Do not use in pregnant or lactating bitches or in dogs intended for breeding.
Do not use in cases of hypersensitivity to the active substance or to any of the excipients.
Do not use in dogs less than 2 years of age or less than 3 kg bodyweight.
Do not use in dogs with gastrointestinal bleeding.
For any mast cell tumour treatable by surgery, surgery should be the first choice of treatment.
Dogs should be carefully monitored. Dose reductions and/or dose interruptions may be needed to manage adverse events. Treatment should be reviewed weekly for the first six weeks and every six weeks thereafter or at intervals deemed appropriate by the veterinarian. Evaluations should include assessment of clinical signs reported by the pet owner.
To appropriately use the dose adjustment table it is advised that a complete blood cell count, serum chemistry panel and urinalysis be conducted prior to initiation of treatment and approximately one month after treatment is initiated; thereafter at approximately six week intervals or as determined by the veterinarian. Periodic monitoring of laboratory variables should be completed in the context of the clinical signs and condition of the animal and results of laboratory variables at prior visits.
The safety of Palladia was evaluated in mast cell tumour-bearing dogs with the following:
•Absolute neutrophil count > 1500/microlitre
•Hematocrit > 25%
•Platelet count > 75,000/microlitre
•ALT or AST < 3 X upper normal limit
•Bilirubin < 1.25 X upper normal limit
•Creatinine < 2.5 mg/dl
•Blood urea nitrogen < 1.5 X upper normal limit
Palladia can cause vascular dysfunction which can lead to oedema and thromboembolism, including pulmonary thromboembolism. Discontinue treatment until clinical signs and clinical pathology have normalised. Before performing surgery, discontinue treatment for at least 3 days in order to assure vasculature homeostasis.
If systemic mastocytosis is present, standard pre-emptive care (e.g., H-1 and H-2 blockers) should be implemented prior to initiation of Palladia to avoid or minimize clinically significant mast cell degranulation and subsequent potentially severe systemic side effects.
Palladia has been associated with diarrhoea or gastrointestinal bleeding which may be severe and requires prompt treatment. Dose interruptions and dose reductions may be needed depending upon the severity of clinical signs.
In rare cases, serious and sometimes fatal gastrointestinal complications including gastrointestinal perforation occurred in dogs treated with Palladia. If gastrointestinal ulceration is suspected, whether or not due to Palladia or to mast cell tumour degranulation, stop the administration of Palladia and treat appropriately.
Toceranib is metabolised in the liver and in the absence of any studies on the effects of renal or hepatic impairment, should be used with caution in dogs suffering from hepatic disease.
Treatment should be permanently discontinued if severe adverse events recur or persist despite appropriate supportive care and dose reduction as described in the following table.
Dose Adjustment Based on Clinical Signs / Pathology |
Clinical signs / pathology | Dose Adjustment* |
Anorexia |
< 50% food intake ≥2 days | Discontinue treatment and institute dietary modification ± supportive care until food intake improves, then decrease dose by 0.5 mg/kg |
Diarrhoea |
< 4 watery stools/day for < 2 days or soft stools | Maintain dose level and institute supportive care |
> 4 watery stools/day for ≥ 2 days | Discontinue treatment until formed stools and institute supportive care, then decrease dose by 0.5 mg/kg |
Gastrointestinal Bleeding |
Fresh blood in stool or black tarry stool for >2 days or frank haemorrhage or blood clots in stools | Discontinue treatment and institute supportive care until resolution of all clinical signs of blood in stools, then decrease dose by 0.5 mg/kg |
Hypoalbuminemia (albumin) |
Albumin < 1.5 g/dl | Discontinue treatment until >1.5 g/dl and clinical signs normal, then decrease dose by 0.5 mg/kg |
Neutropenia (neutrophil count) |
> 1000/µl | Maintain dose level |
< 1000/µl or neutropenic fever or infection | Discontinue treatment until >1000/µl and clinical signs normal, then decrease dose by 0.5 mg/kg |
Anaemia (haematocrit) |
> 26% | Maintain dose level |
< 26% | Discontinue treatment until > 26%, then decrease dose by 0.5 mg/kg |
Hepatic toxicity (ALT, AST) |
> 1X – 3X upper normal limit | Maintain dose level; discontinue hepatotoxic drugs, if used |
> 3X upper normal limit | Discontinue treatment until ≤3X upper normal limit, discontinue hepatotoxic drugs, if used, then decrease dose by 0.5 mg/kg |
Renal Toxicity (creatinine) |
<1.25 X upper normal limit | Maintain dose level |
≥1.25 X upper normal limit | Discontinue treatment until < 1.25 X upper normal limit, then decrease dose by 0.5 mg/kg |
Concurrent anaemia, azotaemia, hypoalbuminaemia and hyperphosphataemia |
Discontinue treatment for 1 to 2 weeks until values have improved and albumin > 2.5 g/dl, then decrease dose by 0.5 mg/kg. |
* A 0.5 mg/kg dose decrease is a decrease from 3.25 mg/kg to 2.75 mg/kg, or from 2.75 mg/kg to 2.25 mg/kg. The dose should not be < 2.2 mg/kg.
No interaction studies have been performed with toceranib. No information relating to potential cross resistance with other cytostatic products is available.
As toceranib is eliminated to a large extent by metabolism in the liver, the combination with other drugs capable of inducing or inhibiting liver enzymes should be used with caution.
It is not known to what extent toceranib could affect the elimination of other drugs.
Use non-steroidal anti-inflammatory drugs with caution in conjunction with Palladia due to an increased risk of gastrointestinal ulceration or perforation.
Adverse reactions:
Dogs:
Very common (>1 animal / 10 animals treated): | Mild to moderate: Diarrhoea, vomiting, blood in faeces, haemorrhagic diarrhoea, digestive tract haemorrhage Anorexia, dehydration, lethargy, weight loss Lameness, musculoskeletal disorder Dermatitis, pruritus Decreased haematocrit, hypoalbuminaemia, elevated alanine aminotransferase (ALT), neutropenia, thrombocytopaenia |
Common (1 to 10 animals / 100 animals treated): | Mild to moderate: Localised pain, general pain, polydipsia, pyrexia Depigmentation of the nasal plane, hair coat discolouration, alopecia Nausea, flatulence Tachypnoea Urinary tract infection Elevated total bilirubin, elevated creatinine Severe: Anorexia, dehydration, pyrexia, weight loss, septicaemia, lethargy Diarrhoea, vomiting, blood in faeces, haemorrhagic diarrhoea, digestive tract haemorrhage, duodenal ulcer, nausea Skin necrosis Decreased haematocrit, elevated alanine aminotransferase (ALT) |
Uncommon (1 to 10 animals / 1,000 animals treated): | Severe: Lameness, musculoskeletal disorder Circulatory shock |
Results from the clinical field study involving 151 treated and placebo-treated dogs showed that the clinical signs of the disease (mast cell tumour) and treatment related adverse reactions are very similar in nature.
•There were two deaths that were possibly treatment related. In one dog, pathology findings revealed vascular thrombosis with disseminated intravascular coagulopathy (DIC) and pancreatitis. The other dog died following gastric perforation.
•There were two further deaths; however, relation to treatment could not be established.
•Two dogs developed epistaxis that was not associated with thrombocytopenia. Another dog developed epistaxis with concurrent disseminated intravascular coagulopathy.
•Three dogs had seizure-like activity; however, relation to treatment could not be established.
Reporting adverse events is important. It allows continuous safety monitoring of a veterinary medicinal product. Reports should be sent, preferably via a veterinarian, to either the marketing authorisation holder or its local representative or the national competent authority via the national reporting system. See the package leaflet for respective contact details.
User warnings:
Palladia may impair male and female fertility and embryo/foetal development. Avoid skin contact with the tablets, faeces, urine, and vomit of treated dogs. The tablets must be administered as a whole and should not be broken or ground. If a broken tablet is rejected by the dog after chewing, it should be disposed of. Wash hands thoroughly with soap and water following handling of the product, and disposing of vomit, urine, or faeces of treated dogs.
Pregnant women should not routinely administer Palladia, should avoid contact with faeces, urine and vomit from treated dogs and broken or moistened Palladia tablets.
Ingestion of Palladia may be harmful for children. Children must not come into contact with the product. Keep children away from faeces, urine or vomit of treated dogs.
Gastrointestinal discomfort such as vomiting or diarrhoea may occur if this drug is accidentally ingested. In the case of accidental ingestion, seek medical advice immediately and show Package Leaflet or label to the physician.