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ITRACONAZOLE100 MG CAPSULES HARD

Active substance(s): ITRACONAZOLE / ITRACONAZOLE / ITRACONAZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Itraconazole100 mg capsules, hard

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 100 mg of itraconazole.
Excipient: Each hard capsule contains 224.31 mg sucrose.
For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Hard capsule.
No. 0 hard gelatin capsules, opaque green cap and body, containing yellowish-beige
spherical micro-granules

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
- Vulvovaginal candidiasis,
- Oral candidiasis,
- Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton
spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea
corporis, tinea manuum,
- Pityriasis versicolor,
- Onychomycoses caused by dermatophytes and/or yeasts,
- Systemic candidiasis,
- Cryptococcal infections (including cryptococcal meningitis). In immunosuppressed
patients suffering from cryptococcosis and in patients with cryptococcosis of the CNS
itrakonazol is indicated only if the usually recommended initial therapy seems to be
inappropriate or ineffective,
- Histoplasmosis,
- Aspergillosis. Itraconazole can be used to treat patients suffering from invasive
aspergillosis who were found to be refractory or intolerant to Amphotericine B,
- Maintenance therapy in AIDS patients to prevent relapse of underlying fungal
infection who were found to be refractory or intolerant to first-line systemic anti-fungal
therapy is inappropriate or has proved ineffective.
Due to PK properties, orally administered itraconazole (capsules) should not be used as
the initial treatment in patients with severe life-threatening forms of systemic mycoses.
Oral forms should be used as a continuation therapy, after initial treatment with i.v.
itraconazole (see section 4.4).
Consideration should be given to official guidance regarding the appropriate use of
antifungal agents.

4.2

Posology and method of administration

Route of administration: Oral use.
For maximum drug absorption itraconazole should be taken immediately following a
meal.
Capsules must be swallowed whole.
INDICATIONS
Gynecological infections:
- Vulvovaginal candidosis
Dematological/ophthalmic indications:
- Pityriasis versicolor

DOSE

DURATION OF
TREATMENT

200 mg b.i.d. or
200 mg o.d.1

1 day
3 days

200 mg o.d.

7 days

- Tinea corporis, tinea cruris

100 mg o.d. or
15 days or
200 mg o.d.
7 days1
- Tinea pedis, tinea manuum
100 mg o.d.
30 days
- Oral candidiasis
100 mg o.d.
15 days1
1
In some patients with compromised immune systems, such as neutropenic,
AIDS or transplant patients, the bioavailability of oral itraconazole may be
diminished. In these cases the dose may have to be doubled.
Onychomycoses
Onychomycoses can be treated using a pulse or a continuous regime.
- Pulse treatment (see table below):
Pulse itraconazole treatment consists of taking two capsules twice a day (200 mg b.i.d.)
for one week.
For fingernail infections two pulse treatments are recommended, and for toenail
infections, three. Each pulse should be separated by a period of three weeks with no
treatment. Clinical response can be seen by in the form of nail growth when the
treatment is ended.
Week Week Week Week
Week Week Week
Location of
Week 5
1
2
3
4
6
7
8
onychomycoses
Toenails with
Second
First
No itraconazole
No itraconazole
or without
pulse
pulse
therapy
therapy
fingernail
cycle
cycle
involvement
Second
First
No itraconazole
Finger nails
pulse
pulse
therapy
only
cycle
cycle

Week
9
Third
pulse
cycle

- Continuous treatment:
Two capsules a day (200 mg o.d.) for three months.

1

We have recieved a few complaints from UK pharmacists stating that q.d. is confusing as on a
prescription q.d.s. is four times a day, and once daily should be o.d. Therefore, to avoid incorrect
dosage being given, we propose to change these abbreviations.

The rate of elimination of itraconazole in skin and nail tissue is slower than in blood
plasma. Optimum clinical and mycological response is reached two to four weeks after
treatment for skin infections, and six to nine months after treatment for nail infections.
Systemic mycoses (doses vary depending on the infecting organism)
The length of treatment for systemic fungal infections should be dictated by the
mycological and clinical response to therapy:
AVERAGE
DURATION
2-5 months

INDICATIONS

DOSE

Aspergillosis

200 mg o.d.

Candidiasis

100-200 mg
o.d.
200 mg o.d.

3 weeks-7
months

200 mg b.i.d.

2 months – 6
months
8 months

Non-meningeal
cryptococcosis
Cryptococcal meningitis
Histoplasmosis

200 mg o.d.
200 mg b.i.d.

10 weeks

COMMENTS
Increase dose to
200 mg b.i.d. in the
case of widespread
infection
Maintenance therapy
(meningeal cases):
200 mg o.d.

- Decreased gastric acidity:
Absorption of itraconazole is impaired when gastric acidity is decreased. For
information on patients with achlorhydria and patients on acid secretion suppressors or
taking acid neutralising medicinal products, (see section 4.4).
Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole
blood levels and lack of efficacy. In such cases, blood level monitoring and if necessary
dose adjustment might be indicated.
Use in children
Itraconazole should not be administered to children as there is limited clinical data
describing the pediatric use of this drug (see section 4.4).
Use in elderly patients
Not recommended
Use in patients with hepatic impairment
Limited data are available on the use of oral itraconazole in patients with hepatic
impairment. Caution should be exercised when this drug is administered in this patient
population. (see section 5.2)
Use in patients with renal impairment
Limited data are available on the use of oral itraconazole in patients with renal
impairment. Caution should be exercised when this drug is administered in this patient
population.

4.3

Contraindications
• Itraconazole capsules are contraindicated in patients with known hypersensitivity to
itraconazole or to any of the excipients.

• Co-administration of the following drugs is contraindicated with itraconazole
capsules (see also section 4.5):
- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole,
bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine,
pimozide, quinidine, sertindole and terfenadine are contraindicated with
itraconazole capsules. Co-administration may result in increased plasma
concentrations of these substrates, which can lead to QT prolongation and rare
occurrences of torsade de pointes.
- CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin
and simvastatin
- Triazolam and oral midazolam
- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine
and methylergometrine (methylergonovine)
- Eletriptan
- Nisoldipine
• Itraconazole capsules should not be administered to patients with evidence of
ventricular dysfunction such as congestive heart failure (CHF) or a history of
CHF except for the treatment of life-threatening or other serious infections (see
section 4.4).
• Itraconazole capsules must not be used during pregnancy (except for life-threatening
cases). See Section 4.6.
Women of childbearing potential taking itraconazole should use contraceptive
precautions. Effective contraception should be continued until the menstrual period
following the end of itraconazole therapy.

4.4

Special warnings and precautions for use
Cross-hypersensitivity
There is no information regarding cross-hypersensitivity between itraconazole and
other azole antifungal agents. Caution should be used in prescribing itraconazole
capsules to patients with hypersensitivity to other azoles.
Cardiac effects
In a healthy volunteer study with itraconazole IV, a transient asymptomatic decrease of
the left ventricular ejection fraction was observed; this resolved before the next
infusion. The clinical relevance of these findings to the oral formulations is unknown.
Itraconazole has been shown to have a negative inotropic effect and itraconazole has
been associated with reports of congestive heart failure. Heart failure was more
frequently reported among spontaneous reports of 400 mg total daily dose than among
those of lower total daily doses, suggesting that the risk of heart failure might increase
with the total daily dose of itraconazole.
Itraconazole should not be used in patients with congestive heart failure or with a
history of congestive heart failure unless the benefit clearly outweighs the risk. This
individual benefit/risk assessment should take into consideration factors such as the
severity of the indication, the dosing regimen (e.g., total daily dose), and individual risk
factors for congestive heart failure. These risk factors include cardiac disease, such as
ischemic and valvular disease; significant pulmonary disease, such as chronic
obstructive pulmonary disease; and renal failure and other edematous disorders. Such
patients should be informed of the signs and symptoms of congestive heart failure,
should be treated with caution, and should be monitored for signs and symptoms of

congestive heart failure during treatment; if such signs or symptoms do occur during
treatment, itraconazole should be discontinued.
Calcium channel blockers can have negative inotropic effects which may be additive to
those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium
channel blockers. Therefore, caution should be used when co-administering
itraconazole and calcium channel blockers (see section 4.5) due to an increased risk of
CHF.
Hepatic effects
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver
failure, have occurred with the use of itraconazole. Most of these cases involved
patients who, had pre-existing liver disease, were treated for systemic indications, had
significant other medical conditions and/or were taking other hepatotoxic drugs. Some
patients had no obvious risk factors for liver disease. Some of these cases were
observed within the first month of treatment, including some within the first week.
Liver function monitoring should be considered in patients receiving itraconazole
treatment. Patients should be instructed to promptly report to their physician signs and
symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue,
abdominal pain or dark urine. In these patients treatment should be stopped
immediately and liver function testing should be conducted. In patients with raised liver
enzymes or active liver disease, or who have experienced liver toxicity with other
drugs, treatment should not be started unless the expected benefit exceeds the risk of
hepatic injury. In such cases liver enzyme monitoring is necessary.
Reduced gastric acidity
Absorption of itraconazole from itraconazole capsules is impaired when gastric acidity
is reduced. In patients also receiving acid neutralizing medicines (e.g. aluminium
hydroxide) these should be administered at least 2 hours after the intake of itraconazole
capsules. In patients with achlorhydria such as certain AIDS patients and patients on
acid secretion suppressors (e.g., H2-antagonists, proton pump inhibitors) it is advisable
to administer itraconazole capsules with a cola beverage.
Use in children
Clinical data on the use of itraconazole capsules in paediatric patients is limited.
Itraconazole capsules should not be used in paediatric patients unless the potential
benefit outweighs the potential risks.
Use in elderly
Clinical data on the use of itraconazole capsules in elderly patients is limited.
Itraconazole capsules should not be used in these patients unless the potential benefit
outweighs the potential risks.
Hepatic impairment
Limited data are available on the use of oral itraconazole in patients with hepatic
impairment. Caution should be exercised when the drug is administered in this patient
population (see section 5.2).
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal
impairment. Caution should be exercised when this drug is administered in this patient
population. The oral bioavailability of itraconazole may be lower in patients with renal
insufficiency. Dose adaptation may be considered.
Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment
with itraconazole. Several of these reports included concurrent administration of
quinidine which is contraindicated (see sections 4.3 and 4.5). The hearing loss usually
resolves when treatment is stopped, but can persist in some patients.
Immunocompromised patients
In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant
patients), the oral bioavailability of itraconazole capsules may be decreased.
Patients with immediately life-threatening systemic fungal infections
Due to the pharmacokinetic properties (see section 5.2), itraconazole capsules are not
recommended for initiation of treatment in patients with immediately life-threatening
systemic fungal infections.
Patients with AIDS
In patients with AIDS having received treatment for a systemic fungal infection such as
sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal and nonmeningeal) and who are considered at risk for relapse, the treating physician should
evaluate the need for a maintenance treatment.
Neuropathy
If neuropathy occurs that may be attributable to itraconazole capsules, the treatment
should be discontinued.
Disorders of Carbohydrate Metabolism
This drug contains sucrose. Patients with rare hereditary problems of fructose
intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency
should not take this medicine.
Cross-resistance
In systemic candidosis, if fluconazole-resistant strains of Candida species are
suspected, it cannot be assumed that these are sensitive to itraconazole, hence their
sensitivity should be tested before the start of itraconazole therapy.
Interaction potential
Itraconazole has a potential for clinically important drug interactions (see section 4.5).
Itraconazole should not be used within 2 weeks after discontinuation of treatment with
CYP3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin,
carbamazepine, Hypericum perforatum (St. John’s wort). The use of itraconazole with
these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment
failure.

4.5

Interaction with other medicinal products and other forms of interaction
Drugs affecting the absorption of itraconazole
Drugs that reduce the gastric acidity impair the absorption of itraconazole from
itraconazole capsules (see section 4.4).
Drugs affecting the metabolism of itraconazole
Itraconazole is mainly metabolised through the cytochrome CYP3A4.
Interaction studies have been performed with rifampicin, rifabutin and phenytoin,
which are potent inducers of CYP3A4. Since the bioavailability of itraconazole and
hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may
be largely reduced, the combination of itraconazole with these potent enzyme inducers
is not recommended. No formal study data are available for other enzyme inducers,

such as carbamazepine, Hypericum perforatum (St John’s Wort), phenobarbital and
isoniazid, but similar effects should be anticipated.
Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and
erythromycin may increase the bioavailability of itraconazole.

-

-

Effect of itraconazole on the metabolism of other drugs
Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A
family. This can result in an increase and/or a prolongation of their effects, including
side effects. When using concomitant medication, the corresponding label should be
consulted for information on the route of metabolism. After stopping treatment,
itraconazole plasma concentrations decline gradually, depending on the dose and
duration of treatment (see section 5.2). This should be taken into account when the
inhibitory effect of itraconazole on co-medicated drugs is considered.
Examples are:
The following drugs are contraindicated with itraconazole:
Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl),
mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated
with itraconazole since co-administration may result in increased plasma
concentrations of these substrates, which can lead to QT prolongation and rare
occurrences of torsade de pointes;
CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin
and simvastatin;
Triazolam and oral midazolam;
Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine),
ergotamine and methylergometrine (methylergonovine);
Eletriptan;
Nisoldipine.
Caution should be exercised when co-administering itraconazole with calcium channel
blockers due to an increased risk of CHF. In addition to possible pharmacokinetic
interactions involving the drug metabolising enzyme CYP3A4, calcium channel
blockers can have negative inotropic effects which may be additive to those of
itraconazole.
The following drugs should be used with caution, and their plasma concentrations,
effects or side effects should be monitored. Their dosage, if co-administered with
itraconazole, should be reduced if necessary:
Oral anticoagulants;
HIV protease inhibitors such as indinavir, ritonavir and saquinavir;
Certain antineoplastic agents such as, busulphan, docetaxel, trimetrexate and
vinca alkaloids;
CYP3A4 metabolised calcium channel blockers such as dihydropyridines and
verapamil;
Certain immunosuppressive agents: ciclosporin, rapamycin (also known as
sirolimus) and tacrolimus;
Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and
methylprednisolone;
Digoxin (via inhibition of P-glycoprotein);
Others: alfentanil, alprazolam, brotizolam, buspirone, carbamazepine, cilostazol,
disopyramide, ebastine, eletriptan, fentanyl, halofantrine, midazolam IV,
reboxetine, repaglinide, rifabutin.
No interaction of itraconazole with zidovudine (AZT) and fluvastatin has been
observed.
No inducing effects of itraconazole on the metabolism of ethinyloestradiol and
norethisterone were observed.

Effect on protein binding
In vitro studies have shown that there are no interactions on the plasma protein binding
between itraconazole and imipramine, propranolol, diazepam, cimetidine, indometacin,
tolbutamide and sulfamethazine.

4.6

Fertility, pregnancy and lactation
Pregnancy
Itraconazole must not be used during pregnancy except for life-threatening cases where
the potential benefit to the mother outweighs the potential harm to the fetus (see section
4.3).
In animal studies itraconazole has shown reproduction toxicity (see section 5.3).
There is limited information on the use of itraconazole during pregnancy. During postmarketing experience, cases of congenital abnormalities have been reported. These
cases included skeletal, genitourinary tract, cardiovascular and ophthalmic
malformations as well as chromosomal and multiple malformations. A causal
relationship with itraconazole has not been established.
Epidemiological data on exposure to itraconazole during the first trimester of
pregnancy –mostly in patients receiving short-term treatment for vulvovaginal
candidosis– did not show an increased risk for malformations as compared to control
subjects not exposed to any known teratogens.
Women of childbearing potential
Women of childbearing potential taking itraconazole capsules should use contraceptive
precautions. Effective contraception should be continued until the menstrual period
following the end of itraconazole therapy.
Lactation
A very small amount of itraconazole is excreted in human milk. The expected benefits
of itraconazole capsules therapy should therefore be weighed against the potential risk
of breast-feeding. In case of doubt, the patient should not breast-feed.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
When driving vehicles and operating machinery the possibility of adverse reactions
such as dizziness, visual disturbances and hearing loss (see section 4.8), which may
occur in some instances, must be taken into account.

4.8

Undesirable effects
Undesirable effects listed below have been reported in clinical trials with itraconazole
capsules and/or from spontaneous reports from post-marketing experience for all
itraconazole formulations.
In clinical trials involving 2104 itraconazole-treated patients in the treatment of
dermatomycoses or onychomycosis, the most frequently reported adverse experiences
in clinical trials were of gastrointestinal, dermatological, and hepatic origin.

The table below presents adverse drug reactions by System Organ Class. Within each
System Organ Class, the adverse drug reactions are presented by incidence, using the
following convention:
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to
< 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot
be estimated from the available data).
Adverse Drug Reactions
Blood and lymphatic system disorders
Rare
Leukopenia
Not Known
Neutropenia, Thrombocytopenia
Immune system disorders
Uncommon
Hypersensitivity*
Not Known
Anaphylactic Reaction, Anaphylactoid Reaction, Angioneurotic
Oedema, Serum Sickness
Metabolism and nutrition disorders
Not Known
Hypokalemia; Hypertriglyceridemia
Nervous system disorders
Uncommon
Headache, Dizziness, Paraesthesia
Rare
Hypoaesthesia
Not Known
, Peripheral Neuropathy*
Eye disorders
Rare
Not Known

Visual Disturbance
Vision Blurred and Diplopia

Ear and labyrinth disorder
Rare
Tinnitus
Not Known
Transient or permanent Hearing Loss*
Cardiac disorders
Not Known
Congestive Heart Failure*
Respiratory, thoracic and mediastinal disorders
Not Known
Pulmonary Oedema
Gastrointestinal disorders
Common
Abdominal Pain, Nausea
Uncommon
Vomiting, , Diarrhoea, Constipation, Dyspepsia, Dysgeusia,
Flatulence
Rare
Pancreatitis
Hepatobiliary disorders
Uncommon
Hyperbilirubinaemia,
Alanine
Aminotransferase
Aspartate Aminotransferase Increased
Rare
Hepatic Enzyme Increased
Not Known
Acute Hepatic Failure*, Hepatitis, Hepatotoxicity*

Increased,

Skin and subcutaneous tissue disorders
Common
Rash
Uncommon
Urticaria, Alopecia, Pruritus
Not known
Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Erythema
Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis,
Photosensitivity
Musculoskeletal and connective tissue disorders
Not Known
Myalgia, Arthralgia
Renal and urinary disorders
Rare
Pollakiuria
Not Known
Urinary Incontinence
Reproductive system and breast disorders
Uncommon
Menstrual Disorders
Not known
Erectile Dysfunction
General disorders and administration site conditions
Uncommon
Oedema
Rare
Pyrexia
* see section 4.4.

4.9

Overdose
No data are available.
In the event of an overdose, supportive measures should be employed. Within the first
hour after ingestion, gastric lavage may be performed. Activated charcoal may be given
if considered appropriate.
Itraconazole cannot be removed by hemodialysis.
No specific antidote is available.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.
ATC code: J02A C02
Mode of action
Itraconazole inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and
disruption of membrane synthesis by fungi.
PK/PD relationship
The PK/PD relationship for itraconazole, and for triazoles in general, is poorly
understood and is complicated by limited understanding of antifungal
pharmacokinetics.
Mechanism(s) of resistance

Resistance of fungi to azoles appears to develop slowly and is often the result of several
genetic mutations. Mechanisms that have been described are
• Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target
enzyme)
• Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase
for itraconazole
• Drug-transporter over-expression resulting in increased efflux of itraconazole from
fungal cells (i.e., removal of itraconazole from its target)
• Cross-resistance. Cross-resistance amongst members of the azole class of drugs has
been observed within Candida species though resistance to one member of the
class does not necessarily confer resistance to other azoles.
Breakpoints
Breakpoints for itraconazole have not yet been established for fungi using EUCAST
methods.
Using CLSI methods, breakpoints for itraconazole have only been established for
Candida species from superficial mycotic infections. The CLSI breakpoints are:
susceptible ≤0.125 mg/L and resistant >1 mg/L.
The prevalence of acquired resistance may vary geographically and with time for
selected species, and local information on resistance is desirable, particularly when
treating severe infections. As necessary, expert advice should be sought when the local
prevalence of resistance is such that the utility of the agent in at least some types of
infections is questionable.
The in vitro susceptibility of fungi to itraconazole depends on the inoculum size,
incubation temperature, growth phase of the fungi, and the culture medium used. For
these reasons, the minimum inhibitory concentration of itraconazole may vary widely.
Susceptibility in the table below is based on MIC90 < 1 mg itraconazole/L. There is no
correlation between in vitro susceptibility and clinical efficacy.
Commonly susceptible species
Aspergillus spp.2
Blastomyces dermatitidis1
Candida albicans
Candida parapsilosis
Cladosporium spp.
Coccidioides immitis1
Cryptococcus neoformans
Epidermophyton floccosum
Fonsecaea spp. 1
Geotrichum spp.
Histoplasma spp.
Malassezia (formerly Pityrosporum) spp.
Microsporum spp.
Paracoccidioides brasiliensis1
Penicillium marneffei1
Pseudallescheria boydii
Sporothrix schenckii
Trichophyton spp.
Trichosporon spp.

Species for which acquired resistance may be a problem
Candida glabrata3
Candida krusei
Candida tropicalis3
Inherently resistant organisms
Absidia spp.
Fusarium spp.
Mucor spp.
Rhizomucor spp.
Rhizopus spp.
Scedosporium proliferans
Scopulariopsis spp.
1
These organisms may be encountered in patients who have returned from
travel outside Europe.
2
Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
3
Natural intermediate susceptibility.

5.2

Pharmacokinetic properties
General pharmacokinetic characteristics

The pharmacokinetics of itraconazole has been investigated in healthy subjects,
special populations and patients after single and multiple dosing. In general,
Itraconazole is rapidly absorbed. Peak plasma concentrations are reached within
2 to 5 hours after oral administration. Itraconazole is extensively metabolised by
the liver into a large number of metabolites. The main metabolite is hydroxyitraconazole, with plasma concentrations about twice those of unchanged
itraconazole. The mean elimination half-life of itraconazole is about 17 hours
after a single dose and increases to 34-42 hours after repeated dosing.
Itraconazole has non-linear pharmacokinetics, and consequently itraconazole
accumulates in plasma during multiple dosing. Steady-state concentrations are
generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold
higher than those seen after a single dose. Plasma levels are undetectable 7 days
after suspending itraconazole treatment. Itraconazole clearance decreases at
higher doses due to saturable hepatic metabolism. Itraconazole is excreted as
inactive metabolites to about 35% in urine within one week and to about 54%
with feces.
Absorption

Itraconazole is rapidly absorbed after oral administration. Peak plasma
concentrations of the unchanged drug are reached within 2 to 5 hours following
an oral dose. The observed absolute bioavailability of itraconazole is about
55%. Oral bioavailability is maximal when the capsules are taken immediately
after a full meal.
Distribution

Most of the itraconazole in plasma is bound to protein (99.8%) with albumin
being the main binding component (99.6% for the hydroxy- metabolite). It has
also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is
present as free drug. Itraconazole is distributed in a large apparent volume in the
body (> 700 L), suggesting its extensive distribution into tissues: Concentrations
in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to
three times higher than corresponding concentrations in plasma. Brain to plasma

ratios were about 1 as measured in beagle dogs. The uptake into keratinous
tissues, skin in particular, is up to four times higher than in plasma.
Biotransformation

Itraconazole is extensively metabolised by the liver into a large number of
metabolites. One of the main metabolites is hydroxy-itraconazole, which has in
vitro antifungal activity comparable to itraconazole. Plasma concentrations of
the hydroxy-itraconazole are about twice those of itraconazole.
As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in
the metabolism of itraconazole.
Elimination

Itraconazole is excreted as inactive metabolites to about 35% in urine within one
week and to about 54% with feces. Renal excretion of the parent drug accounts
for less than 0.03% of the dose, whereas fecal excretion of unchanged drug
varies between 3 – 18% of the dose. Itraconazole clearance decreases at higher
doses due to saturable hepatic metabolism.
Itraconazole absorption by keratinous tissue, especially skin, is four times that of
plasma and itraconazole elimination is related to skin regeneration. Whereas plasma
levels are undetectable 7 days after suspending itraconazole treatment, in skin
therapeutic levels of the drug can be found for 2-4 weeks following the four-week
course of treatment. Levels of itraconazole were found in the nail keratin one week
after start of treatment, persisting for a period of at least six months following a threemonth treatment.
Special Populations

Hepatic Insufficiency: A pharmacokinetic study using a single 100 mg dose of
itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic
subjects. No statistically significant differences in AUC∞ were seen between
these two groups. A statistically significant reduction in average Cmax (47%) and
a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of
itraconazole were noted in cirrhotic subjects compared with healthy subjects.
Data are not available in cirrhotic patients during long-term use of itraconazole.
(See sections 4.2 Posology and method of administration and 4.4 Special
warnings and special precautions for use).
Renal Insufficiency: Limited data are available on the use of oral itraconazole in
patients with renal impairment. Caution should be exercised when the drug is
administered in this patient population.

5.3

Preclinical safety data
Nonclinical data on itraconazole revealed no indications for gene toxicity,
primary carcinogenicity or impairment of fertility. At high doses, effects were
observed in the adrenal cortex, liver and the mononuclear phagocyte system but
appear to have a low relevance for the proposed clinical use. Itraconazole was
found to cause a dose-related increase in maternal toxicity, embryotoxicity and
teratogenicity in rats and mice at high doses. A global lower bone mineral
density was observed in juvenile dogs after chronic itraconazole administration,

and in rats, a decreased bone plate activity, thinning of the zona compacta of the
large bones, and an increased bone fragility was observed.

6
6.1

PHARMACEUTICAL PARTICULARS
List of excipients
Capsule content:
Sugar spheres (maize starch and sucrose)
Poloxamer 188
Hypromellose 6 cP
Capsule Cap/body:
Gelatin

Indigo carmine (E 132)
Quinoline Yellow (E 104)
Titanium dioxide (E 171)

6.2

6.3

Incompatibilities
Not applicable.

Shelf life
2 years.

6.4

6.5

Special precautions for storage
Do not store above 25ºC.

Nature and contents of container
Aluminum/aluminum blister pack
Packs of 4, 6, 7, 14, 15, 16, 18, 28, 32 and 60 capsules.
100 capsule packages for hospital use.
Not all pack sizes may be marketed.

6.6

7

Special precautions for disposal
No special requirements.

MARKETING AUTHORISATION HOLDER
UNIVERSAL FARMA, S.L.
Gran Via Carlos III, 98,

7th floor
08028 Barcelona

Spain

8

MARKETING AUTHORISATION NUMBER(S)
PL 19706/0006

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
02/02/2011

10

DATE OF REVISION OF THE TEXT
07/03/2013

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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