of 122 (7%) vomited during the journey after treatment with CERENIA Tablets. The probability that a dog in this study, prone to motion
sickness would NOT vomit during a journey if treated with CERENIA Tablets was 93%, while the probability was 48% if treated with placebo.
CATS:
In a field study, 195 cats were presented to veterinary hospitals with a history of vomiting associated with various clinical conditions including
gastroenteritis, gastritis, pancreatitis, inflammatory bowel disease, neoplasia, and hepatic lipidosis. Cats were treated with CERENIA Injectable
Solution or placebo (in a ratio of 2:1) and observed in the veterinary hospital for 24 hours for the presence of an emetic event(s) defined
as the observation of the act of vomiting or the presence of vomitus. Cats could continue antiemetic treatment every 24 hours for up to 5
consecutive days at the discretion of the clinician. Of 165 cats included in the analysis for effectiveness, 2 CERENIA-treated cats (1.8%)
vomited 1 time each and 10 placebo-treated cats (18.5%) vomited a total of 15 times in the first 24 hours post treatment.
Percent of Cats Vomiting for Each Study Day by Treatment
Study Day
Day 0
Day 1
Pharmacokinetic Parameters in Beagle Dogs (Mean±SD or range)
SC at 1 mg/kg (n=6)
PO at 2 mg/kg (n=8)
PO at 8 mg/kg (n=8)
860±137
561±322
7840±5600
92±34
81±32
776±604
T1/2 (hr)
8.84 (6.07-17.7)
4.03 (2.48-7.09)
5.46 (3.39-7.65)
Tmax (hr)
0.75±1.11
1.9±0.5
1.7±0.7
AUC0-inf (hr*ng/mL)
Cmax (ng/mL)
Day 3
The absolute bioavailability of maropitant was much higher following SC injection (91% at 1 mg/kg) than after PO administration (24% at
2 mg/kg). Oral bioavailability may be underestimated due to the presence of nonlinear kinetics and the resulting longer T1/2 seen after
intravenous (IV) administration. Although hepatic first-pass metabolism contributed to the relatively low bioavailability after an oral dose,
prandial status does not significantly affect the extent of oral bioavailability. Greater than dose-proportional drug exposure can be expected
with an increase in dose (1-16 mg/kg PO). Systemic clearance of maropitant following IV administration was 970, 995, and 533 mL/hr/kg at
doses of 1, 2 and 8 mg/kg, respectively. An accumulation ratio of 1.5 was observed following once-daily use of maropitant for five consecutive
days at 1 (SC) or 2 mg/kg (PO). Urinary recovery of ­maropitant and its major metabolite was minimal (<1% each). The hepatic metabolism of
maropitant involves two cytochrome P-450 isoenzymes: CYP2D15 and CYP3A12. Based on in vitro enzyme kinetics data, it is believed that the
non-linear kinetics may be partially associated with saturation of the low capacity enzyme (CYP2D15). However as doses increase (20-50 mg/kg PO),
dose proportionality is re-­established. Based upon in vitro enzyme kinetics, involvement of a high capacity enzyme (CYP3A12) may contribute
to this return to dose linearity. Plasma protein binding of maropitant was high (99.5%).
Based on differences in plasma trough concentrations from a single study, the exposure of 10 week old puppies to maropitant may be lower
than that observed in adult dogs, particularly after doses of 1 or 2 mg/kg.
CATS:
The pharmacokinetic profile of maropitant when administered as a single subcutaneous dose of 1 mg/kg body weight to 8 cats was
characterized by a mean (range) maximum concentration (Cmax) in plasma of approximately 165 (108-332) ng/mL. Cmax was achieved
on average 0.32 (0.25-0.5) hours post-dosing (Tmax). Peak concentrations were followed by a decline in systemic exposure with a mean
apparent elimination half-life (t½) of 16.8 (10.3-32.8) hours and mean area under the curve (AUC0-∞) of 3490 (1440-6760) hr*ng/mL. There
appears to be an age-related effect on the pharmacokinetics of maropitant in cats with kittens (16 wks) having faster clearance than adults.
The mean bioavailability of maropitant after subcutaneous administration in cats was 91.3%. The mean total body clearance (CL) and volume
of distribution at steady-state (Vss) determined after intravenous administration at 0.25 mg/kg to 8 cats was 0.27 (0.14-0.59) L/h/kg and
3.04 (2.27 to 3.80) L/kg, respectively. Maropitant displays linear kinetics when administered subcutaneously within the 0.25 – 3 mg/kg dose
range. Following repeated subcutaneous administration of once-daily doses of 1 mg/kg body weight for 5 consecutive days, accumulation was
250%. Maropitant undergoes cytochrome P450 (CYP) metabolism in the liver. CYP1A and CYP3A-related enzymes were identified as the feline
isoforms involved in the hepatic biotransformation of maropitant. Renal and fecal clearances are minor routes of elimination for maropitant,
with less than 1% of a 1 mg/kg subcutaneous dose appearing in the urine or feces as maropitant. For the major metabolite, 10.4% of the
maropitant dose was recovered in urine and 9.3% in feces. Plasma protein binding of maropitant in cats was estimated to be 99.1%.
EFFECTIVENESS:
DOGS
Prevention and Treatment of Acute Vomiting
In laboratory model studies, CERENIA Tablets dosed at a minimum of 2 mg/kg BW reduced the number of emetic events associated with
established neural (central) and humoral (peripheral) stimuli. Following administration of apomorphine (central emetic stimuli), vomiting was
observed in 33% (4 of 12) of Beagle dogs treated with CERENIA Tablets and 100% (12 of 12) of Beagle dogs treated with placebo tablets.
Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 33% (4 of 12) of Beagle dogs treated with
CERENIA Tablets and in 83% (10 of 12) of Beagle dogs treated with placebo tablets.
In laboratory model studies, CERENIA Injectable Solution administered at 1 mg/kg in Beagle dogs reduced the number of emetic events
associated with established neural (central) and humoral (peripheral) stimuli. Following administration of apomorphine (central emetic stimuli),
vomiting was observed in 16.7% (2 of 12) of dogs treated with CERENIA Injectable Solution and 83.3% (10 of 12) of placebo-treated dogs.
Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 25% (3 of 12) of dogs treated with CERENIA
Injectable Solution and in 100% (12 of 12) of dogs treated with placebo.
In a study of veterinary cancer patients, dogs were treated with CERENIA Injectable Solution or placebo either 1 hour prior to cisplatin
(prevention) or after the first vomiting episode following cisplatin (treatment) and monitored for 5 hours. In the groups evaluated for
prevention of vomiting, 94.9% (37/39) of the dogs administered CERENIA Injectable Solution and 4.9% (2/41) of the dogs administered
placebo did not vomit. In the groups evaluated for treatment, 21% (8/38) of the dogs administered CERENIA Injectable Solution and 5.1%
(2/39) of the dogs administered placebo had no further episodes of vomiting following treatment.
In a study of 275 canine patients presented to veterinary hospitals with a history of acute vomiting, dogs were initially administered CERENIA
Injectable Solution or placebo on Day 0. Following the initial dose, dogs allocated to the CERENIA group were treated with either CERENIA
Tablets at a minimum of 2 mg/kg orally or Injectable Solution at 1 mg/kg subcutaneously once daily at the discretion of the clinician. Dogs
allocated to the placebo group were treated using either an injectable placebo solution or placebo tablets once daily at the discretion of the
clinician. Of the 199 dogs included in the analysis for effectiveness, 27 of 54 dogs (50%) in the placebo group displayed vomiting at some
time during the study and 31 of 145 dogs (21.4%) in the CERENIA-treated group displayed vomiting during the study period.
Percent of Vomiting for Each Study Day, Based Upon Treatment and Route of Administration.
Days
Day 0
Treatment
Route
# dogs
# vomited
% vomited
Placebo (54)
SC
54
15
28%
CERENIA (145)
SC
145 (143*)
14
10%
PO
22
3
14%
SC
23
16
70%
PO
67
2
3%
SC
41
16
39%
PO
7
2
29%
SC
9
6
67%
PO
24
0
0%
SC
13
8
62%
PO
2
0
0%
SC
4
1
25%
PO
14
0
0%
Placebo (45)
Day 1
CERENIA (108)
Placebo (16)
Day 2
CERENIA (37)
Placebo (6)
Day 3
CERENIA (21)
Placebo (2)
Day 4
CERENIA (7)
Day 5
CERENIA (1)
Day 2
Day 4
Treatment
# cats
# vomited
% vomited
Placebo
54
10
18.5
CERENIA
111
2
1.8
Placebo
20
4
20
CERENIA
34
1
2.9
Placebo
9
2
22.2
CERENIA
8
0
0
Placebo
5
0
0
CERENIA
5
0
0
Placebo
3
0
0
CERENIA
1
0
0
ANIMAL SAFETY:
DOGS:
Laboratory and field studies have demonstrated that CERENIA Injectable Solution is well tolerated in dogs after subcutaneous administration.
Target Animal Safety Study for Acute Vomiting
Fifty six Beagle dogs (28 males and 28 females) approximately 16 weeks of age were administered CERENIA Injectable Solution
subcutaneously once daily for 15 days at 0, 1, 3, and 5 mg/kg. There were 8 dogs (4 males and 4 females) in the 1 mg/kg group and 16 dogs
(8 males and 8 females) in all other groups. The primary treatment-related findings were injection site reactions. Swelling, thickened skin, or
pain at one or more of the injection sites on one or more days of the study were observed in 6 of 16 animals treated with 3 mg/kg/day and 5
of 16 animals treated with 5 mg/kg/day. Additionally, the activated partial thromboplastin time (APTT) was prolonged (67.5 seconds, reference
range 9-15 seconds) in one male dog in the 1 mg/kg group on study day 15. Relationship of the prolonged APTT to drug administration could
not be determined.
Beagle dogs approximately 8 weeks of age were administered CERENIA Injectable Solution subcutaneously once daily for 15 days at 0, 1, 3,
and 5 mg/kg using a protocol similar to the previous study. A dose dependent increase in frequency and severity of bone marrow hypoplasia
was observed histologically, One placebo-treated dog died on day 14 of the study and was diagnosed with suppurative pancreatitis and
esophagitis. Interpretation of the study results is complicated by the health status of study animals. Dogs used in the study were weaned early,
minimally acclimated to the test facility, and many of the dogs in the study tested positive for coccidia.
Beagle dogs approximately 10 weeks of age were administered either placebo tablets for 2 days, CERENIA Tablets at 8 mg/kg for 2 days,
placebo (saline) subcutaneously (SC) for 5 days, CERENIA Injectable Solution at 1 mg/kg SC for 5 days, or CERENIA Tablets at 2 mg/kg for
5 days (8 dogs in each dose group). Mild pain associated with injection was noted in more dogs and lasted longer in dogs that received
maropitant injections compared to saline. Males administered CERENIA at 8 mg/kg orally for 2 days had a decrease in food consumption.
Body weight and food consumption were variable throughout the 4 week acclimatization period. Two dogs that received 8 mg/kg maropitant
orally for 2 days were below the reference range for reticulocyte counts. Decreases in reticulocyte counts were also seen in 4 (of 8) placebo
treated dogs (SC saline for 5 days). Hypocellular femoral bone marrow described as “minimal” was seen in 1 male that received 1 mg/kg
maropitant SC for 5 days; reticulocyte counts were not available for this dog.
Target Animal Safety Study for Motion Sickness
Forty Beagle dogs (20 males and 20 females) between 16 - 18 weeks of age were administered CERENIA Tablets orally once daily for 6 days at
0, 8 and 24 mg/kg. There were 16 dogs (8 males and 8 females) in the 0 and 24 mg/kg groups and 8 dogs (4 males and 4 females) in the
8 mg/kg group. At 24 mg/kg, CERENIA Tablets caused decreases in food consumption, with decreases in body weight, liver and testis weight;
and an increase in RBC count indicating hemoconcentration, but the effects on feed consumption, body weight, and RBCs did not persist in
the post-treatment recovery period (beyond Day 5).
Beagle dogs approximately 8 weeks of age were administered CERENIA Tablets orally once daily for 6 days at 0, 8, and 24 mg/kg using a
protocol similar to the previous study. One dog in the 24 mg/kg/day group died of unknown causes on study day 2 and a dose dependent
increase in occurrence and severity of bone marrow hypoplasia and lymphoid depletion was observed histologically. Interpretation of these
study results is complicated by the health status of study animals. Dogs used in the study were weaned early, minimally acclimated to the
test facility, and many of the dogs in the study tested positive for coccidia. Additionally, some dogs in the study tested positive for canine
parvovirus, however, clinical parvoviral disease was not definitively diagnosed.
Tolerance Study
Twenty four Beagle dogs (14 males and 10 females) between 11 and 25 weeks of age were administered CERENIA Tablets in 2 phases with
8 dogs per group. In the first phase the dogs were administered 0, 20 or 30 mg/kg orally once daily for 7 days and in the second phase 0,
40, or 50 mg/kg once daily for 7 days. CERENIA Tablets administered at 20 and 30 mg/kg caused occasional vomiting. CERENIA Tablets
administered at 40 mg/kg and 50 mg/kg caused clinically relevant signs of weight loss, vomiting, soft stools, weakness, lethargy, salivation
and hypokalemia. Additionally, leukopenia characterized by a neutropenia and a trend toward decreasing plasma phosphorus values was seen.
Decreased heart rate and prolonged corrected QT intervals were seen in all treatment groups in a dose dependent manner.
CATS:
Thirty-two domestic short hair cats (16 males and 16 females) approximately 16 weeks of age were administered CERENIA Injectable Solution
subcutaneously once daily for 15 days at 0, 1, 3, and 5 mg/kg. There were 8 cats (4 males and 4 females) in each group. Treatment-related,
dose dependent findings included pain associated with injection of CERENIA and injection site heat, pain, redness, and firmness. Pain on
injection was observed in 5% of cats at 0 mg/kg, 50% of cats at 1 mg/kg, and 75% of cats at 3 and 5 mg/kg. Injection site firmness >10 mm
in diameter was observed at one or more of the injection sites, on one or more days of the study, in 1 of 8 cats at 1 mg/kg, 7 of 8 cats at
3 mg/kg, and 7 of 8 cats at 5 mg/kg. There was a statistically significant reduction (p=0.0171) in food intake at 5 mg/kg compared to cats at
0 mg/kg. One cat at 5 mg/kg was lethargic on Days 12, 13, and 14 of the study. Increased skin turgor was observed in 1 cat at 3 mg/kg on
Days 10 and 11, 1 cat at 3 mg/kg on Day 12, and 1 cat at 5 mg/kg on Day 12. At gross necropsy, there were no treatment-related findings.
Histopathologic evaluation of injection sites revealed a dose dependent inflammatory response.
STORAGE CONDITIONS:
CERENIA Tablets should be stored at controlled room temperature 20°-25°C (68°-77°F) with excursions between 15°-30°C (59°-86°F).
CERENIA Injectable Solution should be stored at controlled room temperature 20-25°C (68-77°F) with excursions between 15-30°C (59-86°F).
After first vial puncture, CERENIA Injectable Solution should be stored at refrigerated temperature 2-8°C (36-46°F). Use within 90 days of first
vial puncture. Stopper may be punctured a maximum of 25 times.
HOW SUPPLIED:
CERENIA peach-colored tablets are scored with a break line, and contain 16, 24, 60 or 160 mg of maropitant as maropitant citrate per tablet.
Each tablet is marked with “MPT” and the tablet strength on one side and the Pfizer logo on the other. Each tablet size is packaged in blister
packs containing 4 tablets per perforated sheet.
CERENIA Injectable Solution is supplied in 20 mL amber glass vials. Each mL contains 10 mg of maropitant as maropitant citrate.
Made in France
NADA #141-262, Approved by FDA
NADA #141-263, Approved by FDA
Distributed by: Pfizer Animal Health, Div. of Pfizer Inc, NY, NY 10017
Revised: May 2012
SC
7
5
71%
Distributed by:
PO
1
0
0%
Pfizer Animal Health
SC
1
1
100%
PO
5
0
0%
SC
2
1
50%
SC
1
0
0%
*2 dogs administered CERENIA were not observed on Day 0. Their vomiting status was unknown. 143 was used in the denominator for % vomited.
Div. of Pfizer Inc
NY, NY 10017
CER0611006 © 2011 Pfizer Inc. All rights reserved. Printed in USA/December 2011
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