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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Itraconazole 100mg Capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule, hard contains 100mg of itraconazole.

Excipient: Each capsule, hard contains 224.31mg sucrose.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

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 Itraconazole 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 Amphotericin 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	DOSE	DURATION OF TREATMENT
Gynecological infections: - Vulvovaginal candidosis	200 mg b.i.d. or 200 mg o.d.	1 day 3 days
Dematological/ophthalmic indications: - Pityriasis versicolor	200 mg o.d.	7 days
- Tinea corporis, tinea cruris	100 mg o.d. or	15 days or
	200 mg o.d.	7 days
- Tinea pedis, tinea manuum	100 mg o.d.	30 days
- Oral candidiasis	100 mg o.d.	15 days1

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.

Location of onychomycoses	Week 1	Week Week Week 2 3 4	Week 5	Week Week Week 6 7 8	Week 9
Toenails with or without fingernail involvement	First pulse cycle	No itraconazole therapy	Second pulse cycle	No itraconazole therapy	Third pulse cycle
Finger nails only	First pulse cycle	No itraconazole therapy	Second pulse cycle

- Continuous treatment:

Two capsules a day (200 mg o.d.) for three months.

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:

INDICATIONS	DOSE	AVERAGE DURATION	COMMENTS
Aspergillosis	200 mg o.d.	2-5 months	Increase dose to 200 mg b.i.d. in the
Candidiasis	100-200 mg	3 weeks-7	case of widespread
	o.d.	months	infection
Non-meningeal cryptococcosis	200 mg o.d.	10 weeks	Maintenance therapy (meningeal cases):
Cryptococcal meningitis	200 mg b.i.d.	2 months - 6 months	200 mg o.d.
Histoplasmosis	200 mg o.d. 200 mg b.i.d.	8 months

- 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 4.3).

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 metabolized 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. Coadministration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

-    CYP3A4 metabolized 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 non-meningeal) 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 100mg Capsules, hard (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 enzyme 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.

Effects 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.

The following drugs are contraindicated with itraconazole:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Itraconazole 100mg Capsules, hard 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 congestive heart failure. 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 ritonavir, indinavir, saquinavir;

-    Certain antineoplastic agents such as, busulfan, docetaxel and trimetrexate and vinca alkaloids;

-    CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;

-    Certain immunosuppressive agents: cyclosporine, tacrolimus, rapamycin (also known as sirolimus);

-    Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;

-    Digoxin (via inhibition of P-glycoprotein)

Others: cilostazol, disopyramide, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, repaglinide, fentanyl, halofantrine, reboxetine, eletriptan.

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 100mg Capsules, hard must not be used during pregnancy with the exception of life-threatening cases where the potential benefits to the mother outweighs the potential harm to the foetus (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 post-marketing 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 100mg Capsules, hard should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itraconazole 100mg Capsules, hard 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 effects have been observed. 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	Visual Disturbance
Not Known	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
Gastrointestina	disorders
Common	Abdominal Pain, Nausea
Uncommon	Vomiting, , Diarrhoea, Constipation, Dyspepsia, Dysgeusia, Flatulence
Rare	Pancreatitis
Hepatobiliary t	isorders
Uncommon	Hyperbilirubinaemia, Alanine Aminotransferase Increased, Aspartate Aminotransferase Increased
Rare	Hepatic Enzyme Increased
Not Known	Acute Hepatic Failure*, Hepatitis, Hepatotoxicity*
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 44 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 14a-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.

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 hydroxy-itraconazole,

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 three-month 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 C_max (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 PHARMACEUTICAL PARTICULARS

6.1 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 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents of container

Aluminum/aluminum blister pack

Packs of 4, 6, 7, 14, 15, 16, 18, 28, 30, 32 and 60 capsules.

100 capsule packages for hospital use.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegur 76-78, 220 Hafnarfjordur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0228

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/01/2010

10    DATE OF REVISION OF THE TEXT

30/11/2012

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.