PALLADIA Tretment Informtion for Dog Owners Prescriing veterinrin s contct informtion: PALLADIA Tretment for Your Dog Wht you should know out PALLADIA PALLADIA is mediction used to tret mst cell tumors, common form of cncer in dogs PALLADIA works y killing tumor cells nd cutting off the lood supply to the tumor PALLADIA tretment cuses the tumor to dispper, shrink, or stop growing in some dogs Plese refer to the ttched Client Informtion Sheet. It explins the side effects ssocited with PALLADIA, s well s how to sfely give PALLADIA to your dog. Your dog s follow-up visit is: When: With: Where: During the visit, the following lortory tests/checks will e performed: q Complete lood count (CBC) q Serum chemistry profile q Urinlysis q emoccult q Weight q q Specil instructions: IMPORTAT SAFETY IFORMATIO: During clinicl studies, the most common dverse events ssocited with PALLADIA included: dirrhe, norexi (including decresed ppetite), lethrgy, neutropeni, emesis, lmeness, weight loss, musculoskeletl disorder, nd lood in stool/gi leed/hemorrhgic dirrhe. PALLADIA my cuse vsculr dysfunction, which cn led to edem nd thromoemolism, including pulmonry thromoemolism. Serious nd sometime ftl GI complictions, including GI perfortion, hve occurred rrely in dogs treted with PALLADIA. If GI ulcertion is suspected stop drug dministrtion nd tret ppropritely. Children should not come in contct with PALLADIA. In ddition, ll individuls, including children nd pregnnt women, should void direct contct with roken or prtilly dissolved PALLADIA tlets or iologicl wste from dogs treted with PALLADIA. To report suspected dverse rection cll Zoetis t 1-888-963-8471. See full Prescriing Informtion, ttched. All trdemrks re the property of Zoetis Services LLC or relted compny or licensor unless otherwise noted. 2017 Zoetis Services LLC. All rights reserved. PAL-00082
(tocerni phosphte) Tlets Antineoplstic For orl use in dogs only Cution: Federl (USA) lw restricts this drug to use y or on the order of licensed veterinrin. Description: PALLADIA, multi-kinse inhiitor trgeting severl receptor tyrosine kinses (RTK), is the phosphte slt of tocerni. The empiricl formul is C 22 25 F 4 O 2 3 O 4 P nd the moleculr weight is 494.46. The chemicl nme is (Z)-5-[(5-Fluoro-2-oxo-1,2-dihydro- 3-indol-3-ylidene)methyl]-2,4-dimethyl--(2-pyrrolidin-1-ylethyl)-1pyrrole-3-croxmide phosphte. Tocerni phosphte is smll molecule with n indolinone chemicl structure. The chemicl structure of tocerni phosphte is F O 3C Indictions: PALLADIA tlets re indicted for the tretment of Ptnik grde II or III, recurrent, cutneous mst cell tumors with or without regionl lymph node involvement in dogs. Dosge nd Administrtion: Alwys provide Client Informtion Sheet with prescription. Administer n initil dosge of 3.25 mg/kg (1.48 mg/l) ody weight, orlly every other dy (see Tle 1). Dose reductions of 0.5 mg/kg (to minimum dose of 2.2 mg/kg (1.0 mg/l) every other dy) nd dose interruptions (cesstion of PALLADIA for up to two weeks) my e utilized, if needed, to mnge dverse rections (see Tle 2 s well s Wrnings nd Precutions). Adjust dose sed on pproximtely weekly veterinry ssessments for the first 6 weeks nd pproximtely every 6 weeks, therefter. PALLADIA my e dministered with or without food. Do not split tlets. Tle 1. 3.25 mg/kg Dose Chrt Dog Body Weight umer of Tlets Pounds Kilogrms Dose 10 mg 15 mg 50 mg 11.0 11.8 5.0-5.3 15 mg 1 11.9 15.2 5.4-6.9 20 mg 2 15.3 18.5 7.0-8.4 25 mg 1 1 18.6 22.0 8.5-10.0 30 mg 2 22.1 25.4 10.1-11.5 35 mg 2 1 25.5 28.7 11.6-13.0 40 mg 1 2 28.8 32.2 13.1-14.6 45 mg 3 32.3 35.5 14.7-16.1 50 mg 1 35.6 38.8 16.2-17.6 55 mg 1 3 38.9 42.3 17.7-19.2 60 mg 1 1 42.4 45.6 19.3-20.7 65 mg 1 1 45.7 50.7 20.8-23.0 70 mg 2 1 50.8 59.3 23.1-26.9 80 mg 2 1 59.4 65.9 27.0-29.9 95 mg 3 1 66.0 71.2 30.0-32.3 100 mg 2 71.3 76.3 32.4-34.6 110 mg 1 2 76.4 79.6 34.7-36.1 115 mg 1 2 79.7 84.7 36.2-38.4 120 mg 2 2 84.8 94.8 38.5-43.0 130 mg 2 2 94.9 105.0 43.1-47.6 150 mg 3 105.1 110.0 47.7-49.9 160 mg 1 3 110.1 113.5 50.0-51.5 165 mg 1 3 113.6 118.6 51.6-53.8 170 mg 2 3 118.7 128.8 53.9-58.4 180 mg 2 3 128.9 138.9 58.5-63.0 200 mg 4 139.0 144.0 63.1-65.3 210 mg 1 4 144.1 157.6 65.4-71.5 215 mg 1 4 157.7 173.1 71.6-78.5 250 mg 5 173.2 177.9 78.6-80.7 260 mg 1 5 178.0 191.6 80.8-86.9 265 mg 1 5 191.7 220.5 87.0-100.0 300 mg 6 O C 3. 3PO 4 Tle 2. Dose Modifiction Bsed on Toxicity Oserved Toxicity Dose Adjustment eutropeni >1000/μL Mintin dose level 1000/μL or neutropenic fever or Stop drug until >1000/μL nd clinicl infection signs norml; then decrese dose y 0.5 mg/kg Renl Toxicities (Cretinine) <2.0 mg/dl Mintin dose level 2.0 mg/dl Stop drug until <2.0 mg/dl then decrese dose y 0.5 mg/kg Alumin <1.5 g/dl Stop drug until >2.5 g/dl then decrese dose y 0.5 mg/kg emtocrit <26% Stop drug until >30% then decrese dose y 0.5 mg/kg Dirrhe <4 wtery stools/dy for less thn 2 dys Mintin dose level nd institute supportive cre 4 wtery stools/dy or 2 dys Stop drug until formed stools nd institute supportive cre. When dosing is resumed, decrese dose y 0.5 mg/kg GI Bleeding Fresh lood in stool or lck trry stool for > 2 dys or frnk hemorrhge or lood clots in stool. Stop drug nd institute supportive cre until resolution of ll clinicl signs of lood in stool, then decrese dose y 0.5 mg/kg. Contrindictions: Do not use in dogs used for reeding, or for pregnnt or lctting itches (see Clinicl Phrmcology). Wrnings: PALLADIA my cuse vsculr dysfunction which cn led to edem nd thromoemolism, including pulmonry thromoemolism. Discontinue drug until clinicl signs nd clinicl pthology hve normlized. To ssure vsculture homeostsis, wit t lest 3 dys fter stopping drug efore performing surgery (see Adverse Rections). Serious nd sometimes ftl gstrointestinl complictions including gstrointestinl perfortion hve occurred rrely in dogs treted with PALLADIA (see Adverse Rections). If gstrointestinl ulcertion is suspected, stop drug dministrtion nd tret ppropritely. umn Wrnings: OT FOR USE I UMAS. KEEP TIS AD ALL MEDICATIOS OUT OF TE REAC OF CILDRE. Children should not come in contct with PALLADIA. Keep children wy from feces, urine, or vomit of treted dogs. To void exposure to drug, wsh hnds with sop nd wter fter dministering PALLADIA nd wer protective gloves to prevent direct contct with feces, urine, vomit, nd roken or moistened PALLADIA tlets. Plce ll wste mterils in plstic g nd sel efore generl disposl. If eyes re ccidentlly exposed to the drug, rinse eyes with wter immeditely. In cse of ccidentl ingestion y person, seek medicl dvice immeditely, show the pckge insert or lel to the physicin. Gstrointestinl discomfort such s vomiting or dirrhe my occur if this drug is ccidentlly ingested. Pregnnt women, women who my ecome pregnnt, or nursing mothers should py specil ttention to these hndling precutions. (See hndling instructions ove.) PALLADIA, like other drugs in its clss, prevents the formtion of new lood vessels in tumors. In similr mnner, PALLADIA my ffect lood vessel formtion in the developing fetus nd my hrm n unorn y (cuse irth defects). For pregnnt women, ccidentl ingestion of PALLADIA my hve dverse effects on pregnncy. Precutions: Temporrily discontinue the use of PALLADIA if nemi, zotemi, hypoluminemi, nd hyperphosphtemi occur simultneously. Resume tretment t dose reduction of 0.5 mg/kg fter 1 to 2 weeks when vlues hve improved nd lumin is >2.5 g/dl. Temporry tretment interruptions my e needed if ny one of these occurs lone: hemtocrit <26%, cretinine 2.0 mg/dl or lumin <1.5 g/dl. Then resume tretment t dose reduction of 0.5 mg/kg once the hemtocrit is >30%, the cretinine is <2.0 mg/dl, nd the lumin is >2.5 g/dl. Temporrily discontinue the use of PALLADIA if neutrophil count is 1000/μL. Resume tretment fter 1 to 2 weeks t dose reduction of 0.5 mg/kg, when neutrophil count hs returned to >1000/μL. Further dose reductions my e needed if severe neutropeni reoccurs.
The presence of systemic mst cell tumor prior to tretment my predispose dog to cliniclly significnt mst cell degrnultion with possile severe systemic dverse rections when treted with PALLADIA. Attempts should e mde to rule out systemic mstocytosis prior to initition of tretment with PALLADIA. PALLADIA hs een ssocited with severe dirrhe or GI leeding tht requires prompt tretment. Dose interruptions nd dose reductions my e needed depending upon the severity of clinicl signs. (See Tle 2 in Dosge nd Administrtion.) Use non-steroidl nti-inflmmtory drugs with cution in conjunction with PALLADIA due to n incresed risk of gstrointestinl ulcertion or perfortion. PALLADIA is metolized in the liver. Co-dministrtion of PALLADIA with strong inhiitors of the CYP3A4 fmily my increse PALLADIA concentrtions. The effect of concomitnt medictions tht my inhiit the metolism of PALLADIA hs not een evluted. Drug comptiility should e monitored in ptients requiring concomitnt medictions. The sfe use of PALLADIA hs not een evluted in dogs less thn 24 months of ge or weighing less thn 5 kg. Adverse Rections: A US clinicl field study comprised of 6-week msked phse, followed y n open-lel phse, evluted the sfety nd effectiveness of PALLADIA in 151 client-owned dogs tht hd Ptnik grde II or III, recurrent, cutneous mst cell tumors with or without regionl lymph node involvement. The most common dverse rections reported during the msked phse re summrized in Tle 3; those reported during the entire study (msked phse comined with the open-lel phse) re summrized in Tle 4. Tle 3. Summry of the most common dverse rections during the msked phse Plceo (n = 64) PALLADIA (n = 87) Adverse Rection Any Grde Grde 3 or 4 Any Grde Grde 3 or 4 Dirrhe 26.6% 3.1% 46.0% 6.9% Anorexi 31.3% 6.3% 39.1% 6.9% Lethrgy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lmeness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 0.0% 14.9% 1.1% Blood in stool/gi leed/ hemorrhgic dirrhe 3.1% 0.0% 12.6% 2.3% Musculoskeletl disorder 6.3% 0.0% 11.5% 1.1% Dehydrtion 4.7% 0.0% 9.2% 2.3% Dermtitis 9.4% 1.6% 9.2% 0.0% Pruritus 4.7% 0.0% 9.2% 0.0% Tchypne 4.7% 0.0% 8.0% 1.1% Loclized pin 4.7% 0.0% 8.0% 0.0% use 3.1% 0.0% 8.0% 1.1% Generl pin 4.7% 1.6% 6.9% 0.0% Polydipsi 7.8% 0.0% 6.9% 0.0% Pyrexi 3.1% 0.0% 5.7% 2.3% Fltulence 3.1% 0.0% 5.7% 0.0% Pigmenttion disorder 1.6% 0.0% 5.7% 0.0% Lortory Anormlity Any Grde c Grde 3 or 4 c Any Grde c Grde 3 or 4 c eutropeni 6.3% 0.0% 46.0% 0.0% Thromocytopeni 20.3% 0.0% 24.1% 0.0% Incresed lnine minotrnsferse 21.9% 4.7% 24.1% 1.1% ypoluminemi 7.8% 0.0% 12.6% 0.0% Decresed hemtocrit 7.8% 0.0% 5.7% 3.4% yperiliruinemi 1.6% 1.6% 5.7% 0.0% Incresed cretinine 4.7% 0.0% 5.7% 0.0% Urinry trct infection 1.6% 0.0% 5.7% 0.0% The men time on study during the msked phse ws 37.0 dys for PALLADIA-treted dogs (medin, 42.0 dys) nd 27.6 dys for plceo-treted dogs (medin, 21.0 dys); no djustments were mde in the sttisticl comprisons for this disprity. Investigtors ssigned severity grde of 1, 2, 3 or 4 (1 - lest severe; 4 - most severe). c Grding of lortory normlities ws sed on the tionl Cncer Institute s Common Toxicity Criteri guideline dpted for cnines (1 - lest severe; 4 - most severe). Tle 4. Summry of the most common dverse rections during the study (msked phse comined with the open-lel phse) PALLADIA (n = 145) Adverse Rections Any Grde Grde 3 or 4 Dirrhe 58.6% 8.3% Anorexi 49.7% 8.3% Vomiting 47.6% 9.7% Lethrgy 39.3% 4.1% Lmeness 22.8% 0.0% Weight loss 21.4% 2.8% Blood in stool/gi leed/ hemorrhgic dirrhe 18.6% 2.8% Dehydrtion 15.2% 2.1% Pruritus 12.4% 0.0% Pigmenttion disorder 11.7% 0.0% Dermtitis 11.0% 0.0% Musculoskeletl disorder 11.0% 0.0% Generl pin 8.3% 0.0% Otitis extern 8.3% 0.0% Tchypne 8.3% 0.0% use 7.6% 1.4% Polydipsi 7.6% 0.0% Pyrexi 6.9% 2.8% Arthritis 6.2% 0.0% Loclized edem 6.2% 0.0% Bcteril skin infection 5.5% 0.0% Conjunctivitis 5.5% 0.0% Lortory Anormlity Any Grde c Grde 3 or 4 c eutropeni 44.8% 1.4% ypoluminemi 28.3% 1.4% Thromocytopeni 28.3% 2.1% Incresed lnine minotrnsferse 27.6% 4.1% Decresed hemtocrit 11.0% 2.8% Incresed cretinine 13.8% 1.4% yperiliruinemi 6.9% 0.0% Urinry trct infection 7.6% 0.0% The durtion of tretment with PALLADIA rnged from 2 to 812 dys (men, 144 dys; medin, 68 dys). All dogs received t lest 1 dose of PALLADIA. Investigtors ssigned severity grde of 1, 2, 3 or 4 (1 lest severe; 4 most severe). c Grding of lortory normlities ws sed on the tionl Cncer Institute s Common Toxicity Criteri guideline dpted for cnines (1 lest severe; 4 most severe). Other dverse events were reported ut occurred in < 5% of dogs. Any individul dog my hve hd multiple dverse events. There were 5 deths during this study tht were possily drug relted. Pthology findings generlly reveled evidence of vsculr dysfunction including pulmonry thromoemolism (post-opertive); multi-orgn filure ssocited with vsculitis nd thromosis; vsculr thromosis with disseminted intrvsculr cogulopthy (DIC) nd pncretitis; nd vsculitis with DIC. One dog died secondry to gstric perfortion; the durtion of tretment with PALLADIA ws 221 dys nd there ws no evidence of mst cell tumor t necropsy. These deths occurred in the presence or sence of gross-disese; tretment durtions rnged from 18 to 221 dys. The reltionship of the following deths to drug re unknown. One dog, first treted for 3 weeks with plceo, died of unknown cuse 7 dys fter initition of PALLADIA therpy. Another dog died of unknown cuse 92 dys fter initition of PALLADIA therpy. o necropsy ws conducted in either dog. Twenty seven dogs developed some form of gstrointestinl leeding with 2.8% of dogs hving severe leeding. One dog developed gstric ulcertion which ws possily drug relted. Three dogs died from gstric (1 dog) or duodenl (2 dogs) perfortions during the study. One dog with duodenl perfortion received only 1 dose of study drug nd, therefore, ws not considered drug relted. Seven dogs developed nsl depigmenttion within the first few weeks of tretment. Eleven dogs developed cot color or skin chnges during the study. Two of these dogs hd complete cot color chnges from fwn to white nd from deep red to londe. Seven dogs experienced lopeci. There is drug relted effect on ody weight: 20.0% of dogs hd >13% weight loss in the msked plus open-lel phse ttriutle to drug. Of these, 5 dogs hd >25% weight loss. Three dogs hd seizure-like ctivity while on study drug. It cn not e determined if these were drug relted. Two dogs developed epistxis tht ws not ssocited with thromocytopeni. Another dog developed epistxis with concurrent disseminted intrvsculr cogulopthy. For copy of the Sfety Dt Sheet (SDS) or to report dverse events cll Zoetis t 1-888-963-8471.
Informtion for Dog Owners: Alwys provide Client Informtion Sheet with prescription nd review with owners. Owners should e dvised on possile dverse rections nd when to stop drug nd cll the veterinrin. Owners should e dvised of the hndling instructions. Clinicl Phrmcology: Mechnism of Action: Tocerni phosphte is smll molecule tht hs oth direct ntitumor nd ntingiogenic ctivity. In non-clinicl phrmcology studies, tocerni selectively inhiited the tyrosine kinse ctivity of severl memers of the split kinse receptor tyrosine kinse (RTK) fmily, some of which re implicted in tumor growth, pthologic ngiogenesis, nd metsttic progression of cncer. Tocerni inhiited the ctivity of Flk-1/KDR tyrosine kinse (vsculr endothelil growth fctor receptor, VEGFR2), pltelet-derived growth fctor receptor (PDGFR), nd stem cell fctor receptor (Kit) in oth iochemicl nd cellulr ssys. Tocerni hs een shown to exert n ntiprolifertive effect on endothelil cells in vitro. Tocerni tretment cn induce cell cycle rrest nd susequent poptosis in tumor cell lines expressing ctivting muttions in the split kinse RTK, c-kit. Cnine mst cell tumor growth is frequently driven y ctivting muttions in c-kit. 1, 2 Other compounds in the ntingiogenesis clss of ntineoplstic gents re known to increse emryolethlity nd fetl normlities. As ngiogenesis is criticl component of emryonic nd fetl development, inhiition of ngiogenesis following dministrtion of PALLADIA should e expected to result in dverse effects on the pregnncy in the itch. Phrmcokinetics Following intrvenous dministrtion, the phrmcokinetics of tocerni is chrcterized y very lrge volume of distriution (>20 L/kg, indicting prtitioning into tissues), terminl elimintion hlf-life of out 16 hrs, nd clernce of >1 L/hr/kg. With regimen of 3.25 mg free se equivlent (fe)/kg doses of tocerni dministered y tlet orlly every other dy for 2 weeks (7 doses), the phrmcokinetic prmeters of tocerni in plsm in helthy Begle dogs (etween 7.2 12.5 kg) re shown in the tle elow. Tle 5. Phrmcokinetic Prmeters Phrmcokinetic Prmeters Totl (n=11; 6M, 5F) Totl (n=10; 5M, 5F) (Men + 1SD) Dose 1 Dose 7 Elimintion hlf-life, t 1/2 (h) 16.4 ± 3.6 17.2 ± 3.9 Time to mximum plsm concentrtion, T mx (h) 5.3 ± 1.6 6.2 ± 2.6 Mximum plsm concentrtion, C mx (ng/ml) 86 ± 22 109 ± 41 C min (ng/ml), 12.7 ± 6.0 18.7 ± 8.3 Are under the plsm concentrtion time-curve, AUC 0-48 (ng h/ml) 1833 ± 508 2635 ± 939 Dose-normlized vlue (djusted to 3.25 mg/kg dose) C min is the concentrtion t 48 h post-dose, which corresponds to the dose intervl. Orl iovilility of tocerni is 77%. PALLADIA is highly protein ound t 91% to 93%. It should e noted tht despite the homogeneity of sujects included in this study, lrge etween-suject vriility ws oserved. Regrdless of the route of dministrtion, liner phrmcokinetics hs een oserved t doses up to 5 mg/kg twice dily. Using n in vitro heptocyte nd liver microsome test system, the Z isomer ws found to e metolized to the -oxide derivtive of tocerni in dogs, humns, cts, nd rts. Although smll gender difference ws oserved in the in vitro study (81% conversion in mle dogs, 56% conversion in femle dogs) no differences in tocerni phrmcokinetics ws oserved in vivo. The effects of renl impirment, heptic impirment or reed on the phrmcokinetics of tocerni hve not een investigted. Effectiveness: The effectiveness nd sfety of PALLADIA orl tlets for the tretment of mst cell tumors ws evluted in rndomized, plceo-controlled, doule-msked, multicenter clinicl field study. The purpose of this study ws to evlute the effectiveness nd sfety of PALLADIA in the tretment of mst cell tumors in dogs tht hd recurrent mesurle disese fter surgery nd to evlute ojective response (complete or prtil response). PALLADIA tretment ws compred to plceo tretment using response rtes t the end of the 6-week msked phse. Response rtes were determined using the tionl Cncer Institute s Response Evlution Criteri in Solid Tumors Guideline 3 which ws modified specificlly for the evlution of cnine mst cell tumors. One-hundred-fifty-three dogs were rndomly ssigned to tretment with either 3.25 mg/kg PALLADIA (n = 88) or plceo (n = 65) orlly, every other dy for 6 weeks, or until disese progression or withdrwl from the study for nother cuse. Tretment ws unmsked t the time of disese progression: dogs receiving plceo were then offered crossover to open-lel PALLADIA; dogs receiving PALLADIA were discontinued from the study. Dogs were required to hve Ptnik grde II or III, recurrent, cutneous mst cell tumors with or without regionl lymph node involvement. At lest 1 tumor hd to e t lest 20 mm in dimeter. Dogs hd limit of 1 completed rdition protocol nd limit of 1 prior systemic chemotherpy regimen. Dogs with evidence of systemic mst cell tumor were excluded. Tretment with systemic corticosteroids during the study or within 14 dys prior to study initition ws not permitted. If needed to mnge dverse rections, dose interruptions (cesstion of PALLADIA for up to 2 weeks) were prescried nd/or dosge ws reduced to s low s 2.2 mg/kg. The effectiveness nlysis showed sttisticlly significnt dvntge for PALLADIA over plceo in the primry effectiveness endpoint of ojective response t the end of the six week msked phse. Ojective response is complete response + prtil response. Prtil response is 30% decrese in the sum of the longest dimeter of trget lesions, tking s reference the seline sum, non-progression of non-trget lesions nd ppernce of no new lesions. Mst Cell Tumor Primry Effectiveness Endpoint Results Effectiveness Prmeter Plceo (n = 63) PALLADIA (n = 86) P-vlue Ojective Response Rte * 7.9% 37.2% < 0.001 * The difference in ojective response rte etween groups ws not significntly ssocited with tumor urden (presence vs. sence of regionl lymph node involvement) or tumor grde (P > 0.05). During the study, PALLADIA ws dministered concomitntly with other medictions such s ntimicroils, -2 receptor lockers, ntihistmines, nti-emetics, non-steroidl ntiinflmmtory drugs, loclly-cting nti-ulcer medictions, opite gstrointestinl motility modifiers, opioids, vccines, nthelmintics, ntiprsitics, nd topicl/ophthlmic/otic corticosteroid preprtions. During the open-lel phse only, 5 dogs received rief course of short-cting corticosteroids. Animl Sfety: In the trget niml sfety study presented elow, PALLADIA ws demonstrted to hve nrrow mrgin of sfety; dogs eing treted with PALLADIA should e monitored for dverse rections which my indicte dose djustment is required. Two dogs in the 6 mg/kg group were euthnized for clinicl toxicities on Dys 23 nd 27 of the study, respectively. Tocerni ws dministered orlly to 20 mle nd 20 femle dult Begle dogs (pproximtely 2 yers of ge) t doses of 0 mg/kg (plceo, 12 dogs), 2 mg/kg (0.5X, 8 dogs), 4 mg/kg (1X, 12 dogs), or 6 mg/kg (1.5X, 8 dogs) once every other dy for 13 consecutive weeks without dose interruption. Tocerni cused weight loss, decresed feed consumption, pncretic, gondl, drenl, muscle, nd hemtopoietic chnges. Feed consumption ws decresed in the 6 mg/kg group compred to plceo, with the lrgest difference in mens occurring t Dy 35. Decrese in ody weights in the 4 mg/kg group were seen t Dy 31 nd in the 6 mg/kg group t Dy 15 compred with plceo nd continued through the study. Dose relted lmeness, oserved lmost exclusively in the hind lims, nd lim pin ws greter in ll tretment groups s compred to plceo, with the 6 mg/kg group demonstrting the highest incidence. Stiffness nd wekness were noted to occur lmost exclusively in the 6 mg/kg group. Redness of orl mucos ws oserved in ll tretment groups. One dog in the 4 mg/kg group hd orl ulcertions nd one dog in the 6 mg/kg group hd skin ulcertions, oth with cteril infections present. Dirrhe or soft stool were seen in ll four groups. emtology nlyses showed decreses in hemtocrit, hemogloin, nd erythrocyte count nd decrese in reticulocyte count in the 4 nd 6 mg/kg groups tht tended to recover sufficiently to limit further erythrocyte count decreses. White lood cell counts were significntly lower cross the study in ll treted groups compred to plceo, primrily due to decrese in neutrophils. Lymphocytes decresed to lesser degree, especilly t the low dose. Eosinophils nd sophils showed mrked, persistent decreses. Monocytes were not ffected. Pltelet counts incresed slightly in 4 nd 6 mg/kg groups. Increses were oserved in firinogen in the 4 nd 6 mg/kg group. Increses were oserved in sprtte minotrnsferse, cretine kinse, nd serum phosphorus concentrtions in the 4 nd 6 mg/kg groups. Increses in lkline phosphtse were seen in the 6 mg/kg group. An increse in mylse ws seen in one dog in ech of the tretment groups. An increse in serum potssium ws seen in one dog in the 6 mg/kg group. Increses in lctte dehydrogense nd gloulins were oserved in the 6 mg/kg group. Tretment-relted microscopic chnges included slight to mrked reduction in cellulrity of sternl nd femorl one mrrow. There ws corresponding mild extrmedullry hemtopoiesis, minly erythropoiesis, in the spleen. In the pncres, dose-relted slight to moderte cinr degrnultion, chrcterized y diffuse loss of zymogen grnules, occurred. In the drenl glnds, miniml corticl congestion/hemorrhge occurred t ll doses, with suggestive dose-reltionship. Adrenl corticl vcuoltion ws noted with low frequency in ll groups. Dose relted chnges were noted in reproductive orgns of oth sexes. Mles showed dose-relted germ cell depletion, tuulr vcuoltion, nd reductions in numers of mture spermtozo. In femles, ovries showed reduced incidence of mture/regressing corpor lute nd n incresed incidence of smll follicles. Two dogs (one mle, one femle) in the 6 mg/kg group were euthnized for tretmentrelted clinicl toxicities on Dys 23 nd 27 of the study, respectively. Onset of the terminl syndrome ws seen s mrkedly reduced feed intke nd melen. Over the following 9 dys, the decresed feed intke progressed to ner-complete norexi nd hemtochezi ppered. Weight loss, lethrgy, hindlim lmeness nd wekness were oserved. The following clinicl pthology results re consistent with chnges seen in the other dogs in the 6 mg/kg group s well s chnges due to the dogs deilitted conditions just prior to euthnsi. Both dogs hd increses in totl protein, gloulins, phosphorus, cholesterol, triglycerides nd firinogen. One dog hd pncytopeni, decresed hemtocrit, hemogloin, reticulocytes, lumin, nd PT nd incresed nds. emturi ws lso present. The other dog lso hd decresed lymphocytes, eosinophils, chloride, nd sodium nd increses in RBC, hemtocrit, hemogloin, pltelets, ALP, mylse, cretinine, BU, mgnesium, potssium, nd totl iliruin. Clotting profile showed decresed PT nd incresed in PTT in oth dogs. These dogs showed lymphoid depletion in lymph nodes, thymus, nd gut-ssocited lymphtic tissues nd mild to mrked gstrointestinl lesions in ddition to the microscopic findings descried in nimls surviving to the end of the study. These two dogs lso hd lesions in the gstrointestinl trct, kidneys, pncres, pituitry glnd nd drenl glnds. Storge Conditions: Store t controlled room temperture 20 to 25 C (68 to 77 F). ow Supplied: PALLADIA tlets contin 10 mg, 15 mg, or 50 mg of tocerni s tocerni phosphte per tlet. The tlets re pckged in 30 count ottles.
References: u London CA, nnh AL, Zdovosky R, et l. Phse I Dose-Esclting Study of SU11654, Smll Molecule Receptor Tyrosine Kinse Inhiitor, in Dogs with Spontneous Mlignncies. Clinicl Cncer Reserch 9(7):2755-2768; 2003 v Pryer K, Lee LB, Zdovosky R, et l. Proof of Trget for SU11654: Inhiition of KIT phosphoryltion in Cnine Mst Cell Tumors. Clinicl Cncer Reserch 9(15): 5729-5734; 2003 w http://ctep.cncer.gov/protocoldevelopment/ ADA #141-295, Approved y FDA Revised: August 2015 Mnufctured y: Pfizer Inc, Ascoli, Itly Distriuted y: Zoetis Inc., Klmzoo, MI 49007 Client Informtion Sheet (tocerni phosphte) Tlets This summry contins importnt informtion out PALLADIA. You should red this informtion efore you strt giving your dog PALLADIA nd review it ech time the prescription is refilled s there my e new informtion. This sheet is provided only s summry nd does not tke the plce of instructions from your veterinrin. Tlk with your veterinrin if you do not understnd ny of this informtion or if you wnt to know more out PALLADIA. Wht is PALLADIA? PALLADIA, tyrosine kinse inhiitor, is drug used to tret mst cell tumors, common form of cncer tht ffects dogs. PALLADIA works in two wys: By killing tumor cells. By cutting off the lood supply to the tumor. Your veterinrin hs decided to include PALLADIA s prt of your dog s tretment pln for mst cell tumor. Other types of tretment, such s surgery, drug tretment nd/or rdition my e included in the pln. Be sure to spek with your veterinrin out ll prts of your dog s tretment pln. Wht do I need to tell my veterinrin out my dog efore dministering PALLADIA? Tell your veterinrin out ll other medictions your pet is tking, including: prescription drugs; over the counter drugs; hertworm, fle & tick medictions; vitmins nd supplements, including herl medictions. Tell your veterinrin if your dog is pregnnt, nursing puppies, or is intended for reeding purposes. ow do I give PALLADIA to my dog? PALLADIA should e given to your dog y mouth (orlly). PALLADIA my e hidden inside tret; e certin your dog swllows the entire tlet(s). Follow your veterinrin s instructions for how much nd how often to give PALLADIA. See the ndling Instructions section elow in order to dminister PALLADIA sfely to your dog. ow will PALLADIA ffect my dog? PALLADIA my help shrink your dog s tumor. Like other cncer tretments, it cn e difficult to predict whether your dog s tumor will respond to PALLADIA, nd if it does respond, how long it will remin responsive to PALLADIA. Regulr check ups y your veterinrin re necessry to determine whether your dog is responding s expected, nd to decide whether your dog should continue to receive PALLADIA. Wht re some possile side effects of PALLADIA? Like ll drugs, PALLADIA my cuse side effects, even t the prescried dose. Serious side effects cn occur, with or without wrning, nd my in some situtions result in deth. The most common side effects which my occur with PALLADIA include dirrhe, decresed/loss of ppetite, lmeness, weight loss nd lood in the stool. Stop PALLADIA immeditely nd contct your veterinrin if you notice ny of the following chnges in your dog: Refusl to et Vomiting or wtery stools (dirrhe), especilly if more frequent thn twice in 24 hours Blck trry stools Bright red lood in vomit or stools Unexplined ruising or leeding Or if your dog experiences other chnges tht concern you There re other side effects which my occur. For more complete list, sk your veterinrin. ndling Instructions Wht do I need to know to hndle PALLADIA sfely? Becuse PALLADIA is n nti-cncer drug, extr cre must e tken when hndling the tlets, giving the drug to your dog, nd clening up fter your dog. PALLADIA is not for use in humns. You should keep PALLADIA in secure storge re out of the rech of children. Children should not come in contct with PALLADIA. Keep children wy from feces, urine, or vomit of treted dogs. If you re pregnnt, nursing mother, or my ecome pregnnt nd you choose to dminister PALLADIA to your dog, you should e prticulrly creful nd follow the hndling procedures descried elow. PALLADIA prevents the formtion of new lood vessels in tumors. In similr mnner, PALLADIA my ffect lood vessel formtion in the developing fetus nd my hrm n unorn y (cuse irth defects). For pregnnt women, ccidentl ingestion of PALLADIA my hve dverse effects on pregnncy. If PALLADIA is ccidentlly ingested y you or fmily memer, seek medicl dvice immeditely. It is importnt to show the treting physicin copy of the pckge insert or lel. In cses of ccidentl humn ingestion of PALLADIA, you my experience gstrointestinl discomfort, including vomiting or dirrhe. The following hndling procedures will help to minimize exposure to the ctive ingredient in PALLADIA for you nd other memers of your household: Anyone who dministers PALLADIA to your dog should wsh their hnds fter hndling tlets. When you or others re hndling the tlets: Do not split or rek the tlets to void disrupting the protective film coting. PALLADIA tlets should e dministered to your dog immeditely fter they re removed from the ottle. Protective gloves should e worn if hndling roken or moistened tlets. If your dog spits out the PALLADIA tlet, the tlet will e moistened nd should e hndled with protective gloves. If the PALLADIA tlet is hidden in food, mke sure tht your dog hs eten the entire dose. This will minimize the potentil for exposure to children or other household memers to PALLADIA. Clening up fter your dog: Becuse PALLADIA is present in the stool, urine nd vomit of dogs under tretment, you must wer protective gloves to clen up fter your treted dog. While your dog receives PALLADIA, plce the stool, feces or vomit, nd ny disposle towels used to clen up in plstic g which should e seled for generl household disposl. This will minimize the potentil for exposure to people in contct with the trsh. You should not wsh ny items soiled with stool, urine or vomit from your dog with other lundry. This client informtion sheet gives the most importnt informtion out PALLADIA. For more informtion out PALLADIA, tlk with your veterinrin. To report suspected dverse rection cll Zoetis t 1-888-963-8471. Mnufctured y: Pfizer Inc, Ascoli, Itly Distriuted y: Zoetis Inc., Klmzoo, MI 49007 Revised: August 2015 4304302.03A&P