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|Drug Name and Strength||Toceranib phosphate 50mg|
|Indication||Treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumours with or without regional lymph node involvement in dogs.|
|Contraindications||Do not use in breeding dogs and pregnant or lactating bitches. Other compounds in the antiangiogenesis class of antineoplastic agents are known to increase embryolethality and fetal abnormalities. As angiogenesis is a critical component of embryonic and foetal development, inhibition of angiogenesis following administration of Palladia should be expected to result in adverse effects on pregnancy in the bitch.|
|Actions||Palladia, a multikinase inhibitor targeting several receptor tyrosine kinases (RTK), is the phosphate salt of toceranib. The empirical formula is C22H25FN4O2H3O4P and the molecular weight is 494.46. The chemical name is (Z)-5-[(5-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1Hpyrrole-3-carboxamide phosphate. Toceranib phosphate is a small molecule with an indolinone chemical structure.Pharmacology Mechanism of action. Toceranib phosphate is a small molecule multikinase inhibitor that has demonstrated direct antitumour and antiangiogenic activity in in vivo and in vitro studies. In nonclinical pharmacology studies, toceranib selectively inhibited the tyrosine kinase activity of several members of the split kinase RTK family, some of which are implicated in tumour growth, pathological angiogenesis, and metastatic progression of cancer. Toceranib inhibited the activity of Flk-1/KDR tyrosine kinase (vascular endothelial growth factor receptor, VEGFR2), platelet derived growth factor receptor (PDGFR), and stem cell factor receptor (Kit) in both biochemical and cellular assays. Toceranib exerts an antiproliferative effect on endothelial cells in vitro . Toceranib treatment can induce cell cycle arrest and subsequent apoptosis in tumour cell lines expressing activating mutations in the split kinase RTK, c-Kit. Canine mast cell tumour growth is frequently driven by activating mutations in c-Kit. Effectiveness. The effectiveness and safety of Palladia oral tablets for the treatment of mast cell tumours was evaluated in a randomised, placebo controlled, double blinded, multicentre clinical field study. The purpose of this study was to evaluate the effectiveness and safety of Palladia in the treatment of mast cell tumours in dogs that had recurrent measurable disease after surgery and to evaluate objective response (complete or partial response). Palladia treatment was compared to placebo treatment using response rates at the end of the 6 week blinded phase. Response rates were determined using the United States National Cancer Institute's Response Evaluation Criteria in Solid Tumours Guideline 3 which was modified specifically for the evaluation of canine mast cell tumours. A total of 153 dogs were randomly assigned to treatment with either Palladia 3.25 mg/kg ( n = 88) or placebo ( n = 65) orally, every other day for six weeks, or until disease progression or withdrawal from the study for another cause.The effectiveness analysis showed a statistically significant advantage for Palladia over placebo in the primary effectiveness endpoint of objective response at the end of the blinded phase. Objective response is defined as the sum of the complete and partial responses. Partial response is ≥ 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum, nonprogression of nontarget lesions and appearance of no new lesions.Treatment was unblinded at the time of disease progression. Dogs receiving placebo were offered crossover to open label Palladia; dogs receiving Palladia who displayed progressive disease in the blinded phase were discontinued from the study. Out of the 151 dogs entered in the blinded phase, 111 continued onto the next, extended phase of the study. For the placebo escape dogs, the reference baseline for response calculations used the tumour assessments obtained just prior to the first dose of Palladia. The primary effectiveness endpoint of the extended phase was the biological response rate. The biological response rate is defined as the sum of the complete and partial responses, and the stable disease response. Complete and partial response definitions are consistent with the blinded phase, and stable disease is defined as no new lesions and absence of criteria for response or progressive disease. The biological response rate for the extended phase of the study was 59.5%.Dogs were required to have Patnaik grade II or III, recurrent, cutaneous mast cell tumours with or without regional lymph node involvement. At least one tumour had to be at least 20 mm in diameter. Dogs had a limit of one completed radiation protocol and a limit of one prior systemic chemotherapy regimen. Dogs with evidence of systemic mast cell tumour were excluded. Treatment with systemic corticosteroids during the study or within 14 days prior to study initiation was not permitted. If needed to manage adverse reactions, dose interruptions (cessation of Palladia for up to two weeks) were prescribed and/or dosage was reduced to as low as 2.2 mg/kg.Tumours of enrolled dogs were evaluated for the presence of a c-Kit internal tandem duplication (ITD). During the combined blinded and open label phases, dogs whose tumours were positive for the c-Kit ITD had a higher objective response rate compared to those negative for the c-Kit ITD.During the study, Palladia was administered concomitantly with other medications such as antimicrobials, H2-receptor blockers, antihistamines, antiemetics, nonsteroidal anti-inflammatory drugs, locally acting antiulcer medications, opiate gastrointestinal motility modifiers, opioids, vaccines, anthelmintics, antiparasitics, and topical or ophthalmic or otic corticosteroid preparations. During the open label phase only, five dogs received a brief course of short acting corticosteroids.The duration of treatment with Palladia ranged from two to 812 days (mean, 144 days; median, 68 days). All dogs received at least one dose of Palladia.|
|Precautions||The safe use of Palladia has not been evaluated in dogs less than 24 months of age or weighing less than 5 kg, therefore more intensive monitoring of dogs in these classes should be undertaken. Stop Palladia immediately and contact a veterinarian if you notice any of the following changes in your dog: refusal to eat; vomiting or watery stools (diarrhoea), especially if more frequent than twice in 24 hours; black tarry stools; bright red blood in vomit or stools; unexplained bruising or bleeding; or if your dog experiences other changes that concern you.There are other side effects which may occur. For a more complete list, ask your veterinarian. General safety precautions. Do not break or crush tablets. Toceranib may cause birth defects. For pregnant women, accidental ingestion of Palladia may have adverse effects on pregnancy. Women of child bearing age are advised to wear gloves when administering this product and should pay special attention to these handling precautions. Pregnant women and lactating mothers should not routinely administer Palladia, and should avoid contact with faeces, urine and vomitus from treated dogs and broken or moistened Palladia tablets. Children should not come into contact with this drug. Keep children away from vomitus, faeces and urine of treated dogs. To avoid exposure to drug, wash hands with soap and water after administering Palladia and wear protective gloves to prevent direct contact with vomitus, faeces and urine of treated dogs and/or when cleaning up broken or moistened tablets. Additional safety information. Palladia, like other drugs in its class, prevents the formation of new blood vessels in tumours. In a similar manner, Palladia may affect blood vessel formation in the developing fetus and may harm an unborn baby.First Aid If eyes are accidentally exposed to the drug, rinse eyes with water immediately. In case of accidental ingestion by a person, seek medical advice immediately, show the package leaflet or label to the doctor. Gastrointestinal discomfort such as vomiting or diarrhoea may occur if this drug is accidentally ingested. If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 131 126. Refer to the material safety data sheet.Disposal Place all waste materials in a plastic bag and seal before general disposal.|
|Dosage and Administration||Administer an initial dosage of 3.25 mg/kg bodyweight orally every second day. Dose reductions of 0.5 mg/kg (to a minimum dose of 2.2 mg/kg every second day) and dose interruptions (cessation of Palladia for up to two weeks) may be used, if needed, to manage adverse reactions. Adjust dose based on approximately weekly veterinary assessments for the first six weeks and approximately every six weeks thereafter. Palladia may be administered with or without food. Tablets must not be split. Do not break or crush tablets. Refer to product leaflet for further advice.Dose guide (tablets). 5 to 5.3 kg bodyweight. 1 x 15 mg (orange). 5.4 to 6.9 kg. 2 x 10 mg (blue). 7.0 to 8.4 kg. 1 x 10 mg (blue) and 1 x 15 mg (orange). 8.5 to 10.0 kg. 2 x 15 mg (orange). 10.1 to 11.5 kg. 2 x 10 mg (blue) and 1 x 15 mg (orange). 11.6 to 13.0 kg. 1 x 10 mg (blue) and 2 x 15 mg (orange). 13.1 to 14.6 kg. 3 x 15 mg (orange). 14.7 to 16.1 kg. 1 x 50 mg (red). 16.2 to 17.6 kg. 1 x 10 mg (blue) and 3 x 15 mg (orange). 17.7 to 19.2 kg. 1 x 10 mg (blue) and 1 x 50 mg (red). 19.3 to 20.7 kg. 1 x 15 mg (orange) and 1 x 50 mg (red). 20.8 to 23.0 kg. 2 x 10 mg (blue) and 1 x 50 mg (red). 23.1 to 26.9 kg. 2 x 15 mg (orange) and 1 x 50 mg (red). 27.0 to 29.9 kg. 3 x 15 mg (orange) and 1 x 50 mg (red). 30.0 to 32.3 kg. 2 x 50 mg (red). 32.4 to 34.6 kg. 1 x 10 mg (blue) and 2 x 50 mg (red). 34.7 to 36.1 kg. 1 x 15 mg (orange) and 2 x 50 mg (red). 36.2 to 38.4 kg. 2 x 10 mg (blue) and 2 x 50 mg (red). 38.5 to 43.0 kg. 2 x 15 mg (orange) and 2 x 50 mg (red). 43.1 to 47.6 kg. 3 x 50 mg (red). 47.7 to 49.9 kg. 1 x 10 mg (blue) and 3 x 50 mg (red). 50.0 to 51.5 kg. 1 x 15 mg (orange) and 3 x 50 mg (red). 51.6 to 53.8 kg. 2 x 10 mg (blue) and 3 x 50 mg (red). 53.9 to 58.4 kg. 2 x 15 mg (orange) and 3 x 50 mg (red). 58.5 to 63.0 kg. 4 x 50 mg (red).|
|Storage||Store below 30°C (room temperature).|
|MSDS (external link)||https://www.zoetis.com.au/documents/e/1907/8921,2012%20MSDS%20Palladia%20Tablets.pdf|
|Label (external link)||http://websvr.infopest.com.au/LabelRouter?LabelType=L&ProductCode=64617|
|Manufacturer||Zoetis Australia Pty Ltd|