Itrafungol prezentare

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

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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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22. Engelen M. and Gypen L. Acceptability of itraconazole 10 mg/ml oral solution incats: comparison of two different formulations. Janssen Animal Health, Beerse, Belgium, August 1997, 46p.

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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 in naturally infected cats. Bio-Pharma, Beerse, Belgium, February 1998, 194p.

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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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