Itrafungol ™

An innovative approach to dermatophytosis

Produced by Janssen Animal Health

Tu r n h o u t s e w e g 3 0

2340 Beerse

Belgium © 2004
 Itrafungol
TA B L E O F C O N T E N T S

1. Introduction:
Dermatophytosis in cats and humans 4-6

2. Physicochemical and
pharmacodynamic properties 7-9
7
3. 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
7
 1. INTRODUCTION

Dermatophytosis in cats and humans

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.
Keratinized
skin layer
Only a few dermatophilic (literally ‘skin-loving’) species are
Hair shaft
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
Zone of
keratinization frequent (1, 2).

Hair bulb
Sebaceous
gland
Hair follicle

Blood vessel

Normal structure of cat skin and hairs

Light microscopic image of M. canis spores Scanning electron microscopic image of

(arthroconidia) around an invaded hair penetrating fungal hyphae along the hair shaft
©
Prof. J. Declercq, FVM, Ghent University - Belgium

4
 Dermatophyte prevalence and clinical signs in cats
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).
Pronounced dorsal hair loss and erythema
©
Dr. J. Fontaine, Belgium
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.
Seborrhoea and crusts on the tail
Crusty alopecic lesion on the nose Multiple erythematous alopecic
©
Dr. J. Fontaine, Belgium lesions on the ear
©
Dr. J. Fontaine, Belgium
5
 Cat dermatopytes as a zoonosis

Tinea unguium Tinea corporis Tinea capitis M. canis is the most commonly isolated zoophilic dermatophyte
©
Dr. J. Fontaine,
Belgium 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.

6
2. PHYSICOCHEMICAL AND PHARMOCODYNAMIC PROPERTIES

Chemical structure and molecular formula

Itraconazole is a synthetic, highly lipophilic, water insoluble,

Tr i a z o l e r i n g
Itraconazole molecular formula: C35H38C12N8O4
THE ADDITION OF A TRIAZOLE MOIETY ALLOWS
FOR AN INCREASED SPECTRUM OF ACTIVITY AND
IMPROVED SAFETY PROFILE .
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.

NORMAL ERGOSTEROL SYNTHESIS AND Mode of action

SITE OF ACTION OF ITRACONAZOLE:

Acetyl Coenzyme A Itraconazole’s main site of action is the fungal endoplasmatic

▼ reticulum, where it inhibits the cytochrome P-450 14-demethylase.
Squalene
▼ By impairing C14-demethylation of eburicol, the synthesis of
2,3-Oxidosqualene
▼ ergosterol (which is essential in maintaining fungal cell wall
Lanosterol integrity and activity) is hampered (8). This results in a cascade
▼
24-Methylene dihydrolanosterol (eburicol) of perturbations that together lead to antifungal activity:
▼
cyt P-450 14-DM Inhibition by itraconazole
• The availability of ergosterol is decreased, while compounds
▼
4,4-Dimethyl-ergostatrienol involved in the production of ergosterol (14-methylated sterols
▼
and 3-ketosteroids) accumulate, further destabilising fungal
Ergosterol
membranes.
• Lack of ergosterol synthesis results in an uncoordinated
SCHEMATIC REPRESENTATION OF THE MECHANISM
OF ACTION OF ITRACONAZOLE:
synthesis of the primary septum of yeasts and of the septa
and primary wall of hyphae.
LANOSTEROL ERGOSTEROL • Changes in the sterol structure lead to an alteration in
fatty acid composition and profoundly alter the activities of
membrane-bound enzymes.
Cyt.P450
14

4
CH3 These changes make the fungal cell susceptible to osmotic
HO HO
H3C CH3
damage and subsequently to phagocytosis by host cells,
ITRACONAZOLE
which results in cell death.

DECREASED ACTIVITY UNCOORDINATED

DETERIORATED
OF MEMBRANE-BOUND SYNTHESIS
MEMBRANES
ENZYMES OF CHITIN

7
FUNGITOXIC ACTIVITY
Pharmacodynamic properties

Itraconazole, a third generation azole with an added triazole ring allows for:

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).
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).

Some of the important pathogens against which itraconazole’s BINDING OF ITRACONAZOLE

antifungal activity has been demonstrated are: TO THE FUNGAL HAEM STRUCTURE:

Microspor um spp. Tr i p h o p h y t o n s p p . Malassezia spp.

©
Prof. J. Declercq, FMV, Ghent
University, Belgium

Itraconazole
molecule
Asper gillus spp. Candida spp. Cr yptococcus
neoformans Binding with fungal
c y t o c h r o m e P- 4 5 0

High specificity
for fungal
▼

Specific shape
CYP-450

Triazole +
non-ligating
Histoplasma spp. Sporothrix schenkii Coccidioides immitis High affinity
portion
for fungal
▼

cell membrane
Pronounced
▼

lipophilicity

Strong affinity
▼

for tissues
especially skin

8
 C) A higher safety margin D) Superior antifungal potency and fungicidal activity

Itraconazole has a high affinity and a high specificity for the fungal The superior in vitro antifungal potency of itraconazole versus
cytochrome P-450: the N atom of the triazole ring binds to the other antimycotics has been shown by Odds et al. (13,14).
fungal haem iron at the catalytic site and forms a stable complex In the model they used, antifungal activity is expressed as the
that prevents the oxygen-induced activation of this coenzyme. mean relative inhibition factor (RIF), which represents antimycotic
Furthermore, the selectivity for the fungal cytochrome P-450 is activity in relation to a fixed number of pathogenic dermatophytes
mediated by a high affinity for the highly lipophilic ‘tail’ of the and Aspergillus spp. The RIF is expressed as a percentage of
triazole molecule, which it binds to an apoprotein portion of the control fungal growth: an RIF of 100% indicates no measurable
fungal cytochrome molecule. Consequently, at concentrations antifungal activity and an RIF of 1% optimal antifungal activity.
that inhibit the fungal coenzyme, itraconazole has little effect on
mammalian cytochrome P-450. This specificity reduces the
The mean relative inhibition factors (%) of itraconazole and other
potential for drug interactions with mammalian biochemical
antimycotics:
pathways in which cytochromes play a role, and improves the
Antifungal agent Dermatophytes Aspergillus spp.
efficacy and safety profile of itraconazole (11,12).
Itraconazole 12 25
Ketoconazole 18 55
Griseofulvin 58 97
Nystatin 46 68

1%: optimal antifungal activity

100%: no antifungal activity

Fu n g a l h a e m s t r u c t u r e
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)
Strain
10 100 1000

M. canis 6h 2h 0.17h

T. mentagrophytes 6h 1h 0.17h

No interference
C. albicans 24h 3h 0.25h
with cat CYP-450
▼

Wide safety margin

at therapeutic
concentrations A. fumigatus 24h 4h 0.25h

Low therapeutic Moreover, against dermatophytes, fungicidal activity in serum

Allowing low daily doses
▼

concentrations
proceeded even faster than in broth media (16):
After 10 min at 100 µg/ml
After 4h at 10 µg/ml
Prolonged thera- Allowing short
▼

peutic effect treatment schedules

9
 3. PHARMACOKINETIC PROFILE

DIAGRAMMATIC REPRESENTATION OF COMPLEX FORMATION

BETWEEN CYCLODEXTRIN AND ITRACONAZOLE
IN THE ITRAFUNGOL™ ORAL SOLUTION:

HYDROPHILIC
PART

HYDROPHOBIC
OR LIPOPHILIC
PART

CYCLODEXTRIN
MOLECULE GUEST MOLECULE

WATER MOLECULE

ATTRACTION

REPULSION
CYCLODEXTRIN / GUEST MOLECULE COMPLEX

Since itraconazole is insoluble in water, a solubilising excipient, CHEMICAL STRUCTURE OF CYCLODEXTRIN:

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
A major breakthrough in the development of antifungal therapy
results in complexation to form a soluble complex.
was signalled by the correlation of tissue pharmacokinetics
at specific body sites with dosage, duration of therapy and
EXCELLENT ORAL BIOAVAILABILITY efficacy. Itraconazole is highly lipo- and keratophilic, which enables
THANKS TO THE ADDITION OF THE EXCIPIENT
a short duration of therapy thanks to a therapeutic reservoir in
HP - ß - CYCLODEXTRIN .
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.

10
A) Plasma pharmacokinetics and metabolisation RAPID ABSORPTION:
2

PLASMA CONCENTRATIONS, µ g/ml

When the ItrafungolTM registered pulse treatment schedule 1

(5 mg/kg/day for 3 alternating weeks) is used, the following 0,5

plasma kinetic profile is observed (17,18):

0,2

0,1
• Rapid absorption from the gastrointestinal tract with mean
0,05

peak plasma levels 1 to 2 hours after administration

0,02
• Doubling of the mean peak plasma concentration after 7 days
of dosing (day 1: 0.525 µg/ml; day 7: 1.05 µg/ml) 0,01

0 4 8 12 16 20 24
• 20-30% increase in 24-h plasma concentrations during the
TIME POST-DOSE, h
2 nd and 3 rd week of dosing
Itraconazole - day 1 Hydroxy - itraconazole - day 1
• T1/2 of 12 hours after a single administration
Mean plasma concentrations of itraconazole and hydroxy-itraconazole
• T1/2 of 36 hours after repeated administration on day 1 after the start of treatment.
Quantifications were performed with HPLC analysis.
• A virtually complete washout of plasma 1 week after the end
of repeated dosing.
VIRTUALLY COMPLETE WASH-OUT OF PL ASMA:
3
MEAN CONCENTRATIONS, µ g/ml

Itraconazole is metabolised in the liver into many metabolites,

2,5
of which hydroxy-itraconazole has antifungal properties (19).
In fact, hydroxy-itraconazole has been shown to have an in vitro 2

antifungal activity comparable to that of itraconazole. 1,5

A plasma pharmacokinetic profile has been observed that was

1

similar to that of itraconazole, but at lower concentrations.

0,5

0 1 2 3 4 5 6 7

TIME (WEEKS)

Plasma

Mean plasma concentrations after repeated pulse treatment.

11
B) Target tissue pharmacokinetics C) Excretion routes in the target tissues

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.
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

BUILD-UP OF THERAPEUTIC RESERVOIR IN HAIR: • ItrafungolTM reaches all layers of the epidermis by passive
3,5 diffusion.
MEAN CONCENTRATIONS, µ g/ml

The uptake of itraconazole in the basal cells of hair follicles and

2,5

epidermal cells ensures new hairs and skin are fully cleared and
2
healthy.
1,5

1 The pronounced uptake of itraconazole in sebaceous glands

0,5
allows for a rapid distribution over the entire hair (root, middle
and tip).
0
0 1 2 3 4 5 6 7

TIME (WEEKS)
D) Excretion routes from the systemic circulation
Hair Plasma Therapeutic concentration

Mean itraconazole plasma and hair concentrations with the registered

treatment schedule of 5 mg/kg/day for 3 alternating weeks. In laboratory animals and humans, metabolites of ItrafungolTM are
mainly excreted with the bile (20).

ITRACONAZOLE HAIR / PL ASMA RATIOS UP TO 2 WEEKS

AF TER THE END OF 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).
Routes of excretion of Itrafungol™ in the target tissues

12
 4 . T R E AT M E N T S C H E D U L E

The ItrafungolTM therapeutic treatment schedule of choice

for cats is:

5 mg/kg/day for 3 alternating weeks

PULSE 1 PULSE 2 PULSE 3
7 days 7 days 7 days 7 days 7 days
treatment no treatment treatment no treatment treatment

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 5. CONVENIENCE OF USE
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.
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).

HIGH ACCEPTABILITY:

92% of cats readily accept the

ITRAFUNGOLTM ORAL SOLUTION

13
 6. CLINICAL EFFICACY

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
ITRAFUNGOL™ ’ S UNIQUE PHARMACOKINETIC
in multiple cat households. Furthermore, most of included cats PROPERTIES ALLOW FOR A VERY FAST- ACTING
(21/24) had previously been treated for dermatophytosis. AND LONG - LASTING PROTECTIVE COVER AS
WELL AS A HIGHLY EFFICACIOUS
The degree of environmental disinfection in the households was
COST- EFFECTIVE TREATMENT.
variable. Inclusion criteria were: lesions suspicious of dermato-
phytosis as well as Wood’s Lamp and M. canis positivity.
Conclusion

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.
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.

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
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.

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.

14
Comparative trials of itraconazole vs. griseofulvin (26, 27)

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

FASTER MYCOLOGICAL CURE WITH ITRAFUNGOL™:
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 56 20%
FASTER
ITRAFUNGOLTM

were performed. Treatments were initiated 4 weeks after experi-

mental infection.
70 GRISEOFULVIN

TIME (DAYS) 10 20 30 40 50 60 70 80

Both treatments were effective in the treatment of dermatophytosis

in cats. However, for the itraconazole treated cats, mycological Time to mycological cure for itraconazole and
griseofulvin
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.

15
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.

FASTER CLINICAL CURE RATE:

CURE RATE (%) Conclusion

100
These results clearly demonstrate that Itrafungol™ is a more effective

94 antifungal agent with a faster clinical, Wood’s Lamp and mycological

80
87 83
response than griseofulvin. This superior efficacy of Itrafungol™ can be
explained by its potential fungicidal activity and unique pharmacokinetic
75 properties allowing for a fast and pronounced excretion via sebaceous
60
glands as well as a long-lasting cover thanks to the progressive build-
up in keratin-containing structures, such as skin and hairs.
GRISEOFULVIN

GRISEOFULVIN
ITRAFUNGOL

ITRAFUNGOL

40 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.
20

WOOD'S CLINICAL CURE THE SUPERIOR EFFICACY OF ITRAFUNGOL ™

LAMP CURE COMPARED TO GRISEOFULVIN IS CHARACTERIZED
I t r a f u n g o l ™ a n d g r i s e o f u l v i n W o o d ’ s L a m p a n d p e r- p r o t o c o l
analyzed clinical cure rates (day 63)
BY A FASTER AND HIGHER CLINICAL AND
MYCOLOGICAL RESPONSE .
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.

16
 7. SAFETY PROFILE

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, IMPROVED SAFETY PROFILE THANKS TO THE
anorexia, vomiting or diarrhoea as well as reversible blood HIGH FUNGAL SPECIFICITY AND PULSE
TREATMENT SCHEDULE .
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.

17
 8. REFERENCES

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-infected
cats. J Med Vet Mycol. 1992;30(3):257-259.
4. Mignon B.R. and Losson B.J. Prevalence and characterization of Microsporum
canis carriage in cats. Med Vet Mycol. 1997 Jul-Aug;35(4):249-256
21. Sparkes A.H. et al. Microsporum canis inapparent carriage by cats and the
viability of arthrospores. J Small Anim Pract 1994;35:397-401.
22. Engelen M. and Gypen L. Acceptability of itraconazole 10 mg/ml oral solution in
cats: comparison of two different formulations. Janssen Animal Health, Beerse,
Belgium, August 1997, 46p.
23. Engelen M. et al. Efficacy of oral itraconazole against Microsporum canis
dermatophytosis in naturally infected cats: evaluation and comparison of
4 different treatment schedules under field conditions. Janssen Pharmaceutica,
Beerse, Belgium, September 1993, 28p.

5. Sparkes A.H. et al. Prevalence and characterization of Microsporum canis 24. Colombo S. et al. Efficacy of itraconazole as a combined continuous/pulse
carriage in cats. J Med Vet Mycol. 1997 Jul-Aug;35(4):249-56. therapy in feline dermatophytosis: preliminary results in nine cases. Vet Derm
2001;12:347-350.
6. Arrese J.E. Urban and rural mycozoonoses. Rev Med Liege.
2000 Nov;55(11):998-1002. 25. Cauwenbergh G. et al. Pharmacokinetic profile or orally administered itraconazole
in the human skin. J Am Acad Dermatol 1988;18:263-268.
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. 26. Moriello K.A. and Deboer D.J. Efficacy of griseofulvin and itraconazole in the
1998 Apr;138(4):658-60. treatment of experimentally induced dermatophytosis in cats.
J Am Vet Med Ass 1995;207(4):439-444.
8. Vanden Bossche H. et al. P450 inhibitors of use in medical treatment: focus on
mechanisms of action. Pharmacol Ther. 1995;67(1):79-100. 27. Rosillon D. et al. Multicenter, double blind, field trial to compare the efficacy
and safety of itraconazole with griseofulvin in the treatment of dermatophytosis
9. Van Cutsem J. Oral and parenteral treatment with itraconazole in various superficial
in naturally infected cats. Bio-Pharma, Beerse, Belgium, February 1998, 194p.
and systemic experimental fungal infections. Comparisons with other antifungals
and combination therapy. Br J Clin Pract Suppl. 1990 Sep;71:32-40. 28. Engelen M. and Biermans R. Tolerance of oral itraconazole in kittens: pilot trial.
Janssen Research Foundation, Beerse, Belgium, September 1993, 10p.
10. Van Cutsem J. The in vitro antifungal spectrum of itraconazole. Mycoses.
1989;32(Suppl.1):14-34. 29. Boothe D.M. et al. Itraconazole disposition after single oral and intravenous and
multiple oral dosing in healthy cats. Am J Vet Res 1997;58(8).
11. Vanden Bossche H. et al. Mode of action of antifungal agents.
British Mycological Society. 1984:321. 30. Demblon D. et al. Tolerability of itraconazole oral solution after repeated dosing
in pregnant and lactating queens, Bio-Pharma, Belgium, October 1996, 46p.
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. 31. Back D.J. and Tija J.F. Comparative effects of the antimycotic drugs ketoconazole,
fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin
13. Odds F.C. A survey of old and new antifungal tests in vitro. In: Iwata K. and
by human liver microsomes. Br J Pharmacol 1991;32:624-626.
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.
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against dermatophytes; in vivo in trichophytosis in guinea-pigs. 18th World
Congress of Dermatology, New York City, New York, USA, June 1218,1992:240.
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treated orally at 5 mg/kg/day following the proposed therapeutic treatment
schedule. Janssen Research Foundation, Beerse, Belgium, November 1997, 55p.
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infected 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 ONLY
Oral solution for the treatment of dermatophytosis in cats caused by Microsporum
canis.
COMPOSITION
Active ingredient: itraconazole Ph. Eur. 10 mg/ml.
Other ingredients include: propylene glycol, sorbitol, sodium saccharin
CHARACTERISTICS
The mode of action of itraconazole is based on its binding ability to fungal
cytochrome P-450 iso-enzymes. This inhibits the synthesis of ergosterol and
affects membrane-bound enzyme function and membrane permeability.
This effect is irreversible and causes structural degeneration.
INDICATIONS
Treatment of dermatophytosis in cats caused by Microsporum canis.
DOSAGE AND ADMINISTRATION
The solution is administered directly into the mouth by means of the enclosed
graduated 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 days
without treatment.
dermatophytosis it is recommended to clip the entire hair coat. Care should be
taken not to cause trauma to the underlying skin during hair clipping.
Furthermore it is recommended that disposable gloves are worn during treatment
of the affected animals. The hairs should be disposed of appropriately and all
instruments, clippers etc. should be disinfected.
Measures to prevent introduction of M. canis into groups of cats may include
isolation of new cats, isolation of cats returning from shows or breeding, exclusion
of visitors and periodic monitoring by Wood’s lamp or by culturing for M. canis.
Undesirable effects
Salivation, vomiting, diarrhoea and anorexia may occasionally occur. These effects
are usually mild and transient.
Pregnancy and lactation
Do not use in pregnant or lactating queens.
Interactions with other drugs
In vitro and in vivo studies, indicate that itraconazole does not interfere with
mammalian drug metabolising enzymes, minimizing the risk of interactions with
concomitantly administered drug. However, care should be taken when co-adminis-
tering the following drugs, as there may be potential for interaction: phenobarbital,
digoxin, methylprednisolone.

Overdose
5 mg/kg/day for 3 alternating weeks After a 5x overdose of itraconazole administered for 6 weeks, reversible clinical
PULSE 1 PULSE 2 PULSE 3 side effects can be seen: rough hair coat, decreased food intake and reduced body
weight gain.
7 days 7 days 7 days 7 days 7 days A 3x overdose for 6 weeks did not result in clinical side effects.
treatment no treatment treatment no treatment treatment
Both after a 3x and a 5x overdose for 6 weeks, adaptive liver changes may occur
(increased bilirubin, AST, ALT and AP).

The dosing syringe shows graduations per 100 gram of body weight. Fill the syringe Warnings
by pulling the plunger until the correct body weight of the cat is indicated on the For animal use only.
syringe (Fig.1). Treat the animal by slowly and gently injecting the liquid into the Keep out of reach of children.
mouth, allowing the cat to swallow the product (Fig. 2). Wear latex gloves when handling the animal during treatment. Wash hands after use.
Avoid contamination of the solution.

Disposal
Dispose of empty packaging and containers in the household refuse.
Return any unused product to the veterinary surgery.

PHARMACEUTICAL PRECAUTIONS
Itrafungol™ should not be stored above 25°C.
In-use shelf life: 5 weeks when the container is opened for the first time, the date
on which any product remaining in the container should be discarded should be cal-
(Fig.1) (Fig.2) 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.
Clinical studies have indicated that the time period between clinical and mycological After dosing the syringe should be removed from the bottle, washed and dried and
cure may vary. It is therefore advised to minimize the risk of re-infection or spread the cap should be screwed back on tightly.
of infection by keeping healthy animals separate from animals that are being treat-
ed. Cleaning and disinfection of the environment with appropriate products is highly PRESENTATION
recommended – especially in case of group problems. Amber glass bottle containing 52 ml oral solution, packed in a cardboard box with
In exceptional cases, a prolonged time between mycological and clinical cure may a graduated dosing syringe.
be observed. In such cases, a repeated treatment may be necessary. some cases
of dermatophytosis may never be completely cured. FURTHER INFORMATION
Manufacturer:
CONTRA-INDICATIONS AND WARNINGS Janssen Pharmaceutica N.V.
Contra-indications Turnhoutseweg 30
Do not administer to cats with hypersensitivity to itraconazole or one of the other B-2340 Beerse
ingredients. Do not administer to cats with impaired liver function. Belgium
Marketing Authorisation Holder:
Special warnings Janssen Animal Health
Treatment of dermatophytosis should not be limited to treatment of the infected A division of Janssen-Cilag Ltd, Tel: 01494 567555
animal(s). It should also include disinfection of the environment with appropriate PO Box 79 Fax: 01494 567556
fungicidal products, since Microsporum canis spores can survive in the environment Saunderton e-mail: ahealth@jacgb.jnj.com
for up to 18 months. Other measures such as frequent vacuuming, disinfection of High Wycombe
grooming equipment and removal of all potentially contaminated material that Buckinghamshire
cannot be disinfected will minimize the risk of re-infection or spread of infection. HP14 4HJ
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, POM
hair clipping can be limited to the lesions only, whereas in cats with generalized Vm 00242/4054

19
 ™
Itrafungol
T 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 AT O P H Y T O S I S I N C AT S

Excellent and long-lasting efficacy profile

Improved safety for all ages

Easy oral administration

JAH / mar 2004 / Itra / Eng

For more information contact:

JANSSEN ANIMAL HEALTH
Turnhoutseweg 30
2340 Beerse - Belgium
fax: +32(0)14 60 21 00
e-mail: janah@janbe.jnj.com
www.janssenanimalhealth.com
©