Document: document 1 change

• document 0
• document 1

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Itraconazole 10 mg/ml Oral Solution.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 10mg itraconazole.

It also contains 190 microlitres of sorbitol E420, 0.07mmol (1.56mg) sodium

and less than 1mg ethanol per ml of solution.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Oral solution.

Clear yellow solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Itraconazole Oral Solution is indicated in adults:

•    For the treatment of oral and/or oesophageal candidosis in HIV-positive or other immunocompromised patients.

•    As prophylaxis of deep fungal infections anticipated to be susceptible to itraconazole, when standard therapy is considered inappropriate, in patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (ie < 500 cells/pl). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.

Consideration should be given to national and/or local guidance regarding the

appropriate use of antifungal agents.

4.2    Posology and method of administration

Posology

For optimal absorption, Itraconazole Oral Solution should be taken without food (patients are advised to refrain from eating for at least 1 hour after intake).

Treatment of oral and/or oesophageal candidosis: 200 mg (20ml) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.

Treatment of fluconazole resistant oral and/or oesophageal candidosis: 100 to 200 mg (10-20ml) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400mg daily dose should not be used for longer than 14 days if there are no signs of improvement.

Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Almost all proven deep fungal infections occurred in patients reaching neutrophil counts below 100

cells/pl. Treatment was continued until recovery of neutrophils (ie > 1000 cells/pl).

Pharmacokinetic parameters from clinical studies in neutropenic patients demonstrate considerable intersubject variation. Blood level monitoring should be considered particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of Itraconazole Oral Solution.

Use in children

Since clinical data on the use of Itraconazole Oral Solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks. See section 4.4 Special warnings and special precautions for use.

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes (see section 4.8 Undesirable effects).

Use in elderly

Since clinical data on the use of Itraconazole Oral Solution in elderly patients is limited, it is advised to use Itraconazole Oral Solution in these patients only if the potential benefit outweighs the potential risks. See section 4.4 Special warnings and special precautions for use.

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 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment).

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.

Method of administration

For the treatment of oral and/or oesophageal candidosis, the liquid should be swished around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after swallowing.

4.3 Contraindications

Itraconazole Oral Solution is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients listed in section 6.1.

Co-administration of the following drugs is contraindicated with Itraconazole Oral Solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):

•    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 Oral Solution. 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 Oral Solution 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 Special warnings and precautions).

Itraconazole Oral Solution should not be used during pregnancy for non life-threatening indications (see section 4.6 Pregnancy and lactation).

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 Oral Solution 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.

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 400mg 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 Oral Solution 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 dose and duration of the treatment, and individual risk factors for congestive heart failure. 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 Oral Solution should be discontinued.

Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5 Interaction with other medicinal products).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been 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.

Most cases of serious hepatotoxicity 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. 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 patients with impaired hepatic function liver enzyme should be carefully monitored when taking itraconazole.

Use in children

Since clinical data on the use of Itraconazole Oral Solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Use in elderly

Since clinical data on the use of Itraconazole Oral Solution in elderly patients is limited, it is advised to use Itraconazole Oral Solution in these patients only if 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 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment).

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.

Prophylaxis in neutropenic patients

In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Itraconazole Oral Solution in these circumstances.

Treatment of severely neutropenic patients

Itraconazole Oral Solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (see 5.2 Pharmacokinetic properties), Itraconazole Oral Solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

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.

Neuropathy

If neuropathy occurs that may be attributable to Itraconazole Oral Solution, the treatment should be discontinued.

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 Oral Solution 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 CYP 3A4 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.

Itraconazole Oral Solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not be given this medicine.

This medicinal product contains 0.07mmol (1.56mg) sodium per ml of solution. To be taken into consideration by patients on a controlled sodium diet.

The flavouring used in this medicinal product contains small amounts of ethanol (alcohol), less than 1mg per 1ml of solution.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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 levels decline gradually, depending on the dose and duration of treatment (see Section 5.2 Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of itraconazole on comedicated 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 Oral Solution since 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

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 coadministered with itraconazole, should be reduced if necessary:

•    Oral anticoagulants;

•    HIV protease inhibitors such as ritonavir, indinavir, saquinavir;

•    Certain antineoplastic agents such as busulfan, docetaxel, 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 and loperamide. The importance of the concentration increase and the clinical relevance of these changes during the co-administration with itraconazole remain to be established.

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

Women of child-bearing potential:

Women of childbearing potential taking Itraconazole Oral Solution should use effective contraception during treatment. Effective contraception should be continued until the next menstrual period following the end of itraconazole therapy.

Fertility:

There are limited data on the effect of itraconazole on fertility; however, the non-clinical information available suggests that itraconazole has no effect on fertility (see Section 5.3).

Pregnancy:

Itraconazole Oral Solution must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see 4.3 Contraindications).

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.

Studies in animals have shown reproductive toxicity (see 5.3 Preclinical safety data).

Lactation:

A very small amount of itraconazole is excreted in human milk. Itraconazole Oral Solution must not be used during breastfeeding.

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 Undesirable effects), which may occur in some instances, must be taken into account.

4.8 Undesirable effects

Approximately 9% of patients can be expected to experience adverse reactions while taking itraconazole. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological 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).

Immune system disorders
Not Known	Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction, Hypersensitivity*
Metabolism and nutrition disorders
Uncommon	Hypokalemia
Not Known	Hypertriglyceridemia
Nervous system disorders
Common	Headache
Uncommon	Peripheral Neuropathy*, Dizziness
Not Known	Paraesthesia, Hypoaesthesia
Eye disorders
Uncommon	Visual Disorders, including Vision Blurred and Diplopia
Ear and labyrinth disorder
Not Known	Tinnitus; Transient or permanent hearing loss*
Cardiac disorders
Not Known	Congestive Heart Failure*
Respiratory, thoracic and mediastinal disorders
Common	Dyspnoea
Not Known	Pulmonary Oedema
Gastrointestinal t	isorders
Common	Abdominal Pain, Vomiting, Nausea, Diarrhoea, Dysgeusia
Uncommon	Dyspepsia, Constipation
Not Known	Pancreatitis
Hepato-biliary disorders
Common	Hepatic enzyme increased
Uncommon	Hepatitis, Hyperbilirubinaemia
Not Known	Hepatotoxicity*, Acute hepatic failure*
Skin and subcutaneous tissue disorders
Common	Rash
Uncommon	Pruritus
Not Known	Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity
Musculoskeletal and connective tissue disorders
Not Known	Myalgia, arthralgia
Renal and urinary disorders

Not Known	Pollakiuria, urinary incontinence
Reproductive system and breast disorders
Not Known	Menstrual disorders, erectile dysfunction
General disorders and administration site conditions
Common	Pyrexia
Uncommon	Oedema

* see section 4.4.

Paediatric Population

The safety of Itraconazole Oral Solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of Itraconazole Oral Solution for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in

paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

4.9 Overdose

Symptoms:

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for itraconazole (see section 4.8).

Treatment:

In the event of an overdose, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. 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.

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.

3

Natural intermediate susceptibility.

Paediatric Population

The tolerability and safety of itraconazole oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of itraconazole oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to itraconazole were vomiting, abnormal liver function, and abdominal pain.

5.2 Pharmacokinetic properties

General pharmacokinetic characteristics

Peak plasma concentrations are reached within 2.5 hours following administration of the oral solution. As a consequence of non-linear pharmacokinetics, 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. Steady-state Cmax values of about 2pg/ml are reached after oral administration of 200mg once daily. The terminal half life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Absorption

Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of itraconazole are reached within 2.5 hours following administration of the oral solution under fasting conditions. The observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30 % when the oral solution is taken in fasting conditions. Itraconazole exposure is greater with the oral solution than with the capsule formulation when the same dose of drug is given (see section 4.4).

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 and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.

Metabolism

Itraconazole is extensively metabolised by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.

Elimination

Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in faeces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxyl-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabelled dose, faecal excretion of unchanged drug ranges from 3% to 18% of the dose.

As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin

-    where itraconazole can be detected as early as 1 week after start of treatment

-    for at least six months after the end of a 3-month treatment period.

Special Populations

Hepatic Impairment

Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study was conducted in six healthy and 12 cirrhotic subjects who were administered a single 100mg dose of itraconazole as a capsule. A statistically significant reduction in average C_max (47%) and a twofold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects.

Data are not available in cirrhotic patients during long-term use of itraconazole (see sections 4.2 and 4.4).

Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200mg dose of

itraconazole (four 50mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; haemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13ml/min x 1.73m , the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of haemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (T_max, Cmax and AUC_0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.

After a single intravenous dose, the mean terminal half lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49 ml/min), and severe renal impairment (defined in this study as CrCl<20 ml/min) were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.

Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxyl-itraconazole (see sections 4.2 and 4.4).

Paediatric Population

Two pharmacokinetic studies have been conducted in neutropenic children aged 6 months to 14 years in which itraconazole oral solution was administered 5 mg/kg once or twice daily. The exposure to itraconazole was somewhat higher in older children (6 to 14 years) compared to younger children. In all children, effective

plasma concentrations of itraconazole were reached within 3 to 5 days after initiation of treatment and maintained throughout treatment.

Hydroxypropyl-fi-Cyclodextrin

The oral bioavailability of hydroxypropyl-P-cyclodextrin given as a solubiliser of itraconazole in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-P-cyclodextrin alone. This low bioavailability of hydroxypropyl-P-cyclodextrin is not modified by the presence of food and is similar after single and repeated administrations.

5.3 Preclinical safety data

Nonclinical data on itraconazole revealed no indications for genotoxicity, 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

Hydroxypropylbetadex Sorbitol E420 Propylene glycol

Cherry flavour (contains propylene glycol (E1520))

Caramel flavour (contains propylene glycol (E1520) and ethanol)

Sodium saccharin

Hydrochloric acid, concentrated (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Purified water.

6.2    Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life

Six months.

Once the bottle is open, use within 1 month.

6.4    Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5    Nature and contents of container

Amber Type III glass bottle, sealed with a child resistant, tamper evident, polypropylene screw cap, containing 150ml of solution.

A 30ml graduated measuring cup is provided.

6.6    Special precautions for disposal

No special requirements for disposal.

1

   These organisms may be encountered in patients who have returned from travel outside Europe.

2

3

Itraconazole-resistant strains of Aspergillus fumigatus have been reported.