Pfizer Animal Health Technical Bulletin

December 2011

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

Matthew Krecic, DVM, MS, MBA, Robert Lavan, DVM, MS, MPVM, Diplomate ACVIM 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 ) 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 . • 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 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 (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 .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 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 , 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 Vomiting equals suffering. Identifying and densely distributed within the emetic center and countering a specific cause of vomiting is of maropitant acts to directly inhibit vomiting by

primary importance, yet stopping the vomiting blocking substance P binding at these NK1 receptors is also important to address the patient’s in the CNS. immediate physical needs while investigating or The predominant peripheral direct and indirect treating for the specific cause. pathways carry stimuli to induce vomiting through the emetic center and CRTZ, respectively. All Vomiting is a nonspecific clinical sign; it is similar stimuli that cause vomiting converge within the to other vague clinical signs such as lethargy and emetic center; therefore, stimuli, such as toxins depression. Common GI diseases include foreign retained by diseased kidneys, within the circulation bodies, gastroenteritis, inflammatory bowel disease, initially carried to the CRTZ via the peripheral neoplasia (eg, lymphosarcoma), parasitism, and indirect pathway ultimately end within the emetic . Common non-GI diseases include center. Alternatively, the peripheral direct pathway hypoadrenocorticism, hyperthyroidism, kidney carries stimuli from diseased abdominal organs right disease (uremia), disease, and pancreatitis. to the emetic center. The emetic center also directly Additionally, toxins (eg, lead) and medications (eg, receives stimuli that induce vomiting from the digoxin, ) may also cause vomiting. higher brain (ie, cerebrum) via the central pathway. Identifying and countering a specific cause of vomiting The CRTZ likewise also receives stimuli from the is of primary importance, yet stopping the vomiting is vestibular apparatus, which underlies vomiting an important component of addressing the patient’s due to motion sickness. Some diseases can cause immediate physical needs while investigating or vomiting due to multiple pathways. Once the emetic treating for the specific cause. Despite the many causes center and CRTZ receive these stimuli, substance of vomiting, effectively stopping the vomiting while P is released and binds to NK1 receptors within the allowing for further examination is possible with the emetic center and CRTZ. This interaction induces antiemetic CERENIA (maropitant citrate). efferent nerve impulses to the abdominal muscles and diaphragm to start the vomiting reflex. 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 CERENIA was the only agent that effectively days, is labeled for prevention and treatment of acute prevented vomiting regardless of the emetic stimuli. 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 Additionally in laboratory studies, researchers have sickness in dogs. The oral dose for preventing and demonstrated the effectiveness of CERENIA in treating acute vomiting is 2 mg/kg once daily for up to controlling emesis from challenges with two emetics, 5 five consecutive days, and the oral dose for preventing and . When a dog motion sickness is 8 mg/kg once daily for up to two ingests syrup of ipecac, it irritates the stomach, consecutive days. However, a combination of injectable stimulating vomiting via the peripheral direct pathway. and oral CERENIA not to exceed five consecutive Apomorphine administered intravenously (IV) days may be prescribed to dogs with acute vomiting. travels to the CRTZ where it stimulates dopamine CERENIA does not have any known contraindications. receptors, leading to vomiting; this is via the peripheral indirect pathway. Compared to the Since 2007, Cerenia has become the most , , and , prescribed antiemetic, with 74% of all practice CERENIA effectively prevented vomiting regardless of veterinarians prescribing it.3 the emetic stimuli. Researchers showed metoclopramide and chlorpromazine to be effective at preventing vomiting induced by apomorphine but not by syrup of CERENIA became commercially available in the US ipecac. Similarly, researchers showed ondansetron to in 2007. Since then, it has become the most prescribed be effective at preventing vomiting induced by syrup antiemetic, with 74% of all practice veterinarians of ipecac but not by apomorphine. CERENIA was prescribing it.3 Since launch, the recommended length of the only agent that effectively prevented vomiting time the injectable form can be stored once opened has in the vast majority of cases regardless of the emetic been increased. An opened vial of CERENIA now has a stimuli. Since the introduction of CERENIA to the 90-day shelf life, increased from the previously approved marketplace, other CERENIA-related studies have been 28 days. published.6-9 DESCRIPTION OF THE CERENIA US PIVOTAL EFFICACY STUDY A RETROSPECTIVE EXAMINATION OF THE CERENIA US PIVOTAL A summary of the results from the CERENIA US 10 pivotal efficacy study were published in 2008.4 This EFFICACY STUDY study supported the New Animal Drug Application Data from the CERENIA pivotal efficacy study and the approval of CERENIA for use in the treatment was retrospectively examined to determine if the and prevention of acute emesis in dogs. The study performance of CERENIA could be described in was started in August 2003 and the last patient was several subpopulations of dogs sharing common enrolled in June 2004. All dogs had been vomiting at diagnoses that could be driving the vomiting enrollment and all were treated for three to five days. (See Appendix). Approximately 70% (n = 183) of Data were pooled across several vomiting etiologies. the dogs in the pivotal efficacy study were diagnosed The study concluded “in spite of the diverse and with a specific cause of vomiting that included dogs often severe nature of acute or chronic disease in the diagnosed with parvovirus (n = 48), pancreatitis diverse population (various ages and breeds) of enrolled (n = 26), gastroenteritis (n = 67), gastritis (n = 27), dogs, CERENIA demonstrated broad-spectrum or dietary indiscretion (n = 15). In this retrospective utility in treatment and prevention of acute emesis analysis, 137 dogs received CERENIA plus supportive by significantly p( < 0.0012) reducing the percentage care and 46 received supportive care alone. The of dogs exhibiting vomiting following treatment from diagnosis of parvovirus was usually made from a 50% in placebo-treated dogs to 21.8% in dogs given confirmatory fecal enzyme-linked immunosorbent CERENIA.” assay (ELISA) test. The diagnosis of other vomiting causes was made through a combination of clinical

3 signs, vomiting history, physical examination findings When veterinarians prescribe CERENIA for and laboratory tests. Veterinarians could only assign a vomiting or motion sickness, they dispense a single diagnosis for each vomiting dog and could treat medication only available through licensed dogs with supportive care, which usually consisted veterinarians. Pfizer Animal Health does not sell of intravenous (IV) fluids and injectable antibiotics. this medication “over-the-counter” or to retail Dogs were blocked and randomly assigned to groups pharmacies. in a 3:1 ratio (CERENIA:placebo), receiving either a In the licensing study for CERENIA, dogs were once daily dose of CERENIA or placebo, in addition to recruited into the study when their owners took them supportive care. All dogs were hospitalized for three to to the clinic for treatment of vomiting.4 All dogs were five days. treated for three to five days and monitored twice a day for ongoing emesis. Treatment consisted of supportive The initial dose of CERENIA was given as an injection, dosed at 1 mg/kg SC, at the start of the care with or without CERENIA. In a recent Veterinary study (Day 0). Subsequent doses of CERENIA Online Interactive Community Exchange (VOICE) could be given as either an injection or tablet, per Pfizer market research survey of veterinarians on their the label dosing. All dogs in the CERENIA group practice approach to canine vomiting, 67% (n=96/143) received three to five days of treatment. indicated that they had prescribed supportive care alone without an antiemetic for dogs that presented There was a statistically significant cessation of for vomiting.2 This approach is equivalent to the vomiting associated with CERENIA plus supportive control group of dogs in the CERENIA pivotal study care versus supportive care alone detected on the that were treated with supportive care but without first day of the three to five day treatment period an antiemetic. While the initial dose of CERENIA (Appendix Table A1). A statistically significant or placebo in the pivotal study was given as a SC effect of CERENIA was seen in the all causes group injection, the veterinarian had the option of treating the dog for additional days with CERENIA Tablets (p=0.0001), as well as in the parvovirus (p=0.01), or Injection (or identical placebo). The dual routes of pancreatitis (p=0.0001), and gastroenteritis (p=0.0001) administration of CERENIA create an opportunity for subgroups. This action of CERENIA was not the veterinarian to continue antiemetic therapy with statistically significant in dogs that were vomiting an oral medication option (CERENIA Tablets) and/ due to gastritis, but there were only three dogs in the or to allow the pet owner to be part of the treatment analysis with this diagnosis who received supportive team and treat the pet at home for up to 5 days. care only. The subgroup of dogs with a diagnosis of dietary indiscretion was too small to allow for a valid statistical The once daily administration of CERENIA may analysis. be less stressful for the pet and pet owner compared to other medications that must be dosed multiple THE RESOLUTION OF EMESIS AND times a day.

ITS IMPLICATIONS Many dogs receiving CERENIA benefit from the arrest As is seen in the pivotal study, supportive care and of vomiting within the first 24-48 hours. As seen in an antiemetic given to the appropriate patient can the pivotal study, the cumulative proportion of dogs reduce the number of days of clinical illness and speed in the placebo control group needed approximately recovery. Identifying and treating the underlying three days of supportive care to match the proportion cause of vomiting is equally important in reducing the of dogs whose emesis had stopped on the first day of number of days of illness and at speeding recovery. CERENIA therapy (84%, n=115/137). Prior to sending This effective way of symptomatically treating a a vomiting dog home, many veterinarians want to disease validates the pet owners’ reasons for seeking monitor a dog for at least 24 hours after the last care with particular veterinarians and veterinary vomiting episode in order to be sure that emesis has hospitals. stopped. In the VOICE survey, 67% (n = 99/147) of respondents indicated that they keep a dog hospitalized Effective treatment builds trust and confidence for up to 24 hours of monitoring after the last with veterinarians and their staff, validates clients’ observed vomiting episode.2 With CERENIA added to selection of veterinary hospitals, and reinforces the supportive care, veterinarians have the opportunity to veterinarian-client-patient relationship. send a larger percentage of vomiting dogs home sooner.

4 Dogs that stopped vomiting at the start of therapy (Day Medical charges (in 2003 dollars) were calculated for 0) could be observed for 24 hours (Day 1) and sent home the treatment given to vomiting dogs in the CERENIA the morning of Day 2. This occurred in the pivotal pivotal study.4 The actual charges were identified study for about 84% (n=115/137) of the dogs receiving in the medical records for some patients. Often, an CERENIA plus supportive care versus about 57% itemized list of services and medications was created (n=26/46) of dogs receiving placebo plus supportive care. from notes in the medical record. The Veterinary Fee Reference (2009), or other source, was used to Veterinarians were also asked whether rapid find nationalized average charges for each item.11 The control of a patient’s vomiting impacts client consumer price index calculator (www.bls.gov/cpi/)12 confidence. Ninety-one percent responded was used to correct clinic charges back to 2003 dollar that this would somewhat increase or strongly values, which would have been in effect at the time increase client confidence.2 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 In the VOICE survey, veterinarians were asked how day after that (Table 2). The higher charge for the first confident they are in the ability of various antiemetics day of care was associated with the singular costs of to stop vomiting.10 CERENIA received the highest running the initial diagnostic tests, the IV catheter set confidence scores from 87% of respondents, compared with metoclopramide, ondansetron and phenothiazines up, and other first-day procedures. (Table 1). The respondents’ confidence with Any therapy that shortens the length of time that CERENIA is the likely reason they most frequently a pet is hospitalized saves money for the pet owner. prescribed it over the past year. Veterinarians were also Veterinarians may be concerned about the fees that asked whether rapid control of a patient’s vomiting are charged to pet owners and may make decisions impacts client confidence. Ninety-one percent about what services to offer based on their perception (n=128/141) responded that this would somewhat of what pet owners can afford.13 In the CERENIA increase or strongly increase client confidence.2 pivotal study, the average daily charge for hospitalized The presentation of population data from the pivotal care became smaller the longer that the pet was efficacy study allows the veterinarian to see the hospitalized (See Table 2). Veterinarians repeated the positive effect of CERENIA on emesis in a group of treatment program each day during hospitalization dogs. While not predictive of how a specific dog may until the dog was discharged. Because of the respond, it allows veterinarians to see the variability decreasing average daily charge, longer hospitalizations that exists for responses to the medication. While may be less profitable for the hospital. many dogs in the pivotal study received an immediate antiemetic benefit, some dogs, especially those Ongoing vomiting in a hospitalized patient often diagnosed with parvovirus or gastroenteritis, continued means that the cage or pet needs to be cleaned to vomit for several days. 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)

5 2 veterinarians indicated that the charge for a day of increased” to “strongly increased.” Veterinarians hospitalization is often the same, regardless of how commented that the increased stress was derived from many times a cage or pet needs to be cleaned.2 a shared concern for the patient’s well-being, and the fact that these patients take more time for care and Reducing emesis early in the treatment program leave fewer personnel available for other routine daily should decrease staff time and reduce the costs duties. 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 When a dog is admitted to the hospital with vomiting lower benefit for the pet owner. and/or , veterinarians use various diagnostic means to determine whether the dog presents an infectious risk to other animals or humans. A diagnosis Based on this discussion, patients, pet owners, of parvovirus or infectious gastroenteritis, for example, veterinarians, and hospital staff all clearly benefit may require partial isolation or quarantine, which when a vomiting dog is returned to health sooner. increases the work load for the hospital staff.14 In the Adding CERENIA to your current course of therapy VOICE survey, approximately 70% of veterinarians can have a positive impact on the outcome for the indicated that they were somewhat concerned or patient. In the VOICE survey, veterinarians were extremely concerned about the spread of infectious asked to rate how the rapid resolution of a dog’s emesis disease between dogs with vomiting and/or diarrhea affects the quality of life of the dog, the dog’s owner, and other animals in the hospital.2 A medication that and the hospital staff (See Table 3). 2 Eighty-four percent shortens the vomiting interval provides veterinarians of veterinarians said rapid resolution of emesis has a with the option of shortening the hospitalized significant beneficial effect on a dog’s quality of life, with period of the affected dog. Discharging the affected a slightly lower benefit for the pet owner. Discussions dog from the hospital sooner can reduce the risk of about the impact on the quality of life for the pet and disease transmission to other pets that are in the the pet owner revolve around the perceived strength hospital for boarding, office visits, or elective surgery. of the human-animal bond. The beneficial impact on Earlier discharge can also reduce hospital staff time the hospital staff’s quality of life was variable but more required to practice heightened hygiene and the use of evenly distributed between moderate and significant. monitoring equipment, cages, and extra supplies (eg, The results may have to do with concern for the disposable overalls and gloves, and cleaning supplies). animal’s welfare as well as managing the increased Reducing the use of supplies is another way for a workload associated with the humane treatment of hospital to improve profitability; studies have reported hospitalized animals. that the actual costs of goods and services have risen about twice as fast as total revenue for small animal and CONCLUSION mixed animal practices.15 CERENIA is an effective and important antiemetic for When asked in the VOICE survey how a hospitalized the prevention and treatment of acute vomiting of dogs. vomiting dog affects their staff, 72% of responding Based on review of the data from the pivotal efficacy 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 350.00 255.00 223.00 208. 00 over Entire Course of Hospitalization ($)

6 study, CERENIA in addition to supportive care greatly receiving supportive care had no additional vomiting reduced the number of days of vomiting for several compared with 84% (n=115/137) of dogs receiving conditions; supportive care alone is not as effective. supportive care plus CERENIA. The difference in proportional cessation of vomiting between treatment CERENIA-treated dogs not only received a groups on Day 0 was statistically significant p( = 0.0001). single injection at the time of hospitalization but also received three to five more days of If we look at the entire population of dogs over the five-day CERENIA therapy, either as injection or tablets study period, we can see the benefit that CERENIA per label instructions, in order to prevent brings to the resolution of vomiting in Diagram 1 recurrence of vomiting. Therefore, up to five (Kaplan-Meier Plot), comparing the cessation in days of CERENIA along with supportive care vomiting between treatment groups. Supportive compared to supportive care alone significantly care, which includes intraveous fluid therapy, is an contributed to these ill dogs’ return to health appropriate way to treat vomiting. The addition of and discharge from the hospital. Cerenia provides an important population benefit associated with cessation of vomiting.

Rapid resolution of vomiting not only positively A cumulative analysis showed that dogs needed three impacts dogs but also their veterinarians, hospital staff, days of supportive care without an antiemetic to and owners. provide the same population benefit realized by the group that had CERENIA added to supportive care APPENDIX: RETROSPECTIVE 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 EVALUATION OF CERENIA vomiting seen on Day 5 was the last bout of vomiting EFFICACY BY CAUSE OF VOMITING for that dog. Veterinarians were not required to (DIAGNOSIS)1 continue vomiting observations beyond day 5. For all causes of vomiting combined, dogs were 50% All Vomiting Causes Combined more likely to stop vomiting if CERENIA was added Data for this analysis were obtained from the pivotal to supportive care for the next three to five days efficacy study10 and included pooled data from 183 dogs (Risk Rate [RR] = 1.5). diagnosed with parvovirus, pancreatitis, gastroenteritis, Clearly, supportive care, which includes IV fluids, is gastritis, and dietary indiscretion. Forty-six dogs appropriate for a debilitating process that dehydrates received supportive care alone and 137 received the animal and causes electrolyte disturbances. The CERENIA plus supportive care (See Table A-1). At the addition of a once daily dose of CERENIA provides a initiation of therapy on Day 0, 57% (n=26/46) of dogs 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)

7 For many veterinarians, once emesis stops, they respectively, of treatment. can switch their patients to oral CERENIA tablets Parvovirus infection is characterized by profuse for continued in-hospital or at-home treatment. emesis and diarrhea, with or without blood.17 Rapid Parvovirus dehydration and electrolyte imbalance are often associated with death, particularly in young dogs. Parvovirus infection is a powerful driver of emesis in In this study, parvovirus infection was a powerful dogs. Forty-eight dogs were diagnosed with vomiting driver of emesis and provided a strong challenge from parvovirus infection and subsequently included to CERENIA efficacy. On a population basis, the in this analysis, with 14 dogs (mean age 25 weeks) addition of CERENIA to supportive care significantly allocated to receive supportive care alone and shortened the period of emesis and fluid loss in dogs. 34 dogs (mean age 27 weeks) allocated to receive Dogs diagnosed with parvovirus were 37% more supportive care plus once daily CERENIA (See likely to stop vomiting if CERENIA was added to Table A-1). Forty-three percent (n = 6/14) of dogs supportive care (Day 0) and continued for the next had no further vomiting after initiating supportive three to five days (RR = 1.37). care. Fifty-nine percent (n=20/34) of vomiting dogs diagnosed with parvovirus had no further vomiting Pancreatitis once initiating supportive care plus CERENIA. The differential population response between these two Twenty-six dogs were diagnosed with vomiting from treatment groups at the start of treatment (Day 0) was pancreatitis and included in this analysis (supportive statistically significant p( = 0.0135). 83% and 97% of care, n = 8; supportive care plus CERENIA, n the dogs receiving CERENIA with supportive care = 18; See Table A-1). While 63% of dogs had no stopped vomiting within the first 48 hours and by Day 4, 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 With 95% Confidence Limits Proportion of Population that Continues Vomiting that Continues of Population Proportion

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 (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 57% 7% 15% 9% 4% 9% Supportive Careb (n=46) (n=26) (n=3) (n=7) (n=4) (n=2) (n=4) CERENIA + Supportive Care 84% 4% 4% 2% 4% 2% (n=137) (n=115) (n=5) (n=6) (n=3) (n=5) (n=3) Parvovirus 43% 7% 14% 21% 14% Supportive Careb (n=14) 0 (n=6) (n=1) (n=2) (n=3) (n=2) CERENIA + Supportive Care 59% 6% 18% 6% 8% 3% (n=34) (n=20) (n=2) (n=6) (n=2) (n=3) (n=1) Pancreatitis 63% 12% 12% 12% Supportive Careb (n=8) 0 0 (n=5) (n=1) (n=1) (n=1) CERENIA + Supportive Care 94% 6% 0 0 0 0 (n=18) (n=17) (n=1) Gastroenteritis 67% 7% 13% 13% Supportive Careb (n=15) 0 0 (n=10) (n=1) (n=2) (n=2) CERENIA + Supportive Care 90% 2% 2% 2% 4% 0 (n=52) (n=47) (n=1) (n=1) (n=1) (n=2) Gastritis 100% Supportive Careb (n=3) 0 0 0 0 0 (n=3) CERENIA + Supportive Care 92% 8% 0 0 0 0 (n=24) (n=22) (n=2)

Dietary Indiscretion of therapy days five to three All dogs received 33% 33% 17% 17% Supportive Careb (n=6) 0 0 (n=2) (n=2) (n=1) (n=1) CERENIA + Supportive Care 100% 0 0 0 0 0 (n=9) (n=9)

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. alone (Day 0), 94% of the group that had CERENIA supportive care. added to supportive care demonstrated no additional vomiting. This difference at the start of therapy was Dogs diagnosed with pancreatitis were 50% more statistically significant p( = 0.0001). The proportion of likely to stop vomiting if CERENIA was added to dogs with pancreatitis receiving supportive care alone supportive care on Day 0 and continued for the next needed four days of treatment (Day 4) to match the three to five days (RR = 1.5). proportional degree of emesis control seen in the group that started therapy (Day 0) with CERENIA and

9 Gastroenteritis care provided a high degree of emesis control as soon as treatment was started (92%) but emesis control with We analyzed 67 dogs diagnosed with vomiting from CERENIA and supportive care was not statistically gastroenteritis (supportive care, n=15; supportive different from emesis control with supportive care alone. care plus CERENIA, n = 52; See Table A-1). Not One conclusion from this data is gastritis is a mild driver surprisingly, the dogs tended to be young adult of emesis, for which an antiemetic may or may not be to middle-aged dogs. Immediately following the needed. initiation of treatment (Day 0), 67% of dogs receiving supportive care demonstrated no additional vomiting. Dietary Indiscretion When CERENIA was added to supportive care, this population response increased to 90%. This response A diagnosis of dietary indiscretion is often made to therapy on Day 0 was significantly different p( = by questioning the pet owner as to the dog’s recent 0.0001) between groups. In the five-day study period, history. Owners observing their dogs chewing on approximately 87% of the dogs receiving supportive foreign objects or getting into the trash, coupled care alone had stopped vomiting. We do not know if with physical examinations of fairly healthy dogs, those dogs that vomited on Day 5 actually stopped often lead to this diagnosis. In this study, the small vomiting that day or may have vomited after the end number of dogs diagnosed with dietary indiscretion precludes statistical analysis but allows the observation of the study. Compare this with the proportion of that CERENIA was effective in arresting additional dogs (90%) that stopped vomiting as soon as initiating vomiting (See Table A-1). CERENIA and supportive care (Day 0). Dogs diagnosed with gastroenteritis were 40% more Important Safety Information likely to stop vomiting at the start of therapy if CERENIA was added to supportive care for the next The safe use of CERENIA has not been evaluated in three to five days (RR = 1.4). dogs used for breeding, pregnant or lactating bitches, dogs with gastrointestinal obstruction, or dogs that Gastritis have ingested toxins. Use with caution in dogs with hepatic dysfunction. CERENIA is recommended for Compared to the number of dogs diagnosed with dogs 16 weeks and older. The most common adverse parvovirus or gastroenteritis, the pivotal efficacy study reactions reported are (5-13%), lethargy only included a few dogs diagnosed with gastritis or (9%) and post-dose emesis not due to motion sickness dietary indiscretion (See Table A-1). For dogs diagnosed (5-9%). For more information, read the full prescribing with gastritis, the addition of CERENIA to supportive 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 57% 64% 79% 88% 92% Supportive Care (n=46) (n=26/46) (n=29/46) (n=36/46) (n=40/46) (n=42/46) 84% 88% 92% 94% 98% CERENIA + Supportive Care (n=137) (n=115/137) (n=120/137) (n=126/137) (n=129/137) (n=134/137)

10 REFERENCES 11. Veterinary Fee Reference. Vital statistics for your veterinary practice. 6th ed. American Animal 1. Data on file. Outcomes Research and Key Brand Hospital Association; 2009. Clinical Support, Pfizer Animal Health, 2009. 12. Cron WL, Slocum JV, Goodnight DB, et al. 2. Pfizer Animal Health Global Market Research, Executive summary of the Brakke management VOICE Survey. Caring for vomiting dogs. April, and behavior study. J Am Vet Med Assoc. 2011. Data on file. 2000;217(3):332-338.

3. GMR Purchased, Dispensed, and Inventory Report 13. Portner J, Johnson J. Guidelines for reducing pathogens in veterinary hospitals: disinfection for US CERENIA for 4Q 2010. selection, cleaning protocols, and hand hygiene. 4. Ramsey DS, Kincaid K, Watkins JA, et al. Safety Compend Contin Educ Vet. 2010;32(5):E1-E12. and efficacy of injectable and oral maropitant, a 14. Brown JP, Silverman JD. The current and future selective neurokinin 1 receptor antagonist, in a market for veterinarians and veterinary medical randomized clinical trial for treatment of vomiting services in the United States. J Am Vet Med Assoc. in dogs. J Vet Pharmacol Therap. 2008;31:538-543. 1999;215(2):161-183. 5. Sedlacek HS, Ramsey DS, Boucher JF, et al. 15. McCaw DL, Hoskins JD. Canine Viral Enteritis. Comparative efficacy of maropitant and selected In: Greene CE, ed. Infectious Diseases of the Dog drugs in preventing emesis induced by centrally and Cat. 3rd ed. St Louis, Missouri: Saunders- or peripherally acting emetogens in dogs. J Vet Elsevier; 2006; Chapter 8:63-73. 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, 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 -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 , 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: Tablets and Injectable Solution Frequency of Adverse Reactions by Treatment Placebo (n=41) CERENIA (n=77) Adverse Reaction Antiemetic # dogs % occur # dogs % occur CERENIA Tablets Diarrhea 1 2.4 6 7.8 For oral use in dogs only 0 0 4 5.2 CERENIA Injectable Injection site reaction (swelling, pain upon injection) 0 0 3 4 For in dogs and cats Lethargy 1 2.4 2 2.6 CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Adverse reactions seen in a European field study included ataxia, lethargy and injection site soreness in one dog treated with CERENIA DESCRIPTION: Injectable Solution.

Maropitant is a neurokinin (NK1) receptor antagonist that blocks the pharmacological action of substance P in the central nervous system The following adverse reactions were reported during the course of a US field study for the prevention and treatment of acute vomiting in dogs (CNS). Maropitant is the non-proprietary designation for a substituted quinuclidine. The empirical formula is C32H40N2O C6H8O7 H2O and 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 the molecular weight 678.81. The chemical name is (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine citrate to 5 consecutive days: 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. Frequency of Adverse Reactions by Treatment

The chemical structure of maropitant citrate is: Placebo (n=69) CERENIA (n=206) Adverse Reaction # 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 Excoriation 0 0 2 1 sickness in dogs. CERENIA (maropitant citrate) Injectable Solution is indicated for the prevention and treatment of acute vomiting in dogs Other clinical signs were reported but were <0.5% of dogs. and for the treatment of vomiting in cats. The following adverse reactions were reported during US studies for the prevention of vomiting due to motion ­sickness in dogs treated with DOSAGE AND ADMINISTRATION: CERENIA Tablets at a minimum of 8 mg/kg orally one time. Dogs may have experienced more than one of the observed adverse reactions. TABLETS (dogs only) 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. Placebo (n=195) CERENIA (n=208) Adverse Reaction Prevention of Acute Vomiting # dogs % occurrence # dogs % occurrence Minimum of 2 mg/kg BW Dosing Hypersalivation 19 9.7 26 12.5 Dog body weight Number of Tablets Vomiting1 0 0 11 5.3 Pounds Kilograms 16 mg 24 mg 60 mg Muscle Tremors 1 0.5 2 1 1 2.2 – 8.8 1.0 – 4 /2 Sedation/Depression 3 1.5 2 1 8.9 – 17.6 4.1 – 8 1 Retching 3 1.5 1 0.5 17.7 – 26.4 8.1 – 12 1 Flatulence 0 0 1 0.5 26.5 – 52.8 12.1 – 24 2 1 Not associated with motion sickness 52.9 – 66 24.1 – 30 1 The following adverse reactions were reported during a European field study for the prevention of vomiting due to motion ­sickness in dogs 66.1 – 132 30.1 – 60 2 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 CERENIA Tablets may be used interchangeably with CERENIA Injectable Solution for once daily dosing for the prevention of acute vomiting. the observed adverse reactions. For Prevention of Vomiting Due to Motion Sickness in dogs 16 weeks and older Frequency of Adverse Reactions by Treatment 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. Placebo (n=106) CERENIA (n=107) Adverse Reaction Prevention of Vomiting Due to Motion Sickness # dogs % occurrence # dogs % occurrence Minimum of 8 mg/kg BW Dosing Vomiting 4 4 10 9 Dog body weight Number of Tablets Drowsiness/Lethargy/Apathy 1 1 8 8 Pounds Kilograms 16 mg 24 mg 60 mg 160 mg Hypersalivation 2 2 5 5 1 2.2 1 /2 Anxiety 0 0 2 2 1 2.3 – 3.3 1.1 – 1.5 /2 Trembling/Tremors 0 0 2 2 3.4 – 4.4 1.6 – 2 1 Inappetence 0 0 2 2 4.5 – 6.6 2.1 – 3 1 Mucus in stool 0 0 1 1 6.7 – 8.8 3.1 – 4 2 8.9 – 13.2 4.1 – 6 2 CATS: 13.3 – 16.5 6.1 – 7.5 1 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 1 CERENIA Injectable Solution subcutaneously once daily for up to five consecutive days: 16.6 – 22 7.6 – 10 /2 22.1 – 33 10.1 – 15 2 Frequency of Adverse Reactions by Treatment 33.1 – 44 15.1 – 20 1 Placebo (n=62) CERENIA (n=133) 1 Adverse Reaction 44.1 – 66 20.1 – 30 1 /2 # cats % occur # cats % occur 66.1 – 88 30.1 – 40 2 Moderate Response to Injection1,2 1 1.6 30 22.6 88.1 – 132 40.1 – 60 3 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 Dehydration 0 0 3 2.3 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 Lethargy 0 0 2 1.5 for up to 5 consecutive days. Use of refrigerated product may reduce the pain response associated with the injection. Anorexia 0 0 1 0.8 For dogs, CERENIA Injectable Solution may be used interchangeably with CERENIA Tablets for once daily dosing for the prevention of acute vomiting. Hematuria 0 0 1 0.8 INFORMATION FOR USE: Hypersalivation 0 0 1 0.8 CERENIA Tablets have been shown to be effective for the prevention of vomiting (see EFFECTIVENESS), however where the frequency of Injection site swelling 1 1.6 0 0 vomiting is high, orally administered CERENIA may not be absorbed before the next vomiting event occurs. Therefore, initiation of therapy 1 with CERENIA Injectable Solution is recommended. If vomiting persists despite treatment, the case should be re-evaluated. CERENIA is most The clinician observed and graded each cat’s response to injection. effective in preventing vomiting associated with chemotherapy if administered prior to the chemotherapeutic agent. 2 Cat objected to the injection by retreating and vocalizing 3 Cat objected to the injection by retreating, hissing, scratching, and vocalization WARNINGS: Not for use in humans. Keep out of reach of children. In case of accidental ingestion, injection or exposure, seek medical advice. Topical Post-Approval Experience exposure may elicit localized allergic skin reactions in some individuals. Repeated or prolonged ­exposure may lead to skin sensitization. In The following adverse events are based on post-approval adverse drug experience reporting. Not all adverse events are reported to FDA CVM. It is case of accidental skin exposure, wash with soap and water. CERENIA is also an ocular irritant. In case of accidental eye exposure, flush with not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. water for 15 minutes and seek medical attention. The following adverse events for CERENIA Tablets are listed in decreasing order of reporting frequency in dogs: depression/lethargy, anorexia, In puppies younger than 11 weeks of age, histological evidence of bone marrow hypocellularity was observed at higher frequency and greater hypersalivation, vomiting, diarrhea, ataxia, and trembling. 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). Cases of ineffectiveness have been reported PRECAUTIONS: The following adverse events for CERENIA Injectable use in dogs are listed in decreasing order of reporting frequency in dogs: Pain/ 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 vocalization upon injection, depression/lethargy, anorexia, /anaphylactoid reactions (including swelling of the head/face), ataxia, of CERENIA has not been evaluated in dogs or cats with gastrointestinal obstruction, or dogs or cats that have ingested toxins. convulsions, and hypersalivation. Use with caution in patients with hepatic dysfunction because CERENIA is metabolized by CYP3A enzymes (see Pharmacokinetics). Use Cases of death (including euthanasia) have been reported. with caution with other medications that are highly protein bound. The concomitant use of CERENIA with other protein bound drugs has not The following adverse events for CERENIA Injectable use in cats, reported since 2007, are listed in decreasing order of reporting frequency in been studied in dogs or cats. Commonly used protein bound drugs include NSAIDs, cardiac, , and behavioral medications. The cats: depression/lethargy, anorexia, injection site pain, and hypersalivation. 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. For a complete listing of adverse reactions for CERENIA Tablets reported to CVM see: http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055369.htm CERENIA causes dose related decreases in 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. 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: In US field studies in veterinary patients, CERENIA Injectable Solution and Tablets were well tolerated in dogs presenting with various clinical CERENIA Tablets conditions including parvovirus, gastroenteritis, and renal disease. There were no notable differences in mean laboratory values between For motion sickness, prolonged fasting before administration should be avoided. Feeding dogs a small amount of food one hour prior to CERENIA-treated and placebo-treated patients. 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 was used safely in dogs receiving other frequently used veterinary products such as fluid and electrolyte CERENIA Injectable Solution replacement solutions, antimicrobial agents, vaccines, antacids, and antiparasitic agents. The pain or vocalization upon injection resolves within minutes without treatment. Administration of CERENIA Injectable Solution at refrigerated Prevention of Vomiting due to Motion Sickness temperature may mitigate this response (see DOSAGE AND ADMINISTRATION). Allergic reactions typically resolve with treatment within 48 hours 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 after discontinuing CERENIA administration. 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 CLINICAL PHARMACOLOGY: 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. Vomiting is a complex process coordinated centrally by the emetic center which consists of several brainstem nuclei (, CATS: nucleus tractus solitarius, dorsal motor nucleus of the vagus) that receive and integrate sensory stimuli from central and peripheral sources In a field study, 195 cats were presented to veterinary hospitals with a history of vomiting associated with various clinical conditions including and chemical stimuli from the circulation and the cerebrospinal fluid. Maropitant is a neurokinin 1 (NK1) receptor antagonist which acts by gastroenteritis, gastritis, pancreatitis, inflammatory bowel disease, neoplasia, and hepatic lipidosis. Cats were treated with CERENIA Injectable inhibiting the binding of substance P, a neuropeptide of the tachykinin family. Substance P is found in significant concentrations in the nuclei 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 1 comprising the emetic center and is considered the key neurotransmitter involved in emesis. By inhibiting the binding of substance P within 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 the emetic center, maropitant provides broad-spectrum effectiveness against neural (central) and humoral (peripheral) causes of vomiting. consecutive days at the discretion of the clinician. Of 165 cats included in the analysis for effectiveness, 2 CERENIA-treated cats (1.8%) In vivo model studies in dogs have shown that maropitant has antiemetic effectiveness against both central and peripheral emetogens vomited 1 time each and 10 placebo-treated cats (18.5%) vomited a total of 15 times in the first 24 hours post treatment. including apomorphine, cisplatin, and syrup of ipecac. Percent of Cats Vomiting for Each Study Day by Treatment 1Diemunsch P, Grelot L. Potential of substance P antagonists as antiemetics. [Review] [60 refs]. Drugs. 2000;60:533-46. Study Day Treatment # cats # vomited % vomited Pharmacokinetics CERENIA is formulated using sulphobutylether-β-cyclodextrin (SBECD), which exhibits enhanced binding to maropitant at refrigerated Placebo 54 10 18.5 Day 0 temperatures. The enhanced binding affinity reverses rapidly upon warming. CERENIA 111 2 1.8 DOGS: The pharmacokinetic characterization associated with maropitant after oral (PO) or subcutaneous (SC) administration in adult Beagle dogs Placebo 20 4 20 is provided in the table below. Day 1 CERENIA 34 1 2.9 Pharmacokinetic Parameters in Beagle Dogs (Mean±SD or range) Placebo 9 2 22.2 SC at 1 mg/kg (n=6) PO at 2 mg/kg (n=8) PO at 8 mg/kg (n=8) Day 2 CERENIA 8 0 0 AUC0-inf (hr*ng/mL) 860±137 561±322 7840±5600

Cmax (ng/mL) 92±34 81±32 776±604 Placebo 5 0 0 Day 3 T1/2 (hr) 8.84 (6.07-17.7) 4.03 (2.48-7.09) 5.46 (3.39-7.65) CERENIA 5 0 0 T (hr) 0.75±1.11 1.9±0.5 1.7±0.7 max Placebo 3 0 0 The absolute of maropitant was much higher following SC injection (91% at 1 mg/kg) than after PO administration (24% at Day 4 CERENIA 1 0 0 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, ANIMAL SAFETY: prandial status does not significantly affect the extent of oral bioavailability. Greater than dose-proportional drug exposure can be expected DOGS: 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 Laboratory and field studies have demonstrated that CERENIA Injectable Solution is well tolerated in dogs after subcutaneous administration. 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 Target Animal Safety Study for Acute Vomiting maropitant involves two cytochrome P-450 isoenzymes: CYP2D15 and CYP3A12. Based on in vitro enzyme kinetics data, it is believed that the Fifty six Beagle dogs (28 males and 28 females) approximately 16 weeks of age were administered CERENIA Injectable Solution non-linear kinetics may be partially associated with saturation of the low capacity enzyme (CYP2D15). However as doses increase (20-50 mg/kg PO), 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 dose proportionality is re-­established. Based upon in vitro enzyme kinetics, involvement of a high capacity enzyme (CYP3A12) may contribute (8 males and 8 females) in all other groups. The primary treatment-related findings were injection site reactions. Swelling, thickened skin, or to this return to dose linearity. of maropitant was high (99.5%). 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 Based on differences in plasma trough concentrations from a single study, the exposure of 10 week old puppies to maropitant may be lower of 16 animals treated with 5 mg/kg/day. Additionally, the activated partial thromboplastin time (APTT) was prolonged (67.5 seconds, reference than that observed in adult dogs, particularly after doses of 1 or 2 mg/kg. 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. CATS: Beagle dogs approximately 8 weeks of age were administered CERENIA Injectable Solution subcutaneously once daily for 15 days at 0, 1, 3, The pharmacokinetic profile of maropitant when administered as a single subcutaneous dose of 1 mg/kg body weight to 8 cats was and 5 mg/kg using a protocol similar to the previous study. A dose dependent increase in frequency and severity of bone marrow hypoplasia characterized by a mean (range) maximum concentration (Cmax) in plasma of approximately 165 (108-332) ng/mL. Cmax was achieved was observed histologically, One placebo-treated dog died on day 14 of the study and was diagnosed with suppurative pancreatitis and 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 esophagitis. Interpretation of the study results is complicated by the health status of study animals. Dogs used in the study were weaned early, 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 minimally acclimated to the test facility, and many of the dogs in the study tested positive for coccidia. 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 Beagle dogs approximately 10 weeks of age were administered either placebo tablets for 2 days, CERENIA Tablets at 8 mg/kg for 2 days, 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 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 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 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 range. Following repeated subcutaneous administration of once-daily doses of 1 mg/kg body weight for 5 consecutive days, accumulation was maropitant injections compared to saline. Males administered CERENIA at 8 mg/kg orally for 2 days had a decrease in food consumption. 250%. Maropitant undergoes (CYP) metabolism in the liver. CYP1A and CYP3A-related enzymes were identified as the feline Body weight and food consumption were variable throughout the 4 week acclimatization period. Two dogs that received 8 mg/kg maropitant isoforms involved in the hepatic biotransformation of maropitant. Renal and fecal clearances are minor routes of elimination for 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 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 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 dose was recovered in urine and 9.3% in feces. Plasma protein binding of maropitant in cats was estimated to be 99.1%. maropitant SC for 5 days; reticulocyte counts were not available for this dog. EFFECTIVENESS: Target Animal Safety Study for Motion Sickness DOGS 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 Prevention and Treatment of Acute Vomiting 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 In laboratory model studies, CERENIA Tablets dosed at a minimum of 2 mg/kg BW reduced the number of emetic events associated with 8 mg/kg group. At 24 mg/kg, CERENIA Tablets caused decreases in food consumption, with decreases in body weight, liver and testis weight; established neural (central) and humoral (peripheral) stimuli. Following administration of apomorphine (central emetic stimuli), vomiting was and an increase in RBC count indicating hemoconcentration, but the effects on feed consumption, body weight, and RBCs did not persist in 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. the post-treatment recovery period (beyond Day 5). Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 33% (4 of 12) of Beagle dogs treated with 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 CERENIA Tablets and in 83% (10 of 12) of Beagle dogs treated with placebo tablets. 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 In laboratory model studies, CERENIA Injectable Solution administered at 1 mg/kg in Beagle dogs reduced the number of emetic events increase in occurrence and severity of bone marrow hypoplasia and lymphoid depletion was observed histologically. Interpretation of these associated with established neural (central) and humoral (peripheral) stimuli. Following administration of apomorphine (central emetic stimuli), study results is complicated by the health status of study animals. Dogs used in the study were weaned early, minimally acclimated to the 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. test facility, and many of the dogs in the study tested positive for coccidia. Additionally, some dogs in the study tested positive for canine Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 25% (3 of 12) of dogs treated with CERENIA parvovirus, however, clinical parvoviral disease was not definitively diagnosed. Injectable Solution and in 100% (12 of 12) of dogs treated with placebo. Tolerance Study In a study of veterinary cancer patients, dogs were treated with CERENIA Injectable Solution or placebo either 1 hour prior to cisplatin Twenty four Beagle dogs (14 males and 10 females) between 11 and 25 weeks of age were administered CERENIA Tablets in 2 phases with (prevention) or after the first vomiting episode following cisplatin (treatment) and monitored for 5 hours. In the groups evaluated for 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, prevention of vomiting, 94.9% (37/39) of the dogs administered CERENIA Injectable Solution and 4.9% (2/41) of the dogs administered 40, or 50 mg/kg once daily for 7 days. CERENIA Tablets administered at 20 and 30 mg/kg caused occasional vomiting. CERENIA Tablets placebo did not vomit. In the groups evaluated for treatment, 21% (8/38) of the dogs administered CERENIA Injectable Solution and 5.1% administered at 40 mg/kg and 50 mg/kg caused clinically relevant signs of weight loss, vomiting, soft stools, weakness, lethargy, salivation (2/39) of the dogs administered placebo had no further episodes of vomiting following treatment. and hypokalemia. Additionally, leukopenia characterized by a neutropenia and a trend toward decreasing plasma phosphorus values was seen. In a study of 275 canine patients presented to veterinary hospitals with a history of acute vomiting, dogs were initially administered CERENIA Decreased heart rate and prolonged corrected QT intervals were seen in all treatment groups in a dose dependent manner. Injectable Solution or placebo on Day 0. Following the initial dose, dogs allocated to the CERENIA group were treated with either CERENIA CATS: 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 Thirty-two domestic short hair cats (16 males and 16 females) approximately 16 weeks of age were administered CERENIA Injectable Solution allocated to the placebo group were treated using either an injectable placebo solution or placebo tablets once daily at the discretion of the 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, clinician. Of the 199 dogs included in the analysis for effectiveness, 27 of 54 dogs (50%) in the placebo group displayed vomiting at some dose dependent findings included pain associated with injection of CERENIA and injection site heat, pain, redness, and firmness. Pain on time during the study and 31 of 145 dogs (21.4%) in the CERENIA-treated group displayed vomiting during the study period. 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 Percent of Vomiting for Each Study Day, Based Upon Treatment and . 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 Days Treatment Route # dogs # vomited % vomited 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. Placebo (54) SC 54 15 28% Day 0 Histopathologic evaluation of injection sites revealed a dose dependent inflammatory response. CERENIA (145) SC 145 (143*) 14 10% 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). PO 22 3 14% Placebo (45) 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). SC 23 16 70% 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 Day 1 PO 67 2 3% vial puncture. Stopper may be punctured a maximum of 25 times. CERENIA (108) SC 41 16 39% 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. PO 7 2 29% 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 Placebo (16) packs containing 4 tablets per perforated sheet. SC 9 6 67% Day 2 CERENIA Injectable Solution is supplied in 20 mL amber glass vials. Each mL contains 10 mg of maropitant as maropitant citrate. PO 24 0 0% Made in France CERENIA (37) SC 13 8 62% NADA #141-262, Approved by FDA NADA #141-263, Approved by FDA PO 2 0 0% Placebo (6) Distributed by: Pfizer Animal Health, Div. of Pfizer Inc, NY, NY 10017 SC 4 1 25% Day 3 Revised: May 2012 PO 14 0 0% CERENIA (21) SC 7 5 71% Distributed by: PO 1 0 0% Placebo (2) Pfizer Animal Health SC 1 1 100% Day 4 Div. of Pfizer Inc PO 5 0 0% CERENIA (7) NY, NY 10017 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. CER0611006 © 2011 Pfizer Inc. All rights reserved. Printed in USA/December 2011

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