toceranib

For the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs.

For oral use in dogs only. Do not use in dogs used for breeding, or for pregnant or lactating bitches. Do not split tablets. Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Palladia®

PALLADIA tablets are indicated for the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs.

Palladia® 10 mg 15 mg 50 mg (toceranib phosphate) Tablets

Do not use in dogs used for breeding, or for pregnant or lactating bitches (see Clinical Pharmacology).

Palladia® 10 mg 15 mg 50 mg (toceranib phosphate) Tablets

PALLADIA may cause vascular dysfunction which can lead to edema and thromboembolism, including pulmonary thromboembolism. Discontinue drug until clinical signs and clinical pathology have normalized. To assure vasculature homeostasis, wait at least 3 days after stopping drug before performing surgery (see Adverse Reactions ). Serious and sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred rarely in dogs treated with PALLADIA (see Adverse Reactions ). If gastrointestinal ulceration is suspected, stop drug administration and treat appropriately.

Palladia® 10 mg 15 mg 50 mg (toceranib phosphate) Tablets

A US clinical field study comprised of a 6-week masked phase, followed by an open-label phase, evaluated the safety and effectiveness of PALLADIA in 151 client-owned dogs that had Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement. The most common adverse reactions reported during the masked phase are summarized in Table 3; those reported during the entire study (masked phase combined with the open-label phase) are summarized in Table 4. Table 3. Summary of the most common adverse reactions during the masked phaseThe mean time on study during the masked phase was 37.0 days for PALLADIA-treated dogs (median, 42.0 days) and 27.6 days for placebo-treated dogs (median, 21.0 days); no adjustments were made in the statistical comparisons for this disparity. Placebo (n = 64) PALLADIA (n = 87) Adverse Reaction Any GradeInvestigators assigned severity grade of 1, 2, 3 or 4 (1 - least severe; 4 - most severe). Grade 3 or 4 Any Grade Grade 3 or 4 Diarrhea 26.6% 3.1% 46.0% 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 0.0% 14.9% 1.1% Blood in stool/GI bleed/hemorrhagic diarrhea 3.1% 0.0% 12.6% 2.3% Musculoskeletal disorder 6.3% 0.0% 11.5% 1.1% Dehydration 4.7% 0.0% 9.2% 2.3% Dermatitis 9.4% 1.6% 9.2% 0.0% Pruritus 4.7% 0.0% 9.2% 0.0% Tachypnea 4.7% 0.0% 8.0% 1.1% Localized pain 4.7% 0.0% 8.0% 0.0% Nausea 3.1% 0.0% 8.0% 1.1% General pain 4.7% 1.6% 6.9% 0.0% Polydipsia 7.8% 0.0% 6.9% 0.0% Pyrexia 3.1% 0.0% 5.7% 2.3% Flatulence 3.1% 0.0% 5.7% 0.0% Pigmentation disorder 1.6% 0.0% 5.7% 0.0% Laboratory Abnormality Any GradeGrading of laboratory abnormalities was based on the National Cancer Institute's Common Toxicity Criteria guideline adapted for canines (1 - least severe; 4 - most severe). Grade 3 or 4 Any Grade Grade 3 or 4 Neutropenia 6.3% 0.0% 46.0% 0.0% Thrombocytopenia 20.3% 0.0% 24.1% 0.0% Increased alanine aminotransferase 21.9% 4.7% 24.1% 1.1% Hypoalbuminemia 7.8% 0.0% 12.6% 0.0% Decreased hematocrit 7.8% 0.0% 5.7% 3.4% Hyperbilirubinemia 1.6% 1.6% 5.7% 0.0% Increased creatinine 4.7% 0.0% 5.7% 0.0% Urinary tract infection 1.6% 0.0% 5.7% 0.0% Table 4. Summary of the most common adverse reactions during the study (masked phase combined with the open-label phase)The duration of treatment with PALLADIA ranged from 2 to 812 days (mean, 144 days; median, 68 days). All dogs received at least 1 dose of PALLADIA. PALLADIA (n = 145) Other adverse events were reported but occurred in < 5% of dogs. Any individual dog may have had multiple adverse events. Adverse Reactions Any GradeInvestigators assigned severity grade of 1, 2, 3 or 4 (1 – least severe; 4 – most severe). Grade 3 or 4 Diarrhea 58.6% 8.3% Anorexia 49.7% 8.3% Vomiting 47.6% 9.7% Lethargy 39.3% 4.1% Lameness 22.8% 0.0% Weight loss 21.4% 2.8% Blood in stool/GI bleed/hemorrhagic diarrhea 18.6% 2.8% Dehydration 15.2% 2.1% Pruritus 12.4% 0.0% Pigmentation disorder 11.7% 0.0% Dermatitis 11.0% 0.0% Musculoskeletal disorder 11.0% 0.0% General pain 8.3% 0.0% Otitis externa 8.3% 0.0% Tachypnea 8.3% 0.0% Nausea 7.6% 1.4% Polydipsia 7.6% 0.0% Pyrexia 6.9% 2.8% Arthritis 6.2% 0.0% Localized edema 6.2% 0.0% Bacterial skin infection 5.5% 0.0% Conjunctivitis 5.5% 0.0% Laboratory Abnormality Any GradeGrading of laboratory abnormalities was based on the National Cancer Institute's Common Toxicity Criteria guideline adapted for canines (1 – least severe; 4 – most severe). Grade 3 or 4 Neutropenia 44.8% 1.4% Hypoalbuminemia 28.3% 1.4% Thrombocytopenia 28.3% 2.1% Increased alanine aminotransferase 27.6% 4.1% Decreased hematocrit 11.0% 2.8% Increased creatinine 13.8% 1.4% Hyperbilirubinemia 6.9% 0.0% Urinary tract infection 7.6% 0.0% There were 5 deaths during this study that were possibly drug related. Pathology findings generally revealed evidence of vascular dysfunction including pulmonary thromboembolism (post-operative); multi-organ failure associated with vasculitis and thrombosis; vascular thrombosis with disseminated intravascular coagulopathy (DIC) and pancreatitis; and vasculitis with DIC. One dog died secondary to gastric perforation; the duration of treatment with PALLADIA was 221 days and there was no evidence of mast cell tumor at necropsy. These deaths occurred in the presence or absence of gross-disease; treatment durations ranged from 18 to 221 days. The relationship of the following deaths to drug are unknown. One dog, first treated for 3 weeks with a placebo, died of unknown cause 7 days after initiation of PALLADIA therapy. Another dog died of unknown cause 92 days after initiation of PALLADIA therapy. No necropsy was conducted in either dog. Twenty seven dogs developed some form of gastrointestinal bleeding with 2.8% of dogs having severe bleeding. One dog developed gastric ulceration which was possibly drug related. Three dogs died from gastric (1 dog) or duodenal (2 dogs) perforations during the study. One dog with a duodenal perforation received only 1 dose of study drug and, therefore, was not considered drug related. Seven dogs developed nasal depigmentation within the first few weeks of treatment. Eleven dogs developed coat color or skin changes during the study. Two of these dogs had complete coat color changes from fawn to white and from deep red to blonde. Seven dogs experienced alopecia. There is a drug related effect on body weight: 20.0% of dogs had >13% weight loss in the masked plus open-label phase attributable to drug. Of these, 5 dogs had >25% weight loss. Three dogs had seizure-like activity while on study drug. It can not be determined if these were drug related. Two dogs developed epistaxis that was not associated with thrombocytopenia. Another dog developed epistaxis with concurrent disseminated intravascular coagulopathy. For a copy of the Material Safety Data Sheet (MSDS) or to report adverse events call Zoetis at 1-888-963-8471.

Palladia® 10 mg 15 mg 50 mg (toceranib phosphate) Tablets

Administer an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day.

Oral

For oral use in dogs only. Do not use in dogs used for breeding, or for pregnant or lactating bitches. Do not split tablets. Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Palladia®

Always provide Client Information Sheet with prescription. Administer an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day (see Table 1). Dose reductions of 0.5 mg/kg (to a minimum dose of 2.2 mg/kg (1.0 mg/lb) every other day) and dose interruptions (cessation of PALLADIA for up to two weeks) may be utilized, if needed, to manage adverse reactions (see Table 2 as well as Warnings and Precautions ). Adjust dose based on approximately weekly veterinary assessments for the first 6 weeks and approximately every 6 weeks, thereafter. PALLADIA may be administered with or without food. Do not split tablets. Table 1. 3.25 mg/kg Dose Chart Dog Body Weight Number of Tablets Pounds Kilograms 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 Table 2. Dose Modification Based on Toxicity Observed Toxicity Dose Adjustment Neutropenia >1000/µL Maintain dose level ≤1000/µL or neutropenic fever or infection Stop drug until >1000/µL and clinical signs normal; then decrease dose by 0.5 mg/kg Renal Toxicities (Creatinine) <2.0 mg/dL Maintain dose level ≥2.0 mg/dL Stop drug until <2.0 mg/dL then decrease dose by 0.5 mg/kg Albumin <1.5 g/dL Stop drug until >2.5 g/dL then decrease dose by 0.5 mg/kg Hematocrit <26% Stop drug until >30% then decrease dose by 0.5 mg/kg Diarrhea <4 watery stools/day for less than 2 days Maintain dose level and institute supportive care ≥4 watery stools/day or ≥ 2 days Stop drug until formed stools and institute supportive care. When dosing is resumed, decrease dose by 0.5 mg/kg GI Bleeding Fresh blood in stool or black tarry stool for > 2 days or frank hemorrhage or blood clots in stool. Stop drug and institute supportive care until resolution of all clinical signs of blood in stool, then decrease dose by 0.5 mg/kg.

ORAL

Palladia® 10 mg 15 mg 50 mg (toceranib phosphate) Tablets