Palladia - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

PACKAGE LEAFLET:

Palladia 10 mg film-coated tablets for dogs.

Palladia 15 mg film-coated tablets for dogs.

Palladia 50 mg film-coated tablets for dogs.

• 1. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE, IF DIFFERENT

Marketing authorisation holder :

Zoetis Belgium SA

Rue Laid Burniat 1

1348 Louvain-la-Neuve

BELGIUM

Manufacturer responsible for the batch release :

Pfizer Italia s.r.l.

Località Marino del Tronto

63100 Ascoli Piceno (AP)

ITALY

• 2. NAME OF THE VETERINARY MEDICINAL PRODUCT

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(S)

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.

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 evidence of stomach bleeding. Your veterinarian will advise you if this is the case for your dog.

• 6. ADVERSE REACTIONS

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 (more than 1 in 10 animals treated displaying adverse reaction(s)) adverse reactions associated with Palladia tablets are weight loss, diarrhoea, neutropenia (low number of white blood cells), blood in faeces/ haemorrhagic 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 (more than 1 but less than 10 animals in 100 animals treated) which have severe effects, these are vomiting, diarrhoea, anorexia, lethargy, dehydration, skin necrosis, fever, blood in faeces/haemorrhagic 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 (more than 1 but less than 10 animals in 1,000 treated): 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 side effects, even those not already listed in this package leaflet or you think that the medicine has not worked, please inform your veterinary surgeon.

• 7. TARGET SPECIES

Dogs

ft

• 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).

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

• 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.

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(S)

Not applicable

• 11. SPECIAL STORAGE PRECAUTIONS

Keep out of the sight and reach of children.

Do not use this veterinary medicinal product 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 each target species:

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

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. 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 to be taken by the person administering the veterinary medicinal product to animals:

• 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.

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.

Pregnancy, lactation and fertility:

Do not use in pregnant or lactating bitches or in dogs intended for breeding (see section 5). 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 crossresistance 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.

Overdose (symptoms, emergency procedures, antidotes):

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.

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.

• 13. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCT OR WASTE MATERIALS, IF ANY

Ask your veterinary surgeon how to dispose of medicines no longer required. These measures should help to protect the environment.

• 14. DATE ON WHICH THE PACKAGE LEAFLET WAS LAST APPROVED

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

• 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.

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 < 1.5× upper normal limit