PACKAGE LEAFLET

MASIVET 50 mg film-coated tablets for dogs MASIVET 150 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:

   
   

   AB Science S.A.

   3 avenue George V FR-75008 Paris France

   
   

   Manufacturer for batch release:

   
   

   Centre Spécialités Pharmaceutiques Avenue du Midi

   63800 Cournon d’Auvergne France

   
   

   The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

   
   

   

2. NAME OF THE VETERINARY MEDICINAL PRODUCT

   
   

   MASIVET 50 mg film-coated tablets for dogs MASIVET 150 mg film-coated tablets for dogs

   
   

3. STATEMENT OF THE ACTIVE SUBSTANCE(S) AND OTHER INGREDIENT(S)

   
   

   MASIVET is a light-orange, round, film-coated tablet.

   Each tablet contains either 50 mg or 150 mg of masitinib, which is the active substance. Each tablet also contains Sunset yellow FCF (E 110) aluminium lake and Titanium dioxide (E171) as colourants. The tablets are market with “50” or “150” on one side, and with the company logo on the other side.

   
   

4. INDICATION(S)

   
   

   Masivet is for the treatment of dogs with non-resectable mast cell tumours (Grade 2 or 3) with a confirmed mutated c-kit tyrosine kinase receptor.

   
   

5. CONTRAINDICATIONS

   
   

   Your dog should not be given Masivet if it:

   • is pregnant or nursing puppies,

   • is less 6 months of age or weights less than 4 kg,

   • is suffering from inadequate liver or renal function,

   • has an anaemia or low neutrophil count,

   • has an allergic reaction to masitinib, the active ingredient of Masivet or an excipient used in this medicine.

6. ADVERSE REACTIONS

   
   

   Should I expect side effects for my dog during Masivet therapy?

   Masivet like any other medicine may cause adverse reactions. Your veterinarian can best describe these for you.

   
   

   Very common effects:

   • Mild to moderate gastrointestinal reactions (diarrhoea and vomiting) with a mean duration of approximately 21 and 9 days, respectively.

   • Mild to moderate hair loss with a mean duration of approximately 26 days.

     
     

     Common effects:

     Specific measures should be taken by your veterinarian in case of the following reactions (see section 15):

     • Severe renal toxicity may occur in dogs suffering from renal disorders at the start of treatment (including high blood creatinine level or proteinuria).

     • Moderate to severe anaemia (aplastic/haemolytic) with a mean duration of approximately 7 days.

     • Protein-loss syndrome (mainly due to a decrease in serum albumin).

     • Mild or moderate neutropenia with a mean duration of approximately 24 days.

     • Increase in aminotransferase (ALT or AST) with a mean duration of approximately 29 days.

       
       

       Other, commonly observed adverse reactions were in most cases mild or moderate:

     • Lethargy and asthenia with a mean duration of approximately 8 and 40 days, respectively.

     • Decrease in appetite or anorexia with a mean duration of 45 days and 18 days, respectively.

     • Cough (mean duration 23 days).

     • Lymphadenopathy (mean duration 47 days).

     • Oedema (mean duration of oedema was 7 days).

     • Lipoma (mean duration 53 days).

   
   

   What should I do if side effects occur in my dog during Masivet treatment?

   If you notice any serious effects or other effects not mentioned in this leaflet, please inform your

   veterinarian. In case of adverse reactions, your veterinarian may decide to reduce the dose or to discontinue treatment.

   
   

7. TARGET SPECIES

   
   

   Dogs.

   
   

8. DOSAGE FOR EACH SPECIES, ROUTE(S) AND METHOD OF ADMINISTRATION

   
   

   Masivet is for oral use in dogs and should be given according to your veterinarian’s instructions. Your veterinarian will tell you what amount is right for your dog.

   
   

   The recommended dose is 12.5 mg/kg (with a dose range of 11–14 mg/kg) once daily as presented in the table below. In dogs with a bodyweight of less than 15 kg, accurate dosing is not always possible. These dogs may be treated with either 50, 100 or 150 mg, if it is feasible to achieve a target dose of 11–14 mg/kg bw.

   
   

   12.5 mg/kg bw		Number of tablets per day			Dose mg/kg
   Dog body-weight in kg		50 mg 150 mg			lower weight upper weight
   > 15	18	1	plus	1	13.7	11.1
   > 18	22	2	plus	1	13.9	11.4
   > 22	26			2	13.6	11.5
   > 26	30	1	plus	2	13.5	11.7
   > 30	34	2	plus	2	13.3	11.8
   > 34	38			3	13.2	11.8
   > 38	42	1	plus	3	13.2	11.9
   > 42	46	2	plus	3	13.1	12.0
   > 46	50			4	13.0	12.0
   > 50	54	1	plus	4	13.0	12.0
   > 54	58	2	plus	4	13.0	12.1
   > 58	62			5	12.9	12.1
   > 62	66	1	plus	5	12.9	12.1
   > 66	70	2	plus	5	12.9	12.1
   > 70	74			6	12.9	12.2
   > 74	78	1	plus	6	12.8	12.2
   > 78		2	plus	6	12.8

   
   

   If the tablet is regurgitated or vomited within 10 minutes following administration, treatment should be repeated. If the tablet is regurgitated or vomited later than 10 minutes following administration, treatment should not be repeated.

   
   

9. ADVICE ON CORRECT ADMINISTRATION

   
   

   How should I administer Masivet to my dog, and for how long?

   
   

   Tablets should always be administered in the same manner, with 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.

   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. Duration of treatment will be dependent on the response observed. Treatment should be maintained in the case of stable disease, i.e. static, partial or complete tumour response, provided that the product is sufficiently well tolerated. In case of tumour progression, efficacy of treatment is unlikely to be successful and the treatment should be reviewed.

   The treatment should be reviewed after 4 to 6 weeks in order to assess the initial response. Long term treatment should be under regular (at least monthly) veterinary control.

   
   

10. WITHDRAWAL PERIOD

    
    

    Not applicable.

    
    

11. SPECIAL STORAGE PRECAUTIONS

    
    

    Keep out of reach and sight of children. Keep the bottle tightly closed.

    Do not use after the expiry date which is stated on the label after “EXP”.

    
    

12. SPECIAL WARNING(S)

    1. Special precautions for use:

       
       

       Special warnings:

       For any mast cell tumor treatable by syrgery, surgery should be the first choice of treatment. Masitinib treatment should only be used in dogs with non-resectable mast cell tumours and which express the

       mutated c-kit tyrosine kinase receptor. The presence of a mutated tyrosine kinase c-kit receptor must be confirmed prior to treatment.

       
       

       Special precautions for use in animals:

       
       

       What are the special precautions for my dog?

       Dogs should be carefully monitored by your veterinarian (at least every month) and treatment might

       need to be adjusted or discontinued, if necessary.

       The treatment should be discontinued if any of these signs are observed: anaemia, severe neutropenia, severe renal toxicity, hepatic toxicity and/or severe diarrhoea or vomiting persistent after dose reduction.

       Dogs should not be used for breeding while under treatment. Do not use in pregnant or lactating bitches.

       
       

       What are the special precautions to be taken by the person administering Masivet? Repeated dermal contact with masitinib may impair female fertility and foetal development. The active substance of Masivet can cause skin sensitisation.

       • Avoid skin contact with faeces, urine, and vomit of treated dogs.

       • Wear protective gloves while disposing of vomit, urine or faeces of treated dogs.

       • If broken tablets, vomit, urine or faeces of treated dogs come into contact with the skin, rinse immediately with plenty of water.

         The active substance of Masivet can cause severe eye-irritation and serious damage to the eyes.

         • Avoid contact with the eyes.

         • Take care not to touch the eyes before gloves have been removed and disposed of and the hands have been thoroughly washed.

         • If the product comes into contact with the eyes, rinse immediately with plenty of water. People with known hypersensitivity to masitinib should not handle the product.

    In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician. Do not eat, drink, or smoke when treating the dog.

    Children should not have close contact to treated dogs, treated dog faeces or vomit.

    
    

    Can other medications be given while my dog is taking Masivet?

    
    

    There are some medicines that you should not give to your dog during treatment because together, they might cause serious adverse effects.

    Concurrent use of other substances with a high degree of protein binding may compete with masitinib

    binding and thus cause adverse effects.

    Concurrent use of substances which are metabolised by CYP450 isoforms may result in higher or lower plasma levels of either masitinib or those substances.

    Tell your veterinarian about all medicines, including over-the-counter products, that you intend to

    administer to your dog.

    The efficacy of Masivet might be reduced in dogs previously treated with chemotherapy and/or radiotherapy. No information relating to potential cross-resistance with other cytostatic products is available.

    
    

    Overdose:

    The recommended daily dose of 12.5 mg/kg body weight corresponds to the Maximum Tolerated Dose (MTD).

    The main target organs of toxicity in dogs are the gastrointestinal tract, the haematopoetic system, the kidney and the liver.

    In case of adverse events following overdose, treatment should be discontinued until resolution, and

    then resumed at the recommended therapeutic dose level. Please contact your veterinarian.

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

    
    

    Medicines should not be disposed of via wastewater or household waste. Ask your veterinarian 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 product is available on the website of the European Medicines Agency (EMA) .

    
    

15. OTHER INFORMATION

For animal treatment only.

The tablets are available in pack sizes of 30 tablets.

Masivet is a prescription medicine used to treat dog mast cell tumours. Mast cell tumours are cancerous proliferations of mast cells. It is a heterogeneous disease which can be relatively innocent or aggressively malignant. In certain circumstances, mast cell tumours can be life threatening for your dog. Masivet might extend the time before the tumours progress.

Special information for the veterinarian

Dogs should be monitored carefully and professional judgement should be used to determine the need for dose reduction in the event of possible significant adverse reactions.

Monitoring of renal function

Renal function should be adequately monitored every month using dipstick urine testing.

In case of positive semiquantitative dipstick results (protein > 30 mg/dl), urinalysis should be performed to determine urinary protein creatinine (UPC) ratio, and a blood sample to measure

creatinine, albumin and BUN.

If UPC ratio > 2, or creatinine > 1.5 upper limit of normal (ULN), or albumin < 0.75 lower limit of normal (LLN) or blood urea nitrogen (BUN) > 1.5 ULN, discontinue treatment.

Monitoring of Protein loss syndrome

Perform every month a dipstick urine test. In case of positive semi-quantitative dipstick results (protein ≥ 30 mg/dl), perform urinalysis to determine urinary protein creatinine (UPC) ratio.

Perform every month a blood measurement of albumin.

• In case of UPC ratio > 2 or albumin < 0.75 lower limit of normal (LLN), treatment should be interrupted until albumin and UPC values have returned to limit value (UPC ratio < 2 and

  albumin > 0.75 LLN), treatment can then be continued at the same dose.

• If of one of these events (UPC ratio > 2 or albumin < 0.75 LLN) occurs for a second time, treatment should be permanently discontinued.

  
  

  Anaemia and/or haemolysis

  Dogs should be carefully monitored for signs of (haemolytic) anaemia. In case of clinical signs of anaemia or haemolysis, haemoglobin, free bilirubin and haptoglobin should be measured and blood

  cell counts (including reticulocyte) should be performed.

  Treatment should be discontinued in case of:

  • Haemolytic anaemia, i.e. haemoglobin < 10 g/dl and haemolysis,

    i.e. free bilirubin > 1.5 ULN and haptoglobin < 0.1 g/dl,

    • Anaemia due to lack of regeneration, i.e. haemoglobin< 10 g/dl and reticulocytes < 80,000/mm3.

Hepatic toxicity (ALT or AST elevation), neutropenia

In case of an increase of ALT or AST > 3 ULN, decrease of neutrophil count < 2,000/mm3 or any other severe adverse events, treatment should be modified as follows:

At the first occurrence, treatment should be interrupted until resolution, and then resumed at the same

dose level;

At the second occurrence of the same event, treatment should be interrupted until resolution; treatment should then be continued with a reduced dose of 9 mg/kg bodyweight/day;

At the third occurrence of the same event, treatment should be interrupted until resolution; treatment should then be continued with a dose further reduced to 6 mg/kg/day;

Treatment should be discontinued, if severe adverse reactions are still encountered at the 6 mg/kg/day

dose.

Summary of thresholds for laboratory evaluations resulting in contra-indication or treatment modification (interruption, dose reduction or discontinuation)

Dose adjustment

The recommended daily dose of 12.5 mg/kg body weight corresponds to the Maximum Tolerated Dose (MTD) that was derived from repeat dose toxicity studies in healthy Beagle dogs. In the case of adverse reactions, doses might be reduced to once daily doses of 9 mg/kg bodyweight (range 7.5–10.5 mg/kg) or 6 mg/kg bw (range 4.5–7.5 mg/kg) according to the tables below.

9 mg per kg bodyweight

Dog body-weight in kg

Number of tablets per day Dose mg/kg

50 mg 150 mg lower weight upper weight

6 mg per kg bodyweight

Dog body-weight in kg

Number of tablets per day Dose mg/kg

50 mg 150 mg lower weight upper weight