ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Palladia 10 mg film-coated tablets for Dogs
Palladia 15 mg film-coated tablets for Dogs
Palladia 50 mg film-coated tablets for Dogs
Active substance:
Each film-coated tablet contains toceranib phosphate equivalent to 10 mg, 15 mg or 50 mg of
toceranib.
Excipients:
For a full list of excipients, see section 6.1.
Film-coated tablets.
Palladia 10 mg: Round shaped, blue coloured tablets
Palladia 15 mg: Round shaped, orange coloured tablets
Palladia 50 mg: Round shaped, red coloured tablets
Each tablet is marked with the Pfizer logo on one side and the strengths (10, 15 or 50) on the other
side.
Dogs
Treatment of non-resectable Patnaik grade II (intermediate grade) or III (high grade), recurrent,
cutaneous mast cell tumours in dogs
.
Do not use in pregnant or lactating bitches or in dogs intended for breeding.
Do not use in case 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 body weight.
Do not use in dogs with gastrointestinal bleeding.
For any mast cell tumour treatable by surgery, surgery should be the first choice of treatment.
2
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 (See section 4.6). 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
3
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/ul
Maintain dose level
≤1000/ul or neutropenic fever or
infection
Discontinue treatment until >1000/l 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.
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.
Very common (more than 1 in 10 animals)
4
Mild to moderate:
Diarrhoea, neutropenia, weight loss, blood in faeces/hemorrhagic diarrhoea/gastrointestinal
bleeding, anorexia, lethargy, vomiting; lameness / musculoskeletal disorder, dehydration,
dermatitis, pruritus; increased alanine aminotransferase, thrombocytopenia, decreased
albumin, decreased haematocrit.
Common (more than 1 but less than 10 animals in 100 animals)
Severe:
Vomiting, diarrhoea, anorexia, lethargy, dehydration, pyrexia, blood in faeces/haemorrhagic
diarrhoea/gastrointestinal bleeding, duodenal ulceration, nausea, septicaemia, skin necrosis,
weight loss; increased alanine aminotransferase, decreased haematocrit.
Mild to moderate:
Localised or general pain, nausea, tachypnea, polydipsia, flatulence, pyrexia, nasal
depigmentation; changes in coat colour, alopecia, urinary tract infection; increased bilirubin,
increased creatinine.
Uncommon (more than 1 but less than 10 animals in 1000 animals)
Severe lameness/musculoskeletal disorder.
Severe circulatory shock
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.
Do not use in pregnant or lactating bitches or in dogs intended for breeding (see section 4.3). 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.
No interaction studies have been performed with toceranib. No information relating to potential cross-
resistance with other cytostatics products is available.
As toceranib likely 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.
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).
5
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 4.5).
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
6
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 4.4, 4.5 and 4.9 for Dose
Adjustment Guidelines.
Not applicable.
Pharmacotherapeutic group: Antineoplastic Agents – Protein-kinase inhibitors
ATCvet code: QL01XE91
5.1 Pharmacodynamic properties
Toceranib is a small molecule, multi-kinase inhibitor, that has both direct anti-tumour and anti-
angiogenic activity. Toceranib selectively inhibits the tyrosine kinase activity of several members of
the split kinase receptor tyrosine kinase (RTK) family some of which are implicated in tumour growth,
pathologic 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 (c-Kit) in both biochemical and cellular
assays. Toceranib exerts an antiproliferative effect on endothelial cells
in-vitro
. Toceranib induces
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 an activating
mutation in c-Kit.
The efficacy and safety of Palladia oral tablets for the treatment of mast cell tumours was evaluated in
a randomised, placebo-controlled, double-masked, multicenter clinical field study involving 151 dogs
with Patnaik grade II or III, recurrent, cutaneous mast cell tumours with/without local lymph node
involvement. The field study comprised a 6-week double-blind placebo controlled phase followed by
an un-blinded phase where all dogs received Palladia for a mean duration of 144 days.
Palladia-treated dogs had a significantly greater objective response rate (37.2%) compared to dogs
treated with placebo (7.9%). After 6 weeks of treatment, a complete response was noted for 8.1% and
partial response was noted for 29.1% of dogs treated with Palladia. There was also a significant
advantage of Palladia over placebo in the secondary efficacy endpoint, time to tumour progression.
Median TTP for Palladia treated dogs was 9 to 10 weeks and for placebo treated dogs it was 3 weeks.
Dogs carrying wild-type c-kit and dogs carrying mutated c-kit responded significantly better to
treatment as compared to placebo.
5.2 Pharmacokinetic particulars
With a regimen of 3.25 mg toceranib/kg bodyweight administered by tablet orally every other day for
2 weeks (7 doses), the following pharmacokinetic parameters of toceranib in plasma in healthy Beagle
dogs were reported: elimination half-life (t
1/2
) 17.2 ± 3.9 hours, time to maximum plasma
concentration (T
max
) approximately 6.2 ± 2.6 hours, maximum plasma concentration (C
max
)
approximately 108 ± 41 ng/ml, minimum plasma concentration (C
min
) 18.7 ± 8.3 ng/ml and the area
under the plasma concentration time-curve (AUC
0-48
) 2640 ± 940 ng·h/ml.
7
Toceranib is highly protein bound at between 91% and 93%. The absolute bioavailability of toceranib
when dosed orally at 3.25 mg/kg was determined to be 86%.
Linear pharmacokinetics were seen irrespective of the route of administration at doses up to 5 mg/kg
given twice daily. In an
in-vitro
study, metabolism of toceranib was primarily to the N-oxide
derivative in dogs and cats. There are no
in vivo
data on the hepatic metabolism in dogs. No gender
differences in pharmacokinetics were observed
in-vivo
. Following oral administration of toceranib
phosphate, approximately 92% of the administered drug is excreted in faeces with another 7%
excreted in urine.
6.1 List of excipients
Tablet Core:
Lactose monohydrate
Cellulose, microcrystalline
Magnesium stearate
Silica, colloidal anhydrous
Crospovidone
Tablet coating:
Palladia 10 mg tablets:
Macrogol, Titanium dioxide (E171), Lactose monohydrate, Triacetin, Hypromellose, Indigo
Carmin Lake (E132)
Palladia 15 mg tablets:
Macrogol, Titanium dioxide (E171), Lactose monohydrate, Triacetin, Hypromellose, Sunset
Yellow Lake (E110), Iron oxide red (E172)
Palladia 50 mg tablets:
Macrogol, Titanium dioxide (E171), Lactose monohydrate, Triacetin, Hypromellose, Talc,
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Shelf-life of the veterinary medicinal product as packaged for sale: 2 years.
6.4 Special precautions for storage
This veterinary medicinal product does not require any special storage conditions.
6.5 Nature and composition of immediate packaging
Cardboard carton containing four aluminium-PVC child resistant blister packs, each blister containing
5 film-coated tablets.
Palladia film-coated tablets are available in 10 mg, 15 mg and 50 mg strength.
8
6.6 Special precautions for the disposal of unused veterinary medicinal product or waste
materials derived from the use of such products
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal
products should be disposed of in accordance with local requirements.
Pfizer Ltd.
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/2/09/100/001 (10 mg tablets)
EU/2/09/100/002 (15 mg tablets)
EU/2/09/100/003 (50 mg tablets)
23/09/2009
16/02/2011
Detailed information on this veterinary medicinal product is available on the website of the European
Medicines Agency (EMA)
http://www.ema.europa.eu
/
.
PROHIBITION OF SALE, SUPPLY AND/OR USE
Not applicable.
9
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS OF THE MARKETING AUTHORISATION
REGARDING SUPPLY OR USE
C. CONDITIONS OR RESTRICTIONS OF THE MARKETING AUTHORISATION
WITH REGARD TO SAFE AND EFFECTIVE USE
D. STATEMENT OF THE MRLs
10
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Pfizer Italia s.r.l.
Località Marino del Tronto
63100 Ascoli Piceno (AP)
Italy
B. CONDITIONS OR RESTRICTIONS OF THE MARKETING AUTHORISATION
REGARDING SUPPLY OR USE
Veterinary medicinal product subject to prescription.
C. CONDITIONS OR RESTRICTIONS OF THE MARKETING AUTHORISATION WITH
REGARD TO SAFE AND EFFECTIVE USE
Not applicable.
D. STATEMENT OF THE MRLs
Not applicable
11
ANNEX III
LABELLING AND PACKAGE LEAFLET
12
A. LABELLING
13
PARTICULARS TO APPEAR ON THE OUTER PACKAGE
Cardboard Carton/tablets
Palladia 10 mg film coated tablets for dogs.
Toceranib
2. STATEMENT OF ACTIVE AND OTHER SUBSTANCES
Each film-coated tablet contains 10 mg toceranib (as toceranib phosphate)
.
Film-coated tablets.
4. PACKAGE SIZE
20 tablets.
5. TARGET SPECIES
Dogs
6. INDICATION(S)
Treatment of non-resectable Patnaik grade II or III, recurrent, cutaneous mast cell tumours in dogs.
7. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
8. SPECIAL WARNING(S), IF NECESSARY
Read the package leaflet before use.
9. EXPIRY DATE
EXP
14
10. SPECIAL STORAGE CONDITIONS
Not Applicable.
11. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal
products should be disposed of in accordance with local requirements.
12. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR
RESTRICTIONS REGARDING SUPPLY AND USE, if applicable
For animal treatment only – to be supplied only on veterinary prescription.
13. THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
Pfizer Ltd.
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
EU/2/09/100/001
16. MANUFACTURER’S BATCH NUMBER
Lot
15
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
{Alu-PVC/Blisters}
Palladia 10 mg film-coated tablets for dogs.
Toceranib
Pfizer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. THE WORDS “FOR ANIMAL TREATMENT ONLY”
For animal treatment only.
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGE
Cardboard Carton/tablets
Palladia 15 mg film coated tablets for dogs.
Toceranib
2. STATEMENT OF ACTIVE AND OTHER SUBSTANCES
Each film-coated tablet contains 15 mg toceranib (as toceranib phosphate).
Film-coated tablets.
4. PACKAGE SIZE
20 tablets.
5. TARGET SPECIES
Dogs
6. INDICATION(S)
Treatment of non-resectable Patnaik grade II or III, recurrent, cutaneous mast cell tumours in dogs.
7. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
8. SPECIAL WARNING(S), IF NECESSARY
Read the package leaflet before use.
9. EXPIRY DATE
EXP
17
10. SPECIAL STORAGE CONDITIONS
Not Applicable.
11. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal
products should be disposed of in accordance with local requirements.
12. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR
RESTRICTIONS REGARDING SUPPLY AND USE, if applicable
For animal treatment only – to be supplied only on veterinary prescription.
13. THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
Pfizer Ltd.
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
EU/2/09/100/002
16. MANUFACTURER’S BATCH NUMBER
Lot
18
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
{Alu-PVC/Blisters}
Palladia 15 mg film coated tablets for dogs.
Toceranib
Pfizer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. THE WORDS “FOR ANIMAL TREATMENT ONLY”
For animal treatment only.
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGE
Cardboard Carton/tablets
Palladia 50 mg film coated tablets for dogs.
Toceranib
2. STATEMENT OF ACTIVE AND OTHER SUBSTANCES
Each film-coated tablet contains 50 mg toceranib (as toceranib phosphate).
Film-coated tablets.
4. PACKAGE SIZE
20 tablets.
5. TARGET SPECIES
Dogs
6. INDICATION(S)
Treatment of non-resectable Patnaik grade II or III, recurrent, cutaneous mast cell tumours in dogs.
7. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
8. SPECIAL WARNING(S), IF NECESSARY
Read the package leaflet before use.
9. EXPIRY DATE
EXP
20
10. SPECIAL STORAGE CONDITIONS
Not Applicable.
11. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal
products should be disposed of in accordance with local requirements.
12. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR
RESTRICTIONS REGARDING SUPPLY AND USE, if applicable
For animal treatment only – to be supplied only on veterinary prescription.
13. THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
Pfizer Ltd.
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
EU/2/09/100/003
16. MANUFACTURER’S BATCH NUMBER
Lot
21
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
{Alu-PVC/Blisters}
Palladia 50 mg film coated tablets for dogs.
Toceranib
Pfizer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. THE WORDS “FOR ANIMAL TREATMENT ONLY”
For animal treatment only.
22
B. PACKAGE LEAFLET
23
PACKAGE LEAFLET FOR:
Palladia 10 mg film coated tablets for dogs
Palladia 15 mg film coated tablets for dogs.
Palladia 50 mg film coated tablets for dogs.
THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE, IF DIFFERENT
Marketing authorisation holder:
Pfizer Ltd
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
Manufacturer for the batch release:
Pfizer Italia s.r.l.
Località Marino del Tronto
63100 Ascoli Piceno (AP)
Italy
Palladia 10 mg film-coated tablets for dogs.
Palladia 15 mg film-coated tablets for dogs.
Palladia 50 mg film-coated tablets for dogs.
Toceranib.
3. STATEMENT OF THE ACTIVE SUBSTANCE(S) AND OTHER INGREDIENT(S)
Each film-coated tablet contains toceranib phosphate equivalent to 10 mg, 15 mg or 50 mg of
toceranib as active substance.
Each tablet also contains lactose monohydrate, cellulose microcrystalline, magnesium stearate, silica
colloidal anhydrous and Crospovidone.
Palladia are round tablets and have a coloured film coat to minimise risk of exposure and to help
identify the correct tablet strength.
Palladia 10 mg: blue
Palladia 15 mg: orange
Palladia 50 mg: red
4. INDICATION
Treatment of non-resectable Patnaik grade II (intermediate grade) or III (high grade), recurrent,
cutaneous mast cell tumours.
5. CONTRAINDICATIONS
Do not use in pregnant or lactating bitches or in dogs intended for breeding.
24
Do not use in case of hypersensitivity to the active substance or to any of the other ingredients of
Palladia.
Do not use in dogs less than 2 years of age or less than 3 kg body weight
Do not use in dogs with evidence of stomach bleeding. Your veterinarian will advise you if this is the
case for your dog.
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.
Some very common (
i.e.
in more than 10% of dogs) adverse reactions associated with Palladia tablets
are weight loss, diarrhoea, neutropenia (low number of white blood cells), blood in faeces/,
hemorrhagic diarrhoea/gastrointestinal bleeding, anorexia, lethargy, vomiting; lameness /
musculoskeletal disorder, dehydration, dermatitis, pruritus (skin irritation/scratching); increased
alanine aminotransferase, thrombocytopenia, decreased albumin, decreased haematocrit.
There were other side effects that are seen commonly (
i.e.
in 1% – 10% of dogs ) which have severe
effects, these are vomiting, diarrhoea, anorexia, lethargy, dehydration, skin necrosis, fever, blood in
faeces/hemorrhagic diarrhoea/gastrointestinal bleeding and ulcers, nausea, septicaemia, weight loss,
increased alanine aminotransferase and decreased haematocrit .
Also seen commonly but with less severe effects, were localised or general pain, nausea, flatulence ,
tachypnea, polydipsia, fever, urinary tract infection, increased bilirubin, increased creatinine, Some
dogs may also show a loss of colour around their nose, some dogs may show a change in coat colour
which appears to lighten and some dogs may lose hair.
The following adverse events were uncommon (
i.e.
in 0.1%-1% of dogs):
Severe lameness/musculoskeletal disorder
Severe circulatory shock.
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.
If you notice any of these serious effects or other effects not mentioned in this leaflet, please inform
your veterinary surgeon.
7. TARGET SPECIES
Dogs
8. DOSAGE FOR EACH SPECIES, ROUTE(S) AND METHOD OF ADMINISTRATION
For oral use.
The initial dose is approximately 3.25 mg/kg bodyweight, given every second day (see dosing table
for details).
25
The number of tablets given to your dog may be adjusted by your veterinarian to manage side effects.
Therefore, the dosage given should be as described by your veterinarian, even if this is different from
the dosing table.
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.
D
OSING
T
ABLE
:
PALLADIA TABLETS:- 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.
9. ADVICE ON CORRECT ADMINISTRATION
Tablets can be administered with or without food.
The tablets must be administered as a whole and should not be divided, broken or ground. If a broken
tablet is rejected by the dog after chewing, it should be disposed of. In order to achieve correct dosing,
tablets of different strengths (“colours”) might need to be combined as described in the table.
If a dose is missed, the next schedule dose should be given as prescribed. Do not increase or double
the dose. If more than the prescribed amount of tablets were given, contact your veterinarian
Dogs should be carefully observed following administration to ensure that each tablet is swallowed.
26
There are some medicines that you should not give to your dog during treatment because together,
they might cause serious adverse effects. Tell your veterinarian about all medicines, including over-
the-counter products, that you intend to administer to your dog.
No information relating to the potential of cross-resistance with other cytostatics products is available.
10. WITHDRAWAL PERIOD
Not applicable
11. SPECIAL STORAGE PRECAUTIONS
Keep out of the reach and sight of children.
Do not use after the expiry date, which is stated on the carton after “EXP”.
This veterinary medicinal product does not require any special storage conditions.
12. SPECIAL WARNING(S)
Special precautions for the dog
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. Your veterinarian may need to
take blood and urine samples from your dog to perform these checks.
Stop Palladia immediately and contact your 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
Treatment should be permanently discontinued if severe adverse events recur or persist, despite
appropriate supportive care and dose reduction.
Special precautions for people
Children should not come in contact with Palladia. Keep children away from faeces, urine or
the vomit of treated dogs.
If you are pregnant, you should not routinely administer Palladia; however, if you choose to
give these tablets to your dog, you should be particularly careful and follow the handling
procedures described below.
If Palladia is accidentally ingested (swallowed or eaten) by you or a family member, seek
medical advice immediately. It is important to show the doctor a copy of this package leaflet.
In cases of accidental ingestion of Palladia, you may experience stomach discomfort,
including vomiting or diarrhoea.
27
The following handling procedures will help to minimise exposure to the active ingredient in Palladia
for you and other members of your household:
Anyone in your household who administers Palladia to your dog should always wash their
hands after handling the tablets.
When you are handling the tablets:
Do not break or grind the tablets.
Palladia tablets should be given to your dog immediately after they are removed from
the blister and should not be left around where they could be handled/swallowed by
children.
The blister should always be returned to the cardboard carton once a tablet or tablets
have been removed.
If the Palladia tablet is “hidden” in food, make sure that your dog has eaten the entire
dose. This will reduce the risk for children or other household members to
accidentally come into contact with Palladia.
13. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCT OR WASTE
MATERIALS, IF ANY
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal
products should be disposed of in accordance with local requirements.
14. DATE ON WHICH THE PACKAGE LEAFLET WAS LAST APPROVED
16/02/2011
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
/.
15. OTHER INFORMATION
Cardboard carton containing four Aluminium-PVC child resistant blister packs.
Each blister contains 5 tablets.
Tablets are available in three different strengths.
Not all pack sizes may be marketed.
For any information about this veterinary medicinal product, please contact the local representative of
the marketing authorisation holder.
België/Belgique/Belgien
Pfizer Animal Health s.a.,
Tél.: +32 (0)2 554 62 11
Luxembourg
Pfizer Animal Health s.a.,
Tél.: + 32 (0)2 554 62 11
Република България
Pfizer Luxembourg SARL
Tel: + 359 2 970 43 21
Magyarország
Pfizer Kft.
Tel: +361 488 3695
Česká republika
Pfizer Animal Health
Tel: +420 283 004 111
Malta
Agrimed Limited
Tel: +356 21 465 797
28
Danmark
Orion Pharma Animal Health
Tlf: +45 49 12 67 65
Nederland
Pfizer Animal Health B.V.,
Tel: +31 (0)10 4064 600
Deutschland
Pfizer GmbH
Tel: +49 30-5500 5501
Norge
Orion Pharma Animal Health
Tlf: +47 40 00 41 90
Eesti
Pfizer Animal Health
Tel: +370 5 269 17 96
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 52 11 57 20
Ελλάδα
Pfizer Hellas A.E.
Τηλ.: +30 210 6785800
Polska
Pfizer Trading Polska Sp. z.o.o.
Tel: +48 22 335 61 00
España
Pfizer S.L.
Tel: +34 91 4909900
Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 55 00
France
Pfizer
Tél: +33 (0)1 58 07 46 00
Romania
Pfizer Romania SRL
Tel: + 0040 21 207 28 93
Ireland
Pfizer Healthcare Ireland, trading as:
Pfizer Animal Health
Tel: +353 (0) 1 467 6500
Slovenija
Pfizer Luxembourg SARL
Tel: +386 (0) 1 52 11 670
Ìsland
Icepharma hf.
Tlf: +354 540 80 00
Slovenská republika
Pfizer Luxembourg SARL o.z.
Tel: + 421 2 3355 5500
Italia
Pfizer Italia S.r.l.,
Tel: +39 06 3318 2933
Suomi/Finland
Pfizer Oy Animal Health,
Puh/Tel: +358 (0)9 4300 40
Kύπρος
Pfizer Hellas A.E.
Τηλ.: +30 210 6785800
Sverige
Orion Pharma Animal Health
Tlf: +46 (0)8 623 64 40
Latvija
Pfizer Animal Health
Tel: +370 5 269 17 96
United Kingdom
Pfizer Ltd
Tel: +44 (0) 1304 616161
Lietuva
Pfizer Animal Health
Tel.: +370 5 269 17 96
29
Special information for the veterinarian
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 < 1.5x 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 have 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 or ≥2 days
Discontinue treatment until formed stools and institute
supportive care, then decrease dose by 0.5 mg/kg
30
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/ul
Maintain dose level
≤1000/ul or neutropenic fever or
infection
Discontinue treatment until >1000/l 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.
31
Source: European Medicines Agency
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