ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
MASIVET 50 mg film-coated tablets for dogs.
MASIVET 150 mg film-coated tablets for dogs.
2.
Active substance:
Each film-coated tablet contains :
Masitinib 50 mg (equivalent to masitinib mesylate 59.6 mg).
Masitinib 150 mg (equivalent to masitinib mesylate 178.9 mg)
Excipients:
For a full list of excipients, see section 6.1
3.
Film-coated tablet
Light-orange, round shape, film-coated tablet embossed with “50” or “150” on one side and the
company logo on the other side.
4.
Dogs.
Treatment of non-resectable dog mast cell tumours (Grade 2 or 3) with confirmed mutated c-kit
tyrosine kinase receptor.
Do not use in pregnant or lactating bitches (see section 4.7).
Do not use in dogs less than 6 months of age or less than 4 kg body weight.
Do not use in dogs suffering from liver impairment, defined as AST or ALT > 3 x Upper Limit of
Normal (ULN). Do not use in dogs suffering from renal function impairment, defined as Urinary
Protein Creatinine (UPC) ratio > 2 or albumin < 1 x Lower Limit of Normal (LLN).
Do not use in dogs with anaemia (haemoglobin < 10 g/dl).
Do not use in dogs with neutropenia defined as absolute neutrophil count < 2000 /mm
3
.
Do not use in case of hypersensitivity to the active substance or to any of the excipients.
For any mast cell tumour treatable by surgery, 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 (see also 5.1).
2/29
Dogs should be carefully monitored and treatment might need to be adjusted or discontinued, if
necessary.
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/mm
3
.
Hepatic toxicity (ALT or AST elevation), neutropenia
In case of an increase of ALT or AST > 3 ULN, decrease of neutrophil count < 2000/mm
3
or any other
severe adverse events, treatment should be modified as follows:
At the first occurrence, treatment should be interrupted until resolution, 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.
Other precautions
Treatment should be permanently discontinued in case of renal toxicity, immune-mediated haemolytic
anaemia (IMHA) and/or anaemia due to lack of regeneration, and if severe neutropenia, and/or severe
diarrhoea and/or severe vomiting persist after dose reduction.
Dogs should not be used for breeding while under treatment.
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Summary of thresholds for laboratory evaluations resulting in contra-indication or
treatment modification (interruption, dose reduction or discontinuation)
M
ANAGEMENT OF
H
EPATIC
T
OXICITY
(ALT or AST)
Contra-indication
Interruption
Dose reduction
Discontinuation
> 3 ULN
> 3ULN
(1
st
time)
> 3 ULN
(2
nd
/3
rd
time)
> 3ULN
(4
th
time)
M
ANAGEMENT OF
N
EUTROPENIA
(
N
eutrophil counts)
Contra-indication
Interruption
Dose reduction
Discontinuation
< 2000 / mm
3
< 2000 / mm
3
(4
th
time)
M
ANAGEMENT OF
P
ROTEIN
-L
OSS
S
YNDROME
(Albuminemia and/or UPC)
< 2000 / mm
3
(1
st
time)
< 2000 / mm
3
(2
nd
/3
rd
time)
Contra-indication
Interruption
Dose reduction
Discontinuation
Albumin < 1 LLN
or UPC > 2
Albumin < 0.75 LLN
or UPC >2
(1
st
time)
Not applicable
Albumin < 0.75 LLN
or UPC > 2
(2
nd
time)
M
ANAGEMENT OF
H
AEMOLYTIC AND AREGENERATIVE
A
N
A
EMIA
(haemoglobin, bilirubin, haptoglobin, reticulocytes)
Contra-indication
Interruption
Dose reduction
Discontinuation
Haemoglobin < 10g/dL
Not applicable
Not applicable
Haemoglobin < 10 g/dL
and either
free bilirubin > 1.5 ULN
and haptoglobin<0.1g/dl
or
reticulocytes<80,000/m
m
3
Special precautions to be taken by the person administering the veterinary medicinal product to
animals
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.
•
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•
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.
Very common
Mild to moderate gastrointestinal reactions (diarrhoea and vomiting) with a mean duration of
approximately 21 and 9 days, respectively.
Mild to moderate alopecia with a mean duration of approximately 26 days.
Common
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.
Specific measures to be taken in case of the above reactions are described in section 4.5.
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).
Do not use in pregnant or lactating bitches. Laboratory studies in rats have shown evidence of
impaired female fertility at dose of 100 mg/kg/day, embryotoxicity and developmental toxicity at dose
above 30 mg/kg/day. Studies in rabbits did however not reveal embryotoxicity or developmental
toxicity.
In vitro
tests with human microsomes demonstrate that concomitant treatment with substances which
are metabolised by CYP450 isoforms may result in higher or lower plasma levels of either masitinib or
those substances. No corresponding information is available for dogs. Hence, caution is advised with
the concurrent use of masitinib and other substances.
Concurrent use of other substances with a high degree of protein binding may compete with masitinib
binding and thus cause adverse effects.
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.
For oral use.
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.
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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.
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.
Tablets should always be administered in the same manner, with food.
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.
The treatment should be reviewed after 4 to 6 weeks in order to assess the initial response. Duration of
treatment depends on the response to treatment. 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, treatment is unlikely to be successful and the treatment
should be reviewed.
Dose Reduction, treatment interruption and treatment discontinuation:
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 (see section 4.5). Doses can be
reduced to 9 mg/kg bodyweight (range 7.5 – 10.5 mg/kg) or 6 mg/kg bw (range 4.5 – 7.5) according to
the tables below.
During clinical studies, the daily dose was decreased due to adverse events in approximately 16% of
treated dogs and mainly due to an increase in transaminases.
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9 mg
per kg bodyweight once daily as presented in the table below.
Number of
tablets per day Dose mg/kg
Dog body-
weight in kg
50
mg
150
mg
lower
weight
upper
weight
>
15.0 19.4
1
10.0
7.7
> 19.4 25.0
1 plus 1
10.3
8.0
> 25.0 30.6
2 plus 1
10.0
8.2
> 30.6 36.1
2
9.8
8.3
> 36.1 41.7
1 plus 2
9.7
8.4
> 41.7 47.2
2 plus 2
9.6
8.5
> 47.2 52.8
3
9.5
8.5
> 52.8 58.3
1 plus 3
9.5
8.6
> 58.3 63.9
2 plus 3
9.4
8.6
> 63.9 69.4
4
9.4
8.6
> 69.4 75.0
1 plus 4
9.4
8.7
> 75.0 80.6
2 plus 4
9.3
8.7
6 mg
per kg bodyweight once daily as presented in the table below.
Number of
tablets per day Dose mg/kg
Dog body-
weight in kg
50
mg
150
mg
lower
weight
upper
weight
>
15.0 20.8
2
6.6
4.8
> 20.8 29.2
1
7.2
5.1
> 29.2 37.5
1 plus 1
6.9
5.3
> 37.5 45.8
2 plus 1
6.7
5.5
> 45.8 54.2
2
6.5
5.5
> 54.2 62.5
1 plus 2
6.5
5.6
> 62.5 70.8
2 plus 2
6.4
5.6
> 70.8 79.2
3
6.4
5.7
> 79.2
1 plus 3
6.3
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.
Overdosing signs were observed in toxicity studies conducted in healthy dogs, treated for 39 weeks at
doses of around 2 times the recommended dose (25 mg masitinib), treated for 13 weeks and 4 weeks at
doses of around 3 times the recommended dose (41.7 mg masitinib), and treated for 4 weeks at doses
of around 10 times the recommended dose (125 mg masitinib). 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.
Not applicable.
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5.
Pharmacotherapeutic group: protein-tyrosine kinase inhibitor,
ATCvet code: QL01XE90
5.1 Pharmacodynamic properties
Masitinib is a protein-tyrosine kinase inhibitor which,
in vitro
, potently and selectively inhibits the
mutated form, in the juxtamembrane (JM) region, of the c-kit receptor. It also inhibits the Platelet
Derived Growth Factor (PDGF) receptor and the Fibroblast Growth Factor Receptor (FGFR3).
In the pivotal clinical field study, dogs of various breeds, ranging in age from two to seventeen years,
were randomly treated with Masivet at a dose of 12.5 mg/kg or with a placebo. In dogs with non-
resectable mast cell tumours, Grade 2 or 3, expressing a mutated tyrosine kinase c-kit receptor,
treatment with Masivet showed a significantly longer Time-to-Tumour Progression (TTP) with a
median of 241 days as compared to 83 days for placebo. Response to treatment with masitinib was
expressed as stable disease; i.e. static, partial or complete response.
Masitinib treatment should only be used in dogs with non-resectable mast cell tumours, 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.
5.2 Pharmacokinetic particulars
Following oral administration in dogs at a dose of 11.2 mg (0.5) per kg of bodyweight, masitinib is
rapidly absorbed and the time to maximal concentration (T
max
) is approximately 2 hours. The
elimination half-life (t½) is approximately 3-6 hours. Masitinib is approximately 93 % bound to
plasma proteins.
Masitinib is metabolised predominantly by N-dealkylation. Excretion takes place in the bile.
6.
6.1 List of excipients
Cellulose, microcrystalline
Povidone K30
Pig Liver powder
Crospovidone
Magnesium stearate
Tablet coating:
Macrogol 3350
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Sunset yellow (E110) aluminium lake.
6.2 Incompatibilities
Not applicable.
8/29
6.3 Shelf life
Shelf life of the veterinary medicinal product as packaged for sale: 24 months.
6.4. Specialprecautionsforstorage
Do not store above 25°C.
6.5 Nature and composition of immediate packaging
White HDPE bottle closed with a thermosealable film and covered by a child-resistant closure cap.
30 ml bottle containing 30 Masivet 50 mg film-coated tablets.
60 ml bottle containing 30 Masivet 150 mg film-coated tablets.
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.
7.
AB Science S.A.
3 avenue George V
75008 Paris
France
+33 (0)1 47 20 00 14
+33 (0)1 47 20 24 11
MASIVET@ab-science.com
8.
EU/2/08/087/001
EU/2/08/087/002
9.
17.11.2008
May 2010
PROHIBITION OF SALE, SUPPLY AND/OR USE
Not applicable.
9/29
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS 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
10/29
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
CRID PHARMA
17 parc des Vautes
34980 Saint Gély du Fesc
France
Centre Spécialités Pharmaceutiques
Avenue du Midi
63800 Cournon d’Auvergne
France
B. CONDITIONS OR RESTRICTIONS OF THE MARKETING AUTHORISATION
REGARDING SUPPLY OR USE
To be supplied only on veterinary prescription.
C. CONDITIONS OR RESTRICTIONS OF THE MARKETING AUTHORISATION WITH
REGARD TO THE SAFE AND EFFECTIVE USE OF THE PRODUCT
Not applicable.
D.
STATEMENT OF THE MRLs
Not applicable.
11/29
ANNEX III
LABELLING AND PACKAGE LEAFLET
12/29
A. LABELLING
13/29
PARTICULARS TO APPEAR ON THE OUTER PACKAGE
Carton Box Labelling
1.
MASIVET 50 mg film-coated tablets for dogs.
2.
STATEMENT OF ACTIVE AND OTHER SUBSTANCES
Masitinib 50 mg
Colourants (E171, E 110)
3.
Film coated tablet
4.
PACKAGE SIZE
30 tablets
5.
Dogs
6.
Treatment of non-resectable dog mast cell tumours (Grade 2 or 3) with confirmed mutated c-kit
tyrosine kinase receptor
7.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
8.
Not applicable
9.
SPECIAL WARNING(S), IF NECESSARY
Avoid contact with eyes or skin.
Read the package leaflet before use
14/29
10.
EXPIRY DATE
EXP {month/year}
11. SPECIAL STORAGE CONDITIONS
Do not store above 25°C
12. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Disposal: read package leaflet.
13. 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.
14. THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
AB Science
3 avenue George V
FR-75008
Paris
France
EU/2/08/087/001
17. MANUFACTURER’S BATCH NUMBER
Lot {number}
15/29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGE UNITS
Label
1.
MASIVET 50 mg film-coated tablets for dogs.
2.
QUANTITY OF THE ACTIVE SUBSTANCE(S)
Masitinib 50 mg
3.
CONTENTS
30 tablets
4.
ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
5.
BATCH NUMBER
Lot {number}
6.
EXPIRY DATE
EXP {month/year}
7. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Disposal: read package leaflet.
8. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR
RESTRICTIONS REGARDING SUPPLY AND USE, if applicable
For animal treatment only.
9.
THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
16/29
AB Science,
3 avenue George V
FR-75008 Paris
France
17/29
PARTICULARS TO APPEAR ON THE OUTER PACKAGE
Carton Box Labelling
1.
MASIVET 150 mg film-coated tablets for dogs.
2.
STATEMENT OF ACTIVE AND OTHER SUBSTANCES
Masitinib 150 mg
Colourants (E171, E 110)
3.
Film coated tablet
4.
PACKAGE SIZE
30 tablets
5.
Dogs
6.
Treatment of non-resectable dog mast cell tumours (Grade 2 or 3) with confirmed mutated c-kit
tyrosine kinase receptor
7.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
8.
Not applicable
9.
SPECIAL WARNING(S), IF NECESSARY
Avoid contact with eyes or skin.
Read the package leaflet before use
18/29
10. EXPIRY DATE
EXP {month/year}
11. SPECIAL STORAGE CONDITIONS
Do not store above 25°C
12. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Disposal: read package leaflet.
13. 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.
14. THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
AB Science
3 avenue George V
FR-75008
Paris
France
EU/2/08/087/002
17. MANUFACTURER’S BATCH NUMBER
Lot {number}
19/29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGE UNITS
Label
1.
MASIVET 150 mg film-coated tablets for dogs.
2.
QUANTITY OF THE ACTIVE SUBSTANCE(S)
Masitinib 150 mg
3.
CONTENTS
30 tablets
4.
ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
5.
BATCH NUMBER
Lot {number}
6.
EXPIRY DATE
EXP {month/year}
7. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR
WASTE MATERIALS, IF ANY
Disposal: read package leaflet.
8. THE WORDS “FOR ANIMAL TREATMENT ONLY” AND CONDITIONS OR
RESTRICTIONS REGARDING SUPPLY AND USE, if applicable
For animal treatment only.
9.
THE WORDS “KEEP OUT OF THE REACH AND SIGHT OF CHILDREN”
Keep out of the reach and sight of children.
20/29
AB Science,
3 avenue George V
FR-75008 Paris
France
21/29
B. PACKAGE LEAFLET
22/29
PACKAGE LEAFLET
MASIVET 50 mg film-coated tablets for dogs
MASIVET 150 mg film-coated tablets for dogs
1.
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
:
CRID PHARMA
17 parc des Vautes
34980 Saint Gély du Fesc
France
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.
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 50mg 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.
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.
23/29
5.
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.
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.
Dogs
24/29
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.
25/29
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.
10. WITHDRAWAL PERIOD
Not applicable
11. SPECIAL STORAGE PRECAUTIONS
Keep out of reach and sight of children.
Do not store above 25°C
Do not use after the expiry date which is stated on the label after “EXP”.
12. SPECIAL WARNING(S)
12.1 Specialprecautionsforuse:
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.
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.
•
26/29
•
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
05/08/2009
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
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:
27/29
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/mm
3
.
Hepatic toxicity (ALT or AST elevation), neutropenia
In case of an increase of ALT or AST > 3 ULN, decrease of neutrophil count < 2000/mm
3
or any other
severe adverse events, treatment should be modified as follows:
At the first occurrence, treatment should be interrupted until resolution, 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)
CONTRA-
INDICATION
DISCONTINUATION
M
ANAGEMENT OF
H
EPATIC
T
OXICITY
(ALT or AST)
DOSE REDUCTION
TREATMENT
> 3 ULN
> 3ULN
(1
st
time)
> 3 ULN
(2
nd
/3
rd
time)
> 3ULN
(4
th
time)
M
ANAGEMENT OF
N
EUTROPENIA
(
N
eutrophil counts)
< 2000 /mm
3
(4
th
time)
M
ANAGEMENT OF
P
ROTEIN
-L
OSS
S
YNDROME
(Albuminemia and/or UPC)
< 2000 /mm
3
(1
st
time)
< 2000 /mm
3
(2
nd
/3
rd
time)
Albumin < 1 LLN
or UPC > 2
Albumin < 0.75 LLN
or UPC >2
(1
st
time)
Not applicable
Albumin < 0.75 LLN
or UPC > 2
(2
nd
time)
M
ANAGEMENT OF
H
AEMOLYTIC AND AREGENERATIVE
A
N
A
EMIA
(haemoglobin, bilirubin, haptoglobin, reticulocytes)
Haemoglobin < 10g/dL
Not applicable
Not applicable
Haemoglobin < 10g/dL
and either
free bilirubin > 1.5 ULN
and haptoglobin<0.1g/dl
or reticulocytes<
80,000/mm
3
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) according to the tables below.
28/29
TREATMENT
INTERRUPTION
< 2000 /mm
3
9 mg
per kg bodyweight
Number of
tablets per day Dose mg/kg
Dog body-
weight in kg
50
mg
150
mg
lower
weight
upper
weight
>
15.0 19.4
1
10.0
7.7
> 19.4 25.0
1 plus 1
10.3
8.0
> 25.0 30.6
2 plus 1
10.0
8.2
> 30.6 36.1
2
9.8
8.3
> 36.1 41.7
1 plus 2
9.7
8.4
> 41.7 47.2
2 plus 2
9.6
8.5
> 47.2 52.8
3
9.5
8.5
> 52.8 58.3
1 plus 3
9.5
8.6
> 58.3 63.9
2 plus 3
9.4
8.6
> 63.9 69.4
4
9.4
8.6
> 69.4 75.0
1 plus 4
9.4
8.7
> 75.0 80.6
2 plus 4
9.3
8.7
6 mg
per kg bodyweight
Number of
tablets per day Dose mg/kg
Dog body-
weight in kg
50
mg
150
mg
lower
weight
upper
weight
>
15.0 20.8
2
6.6
4.8
> 20.8 29.2
1
7.2
5.1
> 29.2 37.5
1 plus 1
6.9
5.3
> 37.5 45.8
2 plus 1
6.7
5.5
> 45.8 54.2
2
6.5
5.5
> 54.2 62.5
1 plus 2
6.5
5.6
62.5 70.8
2 plus 2
6.4
5.6
> 70.8 79.2
3
6.4
5.7
> 79.2
1 plus 3
6.3
29/29
Source: European Medicines Agency
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