Pfizer Animal Health Technical Bulletin December 2011 Value of CERENIA® (maropitant citrate) in the Treatment of Acute Vomiting in Dogs Matthew Krecic, DVM, MS, MBA, 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 kidney failure) pathways. Some serious diseases can stimulate the vomiting reflex through both peripheral pathways. Causes of vomiting include diseases of the gastrointestinal (GI) tract, non-GI tract diseases, exposure to toxins, and motion sickness. • CERENIA (maropitant citrate) is an FDA-approved drug for the prevention of acute vomiting and the prevention of vomiting due to motion sickness in dogs 16 weeks and older. Maropitant is a neurokinin receptor (NK1) antagonist that blocks the binding of the endogenous ligand substance P in the CNS. Substance P is the main CNS neurotransmitter that mediates emesis. Because of its pharmacodynamic action at the central NK1 receptor, CERENIA is broadly effective against vomiting caused by central and peripheral signals. • CERENIA (maropitant citrate) Tablets are indicated for the prevention of acute vomiting and the prevention of vomiting due to motion sickness in dogs. CERENIA Injectable Solution is indicated for the prevention and treatment of acute vomiting in dogs. CERENIA is available as an oral tablet (multiple strengths) and as a solution for subcutaneous (SC) injection. The recommended dosing schedules for CERENIA Tablets are 2 mg/kg body weight once daily for up to five consecutive days for the prevention of acute vomiting, and 8 mg/ kg body weight once daily for up to two consecutive days for prevention of vomiting due to motion sickness. The recommended dosing schedule for CERENIA Injectable Solution is 1 mg/kg body weight once daily subcutaneous for up to five consecutive days for the prevention and treatment of acute vomiting. • A retrospective analysis of the US pivotal efficacy study showed that CERENIA added to supportive care was effective in stopping vomiting in dogs with the specific diagnoses of vomiting due to parvovirus, pancreatitis, and gastroenteritis.1 All brands are the property of Pfizer Inc, its affiliates, and/or its licensors. © 2011 Pfizer Inc. All rights reserved. • The dual routes of administration of CERENIA create an opportunity for the veterinarian to continue antiemetic therapy with an oral option (CERENIA Tablets) and/or to allow the pet owner to treat the pet at home. • The once daily administration of CERENIA may be less stressful for the pet and pet owner compared to other medications that must be dosed multiple times a day. • In a recent Veterinary Online Interactive Community Exchange (VOICE) Pfizer market research survey, 86.5% (n=122/147) of responding veterinarians identified CERENIA as the antiemetic treatment that they were most confident would stop vomiting in dogs.2 • In the same survey, 92% (n=132/143) of responding veterinarians indicated that adding an antiemetic to supportive care shortens recovery time for a vomiting dog, and 99% (n=140/141) of respondents indicated that a medication that shortens the duration of hospitalization and speeds recovery was valuable to their practice.2 • In the same survey, 84% (n=119/141) of responding veterinarians noted that rapid resolution of emesis has a beneficial effect on a dog’s quality of life, and that of the dog owner.2 INTRODUCTION substance P to NK1 receptors. NK1 receptors are 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 canine parvovirus. Common non-GI diseases include center. Alternatively, the peripheral direct pathway hypoadrenocorticism, hyperthyroidism, kidney carries stimuli from diseased abdominal organs right disease (uremia), liver 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, chemotherapies) 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 syrup of ipecac and apomorphine. 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 antiemetics Since 2007, Cerenia has become the most metoclopramide, chlorpromazine, and ondansetron, 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