SPORANOX Oral Solution is indicated:

- 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 (i.e. < 500 cells/µ L). 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.

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

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.

- Treatment of oral and/or oesophageal candidosis: 200 mg (2 measuring cups) 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 (1-2 measuring cups) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400 mg 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/µ L. Treatment was continued until recovery of neutrophils (i.e. > 1 000 cells/µ L).

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 SPORANOX Oral Solution.

Use in patients with gastro-intestinal motility impairment

When treating patients with severe fungal infections or when administering it as fungal prophylaxis to those with abnormal gastro-intestinal motility, patients should be carefully monitored and where appropriate drug therapeutic monitoring should be considered, where available.

Paediatric population

The safety and efficacy of SPORANOX Oral Solution in children has not been established. Currently available data are described in section 4.4 and 5.2 but no recommendation on a posology can be made.

The use of SPORANOX Oral Solution in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks (see section 4.4).

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).

Use in elderly

Since clinical data on the use of SPORANOX Oral Solution in elderly patients are limited, it is advised to use SPORANOX Oral Solution in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see section 4.4).

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. The exposure of itraconazole may be lower in some patients with renal insufficiency and a wide inter-subject variation was observed in these subjects receiving the capsule formulation (see section 5.2). Caution should be exercised when this drug is administered in this patient population and adjusting the dose or switching to an alternative antifungal medication may be considered based on an evaluation of clinical effectiveness.

Method of administration

Precautions to be taken before handling or administering the medicinal product

For instructions on handling of the medicinal product before administration, see section 6.6.

• SPORANOX Oral Solution is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients.

• SPORANOX 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).

• SPORANOX Oral Solution must not be used during pregnancy for non-life-threatening indications (see section 4.6).

• Co-administration of SPORANOX Oral Solution is contraindicated with a number of CYP3A4 substrates such as the examples listed below (see sections 4.4 and 4.5):

Use in patients with gastro-intestinal motility impairment

When treating patients with severe fungal infections or when administering it as fungal prophylaxis to those with abnormal gastro-intestinal motility, patients should be carefully monitored and where appropriate drug therapeutic monitoring should be considered, where available.

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing SPORANOX Oral Solution to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with SPORANOX IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

Itraconazole has been shown to have a negative inotropic effect and SPORANOX 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.

SPORANOX 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 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, SPORANOX should be discontinued.

Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of SPORANOX. 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 SPORANOX 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.

Paediatric population

Clinical data on the use of SPORANOX Oral Solution in paediatric patients are limited. The use of SPORANOX Oral Solution in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.

Use in elderly

Since clinical data on the use of SPORANOX Oral Solution in elderly patients is limited, it is advised to use SPORANOX Oral Solution in these patients only if the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see section 4.4).

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. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolised by CYP3A4.

In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications (see section 5.2).

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency and a wide inter-subject variation was observed in these subjects receiving the capsule formulation (see section 5.2). Caution should be exercised when this drug is administered in this patient population and adjusting the dose or switching to an alternative antifungal medication may be considered based on an evaluation of clinical effectiveness.

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 SPORANOX Oral Solution in these circumstances.

Treatment of severely neutropenic patients

SPORANOX Oral Solution as treatment for oral and/or oesophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (see section 5.2), SPORANOX 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.

Cystic fibrosis

In cystic fibrosis patients, variability in plasma levels of itraconazole leading to subtherapeutic concentrations has been observed. The risk for subtherapeutic concentrations may be higher in < 16 year olds. If a patient does not respond to SPORANOX Oral Solution, consideration should be given to switching to alternative therapy.

Neuropathy

If neuropathy occurs that may be attributable to SPORANOX 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

Co-administration of specific drugs with itraconazole may result in changes in efficacy or safety of itraconazole and/or the co-administered drug. For example, the use of itraconazole with CYP3A4 inducing agents may lead to sub-therapeutic plasma concentrations of itraconazole and thus treatment failure. In addition, the use of itraconazole with some substrates of CYP3A4 can lead to increases in plasma concentrations of these drugs and to serious and/or potentially life threatening adverse events, such as QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. The prescriber should refer to the co-administered medicinal product information for further information regarding serious or life threatening adverse events that could occur in cases of increased plasma concentrations for that medication. For recommendations concerning the co-administration of medicinal products which are contraindicated, not recommended or recommended for use with caution in combination with itraconazole please refer to sections 4.3 and 4.5.

Interchangeability

It is not recommended that SPORANOX Capsules and SPORANOX Oral Solution be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given.

Excipients of SPORANOX Oral Solution

SPORANOX Oral Solution contains 7 920 mg sorbitol in each 40 mL dose which is equivalent to 198 mg/mL. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

SPORANOX Oral Solution contains less than 1 mmol sodium (23 mg) per 40 mL dose, that is to say essentially 'sodium-free'.

SPORANOX Oral Solution contains 0.2 mg of alcohol (ethanol) in each 40 mL dose which is equivalent to 0.005 mg/mL. The amount in 40 mL of this medicine is equivalent to less than 1 mL beer or 1 mL wine. The small amount of alcohol in this medicine will not have any noticeable effects.

SPORANOX Oral Solution contains 16 000 mg cyclodextrin(s) in each 40 mL dose which is equivalent to 400 mg/mL. Cyclodextrins may cause digestive problems such as diarrhoea. There is insufficient information on the effects of cyclodextrin in children < 2 years old. Therefore, a case by case judgement should be made regarding the risk/benefit for the patient with SPORANOX Oral Solution (see section 4.2).

SPORANOX Oral Solution contains 4.2 g propylene glycol in each 40 mL dose which is equivalent to 104 mg/mL and 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 section 4.3). SPORANOX Oral Solution must not be used during lactation (see section 4.6). Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old. Monitoring is required in patients with hepatic or renal impairment because adverse events attributed to propylene glycol have been reported, such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Itraconazole is a strong CYP3A4 inhibitor and, a P-glycoprotein inhibitor and Breast Cancer Resistance Protein (BCRP) inhibitor.

Itraconazole may modify the pharmacokinetics of other substances that share this metabolic or these protein transporter pathways.

Examples of drugs that may impact on the plasma concentration of itraconazole are presented by drug class in Table 1 below. Examples of drugs that may have their plasma concentrations impacted by itraconazole are presented in Table 2 below. Due to the number of interactions, the potential changes in safety or efficacy of the interacting drugs are not included. The list of examples of interacting drugs in the tables below is not comprehensive and therefore the product information of each drug that is co-administered with itraconazole should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.

The interactions described in these tables are categorised as contraindicated, not recommended or to be used with caution with itraconazole taking into account the extent of the concentration increase and the safety profile of the interacting drug (see also sections 4.3 and 4.4 for further information). The interaction potential of the listed drugs was evaluated based on human pharmacokinetic studies with itraconazole, and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g. ketoconazole) and/or in vitro data:

• 'Contraindicated': Under no circumstances is the drug to be co-administered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.

• 'Not recommended': The use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the concomitantly administered drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.

• 'Use with caution': Careful monitoring is recommended when the drug is co-administered with itraconazole. Upon co-administration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.

The interactions listed in these tables have been characterised in studies that were performed with recommended doses of itraconazole. However, the extent of interaction may be dependent on the dose of itraconazole administered. A stronger interaction may occur at a higher dose or with a shorter dosing interval. Extrapolation of the findings with other dosing scenarios or different drugs should be done with caution.

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. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole (see section 5.2).

Table 1: Examples of drugs that may impact the plasma concentration of itraconazole, presented by drug class

Table 2: Examples of drugs that may have their plasma concentrations impacted by itraconazole, presented by drug class

Pregnancy

SPORANOX 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 section 4.3).

In animal studies itraconazole has shown reproduction toxicity (see section 5.3).

Epidemiological data on exposure to SPORANOX 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. Itraconazole has been shown to cross the placenta in a rat model.

Women of childbearing potential

Women of childbearing potential taking SPORANOX Oral Solution should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of SPORANOX therapy.

Breast-feeding

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

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.

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) with SPORANOX Oral Solution treatment identified from clinical trials and/or from spontaneous reporting were dizziness, headache, dysgeusia, dyspnoea, cough, abdominal pain, diarrhoea, vomiting, nausea, dyspepsia, rash, and pyrexia. The most serious ADRs were serious allergic reactions, cardiac failure/congestive heart failure/pulmonary oedema, pancreatitis, serious hepatotoxicity (including some cases of fatal acute liver failure), and serious skin reactions. Refer to subsection Tabulated list of adverse reactions for the frequencies and for other observed ADRs. Refer to section 4.4 (Special warnings and precautions for use) for additional information on other serious effects.

Tabulated list of adverse reactions

The ADRs in the table below were derived from double-blind and open-label clinical trials with SPORANOX Oral Solution involving 889 patients for the treatment of oropharyngeal and oesophageal candidiasis, and from spontaneous reporting.

The table below presents ADRs by System Organ Class. Within each System Organ Class, the ADRs 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).

* see section 4.4.

Description of selected adverse reactions

The following is a list of additional ADRs associated with itraconazole that have been reported in clinical trials of SPORANOX Capsules and SPORANOX IV, excluding the ADR term “ Injection site inflammation” , which is specific to the injection route of administration.

Infections and infestations: Sinusitis, Upper respiratory tract infection, Rhinitis

Blood and lymphatic system disorders: Granulocytopenia

Immune system disorders: Anaphylactoid reaction

Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypomagnesaemia

Psychiatric disorders: Confusional state

Nervous system disorders: Somnolence, Tremor

Cardiac disorders: Left ventricular failure, Tachycardia

Vascular disorders: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders: Pulmonary oedema, Dysphonia

Gastrointestinal disorders: Gastrointestinal disorder, Flatulence

Hepatobiliary disorders: Hepatitis, Jaundice, Hepatic function abnormal

Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis

Renal and urinary disorders: Renal impairment, Pollakiuria, Urinary incontinence

Reproductive system and breast disorders: Erectile dysfunction

General disorders and administration site conditions: Generalised oedema, Face oedema, Chest pain, Pain, Fatigue, Chills

Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal

Paediatric Population

The safety of SPORANOX 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 SPORANOX 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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

Pharmacotherapeutic group: Antimycotic for systemic use, triazole and tetrazole derivative.

ATC code: J02A C02

Mechanism of action

Itraconazole inhibits fungal 14-alpha-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 been established in the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for antifungal agents, version 10.0, valid from 2020-02-04.

There is currently insufficient evidence to set clinical breakpoints for Candida glabrata³, C. krusei³, C. guilliermondi³, Cryptococcus neoformans, and Non-species related breakpoints for Candida.

There is currently insufficient evidence to set clinical breakpoints for Aspergillus niger^4,5 and Non-species related breakpoints for Aspergillus spp.⁵.

¹ Monitoring of azole trough concentrations in patients treated for fungal infection is recommended.

²Area of technical uncertainty (ATU) is 2. Report as R with the following comment: "In some clinical situations (non-invasive infections forms) itraconazole can be used provided sufficient exposure is ensured".

³ The epidemiological cut-off values (ECOFFs) for these species are in general higher than for C. albicans.

⁴ The epidemiological cut-off values (ECOFFs) for these species are in general one two-fold dilution higher than for A. fumigatus.

⁵ The MIC values for isolates of A. niger and A. versicolor are in general higher than those for A. fumigatus. Whether this translates into a poorer clinical response is unknown.

Interpretive breakpoints for itraconazole have not been established for Candida species and filamentous fungi, using Clinical and Laboratory Standards Institute (CLSI) methods, M60 Performance Standards for Antifungal Susceptibility Testing of Yeasts. 2^nd edition, 2020.

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.

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.

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 for possibly related to itraconazole were vomiting, abnormal liver function, and abdominal pain.

Itraconazole

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 C_max and AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state C_max values of about 2 μ g/mL are reached after oral administration of 200 mg 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 278 mL/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 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 hydroxy-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 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as a capsule. A statistically significantly 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. 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 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uraemia: n=7; haemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m², 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, C_max, 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 hydroxy-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-β -Cyclodextrin

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

Itraconazole

Itraconazole is not a primary carcinogen in rats up to 13 mg/kg/day (males) and 52 mg/kg/day (females), or in mice up to 80 mg/kg/day (1-fold of MRHD based on mg/m²/day).

Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, of 40 and 80 mg/kg/day in rats (1- and 2-fold of MRHD based on mg/m²/day), 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. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, (no toxicity was observed up to 20 mg/kg/day (2-fold of MRHD based on mg/m²/day), and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.

Hydroxypropyl-β -cyclodextrin

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. In a rat carcinogenicity study, hydroxypropyl-β -cyclodextrin produced adenocarcinomas in the large intestine (at the 5 000 mg/kg/day dose (3-fold of MRHD of 16 g based on mg/m²/day)) and exocrine pancreatic adenocarcinomas (at all dose levels tested 500, 2 000 and 5 000 mg/kg/day (0.3-, 1.2- and 3-fold of MRHD of 16 g based on mg/m²/day, respectively)). These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of the large intestine adenocarcinomas is low and the mechanism of exocrine pancreatic adenocarcinomas induction not considered relevant to humans.

Reproductive toxicology

Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats from 40 mg/kg/day (1-fold of MRHD based on mg/m²/day) and mice from 80 mg/kg/day (1--fold of MRHD based on mg/m²/day). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia. No teratogenic effects were found in rabbits up to 80 mg/kg/day dose (4-fold of MRHD based on mg/m²/day).

Hydroxypropyl-β (cyclodextrin), sorbitol (liquid non crystallising) E420, propylene glycol E 1520, cherry flavour 1 (contains 1,2-propylene glycol E 1520 and ethanol), cherry flavour 2 (contains 1,2-propylene glycol E 1520), caramel flavour, sodium saccharin, hydrochloric acid and sodium hydroxide (for pH adjustment), purified water.

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

2 years as packaged for sale.

1 month after first opening the container.

Do not store above 25 ° C.

150 ml amber glass bottle, with child-resistant polypropylene screw cap and LDPE liner ring.

A measuring cup graduated to indicate 10 ml is provided.

SPORANOX Oral Solution is supplied in bottles with a child-proof cap, and should be opened as follows: push the plastic screw cap down while turning it counter clockwise.

A measuring cup is supplied with the SPORANOX Oral Solution. Use the measuring cup just as it sits on the bottle. Make sure that the side with the graduations (the side that holds less) is uppermost; that is the side you have to fill. When the arrow on the side points up, the correct side is uppermost.