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Technical BulletinDecember 2011

Pfizer Animal Health

Value of CERENIA® (maropitant citrate) in the Treatment of Acute Vomiting in DogsMatthew 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

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• 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

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

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.

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.

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.

The injectable form (10 mg/ml) of CERENIA, dosed

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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 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 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.”

Since 2007, Cerenia has become the most prescribed antiemetic, with 74% of all practice veterinarians prescribing it.3

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

A RETROSPECTIVE EXAMINATION OF THE CERENIA US PIVOTAL EFFICACY STUDY10

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

CERENIA was the only agent that effectively prevented vomiting regardless of the emetic stimuli.

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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.

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 RESOLUTION OF EMESIS AND ITS IMPLICATIONSAs 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.

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.

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.

Effective treatment builds trust and confidence with veterinarians and their staff, validates clients’ selection of veterinary hospitals, and reinforces the veterinarian-client-patient relationship.

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.

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.

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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.

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

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.

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

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.

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.

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

Maropitant 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)

Phenothiazines - 3.5% (n=5) 12.8% (n=18) 24.8% (n=35) 0.7% (n=1)

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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

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

When asked in the VOICE survey how a hospitalized vomiting dog affects their staff, 72% of responding veterinarians indicated that stress is “somewhat

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.

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

Reducing emesis early in the treatment program should decrease staff time and reduce the costs associated with humane cage care.

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

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.

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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.

Rapid resolution of vomiting not only positively impacts dogs but also their veterinarians, hospital staff, and owners.

APPENDIX: RETROSPECTIVE EVALUATION OF CERENIA EFFICACY BY CAUSE OF VOMITING (DIAGNOSIS)1

All Vomiting Causes CombinedData 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

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).

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.

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.

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).

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 2 1

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) 2.8% (n=4)

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.

Diagram 1 - Response to therapy in a population of vomiting dogs (all vomiting causes combined).

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For many veterinarians, once emesis stops, they can switch their patients to oral CERENIA tablets for continued in-hospital or at-home treatment.

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,

respectively, of 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.

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).

PancreatitisTwenty-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

Cumulative Proportion of Dogs that Continued Vomiting Each Study DayWith 95% Confidence Limits

Prop

orti

on o

f Pop

ulat

ion

that

Con

tinu

es V

omit

ing

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).

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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).

Table A-1

The Performance of CERENIA® in Stopping Vomiting in Dogs in the Pivotal Efficacy Study by Cause of Vomiting (Diagno-sis). Data Are Percent and Number of Dogs.1

Last Day of Vomiting

Treatment Starta Day 1 Day 2 Day 3 Day 4 Day 5

All Vomiting Causes Combined

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)

Parvovirus

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)

Pancreatitis

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

Gastroenteritis

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)

Gastritis

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

Dietary Indiscretion

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

All

do

gs

rece

ived

th

ree

to fi

ve d

ays

of

ther

apy

a. 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.

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Gastroenteritis

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).

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).

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

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.

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

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.

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

0 1 2 3 4

Supportive Care (n=46) 57% (n=26/46)

64% (n=29/46)

79% (n=36/46)

88% (n=40/46)

92% (n=42/46)

CERENIA + Supportive Care (n=137) 84% (n=115/137)

88% (n=120/137)

92% (n=126/137)

94% (n=129/137)

98% (n=134/137)

11

11. Veterinary Fee Reference. Vital statistics for your veterinary practice. 6th ed. American Animal Hospital Association; 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.

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.

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.

15. McCaw DL, Hoskins JD. Canine Viral Enteritis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St Louis, Missouri: Saunders-Elsevier; 2006; Chapter 8:63-73.

REFERENCES1. Data on file. Outcomes Research and Key Brand

Clinical Support, Pfizer Animal Health, 2009.

2. Pfizer Animal Health Global Market Research, VOICE Survey. Caring for vomiting dogs. April, 2011. Data on file.

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.

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.

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.

Tablets and Injectable Solution

Antiemetic

CERENIA TabletsFor oral use in dogs only

CERENIA InjectableFor subcutaneous injection in dogs and cats

CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

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 chemical structure of maropitant citrate is:

INDICATIONS:

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.

DOSAGE AND ADMINISTRATION:

TABLETS (dogs only) For Prevention of Acute Vomiting in dogs 8 weeks and olderAdminister 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.

Prevention of Acute Vomiting Minimum of 2 mg/kg BW Dosing

Dog body weight Number of TabletsPounds Kilograms 16 mg 24 mg 60 mg

2.2 – 8.8 1.0 – 4 1/2

8.9 – 17.6 4.1 – 8 1

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

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 olderAdminister 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.

Prevention of Vomiting Due to Motion Sickness Minimum of 8 mg/kg BW Dosing

Dog body weight Number of TabletsPounds Kilograms 16 mg 24 mg 60 mg 160 mg

2.2 1 1/2

2.3 – 3.3 1.1 – 1.5 1/2

3.4 – 4.4 1.6 – 2 1

4.5 – 6.6 2.1 – 3 1

6.7 – 8.8 3.1 – 4 2

8.9 – 13.2 4.1 – 6 2

13.3 – 16.5 6.1 – 7.5 1

16.6 – 22 7.6 – 10 1/2

22.1 – 33 10.1 – 15 2

33.1 – 44 15.1 – 20 1

44.1 – 66 20.1 – 30 11/2

66.1 – 88 30.1 – 40 2

88.1 – 132 40.1 – 60 3

INJECTABLE (dogs and cats)For Prevention of Acute Vomiting in dogs 8 weeks and older and for the Treatment of Vomiting in cats 16 weeks and olderAdminister 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.

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).

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.

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.

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.

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

Adverse ReactionPlacebo (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.

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

Adverse ReactionPlacebo (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

Hematuria 0 0 2 1

Excoriation 0 0 2 1

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

Adverse ReactionPlacebo (n=195) CERENIA (n=208)

# dogs % occurrence # dogs % occurrence

Hypersalivation 19 9.7 26 12.5

Vomiting1 0 0 11 5.3

Muscle Tremors 1 0.5 2 1

Sedation/Depression 3 1.5 2 1

Retching 3 1.5 1 0.5

Flatulence 0 0 1 0.51 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.

Frequency of Adverse Reactions by Treatment

Adverse ReactionPlacebo (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

Anxiety 0 0 2 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

Adverse ReactionPlacebo (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

Fever/Pyrexia 2 3.2 2 1.5

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 01 The clinician observed and graded each cat’s response to injection.2 Cat objected to the injection by retreating and vocalizing3 Cat objected to the injection by retreating, hissing, scratching, and vocalization

Post-Approval ExperienceThe 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

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.

Cases of death (including euthanasia) have been reported.

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 SolutionThe 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.1Diemunsch P, Grelot L. Potential of substance P antagonists as antiemetics. [Review] [60 refs]. Drugs. 2000;60:533-46.

PharmacokineticsCERENIA 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.

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)

AUC0-inf (hr*ng/mL) 860±137 561±322 7840±5600

Cmax (ng/mL) 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

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:DOGSPrevention and Treatment of Acute VomitingIn 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 Treatment Route # dogs # vomited % vomited

Day 0Placebo (54) SC 54 15 28%

CERENIA (145) SC 145 (143*) 14 10%

Day 1

Placebo (45)PO 22 3 14%

SC 23 16 70%

CERENIA (108)PO 67 2 3%

SC 41 16 39%

Day 2

Placebo (16)PO 7 2 29%

SC 9 6 67%

CERENIA (37)PO 24 0 0%

SC 13 8 62%

Day 3

Placebo (6)PO 2 0 0%

SC 4 1 25%

CERENIA (21)PO 14 0 0%

SC 7 5 71%

Day 4

Placebo (2)PO 1 0 0%

SC 1 1 100%

CERENIA (7)PO 5 0 0%

SC 2 1 50%

Day 5 CERENIA (1) 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.

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 SicknessIn 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 Treatment # cats # vomited % vomited

Day 0Placebo 54 10 18.5

CERENIA 111 2 1.8

Day 1Placebo 20 4 20

CERENIA 34 1 2.9

Day 2Placebo 9 2 22.2

CERENIA 8 0 0

Day 3Placebo 5 0 0

CERENIA 5 0 0

Day 4Placebo 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 VomitingFifty 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 SicknessForty 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 StudyTwenty 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 FranceNADA #141-262, Approved by FDANADA #141-263, Approved by FDADistributed by: Pfizer Animal Health, Div. of Pfizer Inc, NY, NY 10017Revised: May 2012

Distributed by:

Pfizer Animal HealthDiv. of Pfizer Inc NY, NY 10017

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CER0611006 © 2011 Pfizer Inc. All rights reserved. Printed in USA/December 2011