Palladia Film-Coated Tablets for Dogs 1x20 POM-V

Product Description

Target species

Dogs.

Indications for use, specifying the target species

Treatment of non-resectable Patnaik grade II (intermediate grade) or III (high grade), recurrent, cutaneous mast cell tumours in dogs.

Contraindications

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 of less than 3 kg bodyweight.

Do not use in dogs with gastrointestinal bleeding.

Special warnings for each target species

For any mast cell tumour treatable by surgery, surgery should be the first choice of treatment.

Special precautions for use

Special precautions for use in animals

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 tablet 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 minimise 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 (See section "Adverse reactions" below).

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 or ≥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 stool	Discontinue treatment and institute supportive care until resolution of all clinical signs of blood in stool, 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 (hematocrit)
>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, azotemia, hypoalbuminemia and hyperphosphatemia
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.

Special precautions to be taken by the person administering the veterinary medicinal product to animals

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.

Special precautions for the protection of the environment

Not applicable.

Other precautions

Not applicable.

Adverse reactions (frequency and seriousness)

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 tat 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 has 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 the national competent authority via the national reporting system. See the package leaflet for respective contact details.

Use during pregnancy, lactation or lay

Do not use in pregnant or lactating bitches or in dogs intended for breeding (see section "Contraindications"). Other compounds in the anti-angiogenic class of anti-neoplastic agents are known to increase embryolethality and foetal 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 the pregnancy in the bitch.

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with toceranib. No information relating to potential cross-resistance with other cytostatics products is available.

As toceranib is likely 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.

Amount(s) to be administered and administration route

Oral use.

Tablets can be administered with or without food.

The initial recommended dose is 3.25 mg/kg bodyweight, administered every second day (see Dosing table for details).

The dose given should be based on veterinary assessments conducted weekly for the first six weeks and, thereafter, every six weeks. Duration of treatment depends on the response to treatment. Treatment should continue in the case of stable disease, or partial or complete response, provided that the product is sufficiently well tolerated. In case of tumour progression, treatment is unlikely to be successful and should be reviewed.

DOSING TABLE: PALLADIA TABLETS AT 3.25 MG/KG BODYWEIGHT

Dog Bodyweight (kg)	Number of Tablets
	10 mg (blue)		15 mg (orange)		50 mg (red)
5.0* - 5.3			1
5.4 - 6.9	2
7.0 - 8.4	1	plus	1
8.5 - 10.0			2
10.1 - 11.5	2	plus	1
11.6 - 13.0	1	plus	2
13.1 - 14.6			3
14.7 - 16.1					1
16.2 - 17.6	1	plus	3
17.7 - 19.2	1			plus	1
19.3 - 20.7			1	plus	1
20.8 - 23.0	2			plus	1
23.1 - 26.9			2	plus	1
27.0 - 29.9			3	plus	1
30.0 - 32.3					2
32.4 - 34.6	1			plus	2
34.7 - 36.1			1	plus	2
36.2 - 38.4	2			plus	2
38.5 - 43.0			2	plus	2
43.1 - 47.6					3
47.7 - 49.9	1			plus	3
50.0 - 51.5			1	plus	3
51.6 - 53.8	2			plus	3
53.9 - 58.4			2	plus	3
58.5 - 63.0*					4

* The number of tablets required for dogs below 5.0 kg or above 63 kg bodyweight, should be calculated based on the 3.25 mg/kg dosage regime.

Dose adjustment/reduction:

To manage adverse reactions, the dose may be reduced to 2.75 mg/kg bodyweight or further to 2.25 mg/kg bodyweight administered every second day or treatment can be discontinued for up to two weeks (see Dose Adjustment table in section "Special precautions for use" above).

Overdose (symptoms, emergency procedures, antidotes), if necessary

Overdosing signs were observed in a toxicity study conducted in healthy adult Beagle dogs treated with 2 mg/kg, 4 mg/kg or 6 mg toceranib/kg once every other day for 13 consecutive weeks without dose interruption. Toceranib was well tolerated at 2 mg/kg dose level whereas adverse reactions were noted in some dogs treated with 4 mg/kg and thus a NOAEL could not be established.

Dogs in the 6 mg/kg every other day group exhibited the most adverse effects which included decreased food consumption and weight loss. Sporadic dose related lameness, stiffness, weakness and pain in limbs resolved without treatment. Anaemia and neutropaenia and eosinopaenia were dose-related. Two dogs (6 mg/kg) were euthanised at approximately 3 weeks for treatment-related clinical toxicities initiated by decreased feed intake and melena culminating in anorexia, weight loss and hematochezia.

The main target organs of toxicity include the gastrointestinal tract, bone marrow, gonads and musculoskeletal system.

In case of adverse events following overdose, treatment should be discontinued until resolution and then resumed at the recommended therapeutic dose level. See sections "Special warnings for each target species", "Special precautions for use" and "Amount(s) to be administered and administration route" above for Dose Adjustment Guidelines.

Withdrawal period(s)

Not applicable.

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