Zoetis introduces the first approved veterinary for the treatment and prevention of canine emesis.

Dr Liza le Roux • Some stimuli can reach emesis are seen with primary GI disease (BVSc Hons) the emetic center bothdirectly and (stomach to the anus) and includes Veterinary Manager Companion Animal indirectly, for example pancreatitis. gastritis (spoiled food, rubbish, food South/Central Africa intolerance), viral infection (Parvo), Zoetis CERENIA targets NK-1 receptors in foreign body and GI neoplasm. An the emetic center and the CRTZ and example of centrally-induced emesis inhibits the binding of is ketoacidosis. Examples of both erenia (maropitant citrate) peripheral and central stimuli are is a First-in-Class NK-1 Re- Substance P is a key neurotransmitter (CRTZ) and secondary ceptor Antagonist Antiemet- that plays an important part in GI disease which includes pancreatitis, ic for !! Cerenia is the vomiting-it binds to NK-1 receptors! electrolyte imbalance, endogenous first FDA-approved veteri- Vomiting is initiated when Substance P toxins (kidney, , infection) and nary medication indicated for the pre- binds to NK-1 receptors in a “lock-and- exogenous toxin (Lead). vention and treatment of general em- key” effect esis (including emesis induced by In Laboratory studies, Cerenia was chemotherapy) and the prevention of Pharmacodynamic properties proven highly effective in preventing vomiting due to in • Cerenia is a selective antagonist of and treating vomiting induced by: dogs. Cerenia is effective and reliable in Substance P at the NK1 receptor. • CRTZ stimulation (dopamine a broad spectrum of clinical situations • Main effect is to inhibit NK-1 receptors) involving vomiting due to both central receptors at the emetic centre -- and peripheral stimuli, including ves- • Thus effective in treating and • Central and peripheral stimulation tibular stimuli and has a proven safety preventing emesis irrespective (5HT3 receptors) profile. Cerenia is non-sedating and of whether the input is central, -- with once-daily dosing it is easier for peripheral or vestibular. • Peripheral (direct gastric irritant) patients and enhances owner compli- -- ipecac ance. It has a rapid onset of action, Cerenia binds to NK-1 receptors and within 1 hour of SC administration. The prevents the binding of Substance Veterinary patient studies injectable formulation is for clinic use P, thus preventing vomiting. NK-1 Cerenia has been demonstrated to and oral tablets for use both in clinic receptors are found throughout the be superior to human anti-emetics and at home. body, but are in particularly high () in veterinary patient density in the GI tract, and the brain, studies conducted in Europe, both in A quick recap: All vomiting stimuli including the (also reducing the percentage of dogs that converge in the emetic center! known as the chemoreceptor trigger vomit following treatment and the Central and peripheral pathways carry zone), the nucleus tractus solatirus number of vomiting events following vomiting signals to the emetic center (NTS) and the dorsal motor nucleus treatment. either directly, indirectly, or both. of the vagus, all collectively referred to as the emetic centre. They receive Classes of human drugs used in veteri- • The act of vomiting is controlled and integrate sensory stimuli from nary science include: Metoclopramide, and coordinated by the vomiting the abdominal viscera, higher cortical Phenothiazines, , Antihis-

centre in the medulla and cannot areas, and the vestibular system as well tamines, 5HT3 antagonists (Zofran) and occur without an intact vomiting as chemical stimuli from the blood and (Buscopan). centre. cerebrospinal fluid. The NTS is located • Some vomiting stimuli travel within the blood brain barrier and is Metoclopramide is active at both directly to the emetic center, such the main neural input area for emetic dopaminergic (D2) and serotonergic

as those from the higher brain or stimuli. Neurons in the chemoreceptor receptors (5HT3). most gut stimuli. Examples are trigger zone (CRTZ), which lie outside • D2 receptors are predominately anxiety, dietary indiscretion and GI the blood brain barrier, are activated located at the CRTZ, outside the motility problems in response to circulating (humoral) blood brain barrier (peripherally)

• Some vomiting stimuli reach emetogens. • 5HT3 receptors are located both the emetic center indirectly centrally and peripherally. after first being detected by the Therefore, Cerenia is effective in • Metoclopramide is a strong D2

chemoreceptor trigger zone (CRTZ), preventing and treating emesis antagonist but a very weak 5HT3 examples are chemotherapy, irrespective of whether the stimulus is of antagonist (peripheral and central)

motion sickness (vestibular central (neural) or peripheral (humoral) • To completely block 5HT3 receptors apparatus) and renal failure. origin. Examples of peripherally induced very high doses of metoclopramide

10 Volume 3 No 3 Spring/Summer 2013 are required. The efficacy on those canine isoforms involved in the hepatic Cerenia solution for injection should receptors is approx 5-10% of the biotransformation of maropitant. be injected subcutaneously, once daily,

efficacy of another 5HT3 antagonist at a dose of 1 mg/kg body weight (1ml like . CYP3A12 becomes the main per 10 kg bodyweight). metabolizing isoenzyme at high Therefore metoclopramide does not concentrations which may explain the The safety of Cerenia solution for completely inhibit emesis resulting non-linear . The injection has not been established in from peripheral stimulation, and metabolites of maropitant are not dogs less than 8 weeks of age. very high doses may be required to active. do so (with the risk of causing extra- How supplied pyramidal effects) Renal clearance is a minor route of • 20 mL multidose glass vials. elimination, with less than 1% of a1 • Each mL contains 10 mg and treats Unlike , Cerenia is not mg/kg subcutaneous dose appearing 10 kg of body weight a sedative and should not be used as in the urine as either maropitant or a sedative for prevention of vomiting its major metabolite. Renal clearance due to motion sickness or any other of Cerenia was 1.70 mL/kg.hr after a indication. 1 mg/kg dose SID for 5 days and 1.40 mL/kg.h after 8 mg/k SID for 2 days. Pharmacokinetic studies of maropitant The pharmacokinetic profile of in dogs is >99%. maropitant when administered as a single subcutaneous dose of 1 mg/kg Where the frequency of vomiting body weight to dogs was characterised is high, orally-administered Cerenia Oral tablets tablets may not be absorbed before by a maximum concentration (Cmax) in plasma of approximately 92 ng/ml; the next vomiting event occurs and it Indications this was achieved within 0,75 hours may be clinically appropriate to use For use in dogs: Cerenia solution for injection as initial • for the prevention of vomiting post-dosing (Tmax). Peak concentrations were followed by a decline in systemic therapy. including that induced by exposure with an apparent elimination chemotherapy; • for the treatment of vomiting, in half-life (t½) of 8,84 hours. Dosing information: Once- daily dosing in 2 convenient conjunction with Cerenia solution During clinical studies maropitant formulations for injection and in combination plasma levels conferred efficacy from 1 with other supportive measures; hour after administration. • for the prevention of vomiting induced by motion sickness. The of maropitant after subcutaneous administration in dogs The safety of Cerenia tablets has not was 90,7%. The volume of distribution been established in dogs less than 8 at steady–state (Vss) determined after weeks of age. intravenous administration at 1 – 2 mg/kg ranged from approximately For prevention of acute canine 4,4 to 7,0 l/kg. Maropitant displays vomiting: Administer orally at 2 mg/kg linear kinetics when administered once daily for up to 5 consecutive days subcutaneously within the 0,5 – 2 mg/ kg dose range. For prevention of motion sickness: Administer orally at 8 mg/kg once daily Injectable solution (SC) Following repeated subcutaneous for up to 2 consecutive days. For acute canine vomiting—treatment administration of once-daily doses of 1 and prevention. mg/kg body weight for five consecutive Dogs should be fasted 1 hour prior to days, accumulation was 146%. administration and dosed 2 hours prior Cerenia can be used to treat or prevent to travel. Tablets may be given with vomiting either as tablets or as solution Cerenia is primarily metabolized a small amount of food, but do not for injection once daily for up to five by the liver by . wrap tightly in food as this may delay days. Cytochrome P450 isoforms CYP2D15 absorption and alter efficacy. and CYP3A12 were identified as the

Volume 3 No 3 Spring/Summer 2013 11 How supplied Safety studies were conducted References • 16, 24, 60, or 160 mg in blister packs at higher doses and durations: of 4 Scored for accurate dosing. 1. Gardner CJ, Twissell DJ, Dale TJ, et al. • The tablets contain Sunset Yellow In acute emesis (label dose is 1.0 The broad-spectrum antiemetic activity (E110) as a colourant. mg/kg SC and 2 mg/kg tablets) of the novel nonpeptide tachykinin NK1 • The tablets contain lactose. At 3 and 5 times the label dose of receptor antagonist GR203040. Br J Pharmacol. 1995;116:3158-63 CERENIA Injectable Solution for 3 2. Rau S.E., Barber L.G., Burgess K.E. Cerenia has been administered at a times the label duration, mild pain Efficacy of Maropitant in the Prevention dose rate of 2mg/kg to dogs in the fed upon palpation at injection site and of Delayed Vomiting Associated with and fasted state. The bioavailability injection-site lesions were observed in Administration of Doxorubicin to Dogs. J of Cerenia was unaffected. Thus the some dogs. Vet Intern Med 2010;24:1452–1457 presence of food in the stomach or 3. Ramsey D. S. et al. Safety and efficacy upper did not At 1, 3, and 5 times the label dose of of injectable and oral maropitant, affect absorption. CERENIA Tablets for 3 times the label a selective neurokinin1 receptor duration, some dogs showed reduced antagonist, in a randomized clinical trial Concurrent use with other for treatment of vomiting in dogs. J. vet. food consumption and body weight. Pharmacol. Therap. 31, 538–543, doi: medications 10.1111/j.1365-2885.2008.00992.x. In veterinary patient studies Cerenia These changes were not dose 4. Conder G.A. et al. Efficacy and safety has been administered concurrently dependent and did not persist after of maropitant, a selective neurokinin1 with: cessation of treatment. receptor antagonist, in two randomized • antimicrobials (24 products) clinical trials for prevention of vomiting • antiparasiticides (20 products) In motion sickness (label dose 8 due to motion sickness in dogs. J. vet. • anti-inflammatories (14 products) mg/kg tablets) Pharmacol. Therap. 31, 528–532, doi: 10.1111/j.1365-2885.2008.00990.x. • sedatives/anaesthetics (15 At 3 times the label dose of CERENIA 5. Diemunsch P, Grelot L. Potential of products) Tablets for 3 times the label duration, substance P antagonists as . • electrolytes (12 products) decreased food consumption and Drugs 2000;60:533-46. • topical medications (13 products) resultant weight loss were observed. 6. Elwood C, Devauchelle P, Eliott J et al. • vitamins (5 products) JSAP 2010;51:4-22. • neutraceuticals (6 products) The safe use of CERENIA has not been 7. Sedlacek HS et al. J Vet Pharmacol Ther • ACE inhibitors (1 product) evaluated in breeding and pregnant 2008;31:533-537. • other gastrointestinal preparations dogs or lactating bitches, dogs with 8. De la Puente Redondo VA et al. JSAP (19 products) and gastrointestinal obstruction, or dogs 2007;48:93-98. 9. Nausea: European Emesis Council • other miscellaneous (36 products). that have ingested toxins. Knowledge Statement, 2010 p6. Available online at: http://www. In total Cerenia has been administered CERENIA is recommended for use in emesiscouncil.com/emesismanagement in veterinary patient studies with a dogs 8 weeks and older. Use with caution (accessed October 2012). total of 165 different concomitant in dogs with hepatic dysfunction. medications. CERENIA is highly protein The most common adverse reactions bound; its use with other medications noted during clinical studies were that are highly protein bound should , drowsiness/lethargy, be monitored. and .

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12 Volume 3 No 3 Spring/Summer 2013