TRANSLATED
FROM FRENCH USING GOOGLE TRANSLATE.
NATIONAL
COMMISSION OF VETERINARY DRUG EXPERT REPORT OF DRUG
on the CNPV
NOTICE - 02 9/12/2003
Assessment of
adverse effects in the short and medium term oral progestins
based
megestrol acetate used for the prevention and interruption of heat in dogs and
cats of 9 December 2003
I, Gerard
Keck, president of the National Committee of veterinary pharmacovigilance
certify that
the expert report on adverse short and medium term effects of progestin-only
oral-based
megestrol acetate used for the prevention and disruption of heat in dogs and
cats. and conclusions presented in this report were adopted at the meeting of
the National Committee of veterinary pharmacovigilance of 9 December 2003.
Ferns,
2February 2004 GERARDKECK
_____________
INTRODUCTION
The National
Commission of Veterinary Pharmacovigilance has received May 30, 2002 by AFSSA -ANMV
(National Agency for Veterinary Medicinal Products) a request for an opinion on
undesirable effects in short and long-term oral progestins based megestrol
acetate used for the prevention and'. Interruption of heat in carnivores This
request results from two complaints from cat owners and stating, after taking a
veterinarian based drug megestrol acetate in appearance:
a
complicated pyometra of Acute renal failure after a single dose
mammary
tumors after several doses.
In both
cases, uterine infections and breast led to the death of the animal. These
complaints emphasize the lack of information on the risks involved taking this
drug both
on the
package leaflet and when buying from pharmacies (this product is distributed
exclusively
in pharmacies).
These
veterinary drugs basis of megestrol acetate for the carnivores may be
exempted from
the regulation of poisonous substances if:
these
veterinary drugs are administered orally or subcutaneously presented
tablets,
the limit
dose of active ingredient per tablet (unit making) is 20 mg
the
maximum amount of substance is given to the public of 200 mg (Order of 3
December 1986 amending for pets Order of 20 July 1949 on the exemption from the
regulation of
substances poisonous for veterinary medicine.)
In the double
objective of assessing the risks associated with the administration of the
veterinary drugs and reconsider this particular provision to exempt, AFSSA calls
on the Commission to specify the frequency and risk characteristics of the use
of all medicinal products veterinary containing megestrol acetate used for the
prevention and disruption of heat.
4
Megestrol
acetate is a synthetic progestin steroid progesterone derivative used
only by oral.
Its contraceptive effect is due to inhibition at the hypothalamic level of
pulsatile
GnRH secretion and thus secondarily cyclical secretion of pituitary FSH and
LH, thus
inducing a prolonged anoestrus. This molecule, like other synthetic
progestogens, also a non-selective affinity for progesterone receptors present
in the target organs of sex steroid hormones such as the uterus and breasts: the
uterus, megestrol acetate can induce hyperplasia glandulokystique variable
intensity and udder it causes an increase in the local production of growth
factors GH (growth hormone) and IGF 1-5 (insulin like growth factors) leading to
breast enlargement. It also has a central action on the limbic system and
antagonizes the effect of insulin (11). Antiandrogen Its share (11) justifies
its use for hypersexualisme. This study focused on 11 veterinary drugs for which
reports periodic safety were provided by the licensees of marketing. A total of
98 declarations submitted during the period 1994-2002 were studied.70 of these
statements relate to reactions occurring in .cats after administration and 28
other ones occurring in dogs during this period a total of 131,937,960 tablets
were sold-.
This report
is structured as follows:
-Study of
side effects reported in cats
- Study of
reported adverse reactions in dogs
-
Bibliographic data
- Conclusion
and proposals
5
1. STUDY
OF SIDE EFFECTS REPORTED IN THE CAT
1.1. DRUGS
BASED MEGESTROL ACETATE FOR THE PREVENTION AND INTERRUPTION OF HEAT
Eight
veterinary drugs, whose characteristics are reported in Table 1 are available
in veterinary
medicine for the treatment and the interruption of heat in the cat :
Table 1
Veterinary
Drugs based megestrol acetate for the treatment and the interruption
of heat in
the cat
species Brand name dosage/pill pills per pkg. ?
In cats, the
generally recommended for six of the seven drug regimens
Veterinary
are 5 mg / animal every 15 days to prevent heat. For Pilucalm and
Pill'kan5,
the regimen is different (Table 2).
For the
prevention of heat (Table 2), regimens differ from one medicine.
to another
veterinary Some of these veterinary drugs Mégécat, Mégédine can also be
used to treat
miliary dermatitis.
Table 2
progestin
regimens based megestrol acetate available for feline species
Preventing
heat, heat Interruption
Felipil
- Prev - 5 mg daily for 15 days - Int – 5 mg per
day for 3-5 days
Megecat
Prev 5 mg daily for 15 days Int -not given
Megepil
Prev 5 mg daily for 15 days Int - not given
Minipil Prev 5 mg daily for 15 days Int –
not given
Megedine
Prev not given Int 10 mg per day
for 8 days
Pill'ka 5
. Prev- 2.5 mg 3 times per week for 2 months Int-5 mg for 8 days
Pilucalm
Prev - 5 mg/10 kg for 32 days Int-20 mg/10 kg / 8 days
Side effects
(Table 3) differ veterinary drugs:
Table 3
Table 3
translation :
Title :
Contraindications and side / adverse
Column
Headings : Name Submitted side effects Adverse Contraindication
Felipil
S/E -
treatment sometimes results in males and females decreased vagrancy and
sometimes
increased appetite.
A/C -
metritis, pregnancy, diabetes, association with Estrogen
Megecat
S/E -
Increased appetite, weight gain.
A/C -
Diabetes, pregnancy, infection, Reproductive tract pre-pubescent females.
Mégépil
S/E -
tolerance pharmaceutical form Mégépil cat has been evaluated in a clinical
controlled study.
A/C - should
not be administered before the first estrus Do not administer to female pre
-pubescent
Minipil
S/E – No
(none ?)
A/C - Do not
administer to diabetic females with uterine infection, immature,
pregnant or
under estrogenic impregnation treatment.
Megedine
S/E -
Increased appetite, weight gain, hyperplasia glandulocystic.
A/C -
disorders of the reproductive tract and mammary tumors,diabetes,
pregnancy,females. prepubescent Do not use during pregnancy.
Use possible
in case of lactation.
Opochaleurs
S/E -
treatment can cause by prolonged repetitive administration and a
change of
temperament, a development, breast increased
A/C -
gestation appetite,Condition of the unit reproductive,female puberty, diabetes,
breast tumors
Pilucalm
S/E -
megestrol acetate causes in some cases an increase in appetite and weight gain.
These effects
are transient and cease after shortly stopping treatment.
A/C - acetate
megestrol causes no pyometra or ovarian cyst. A bitch treated Pilucalm
20 may be
normally fertilized his next heat with a normal pregnancy and
a normal
range. Like all synthetic progestins, is against Pilucalm indicated in cases of
diabetes,uterine infection and pregnancy. Pilucalm 20 does will not be used if
the female
is under
estrogenic impregnation therapeutic
Pill'kan 5
S/E
-treatment may lead to prolonged repetitive administration and a change of
temperament, a development, breast increased appetite
A/C Do not
use if :
genital
disease,
�diabetes
breast
tumors
in
pregnant females and females prepubescent
7
1.2. SUMMARY
OF SIDE EFFECTS - CHAT
1.2.1.reported cases
Some MAHs
laboratories, as shown in Table 4, the information collected before the
formal
establishment of pharmacovigilance.
Table 4
Period
covered by the periodic safety report
Date on the
market
Distributed
by ?
Period
Only cases
reported since 1994 were considered. All adverse events following the use of
these drugs to treat miliary dermatitis were excluded from this study. In
response to the report, the names of eight veterinary drugs will anonymysé:
Specialty-A,Specialty-B, Specialty-C,Specialty-D, Specialty-E,-Specialty-F,
Specialty-G,Specialty-H
(abbreviation
Sp on the graphs).
Ultimately,
70 cases reported in cats (Figure 1), including 16 fatal cases were evaluated.
Such a statement can report adverse events to one or more animals, these to
total
statements
relate83 treated animals including 20 dead. For two veterinary drugs,
Specialty
Specialty-C and Specialty -D, no cases have been reported.
Figure 1:
Annual distribution of cases by specialty
Figure 1
Cases by brand name
Left column -
Number of cases /Year
Bottom Row –
year
Color coded
by specialty (mfr name)
Figure 2 –
Number of cases by brand name
58 of these
cases involve adverse reactions in females, 9 cases involved
male animals
and 3, no information is given on the sex of animals.
The number of
reported cases was the most important for the specialty-B (48 cases). For other
drugs,veterinary the number of cases is lower: Specialty E-8, A-7,G-4,H- 2
F-1, C-0,D-0
.
I
Figure 3
Distribution of imputation for the reported adverse reactions following the
administration of megestrol acetate in cats
In 70% of
cases, the race of cats is unknown or unspecified. European breeds, Siamese,
Persian and
chartreuse are respectively 22, 4, 3 and 1 of the owners identified.
The case
description is often incomplete, and 55% of them (Figure 3), it was not possible
to establish a link (imputation O) between the observed response and veterinary
medicine based 'acetate megestrol-.
For 4 cases
Specialty E 3 cases and 1 Specialty A case - there is no link between the
adverse effect and the drug symptomatology. for the rest of the synthesis, it
was considered that these four cases "N" should be removed to determine the
profile and calculation of incidence. The remainder of the study focused on 66
cases charged A, B and O.
1.2.3.
Symptomatology
154 clinical
signs were mentioned to describe 66 cases reported. It should be noted that
several signs different clinical can be mentioned to describe each case. Figure
4 below and Table 5 show the relative proportion of these clinical signs.
Figure 4
Major
clinical signs mentioned to describe the side effects in cats
(% sign / 154
clinical signs used to describe cases)
24% Major
Functions
10% other ?
10% Nervous
and behavioral
4% weight
5% Mucosa and
skin
6% Sugar
metabolism
3% fetal
disorders
8% mammary
tumor
5% other
disorders of the mammary gland
3% genital
tract neoplasm
22% other
genital disorders
Major
Functions included all the effects on liver damage, kidney and gastrointestinal
Miscellaneous: General disorders + ineffective in 24% of reported cases of
pyometra are diagnosed and represent approximately 42% (16/38) described in the
lesions of the genital tract. Moreover, in about 20% of cases, tumors of the
mammary gland are also notified. A single case of cancer of the mammary chain
was reported by the owner without the diagnosis has been confirmed by a
veterinarian. Pyometra and mammary tumors were associated only in two cases.
10
Table 5
Clinical
signs mentioned in the case to describe the adverse reactions (case A-BO)
in cats
Number of
times the sign is mentioned ************** clinical signs * Number of
times
reproductive
tract tumor 4
tumor of ovaries or uterus4
Other
diseases of the genital tract 34
Pyometra16
metritis, vaginal discharge uterine hypertrophy 18
tumor of
mammary gland 13
tumor of mammary gland 12
breast carcinoma 1
Other
disorders of the gland mammary 8
hyperplasia mammary- 4
Swelling of the mammary gland
abscess of the mammary gland mammary gland hypertrophy - 4
Reproductive
-4
Fetal Death mummification 4
Efficiency -5
Lack of efficacy- 5
Hyperglycemia
carbohydrate10
Effect on metabolism 8
Hypoglycemia 2
Effect on
skin and mucousa -7
congestion cyanosis Alopecia
Erythema Skin Dehydration 7
Effect on
weight- 6
weight gain, weight loss 6
Signs nervous
and behavioral -16
Hyperesthesia aggressiveness
depression, apathy, lethargy,
ataxia, paresis 16
hyperthermia, hypothermia,
prolapse of the third eyelid -7
Changing hematology: anemia,
lymphocytosis, thrombocytopenia- 4
General
disorders - 36
Kidney and bladder: renal failure,
renal tumor,hematuria, urinary incontinence 5
Liver cirrhosis, jaundice, liver
tumor 5
Lung dyspnea 3
Abdomen Abdominal Pain
peritonitis, pancreatitis,7
Digestive tract: anorexia,
polydipsia salivation, vomiting,constipation, diarrhea 16
Total 154 154
- = Number of fatal cases not considered in this specification – 11
In 54% of
reported cases, no information on the time to onset of adverse events from
the beginning
of treatment is available. However, when we have the information, very large
variations are observed in the timing of onset of pyometra or mammary tumors 2
days after the start of treatment in 10 years for the occurrence of pyometra and
15 days to 6 years for the appearance of a breast tumor.
1.2.4.incidence,
Arbitrarily
the incidence was calculated by taking as a basis the dosage regimen of one
tablet every
15 days to prevent heat. Thus, it has been estimated that the average cat
was likely to
receive 24 tablets per year. Also were considered:
average
sales volume specialties over a year and specialty treated..
the
average number of cases per year for a specialty year
the number
of animals likely to have been during one year
Table 6
Table 6
summarizes all the sales and calculate the incidence veterinary medicinal-.
Specialities
Calculation
of incidence veterinary medicine (case A - B-O) 66 cases cat
Brand
Number pills
sold
Number cases
reported per year
Incidence per
100K pills
Number of
animals treated
Incidence per
100K animals
Figures 5 and 6 provide a graphical illustration of the impact they are
evaluated according to the number of animals treated or the number of tablets
sold
Figure 5:
Number of notifications reported sales figures (annual basis)
Figure 6:
Number of notifications reported to the numbers of animals that have been
treated 
Number of
animals treated (24 tablets per year)
Annual
Incidence per 100K animals treated
13
For
veterinary drugs also used for the treatment of miliary dermatitis, it was not
possible to
estimate the proportion prescribed medications only under contraception. In
addition, for
mixed veterinary drugs (for cats and dogs), it was not possible
to estimate
the proportion of cats actually treated. It is noted that according to
veterinary drugs, the incidence varies between 0 reactions and 4.1379 per
100,000 treated animals and between 0 and 0.1724 reactions 100,000 tablets sold.
In cats, the
overall average incidence of reactions to 0.0645 100,000 tablets sold and
1.55
reactions per 100 000 animals receiving treatment 24 tablets per year, however,
given the uncertainty calculations, these figures should be taken with caution.
February
14.STUDY OF SIDE EFFECTS REPORTED
IN DOGS (did not copy charts)
2.1. DRUGS BASED MEGESTROL ACETATE
FOR THE
PREVENTION AND INTERRUPTION OF
HEAT
As for the cat, notices differ.
Tables 7 and 8 show the veterinary medicinal containing
productsmegestrol acetate
available for the canine species and treatment
recommendedregimens.
Table 7
Veterinary Drugsbased megestrol
acetate available for the canine species
Drugs
Veterinary
content /
compressed package
Pilucalm 20 20 mg 16 tablets
10 mg 16 tablets Pilucalm
Pill'kan May 5 mg sugar8
Pill'kan20 20 8 sugarsmg
Canipil10 mg 20tablets
mg 10Minipil 5, 20 and 30
tablets
mgMegedine 10 16 and 32 tablets
Opochaleurs 10 mg 16 tablets or 8
Table 8
regimens of veterinary medicinal
products containing megestrol acetate
in the canine species
Drugs
VeterinaryPrevention heat
Interruption heat
Minipil 5 mg/10 kg / d 32 d before
heat -
Pilucalm 20 5 mg/10 kg / day 32
days 20 mg/10 kg / day 8 days
Pilucalm 5 mg/10 kg / day 32 days
20 mg/10 kg / day 8 days (1)
Pill'kan May 5 mg/10 kg / j 32
days 20mg/10 kg / day 3 days then ½ dose
for 7 days (2)
Pill'kan May 20 mg/10 kg / day 32
days 20mg/10 kg / day 3 days then ½ dose
for 7 days
Canipil 5 mg / 10 kg / day 1 month
20 mg/10 kg / day 8 days
Opochaleurs 5 mg/10 kg / day 32
days
Megedine - 20 mg/10 kg / day 8
days
(1) other regimens for Pilucalm:
- lactation pseudopregnancy: 20
mg/10 kg / day for 8 days and 20 mg/10 kg, 2 times per week for 2
weeks
- hypersexuality 20 mg/10 kg / day
for 7 days. If improved, continue at a dose of 10 mg/10 kg / day
for 14 days. If administered 40
mg/10 kg / day for 7 days and 10 mg/10 kg / day for 14 days. If
no improvement occurs, discontinue
treatment-.
(2) other regimens for Pill'kan:
Hypersexuality in males: 20 mg/10
kg / day for 8 days, and 10 mg/10 kg / day for 8 days.
Table 9 shows the cons-indications
and side / adverse effects brought on records
and / or on the label of
veterinary medicinal products for dogs.
15
Table 9
Contraindications and side /
adverse
side effects filed Name / adverse
Contraindications and precautions
Minipil No
Do not administer to diabetic
females
with uterine infection, immature,
pregnant
or under estrogenic impregnation
treatment.
PILUCALM
megestrol acetate causes some
incases, increased appetite and
decisionweight. These effects are
transient and cease
shortly after discontinuation
of megestrol acetate does not
cause
pyometra or ovarian cyst. A bitch
treated Pilucalm 20 may
befertilized
normallyhis next heat with
a normal pregnancy and a normal
range.
Like all synthetic progestogens,
Pilucalm is against-indicated in
cases of
diabetes,uterine infection and
pregnancy.
Pilucalm 20 will not be used if
the female is
under estrogenic
impregnationtherapeutic
PILL'KAN
treatment may exceptionally cause
by prolonged and repeated
administration, a
change in temperament
mammary development,
increasedappetite
-.Affection of Reproductive
- Diabetes
- Female in gestation
- prepubescent females
-mammary tumors
CANIPIL Diabetes, pregnancy,
metritis
Do not combine with estrogen
hormones
OPOCHALEURS
Exceptionally, in case
ofadministration:
prolonged and repetitive
behavior modification,development,
breast increased of appetite
Diabetes, pregnancy,
prepubescent females,
reproductive condition of
mammary tumors
MEGEDINE Increased appetite,
weight gain,
hyperplasia glandulocystic.
disorders of the reproductive
tract andtumors,
mammary diabetes, pregnancy,
female
immature. Do not use during
pregnancy-...
Can be used in case of lactation
16
2.2 SUMMARY OF SIDE EFFECTS - DOG
2.2.1. Number of reported cases
Some firms (Table 10) collected
the information before the formal establishment of
pharmacovigilance.
Table 10
Period covered by the periodic
safety report
Date of the
firm marketPeriod
Minipil11/02/1983 CEVA SANTE
ANIMAL 1983 - 12/2002
20 Pilucalm
Pilucalm 24/02/1988 / 28/11/1983
NOVARTIS 1998-2002
Canipil VETO CENTRE 22/07/1987
01/01/1996 - 31/12/2002
Pill'Kan May 18 / 10/1985 CLEMENT
- THEKAN 01/01/1999 - 31/12/2002
21/05/1984 Pill'Kan 20 CLEMENT -
THEKAN 01/01/1999 - 31/12/2002
11/02/1983 Opochaleurs CLEMENT -
01 THEKAN / 01/1999 - 31/12/2002
Megedine ARKOMEDIKA 02/07/1980
01/01/1998 - 31/12/2002
For the remainder of this report
on behalf of the seven veterinary drugs will anonymysé specialties: Specialty I,
J Specialty, Specialty-K-L
Specialty, Specialty-M, N-Specialty, Specialty-O (Sp Abbreviation on
graphs.)
No adverse effects have been
reported in dogs for veterinary medicinal Specialty K,
J Specialty, Specialty Specialty O
and M. For other veterinary drugs, a total of 28 cases have been
reported (Figure 7): 20 cases
Specialty I, 1 L Specialty cases, 7 cases Specialty N. Three of them were in
seriouscases resulting in death of
the animal being treated. 30 dogs were treated.
Figure 7
Number of cases reported per year
in the dog
0
1
2
3
4
5
6
7
Years
Case
sp L
SpI
SpN
94 95 96 97 98 99 00 01 02
17
2.2.2. Imputation
In this species, the description
of the cases is sometimes incomplete, which has established only in
29% of reported cases, probable or
possible relationship (imputation A or B) between the adverse event
and product administered ( Figure
8). However, it should be noted that in two cases reported for Specialty N
(7% of cases), it was clearly
established that the observed effect was not related to the drug administered.
Figure 8
Distribution of imputation for
reported adverse events following administration
of megestrol acetate in dogs
4%
25% 57%
7%
7%
A
B
O
N
Unassessable
2.2.3.symptoms
The two casescharged "N" have been
removed to make the symptomatic profile, the study focused on the26
remainingcases (Figure 9). 57
clinical signs were noted (several clinical signs per case) to
describe the symptoms of these 26
cases as shown in Table 11.
Figure 9
Main clinical signs mentioned to
describe the side effects in dogs
(% sign / number of clinical signs
used for the description of cases)
14%
12%
19%
37%
2% 16%
of the mammary gland disorders
Disorders ofgenital
nervous signs and behavioral
efficiencyMissing:
Hematology and Biochemistry
Major Functions
Major Functions includes all
effects for cardiac lesions, lung, liver, kidney and gastrointestinal
18
As shown in Table 11, only 4 cases
of pyometra were diagnosed following the use product
oftheI and one case of breast
hyperplasia. These pyometra occurred within 11 to 30
days after a few days of treatment
(5-8 when information is available). In addition, several
reports (27% of cases) relate to
complaints about the lack of efficacy (unwanted pregnancy,
pseudopregnancy, persistent
unwanted heat or heat) of these veterinary drugs.
Table 11
Clinical signs mentioned in the
case described adverse reactions (26 cases
AB-O)
Number of
times the
sign is
mentioned
clinical signs * Number of
times
Lack of efficacy Gestation
unwanted, pseudopregnancy April
7Persistence of heat, heat
unintended 3
4 Pyometra
disorders unit genital metritis 8
3
1 ovarian cyst
disorders of thegland
mammaryhyperplasia breast 1 1
nervous andsigns,
9behavioral
Aggression hyperarousal
weakness, apathy
sleepiness, tremors
agitation, depression
Tournis
9
Effect onparameters
haematological and
biochemical11
bleeding
réticulocytose
disorder bleeding
Anemia
leukocytosis,
elevated alanine transferase
High Cholesterol
11
Abdomen: distension 1
Liver: Jaundice 1
Heart: heart failure, tachycardia
2
Lungs: dyspnea, tachypnea 3
Kidney-Bladder: polyuria,
hematuria, hemoglobinuria 5
Major Functions 21
digestive tract: anorexia,
polyphagia, polydipsia,
salivation 9
* = number of fatal cases (3) not
taken into account in this description
19
2.2.4. Incidence
Although several regimens are
available and although the levels of active ingredient
different from a veterinarian to
another drug, it was estimated that for treatment, the number of
tablets can vary between 8 and 32
depending on the veterinary drug . Forveterinary drugs
mixed(for cats and dogs), it was
not possible to estimate the proportion of dogs actually
treatedABO.
Table 12
Calculation of the impact (annual
average) Veterinary medicine
(26 cases - DOG)
Specialty nonbre of
tablets
sold per year
number
Averageof
cases / year
Incidence /
100000comprimés
sold
Treatment
(*)
Number
animals
treated
Incidence /
100,000 Ax
Sp I 2 153 707 2.2222 0.1032 16
134 607 1.6509
Sp J 49 514 0.0000 0.0000 32 49
514 0.0000
Sp K 145 003 0.0000 0.0000 32 145
003 0.0000
Sp L 676 243 0.2000 0.0296 16 42
265 0.4732
Sp M 199 580 0.0000 0.0000 16 12
474 0.0000
Sp N 613 771 0.6250 0.1018 16 38
361 1.6293
sp.Ø 114 824 0.0000 0.0000 8 14
353 0.0000
Total 3952641 3.0472 0.0335-436
5760.5362
*= average number of tablets per
treatment
Figures 10 and 11 provide a
graphic illustration of the impact they are evaluated according
tothe number of animals treated or
the number of tablets sold.
Figure 10: Number of notifications
reported sales figures ( annual basis) in DOG
0
1 000000 000000 000000 000000 000
0002
3
4
5
0.0000
0.0200
0.0400
0.0600
0.0800
0.1000
0.1200
nonbre tablets sold 2153 49 514
145 003 676 243 199 580 613 771 114 824 3 952
Incidence/100 000cp sold 0.1032
0.0000 0.0000 0.0296 0.0000 0.1018 0.0000 0.0335
Sp I Sp Sp J K L Sp Sp Sp M N
sp.ØTotal
20
Figure 11
number of notifications (annual
average) compared to the number of animals which have been
treated (as recommended by 8, 16
or 32 tablets, according to veterinarian medicine)
0
50 000000000000000000000000000
100
000150
200
250
300
350
400
450
500
0.0000
0.2000
0.4000
0.6000
0.8000
1.0000
1.2000
1.4000
1.6000
1.8000
No. of animals treated 134 607 49
514 145 003 42 265 12 474 38 361 14 353 436 576
000 Incidence/100 Ax 1.6509 0.0000
0.0000 0.4732 0.0000 1 6293 0.0000 0.5362
Sp I Sp Sp J K L Sp Sp Sp M N
Total sp.Ø
The average incidence of adverse
effects in dogs was estimated at 0,536 reactions per 100 000animals.
treated However, given the
uncertainties regarding the actual number of tablets ingested during
treatmentand the inability to
establish the proportion of dogs actually treated during treatment with
mixedspecialties (cat-dog), this
figure must be treated with caution-..
21
3 LITERATURE DATA
3.1. LITERATURE DATA AT
THE CAT
3.1. 1.
Data on uterine
Endometrial
hypertrophy due to megestrol acetate is proven in 10 cats previously
ovariectomized receiving 10 to 30 mg of megestrol acetate per week (1). Lesions,
except for a cat that declares a pyometra (lot 30 mg), partially regress after
cessation of treatment. They exist also in non-ovariectomized cats
(14)métropathies:.
A study has
helped to identify the percentage of 1 case per 244 cats treated
for 3.5 years
use.
(22) extended
all progestin (15) can cause pyometra and cystic hyperplasia and acetate
Megestrol is
a relatively benign progestin. Other publications describe the effects on the
uterus in the cat (26)
3.1. 2.
Data on breast
In the feline
species, megestrol acetate causes effects in the breast (17, 21) and of the
Hypertrophy
breast. Authors (9 & 13) have established the link between non-neoplastic
changes dominated by fibroadénomatose frequency and distribution of megestrol
acetate. A survey very recent MANAGED (study in breeding and canine sports
group) led by Dr Martine Lennoz (unpublished results) showed that out of 53
cases of fibroadénomatose, 13 had received a treatment progestagen and that
these blooms can breast occur following impregnation hormonal with normal doses
of megestrol acetate. The appearance of mammary hyperplasia imposes a judgment
of progestagen. Regression of lesions is often incomplete (18) suspected:.
The link
between megestrol acetate and breast cancer has not been proven (3) but
First
publication (10) reports that 3 out of 17 cancers of breast changes are due to
megestrol
acetate and a second (25) reported that 17 cases of breast carcinoma, 4 were
developed on
cats receiving progesterone.
3.1. 3. Other
data
are the many
publications on adverse effects described in the cat following
administration of megestrol acetate as hypoadrenocorticism (5, 6, 17), diabetes
mellitus (17, 20),behavioral changes (aggression or depression, polyphagia) and
weight gain (17, 21).It should be noted that publication (8) highlights the good
tolerance to megestrol acetate.
22.
3.2 LITERATURE DATA IN DOGS (no
edit)
3.2.1. Data on the uterus
In the bitch, progesterone also
induces hyperplasia of the endometrium, pyometra (15) and
cystic hyperplasia (14). As in the
cat, the number métropathies is low. Of 389 dogs
receiving megestrol acetate during
proestrus (4), 0.8% said no and pyometra in
119 dogs treated for anoestrus.
3.2.2. Data on breast
In the bitch, repeated over a long
period of progestin administration can lead to
breast hyperplasia, lactation and
the onset of breast benign nodules (7, 19, 23, 24.)
In their study about 389 dogs
receiving megestrol acetate during proestrus, Burke and
Reynolds (4) found that 5.9% of
bitches have breast enlargement and 1% a
lactation.When megestrol acetate
is distributed during anoestrus (119 dogs) the percentage
decrease (5% and 0.8%).
3.3. INFORMATION RIGHTS
The megestrol acetate for breast
cancer-link process is not documented in the study except for MEGACE specialty
produced by BRISTOL-MYERS SQUIBB is dosed at 160 mg of acetate megestrol and
prescribed during the palliative treatment of carcinoma of the breast
(antiestrogenic effect) in humans.This specialty is cons-indicated in pregnant
women and / or have a history of thromboembolism.
A paragraph on pre-clinical safety
of the summary of product characteristics indicates an
increase in the incidence of
benign and malignant mammary tumors in dogs subjected
to megestrol acetate
administration for seven years. Similar studies in rats and monkeys
have not demonstrated this
phenomenon. The clinical relevance of these observations has not been
established.
MEGACE for the study in the dog
seems to attest to a sensitive species (dog) of the tissue breast to megestrol
acetate.
CONCLUSIONS AND PROPOSALS
It should be
noted that this study took into account cases that occurred before the
establishment of veterinary pharmacovigilance operational since 2001 in France,
to better define the nature of the adverse events following administration of
these veterinary drugs. Since 2001, 33 cases cats and dogs have been reported
including 32 charged A, B or O. As 37,758,167 tablets were sold during this
period, the incidence of 0.088 per 100 000 tablets.
This study
included 98 reports of adverse reactions in cats and dogs. They were
notified in
1994 and recorded December 31, 2002 for a total of 131,937,960 tablets
sold, which
represents about 0,074 cases per 100,000 tablets sold. The incidence of
reactions following administration of the oral progestin products based
megestrol acetate seems so low.
23
In addition,
for six of these cases, it was concluded that the adverse event could not be
linked to progestin ingested.
Notified side
effects for 92 cases charged A, B or O (Table 13) are many and varied as
in cats than
in dogs.
Table 13
Main clinical
signs
Case (A, B,
O)
66 cases cat 26 cases dogs
Fatal 13 3
Tumor of
genital 4 0
Pyometra
16 4
Other
disorders of the reproductive system (metritis, uterine hypertrophy ...)
18 4
tumor of the
mammary gland 13 0
Other
disorders of the breast 8 1
Effect on
sugar metabolism 10 0
nervous and
behavioral signs 16 9
in cats are described:
- in
approximately 54% of reported cases of diseases of the genital tract with
particularly
métropathies
-in 20% of
cases, non-cancerous tumors of the mammary gland, in this case,
literature
data indicate firstly a breast hyperplasia megestrol acetate link
is
established and secondly that the most common injury (fibroadénomatose) may
occur at the beginning of treatment with megestrol acetate. All breast changes
require a
judgment of
non-recommended treatment in the instructions
-in 24% of
cases, nerve and behavioral symptoms (aggression, depression, paresis ...)
with or
without weight gain
-a few
effects.the metabolism of sugar are also identified
in dogs are described:
- 30% of reported cases of
diseases of the genital tract with particularly métropathies
-in less than 4% of cases, breast
hyperplasia;
- in 35% of cases, nerve and
behavioral symptoms (aggression, weakness, drowsiness,
restlessness ..)
The diversity
of the wording of against-indications and side effects have been clearly
identified. Most of the entries highlight the potential for use during
pregnancy, uterine and breast disease, diabetes and association with estrogen.
No one is suggesting the possibility of amétropathie after taking megestrol.
Some entries even emphasize the absence of risk of pyometra. The possibility of
breast modification is discussed. These changes are considered benign or
reversible. The nature of this potentially tumor breast disease is never
considered .Sometimes it is proposed to limit to 18 months duration of treatment
to avoid adverse effects. Moreover, it is important to note that this study of
identify the use of veterinary medicinal products based megestrol acetate in
dermatology to treat feline "miliary dermatitis"(2, 16) can cause different side
effects than observed when using as progestin the fact the duration of
treatment. An implementation of a study pharmacovigilance on megestrol acetate
in the indication "miliary dermatitis" may be initiated-.at the end, as side
effects may occur after the first dose of oral progestin, the terms "short and
long-term "contained in the wording of the referral will not be included in the
publication of the notice that will be on the side effects of progestin-only
oral based Megestrol acetate used for the prevention and interruption of .heat
in dogs and cats
- Given the
relatively low incidence of adverse events reported less than
0.1per
100,000, the relevance of raising the exemption seems unfounded
-A campaign
information with retail distributors, pharmacists and veterinarians,
to raise
awareness of the need to inform future users of the risks of adverse reactions
may occur following the use of oral progestins to prevent or stop the heat in
domestic carnivores, should be launched
-harmonization of labels and conditions should be considered and references
further to
the adverse effects likely to be observed, must included be on the outside
label and, where appropriate, the instructions. The following wording on the
side effects can be proposed: "After single or repeated administration,
affections of the genital tract (hypertrophy, pyometra and uterine tumors) as
well as conditions of the udder (hypertrophy and mammary tumors) were noted,
cases of diabetes and behavioral changes (polyphagia, aggression or apathy) have
also been reported
"-In
addition, it would be:
25
⇒ remind
veterinarians and pharmacists their requirements for reporting
adverse
effects occurred after the administration of these veterinary drugs
in domestic
carnivores
⇒ further
study by the MANAGED (study in reproduction, breeding and Group)
dog sport
and set up a prospective investigation of progestin based megestrol acetate,
the protocol will be established by the pharmacovigilance centers.
26
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Other items
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VN MEYERS-WALLEN Current and Proposed methods for contraception and termination
of pregnancy in dogs and cats JAVMA 1991; 198:1214-1225
JOHNSON SD,
ROOT KUSTRITZ MV OLSON PNS Disorders of the feline uterus and uterine tubes
(oviducts) in Canine and Feline Theriogenology 2001 WB Saunders, Philadelphia:
463-471
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