An innovative approach t o de rma tophy to s i s
Itrafungol™
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Produced by Janssen An ima l Hea l th
Turnhoutseweg 30
2340 Beerse
Be lg ium © 2004
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TA B L E O F C O N T E N T S
Itrafungol
1. Introduction:
Dermatophytosis in cats and humans 4-6
2. Physicochemical and
pharmacodynamic properties 7-9
73. Pharmacokinetic profile 10-12
4. Treatment schedule 13
5. Convenience of use 13
6. Clinical efficacy 14-16
7. Safety profile 17
8. References 18-19
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1 . I N T R O D U C T I O N
D e r m a t o p h y t o s i s i n c a t s a n d h u m a n s
What is dermatophytosis?
Dermatophytosis or ‘ringworm’ is a fungal infection of the
keratin-containing structures such as skin, hair and nails.
Germinating (i.e. developing) spores and hyphae penetrate the
skin’s keratinized layer and hair follicles to produce infection.
They then migrate deeper along the hair shaft.
This process is facilitated by the production of keratolytic
enzymes. Invasion usually stops at the zone of keratinization.
Hyphae are then carried out to the surface by the damaged
growing hair. At this stage the frayed hairs often break off,
resulting in (circular) scaly areas of alopecia.
Only a few dermatophilic (literally ‘skin-loving’) species are
responsible for infection in cats. In the majority of cases
(>95%), Microsporum canis is the isolated pathogen.
Other dermatophytes, such as Trichophyton mentagrophytes,
T. verrucosum, M. gypseum and M. persicolor, are less
frequent (1, 2).
Norma l s t ruc tu re o f ca t sk in and ha i r s
L igh t mic roscop ic image o f M. can is spores(a r th rocon id ia ) a round an invaded ha i r© Prof . J . Dec lercq, FVM, Ghent Univer s i ty - Belg ium
Scann ing e lec t ron mic roscop ic image o f penet ra t ing funga l hyphae a long the ha i r sha f t
P©D
Hai r sha f t
Kera t in i zedsk in laye r
Ha i r bu lb
Ha i r fo l l i c le
Zone o f ke ra t in i za t ion
Sebaceousg land
4
Blood vesse l
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A recent pan-European survey found that the dermatophyte
prevalence in pet cats with suspicious dermatological lesions is
about 30% (2), with higher frequencies in autumn and winter.
Any cat can develop a dermatophyte infection. However, weak or
immunosuppressed animals are more susceptible to the develop-
ment of lesions. Consequently, infection is most commonly seen in:
• Cats aged less than 1 year. Kittens (from 10-14 days) are
particularly prone to infection.
• Pregnant and lactating queens.
• Old or sick cats. Immunosuppressed (such as FIV- and
FeLV-positive) cats may be more susceptible to lesions (3).
Flea or mite infestation might also predispose to infection.
• Cats in breeding colonies and catteries (4).
• Long-haired pure-bred cats (e.g. Persians and Angoras) (5).
f tP ronounced dorsa l ha i r loss and e ry thema©Dr. J . Fontaine , Be lg ium
Sebor rhoea and c rus ts on the ta i l
The clinical signs of dermatophytosis in cats vary widely.
• Typical lesions are characterised by areas of alopecia with
peripheral erythema, scaling and encrustations as well as
broken and frayed hairs that epilate easily.
• Other possible features include: formation of pustules, pruritus,
miliary dermatitis, folliculitis and patchy or generalized alopecia.
• Less frequently, nail bed infections, chin furunculosis, widespread
erythroderma and nodules (in Persian cats) are observed.
• The well-known picture of ring-shaped round patches is fairly
rare and not very specific for fungal dermatitis.
Lesions may affect the whole body, but mainly occur on
the head, ears, tail and front paws. In kittens, severe
inflammatory reactions may occur and the disease may
even be life threatening.
Crus ty a lopec ic les ion on the nose©Dr. J . Fontaine , Be lg ium
Mul t ip le e ry thematous a lopec icles ions on the ear©Dr. J . Fontaine , Be lg ium
Dermatophyte prevalence and clinical signs in cats
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Cat dermatopytes as a zoonosis
M. canis is the most commonly isolated zoophilic dermatophyte
in humans (6). Because of the close relationship between cats
and their owners, cats have been identified as the primary source
of zoonotic infection for humans. It has been established that in
over 50% of families with infected animals, family members have
lesions. This is not surprising as asymptomatic carriers can also
transmit the disease, and infection can be contracted through
direct contact with a cat or indirect contact with an infected
environment. Stray cats are also an important source of infection,
while transmission of zoonotic infections among humans is rare.
In humans lesions are mainly observed in children (6). They are
called ‘Tineae’ and can be present on different parts of the body.
The scalp (Tinea capitis) as well as arms and hands (Tinea corporis)
tend to be most frequently affected (7). The clinical image is
variable but often quite inflammatory and suppurative.
Nail infection (Tinea unguium) is very rare. Through effective
treatment of infected cats and their environment, transmission
to humans is prevented and a healthy human-animal bond can
be ensured.
T inea cap i t i sT inea co rpor i s©Dr. J. Fontaine,Belgium
T inea ungu ium
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2 . P H Y S I C O C H E M I C A L A N D P H A R M O C O D Y N A M I C P R O P E R T I E S
Tr ia zo le r ing
Mode of action
Itraconazole’s main site of action is the fungal endoplasmatic
reticulum, where it inhibits the cytochrome P-450 14-demethylase.
By impairing C14-demethylation of eburicol, the synthesis of
ergosterol (which is essential in maintaining fungal cell wall
integrity and activity) is hampered (8). This results in a cascade
of perturbations that together lead to antifungal activity:
• The availability of ergosterol is decreased, while compounds
involved in the production of ergosterol (14-methylated sterols
and 3-ketosteroids) accumulate, further destabilising fungal
membranes.
• Lack of ergosterol synthesis results in an uncoordinated
synthesis of the primary septum of yeasts and of the septa
and primary wall of hyphae.
• Changes in the sterol structure lead to an alteration in
fatty acid composition and profoundly alter the activities of
membrane-bound enzymes.
These changes make the fungal cell susceptible to osmotic
damage and subsequently to phagocytosis by host cells,
which results in cell death.
FUNGITOXIC ACTIVITY
DETERIORATEDMEMBRANES
DECREASED ACTIVITYOF MEMBRANE-BOUND
ENZYMES
UNCOORDINATEDSYNTHESISOF CHITIN
Cyt.P450
ITRACONAZOLE
ERGOSTEROL
HO
LANOSTEROL
HOH3C
4
14
CH3
CH3
Chemical structure and molecular formula
Itraconazole is a synthetic, highly lipophilic, water insoluble,
broad-spectrum antimycotic agent with a pronounced antifungal
activity against a wide range of pathogenic yeasts and fungi.
Its chemical structure is characterised by the addition of a triazole
moiety. The 5-member triazole ring with 3 nitrogen atoms is
believed to be responsible for the broad spectrum of activity and
low toxicity.
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THE ADDITION OF A TRIAZOLE MOIETY ALLOWSFOR AN INCREASED SPECTRUM OF ACTIVITY ANDIMPROVED SAFETY PROFILE.
Itraconazole molecular formula: C35H38C12N8O4
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Acetyl Coenzyme A
Squalene
2,3-Oxidosqualene
Lanosterol
24-Methylene dihydrolanosterol (eburicol)
cyt P-450 14-DM Inhibition by itraconazole
4,4-Dimethyl-ergostatrienol
Ergosterol
SCHEMATIC REPRESENTATION OF THE MECHANISMOF ACTION OF ITRACONAZOLE:
NORMAL ERGOSTEROL SYNTHESIS ANDSITE OF ACTION OF ITRACONAZOLE:
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BINDING OF ITRACONAZOLETO THE FUNGAL HAEM STRUCTURE:
A) An enlarged spectrum of activity against pathogenic
yeasts and fungi
Itraconazole has been extensively tested in vitro.
Studies of itraconazole against 6000 isolates of 252 fungal
species show that more than 90% of strains are inhibited by less
than 1 µg/ml. Furthermore, at least 97% of the most common
dermatophytes and yeasts are effectively inhibited at these
concentrations (9,10).
Some of the important pathogens against which itraconazole’s
antifungal activity has been demonstrated are:
Pharmacodynamic properties
Itraconazole, a third generation azole with an added triazole ring allows for:
Cocc id io ides immi t isSporoth r i x schenk i iH is top lasma spp.
Cr yptococcusneofor mans
Cand ida spp.Asper g i l lus spp.
Malassez ia spp.©Prof. J. Declercq, FMV, GhentUniversity, Belgium
Tr iphophy ton spp.Mic rospor um spp.
Triazole +non-ligatingportion
Specific shape
Pronouncedlipophilicity
High specificityfor fungalCYP-450
High affinityfor fungalcell membrane
Strong affinityfor tissuesespecially skin
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B) An enhanced tissue penetration and residual effect
Thanks to its highly lipophilic character, itraconazole is readily
available and remains accumulated in target tissues (skin and
hairs) and sebum glands for a much longer period than the
duration of treatment. This enables effective short and safe
periods of pulse treatment and diminishes the chance of a
relapse (see Pharmacokinetic profile).
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I t raconazo lemolecu le
B ind ing w i th funga lcy tochrome P-450
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C) A higher safety margin
Itraconazole has a high affinity and a high specificity for the fungal
cytochrome P-450: the N atom of the triazole ring binds to the
fungal haem iron at the catalytic site and forms a stable complex
that prevents the oxygen-induced activation of this coenzyme.
Furthermore, the selectivity for the fungal cytochrome P-450 is
mediated by a high affinity for the highly lipophilic ‘tail’ of the
triazole molecule, which it binds to an apoprotein portion of the
fungal cytochrome molecule. Consequently, at concentrations
that inhibit the fungal coenzyme, itraconazole has little effect on
mammalian cytochrome P-450. This specificity reduces the
potential for drug interactions with mammalian biochemical
pathways in which cytochromes play a role, and improves the
efficacy and safety profile of itraconazole (11,12).
D) Superior antifungal potency and fungicidal activity
The superior in vitro antifungal potency of itraconazole versus
other antimycotics has been shown by Odds et al. (13,14).
In the model they used, antifungal activity is expressed as the
mean relative inhibition factor (RIF), which represents antimycotic
activity in relation to a fixed number of pathogenic dermatophytes
and Aspergillus spp. The RIF is expressed as a percentage of
control fungal growth: an RIF of 100% indicates no measurable
antifungal activity and an RIF of 1% optimal antifungal activity.
The mean relative inhibition factors (%) of itraconazole and other
antimycotics:
1%: opt ima l an t i funga l ac t i v i t y100%: no ant i funga l ac t i v i t y
Itraconazole has also been shown to exhibit fungicidal activity in
broth media. Itraconazole is fungicidal at low concentrations
against the following clinically relevant pathogens (15):
Fungicidal activity after various contact durations(hours) at the stated concentrations (µg/ml)
No interferencewith cat CYP-450at therapeuticconcentrations
Low therapeuticconcentrations
Prolonged thera-peutic effect
Strain
Antifungal agent Dermatophytes Aspergillus spp.
Itraconazole 12 25
Ketoconazole 18 55
Griseofulvin 58 97
Nystatin 46 68
10 100 1000
M. canis 6h 2h 0.17h
T. mentagrophytes 6h 1h 0.17h
C. albicans 24h 3h 0.25h
A. fumigatus 24h 4h 0.25h
Moreover, against dermatophytes, fungicidal activity in serum
proceeded even faster than in broth media (16):
After 10 min at 100 µg/ml
After 4h at 10 µg/ml
Wide safety margin
Allowing shorttreatment schedules
Allowing low daily doses
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Funga l haem s t ruc tu re
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3 . P H A R M A C O K I N E T I C P R O F I L E
Since itraconazole is insoluble in water, a solubilising excipient,
hydroxypropyl-ß-cyclodextrin was added to ItrafungolTM.
Cyclodextrins are cyclic carbohydrates. They have a unique spatial
configuration in which polar hydroxyl groups are oriented towards
the outside of the cylindrical structure. As a result, this structure
is hydrophilic outside and hydrophobic inside. The hydrophobic
inner cavity forms an ideal chamber in which poorly water-soluble
guest molecules, such as itraconazole, can conceal their most
hydrophobic parts. Contact between such an insoluble compound
and a highly soluble cyclodextrin in an aqueous environment
results in complexation to form a soluble complex.
CYCLODEXTRIN MOLECULE GUEST MOLECULE
WATER MOLECULE
ATTRACTION
REPULSION
HYDROPHILICPART
HYDROPHOBIC OR LIPOPHILICPART
R
R
CYCLODEXTRIN / GUEST MOLECULE COMPLEX
A major breakthrough in the development of antifungal therapy
was signalled by the correlation of tissue pharmacokinetics
at specific body sites with dosage, duration of therapy and
efficacy. Itraconazole is highly lipo- and keratophilic, which enables
a short duration of therapy thanks to a therapeutic reservoir in
the target tissues (skin and hair) but not in the systemic circula-
tion. This reservoir allows intermittent (pulse) therapy regimens
that are highly effective and safe.
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EXCELLENT ORAL BIOAVAILABILITYTHANKS TO THE ADDITION OF THE EXCIPIENTHP-ß-CYCLODEXTRIN.
CHEMICAL STRUCTURE OF CYCLODEXTRIN:
DIAGRAMMATIC REPRESENTATION OF COMPLEX FORMATIONBETWEEN CYCLODEXTRIN AND ITRACONAZOLE
IN THE ITRAFUNGOL™ ORAL SOLUTION:
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A) Plasma pharmacokinetics and metabolisation
When the ItrafungolTM registered pulse treatment schedule
(5 mg/kg/day for 3 alternating weeks) is used, the following
plasma kinetic profile is observed (17,18):
• Rapid absorption from the gastrointestinal tract with mean
peak plasma levels 1 to 2 hours after administration
• Doubling of the mean peak plasma concentration after 7 days
of dosing (day 1: 0.525 µg/ml; day 7: 1.05 µg/ml)
• 20-30% increase in 24-h plasma concentrations during the
2 nd and 3 rd week of dosing
• T1/2 of 12 hours after a single administration
• T1/2 of 36 hours after repeated administration
• A virtually complete washout of plasma 1 week after the end
of repeated dosing.
Itraconazole is metabolised in the liver into many metabolites,
of which hydroxy-itraconazole has antifungal properties (19).
In fact, hydroxy-itraconazole has been shown to have an in vitro
antifungal activity comparable to that of itraconazole.
A plasma pharmacokinetic profile has been observed that was
similar to that of itraconazole, but at lower concentrations.
TIME (WEEKS)0 1 2 3 4 5 6 7
3
2,5
2
1,5
1
0,5
MEA
N C
ON
CEN
TR
ATIO
NS
, g
/ml
µTIME POST-DOSE, h
0 4 8 12 16 20 24
2
1
0,5
0,2
0,1
0,05
0,02
0,01PLA
SM
A C
ON
CEN
TR
ATIO
NS
, g
/ml
µ
Mean plasma concentrat ions after repeated pulse treatment.
Hydroxy - itraconazole - day 1Itraconazole - day 1
Plasma
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RAPID ABSORPTION:
VIRTUALLY COMPLETE WASH-OUT OF PLASMA:
Mean plasma concentrat ions of i t raconazole and hydroxy- i t raconazoleon day 1 a f te r the s ta r t o f t rea tment .Quant i f i ca t ions were per fo rmed w i th HPLC ana l ys i s .
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C) Excretion routes in the target tissues
ItrafungolTM is delivered to the skin and hairs by different routes:
• Itraconazole is incorporated into the basal cells of the skin and
hair follicles. It moves towards the skin surface as cells migrate
and gradually builds up in hairs
• Itraconazole diffuses into the sebaceous glands and reaches
the surface of the skin via the sebum
• ItrafungolTM reaches all layers of the epidermis by passive
diffusion.
The uptake of itraconazole in the basal cells of hair follicles and
epidermal cells ensures new hairs and skin are fully cleared and
healthy.
The pronounced uptake of itraconazole in sebaceous glands
allows for a rapid distribution over the entire hair (root, middle
and tip).
D) Excretion routes from the systemic circulation
In laboratory animals and humans, metabolites of ItrafungolTM are
mainly excreted with the bile (20).
Routes o f exc re t ion o f I t ra fungo l™ in the ta rge t t i ssues
12
B) Target tissue pharmacokinetics
When an ItrafungolTM pulse treatment of 5 mg/kg/day for
3 alternating weeks is carried out, itraconazole is detectable (17):
• In hairs of the back, tail and head within 24 hours of the first
administration
• In almost all hairs after a 7-day treatment.
Itrafungol™ End of week Hair/Plasma ratio
PULSE 1 1 1.12
2 82
PULSE 2 3 2.07
4 120
PULSE 3 5 2.76
7 150
The high hair/plasma ratios clearly illustrate the therapeutic
reservoir of itraconazole in hair and the fast clearance out of
the systemic circulation (17,18). After treatment is stopped,
the spread of itraconazole with sebum and the build-up in hairs
gradually decline. It can therefore be asserted that concentrations
of itraconazole are well above the MIC90 for M. canis (0.1 µg/ml
in various broth media) until at least 2 weeks after the last
administration. The concentrations of hydroxy-itraconazole increase
substantially in the last week of treatment (median concentrations
of 0.058 – 0.186 µg/g).
ITRACONAZOLE HAIR / PLASMA RATIOS UP TO 2 WEEKSAFTER THE END OF TREATMENT:
TIME (WEEKS)
3,5
0
0
1 2 3 4 5 6 7
3
2,5
2
1,5
1
0,5
MEA
N C
ON
CEN
TR
ATIO
NS
, g
/ml
µ
Therapeutic concentrationHair
BUILD-UP OF THERAPEUTIC RESERVOIR IN HAIR:
Mean itraconazole plasma and hair concentrat ions with the registeredt rea tment schedu le o f 5 mg/kg /day fo r 3 a l te rna t ing weeks .
Plasma
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The ItrafungolTM therapeutic treatment schedule of choice
for cats is:
The liquid formulation in combination with the caramel and cherry
flavours makes for a convenient oral administration and excellent
acceptance; when administered with the syringe, 92% of cats
readily accept the ItrafungolTM oral solution (22).
92% of cats readily accept theITRAFUNGOL ORAL SOLUTIONTM
4 . T R E AT M E N T S C H E D U L E
5 . C O N V E N I E N C E O F U S E
PULSE 1
7 daystreatment
7 daysno treatment
PULSE 2
7 daystreatment
7 daysno treatment
PULSE 3
7 daystreatment
5 mg/kg/day for 3 alternating weeks
For optimal efficacy, ItrafungolTM oral solution can best be
administered directly into the mouth before feeding.
Easy dosing is made possible thanks to a graduated dosing
syringe with graduations per 100 g body weight.
Alternatively, the oral solution can be mixed with some cream
or food before administration.
Note: Since spores may survive in the environment up to 18 months
(21), with a heavy infection pressure (e.g. in catteries), topical
treatment and environmental disinfection (with e.g. enilconazole)
are recommended with a view to optimising a mycological cure
and minimizing the risk of reinfection.
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HIGH ACCEPTABILITY:
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6 . C L I N I C A L E F F I C A C Y
Itraconazole efficacy field trials (23, 24)
In a first field study, the Itrafungol™ registered treatment schedule
was tested in 21 long-haired Persian and 3 short-haired domestic,
M. canis naturally infected cats (23). The housing conditions of
the participating cats were variable with the majority (20/24) living
in multiple cat households. Furthermore, most of included cats
(21/24) had previously been treated for dermatophytosis.
The degree of environmental disinfection in the households was
variable. Inclusion criteria were: lesions suspicious of dermato-
phytosis as well as Wood’s Lamp and M. canis positivity.
Using the Itrafungol™ registered treatment schedule of 5 mg/kg/day
for 3 alternating weeks > 90% of cats were clinically cured.
Because of the residual effect of Itrafungol™, cure rates even
increased after the end of treatment (day 63 vs. day 35).
Of the 2 cats that were not fully cured by day 63, one had
reduced lesions and one consisted in an initially generalised case
of dermatophytosis. Data on the presence of immunosuppressive
diseases were not known in those cats.
None of the treated cats experienced side effects.
This fast clinical and mycological response during itraconazole
treatment was also observed in a second study using a combina-
tion of continuous and pulse therapy (24). Nine privately owned
cats were included. They were considered cured when 2 negative
mycological cultures were obtained with an interval of 14 days.
A 100% mycological cure rate was obtained in all animals
56 days after the start of treatment:
- 89% of cats were mycologically negative on day 28 and 42
after the onset of treatment.
- The remaining 11% was mycologically negative on day 42 and 56.
Again, no adverse effects were observed in this trial.
Conclusion
These results demonstrated Itrafungol™ has an excellent efficacy and
safety profile for the treatment of dermatophytosis, even in difficult to
treat populations (Persian cats, relapse cases, multiple cat households).
Typically, Itrafungol™ treatment is characterised by a rapid clinical
improvement and a long-lasting residual effect thanks to a pronounced
excretion in sebaceous glands and a progressive build-up in skin and
hairs. Cure rates will therefore continue to increase after the end of
treatment (day 35) as therapeutic levels were still detected in hairs 2
weeks after the end of treatment. In humans, it was already demon-
strated that itraconazole persists in skin up to 4 weeks (25).
Because of these unique pharmacokinetic properties, Itrafungol™
oral solution pulse therapy allows for a cost-effective and highly
efficacious therapy.
For treating dermatophytosis in general, it is however advised to
concomitantly disinfect the environment and use topical antifungal
treatments, preferably with antisporulant activity such as enilconazole,
as spores may survive in the environment up to 18 months (21) and
cat dermatophytes are highly zoonotic.
ITRAFUNGOL™’S UNIQUE PHARMACOKINETICPROPERTIES ALLOW FOR A VERY FAST-ACTINGAND LONG-LASTING PROTECTIVE COVER ASWELL AS A HIGHLY EFFICACIOUSCOST-EFFECTIVE TREATMENT.
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Comparative trials of itraconazole vs. griseofulvin (26, 27)
TIME (DAYS)10 20 30 40 50 60 70 80
GRISEOFULVIN70
56 ITRAFUNGOLTM
The superior efficacy of itraconazole versus griseofulvin was
demonstrated in 2 comparative field trials:
In a first trial conducted by Moriello and Deboer (26), the clinical
and mycological efficacy of itraconazole and griseofulvin were
evaluated in 2 groups of five barrier-reared, M. canis experimen-
tally infected cats. For both treatments continuous administrations
were performed. Treatments were initiated 4 weeks after experi-
mental infection.
Both treatments were effective in the treatment of dermatophytosis
in cats. However, for the itraconazole treated cats, mycological
cure was obtained faster (56 days after the start of treatment) than
for griseofulvin treated cats (70 days after the start of treatment).
The faster clinical response during itraconazole treatment was
reflected by several observations:
- In the itraconazole-treated group mean lesion size did not
increase over the initial 14 days of treatment while it did in
the griseofulvin-treated group.
- In the itraconazole-treated group, lesions healed faster than
in the griseofulvin-treated group. In fact, clinical improvement
in the itraconazole-treated group was already observed after
1 week of treatment.
- In the itraconazole-treated group significantly fewer satellite
lesions were observed than in the griseofulvin-treated group
14 days after the onset of treatment.
T ime to myco log ica l cu re fo r i t raconazo le andgr i seo fu l v in
15
FASTER MYCOLOGICAL CURE WITH ITRAFUNGOL™:
20%FASTER
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In a second trial (27), the Itrafungol™ registered treatment of
5 mg/kg/day for 3 alternating weeks was compared with continuous
griseofulvin administration (30 to 125 mg/day depending on the
bodyweight) for 35 days. This multi-centre randomised field trial
was conducted in Belgium, France, The Netherlands, Spain and
United Kingdom and included 514 cats of different origins,
breeds and sexes. All cats had clinical lesions suspicious of der-
matophytosis and were Wood’s Lamp and M. canis positive.
In the Itrafungol™ treated group, higher clinical and Wood’s Lamp
cure rates were observed than in the griseofulvin-treated group.
WOOD'S LAMP CURE
CLINICAL CURE
0
20
40
60
80
100
94 87 83 75
ITR
AFU
NG
OL
ITR
AFU
NG
OL
GR
ISEO
FU
LVIN
GR
ISEO
FU
LVIN
CURE RATE (%)
These data illustrate that Itrafungol™ already allows for 83%
clinical and 94% Wood’s Lamp cure rates after only 3 alternating
weeks of pulse therapy in a very heterogeneous population with-
out any topical or environmental disinfection.
THE SUPERIOR EFFICACY OF ITRAFUNGOL™COMPARED TO GRISEOFULVIN IS CHARACTERIZED
BY A FASTER AND HIGHER CLINICAL AND
MYCOLOGICAL RESPONSE.
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Conclusion
These results clearly demonstrate that Itrafungol™ is a more effective
antifungal agent with a faster clinical, Wood’s Lamp and mycological
response than griseofulvin. This superior efficacy of Itrafungol™ can be
explained by its potential fungicidal activity and unique pharmacokinetic
properties allowing for a fast and pronounced excretion via sebaceous
glands as well as a long-lasting cover thanks to the progressive build-
up in keratin-containing structures, such as skin and hairs.
As dermatophytes are common zoonotic infections it is important to
use highly efficacious, preferentially fungicidal (such as Itrafungol™)
or sporicidal agents (such as enilconazole) that act rapidly and are safe.
I t ra fungo l™ and g r i seo fu l v in Wood ’s Lamp and per-p ro toco lana l y zed c l in i ca l cu re ra tes (day 63)
FASTER CLINICAL CURE RATE:
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Tolerability in kittens and adult cats
Itrafungol™ is well tolerated in kittens (from 10 days old)
and adults at a dosage of 5 mg/kg/day (23, 27, 28).
Adverse events and special precautions
Studies performed at recommended dosages have shown that
adverse events are rare (23, 27, 27). Transitory salivation,
anorexia, vomiting or diarrhoea as well as reversible blood
biochemical changes have been observed when three or five
times the recommended dosages were administered.
Precautions should therefore be taken when use is considered
in patients with a liver deficiency. No other pharmacological or
toxic effects have been observed.
Safety in pregnant and lactating queens
Pregnant and lactating queens tolerate the indicated Itrafungol™
treatment schedule well (30). Because safety for the offspring is
not sufficiently documented, precaution is recommended with
reference to use of Itrafungol™, in pregnant and lactating queens.
Drug interactions
No adverse events have been observed concerning drug interac-
tions with Itrafungol™ when it is administered in accordance with
the registered treatment schedule in cats. There are no indications
of major incompatibilities between Itrafungol™ and products
commonly used in veterinary practice.
In humans, elevated cyclosporine blood levels have been observed
in patients receiving itraconazole (31). Also, administration of
enzyme-inducing agents, such as rifampicin, may reduce the
oral bio-availability of itraconazole. Since no specific data on the
concomitant use of these drugs with Itrafungol™ are available in
cats, it is advised to follow cats closely that concomitantly
receive cyclosporine, rifampicin, phenobarbital, digoxin or metyl-
prednisolone.
7 . S A F E T Y P R O F I L E
IMPROVED SAFETY PROFILE THANKS TO THE
HIGH FUNGAL SPECIFICITY AND PULSE
TREATMENT SCHEDULE.
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1. Foil C.S. Fungal diseases, Clin Dermatol. 1994 Oct-Dec; 12(4):529-42.
2. Cabanes F.J. et al. Survey of cat and dog dermatophytosis in Europe. The ECMM working group report. In: Trends in Medical Mycology, 9th Congress of the European Confederation of Medical Mycology, 28th September –1st October 2003, Amsterdam, The Netherlands, p.81.
3. Mancianti F. et al. Mycological findings in feline immunodeficiency virus-infectedcats. J Med Vet Mycol. 1992;30(3):257-259.
4. Mignon B.R. and Losson B.J. Prevalence and characterization of Microsporumcanis carriage in cats. Med Vet Mycol. 1997 Jul-Aug;35(4):249-256
5. Sparkes A.H. et al. Prevalence and characterization of Microsporum caniscarriage in cats. J Med Vet Mycol. 1997 Jul-Aug;35(4):249-56.
6. Arrese J.E. Urban and rural mycozoonoses. Rev Med Liege.2000 Nov;55(11):998-1002.
7. Cuetara M.S. et al. Prevalence of undetected tinea capitis in a prospective school survey in Madrid: emergence of new causative fungi. Br J Dermatol. 1998 Apr;138(4):658-60.
8. Vanden Bossche H. et al. P450 inhibitors of use in medical treatment: focus onmechanisms of action. Pharmacol Ther. 1995;67(1):79-100.
9. Van Cutsem J. Oral and parenteral treatment with itraconazole in various superficialand systemic experimental fungal infections. Comparisons with other antifungalsand combination therapy. Br J Clin Pract Suppl. 1990 Sep;71:32-40.
10. Van Cutsem J. The in vitro antifungal spectrum of itraconazole. Mycoses. 1989;32(Suppl.1):14-34.
11. Vanden Bossche H. et al. Mode of action of antifungal agents.British Mycological Society. 1984:321.
12. Vanden Bossche H. et al. Mode of action studies. Basis for the search of new antifungal drugs. Ann NY Acad Sci.1988;544:191-207.
13. Odds F.C. A survey of old and new antifungal tests in vitro. In: Iwata K. and Vanden Bossche H. (Eds): In vitro and in vivo evaluation of antifungal agents. Elsevier Science Publisheres, Amsterdam, 1986: p13.
14. Odds F.C., Webster C.E., Abbott A.B. Antifungal activity inhibition factors: BAY–9139, bifonazole, butoconazole, isoconazole, itraconazole (R 51211), oxiconazole, Ro 14-4767/002, sulconazole, terconazole and vibunazole (BAY n-7133) compared in vitro with nine established antifungal agents. J. Antimicrob. Chemother. 1984;14:105.
15. Van Cutsem J. Itraconazole: in vitro antifungal spectrum and in vivo efficacy in animal models of fungal infection. Revista Iberoamericana de Micologia (Suppl. 2) 1993:S46-52.
16. Van Cutsem J. The fungicical activity of itraconazole and of terbinafine: In vitroagainst dermatophytes; in vivo in trichophytosis in guinea-pigs. 18th World Congress of Dermatology, New York City, New York, USA, June 1218,1992:240.
17. Sterkens P. Pharmacokinetics of itraconazole and hydroxy-itraconazole in cats treated orally at 5 mg/kg/day following the proposed therapeutic treatment schedule. Janssen Research Foundation, Beerse, Belgium, November 1997, 55p.
18. Monbaliu J. et al. Efficacy of itraconazole against Microsporum canis in naturallyinfected cats: comparison of 4 different treatment schedules.Addendum I: Absorption and plasma levels of itraconazole and of hydroxy-itraconazole. Janssen Animal Health, Beerse, Belgium, October 1993, 7p.
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Itrafungol™
ITRAFUNGOL™ FOR ANIMAL TREATMENT ONLYOral solution for the treatment of dermatophytosis in cats caused by Microsporumcanis.
COMPOSITIONActive ingredient: itraconazole Ph. Eur. 10 mg/ml.
Other ingredients include: propylene glycol, sorbitol, sodium saccharin
CHARACTERISTICSThe mode of action of itraconazole is based on its binding ability to fungalcytochrome P-450 iso-enzymes. This inhibits the synthesis of ergosterol andaffects membrane-bound enzyme function and membrane permeability. This effect is irreversible and causes structural degeneration.
INDICATIONSTreatment of dermatophytosis in cats caused by Microsporum canis.
DOSAGE AND ADMINISTRATIONThe solution is administered directly into the mouth by means of the enclosedgraduated dosing syringe. The daily dosage is 5 mg (0.5 ml)/kg bodyweight per day,for 3 alternate periods of 7 consecutive days of treatment followed by 7 dayswithout treatment.
The dosing syringe shows graduations per 100 gram of body weight. Fill the syringeby pulling the plunger until the correct body weight of the cat is indicated on thesyringe (Fig.1). Treat the animal by slowly and gently injecting the liquid into themouth, allowing the cat to swallow the product (Fig. 2).
Clinical studies have indicated that the time period between clinical and mycologicalcure may vary. It is therefore advised to minimize the risk of re-infection or spreadof infection by keeping healthy animals separate from animals that are being treat-ed. Cleaning and disinfection of the environment with appropriate products is highlyrecommended – especially in case of group problems.In exceptional cases, a prolonged time between mycological and clinical cure maybe observed. In such cases, a repeated treatment may be necessary. some casesof dermatophytosis may never be completely cured.
CONTRA-INDICATIONS AND WARNINGSContra-indicationsDo not administer to cats with hypersensitivity to itraconazole or one of the otheringredients. Do not administer to cats with impaired liver function.
Special warningsTreatment of dermatophytosis should not be limited to treatment of the infectedanimal(s). It should also include disinfection of the environment with appropriatefungicidal products, since Microsporum canis spores can survive in the environmentfor up to 18 months. Other measures such as frequent vacuuming, disinfection ofgrooming equipment and removal of all potentially contaminated material thatcannot be disinfected will minimize the risk of re-infection or spread of infection.Clipping of the hair coat is considered useful because it removes infected hairs,stimulates new hair growth and hastens recovery. In cases with limited lesions,hair clipping can be limited to the lesions only, whereas in cats with generalized
dermatophytosis it is recommended to clip the entire hair coat. Care should betaken not to cause trauma to the underlying skin during hair clipping.Furthermore it is recommended that disposable gloves are worn during treatmentof the affected animals. The hairs should be disposed of appropriately and allinstruments, clippers etc. should be disinfected.
Measures to prevent introduction of M. canis into groups of cats may includeisolation of new cats, isolation of cats returning from shows or breeding, exclusionof visitors and periodic monitoring by Wood’s lamp or by culturing for M. canis.
Undesirable effectsSalivation, vomiting, diarrhoea and anorexia may occasionally occur. These effectsare usually mild and transient.
Pregnancy and lactationDo not use in pregnant or lactating queens.
Interactions with other drugsIn vitro and in vivo studies, indicate that itraconazole does not interfere withmammalian drug metabolising enzymes, minimizing the risk of interactions withconcomitantly administered drug. However, care should be taken when co-adminis-tering the following drugs, as there may be potential for interaction: phenobarbital,digoxin, methylprednisolone.
OverdoseAfter a 5x overdose of itraconazole administered for 6 weeks, reversible clinicalside effects can be seen: rough hair coat, decreased food intake and reduced bodyweight gain.A 3x overdose for 6 weeks did not result in clinical side effects.Both after a 3x and a 5x overdose for 6 weeks, adaptive liver changes may occur(increased bilirubin, AST, ALT and AP).
WarningsFor animal use only.Keep out of reach of children.Wear latex gloves when handling the animal during treatment. Wash hands after use.Avoid contamination of the solution.
DisposalDispose of empty packaging and containers in the household refuse.Return any unused product to the veterinary surgery.
PHARMACEUTICAL PRECAUTIONSItrafungol™ should not be stored above 25°C.In-use shelf life: 5 weeks when the container is opened for the first time, the dateon which any product remaining in the container should be discarded should be cal-culated. A statement of the in-use shelf life of the product is given on this leaflet.This discard date should be written on the space provided on the label.After dosing the syringe should be removed from the bottle, washed and dried andthe cap should be screwed back on tightly.
PRESENTATIONAmber glass bottle containing 52 ml oral solution, packed in a cardboard box witha graduated dosing syringe.
FURTHER INFORMATIONManufacturer:Janssen Pharmaceutica N.V.Turnhoutseweg 30B-2340 BeerseBelgium
Marketing Authorisation Holder:Janssen Animal HealthA division of Janssen-Cilag Ltd, PO Box 79 SaundertonHigh WycombeBuckinghamshireHP14 4HJ
POMVm 00242/4054
Tel: 01494 567555Fax: 01494 567556e-mail: [email protected]
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(Fig.1) (Fig.2)
PULSE 1
7 daystreatment
7 daysno treatment
PULSE 2
7 daystreatment
7 daysno treatment
PULSE 3
7 daystreatment
5 mg/kg/day for 3 alternating weeks
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ItrafungolItrafungolT H E T R E AT M E N T O F C H O I C E
F O R D E R M ATO P H Y TO S I S I N C AT S
Exce l len t and long- las t ing e f f i cacy p ro f i l e
Improved sa fe ty fo r a l l ages
Easy o ra l admin is t ra t ion
For more information contact:JANSSEN ANIMAL HEALTH
Turnhoutseweg 302340 Beerse - Belgium
fax: +32(0)14 60 21 00e-mail: [email protected]
www.janssenanimalhealth.com
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