Sporanox - Pulse – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

SPORANOXTM-Pulse.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Itraconazole 100 mg.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Capsule (Size 0): opaque blue cap and pink transparent body containing coated beads.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Onychomycosis caused by dermatophytes and/or yeasts.

Tinea pedis and/or tinea manuum.

4.2 Posology and method of administration

Sporanox-Pulse is for oral administration and must be taken immediately after a meal for maximal absorption. The capsules must be swallowed whole.

Treatment schedules in adults are as follows:

Indication Dose Remarks

Tinea pedis and/or tinea

manuum

1 pulse treatment A pulse treatment consists of 200 mg bd. for 7 days.

Onychomycosis – fingernails 2 pulse treatments Pulse treatments are separated by a 3-week

Onychomycosis – toenails 3 pulse treatments drug-free interval

Use in children

Clinical data on the use of Sporanox-Pulse in paediatric patients are limited. The use of Sporanox-Pulse in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks. See section 4.4 Special warnings and precautions for use.

In Elderly

Clinical data on the use of Sporanox-Pulse in elderly patients are limited. It is advised to use Sporanox-Pulse 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 Special warnings and precautions for use.

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. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

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 Pharmacokinetic properties – Special Populations, Hepatic impairment)

4.3 Contraindications

• Sporanox-Pulse is contra-indicated in patients with known

  hypersensitivity to itraconazole or to any of the excipients.

• Co-administration of a number of CYP3A4 substrates is contraindicated with Sporanox-Pulse capsules (see sections 4.4 and 4.5). These include:

Irinotecan

Venetoclax (in patients with chronic lymphocytic

leukaemia during dose initiation/titration/ramp-up phase of venetoclax)

that are taking a strong or moderate CYP2D6 inhibitor).

Increased plasma concentrations of these drugs, caused by coadministration with itraconazole, may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious situation may occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Some specific examples are listed in section 4.5 Interaction with other medicinal products and other forms of interaction.

• Itraconazole 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-Pulse must not be used during pregnancy. See section 4.6

  Fertility, pregnancy and lactation.

• Women of childbearing potential taking Sporanox-Pulse should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Sporanox-Pulse 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 Sporanox-Pulse to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Sporanox I.V., 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 Sporanox-Pulse 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-Pulse 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 oedematous 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-Pulse 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 exercised when co-administering itraconazole and calcium channel blockers (see section 4.5Interaction with other medicinal products and other forms of interaction) due to an increased risk of congestive heart failure.

Hepatic effects

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

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-Pulse 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 Pharmacokinetic properties - Special Populations, Hepatic impairment.)

Reduced gastric acidity

Absorption of itraconazole from Sporanox-Pulse is impaired when the gastric acidity is reduced. In patients with reduced gastric acidity, whether from disease (e.g. patients with achlorhydria) or from concomitant medication (e.g. patients taking drugs that reduce gastric acidity), it is advisable to administer Sporanox-Pulse with an acidic beverage (such as non-diet cola). The antifungal activity should be monitored and the itraconazole dose increased as deemed necessary. See section 4.5 Interaction with other medicinal products and other forms of interaction.

Paediatrics

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

Elderly

Clinical data on the use of Sporanox-Pulse capsules in elderly patients are limited. It is advised to use Sporanox-Pulse 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.

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. Caution should be exercised when this drug is administered in this patient population and adjusting the dose 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 section 4.5Interaction with other medicinal products and other forms of interaction). 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 Sporanox-Pulse may be decreased. Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. The dose should be adjusted based on the clinical response in these patients (see section 4.2). Therapeutic blood level monitoring may be necessary.

Patients with immediately life-threatening systemic fungal infections Due to the pharmacokinetic properties (See section 5.2 Pharmacokinetic properties), Sporanox-Pulse are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.

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-Pulse, consideration should be given to switching to alternative therapy.

Neuropathy

If neuropathy occurs which may be attributable to Sporanox-Pulse, treatment should be discontinued.

Disorders of Carbohydrate Metabolism

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Interchangeability

It is not recommended that Sporanox-Pulse 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.

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 Sporanox-Pulse therapy.

Interaction potential

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in section 4.3 Contraindications and 4.5 Interaction with other medicinal products and other forms of interaction.

4.5 Interaction with other medicinal products and other forms of interaction

Itraconazole is mainly metabolized 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. Please refer to the prescribing information of the interacting drug for more information.

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 should 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 coadministration, 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

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4.6 Fertility, pregnancy and lactation

Pregnancy

Sporanox-Pulse is contra-indicated in pregnancy.

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 Sporanox-Pulse 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 child bearing potential

Women of childbearing potential taking Sporanox-Pulse capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Sporanox-Pulse therapy.

Lactation

A very small amount of itraconazole is excreted in human milk. Sporanox-Pulse capsules must not be used during lactation.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) with Sporanox capsules treatment identified from clinical trials and/or from spontaneous reporting were headache, abdominal pain, and nausea. 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 open-label and double-blind clinical trials with Sporanox capsules involving 8499 patients in the treatment of dermatomycoses or onychomycosis, 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).

*see section 4.4 Description of selected adverse reactions

The following is a list of ADRs associated with itraconazole that have been reported in clinical trials of Sporanox Oral Solution and Sporanox I.V., excluding the ADR term “Injection site inflammation”, which is specific to the injection route of administration.

Blood and lymphatic system disorders: Granulocytopenia, Thrombocytopenia

Immune system disorders: Anaphylactoid reaction

Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypokalaemia, Hypomagnesaemia

Psychiatric disorders: Confusional state

Nervous system disorders: Peripheral neuropathy*, Dizziness, Somnolence Cardiac disorders: Cardiac failure, Left ventricular failure, Tachycardia Vascular disorders: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders: Pulmonary oedema, Dysphonia, Cough

Gastrointestinal disorders: Gastrointestinal disorder

Hepatobiliary disorders: Hepatic failure*, Hepatitis, Jaundice Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis Musculoskeletal and connective tissue disorders: Myalgia, Arthralgia Renal and urinary disorders: Renal impairment, Urinary incontinence General disorders and administration site conditions: Generalised oedema, Face oedema, Chest pain, Pyrexia, 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 capsules was evaluated in 165 paediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo controlled trials; 9 open-label trials; and 1 trial had an open-label phase followed by a double-blind phase). These patients received at least one dose of Sporanox capsules for the treatment of fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the commonly reported adverse drug reactions (ADRs) in paediatric patients were Headache (3.0%), Vomiting (3.0%), Abdominal pain (2.4%), Diarrhoea (2.4%), Hepatic function abnormal (1.2%), Hypotension (1.2%), Nausea (1.2%), and Urticaria (1.2%). In general, 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.

4.9 Overdose

Symptoms and signs

In general, adverse events reported with overdose have been consistent with those reported for itraconazole use. (See section 4.8 Undesirable effects)

Treatment

In the event of overdosage, supportive measures should be employed. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

It is advisable to contact a poison control centre to determine the latest recommendations for the management of an overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic classification: (Antimycotics for systemic use, triazole and tetrazole derivatives).

ATC code: J02A C02

Itraconazole, a triazole derivative, has a broad spectrum of activity.

In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

Using CLSI methods, interpretive breakpoints for itraconazole have not been established for Candida species and filamentous fungi.

For itraconazole, breakpoints have only been established by CLSI for Candida spp. from superficial mycotic infections (CLSI M27-A2). The CLSI breakpoints are as follows: susceptible ≤0.125; susceptible, dose-dependent 0.25-0.5 and resistant ≥ 1μg/mL. Interpretive breakpoints have not been established for the filamentous fungi.

EUCAST breakpoints for itraconazole have been established for Aspergillus flavus, A. fumigatus, A. nidulans and A. terreus, and are as follows: susceptible ≤ 1 mg/L, resistant > 1 mg/L. EUCAST breakpoints for itraconazole have been established for Candida albicans and C. dubliniensis, and are as follows: susceptible ≤ 0.06 mg/L, resistant > 0.06 mg/L. EUCAST breakpoints for itraconazole have been established for Candida parapsilosis and C. tropicalis, and are as follows: susceptible ≤ 0.125 mg/L, resistant > 0.125 mg/L. Interpretive breakpoints have not been established by EUCAST for Candida glabrata, C. krusei, C. guilliermondii, Cryptococcus neoformans, Aspergillus niger, and Non-species related breakpoints for Candida and Aspergillus.

EUCAST breakpoints have yet to be established for itraconazole and Candida spp.

In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤1 µg/ml. These include:

Candida spp. (including Candida albicans, Candida tropicalis, Candida parapsilosis, and Candida dubliniensis), Aspergillus spp., Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp., including H. capsulatum, Paracoccidioides brasiliensis, Talaromyces (formerly Penicillium) marneffei, Sporothrix schenckii and Trichosporon spp. Itraconazole also displayed activity in vitro against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp. and various other yeasts and fungi.

Candida glabrata, Candida krusei and Candida guillermondii are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.

The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.

Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

5.2 Pharmacokinetic properties

General pharmacokinetic characteristics

Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. 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 values of 0.5 µg/ml, 1.1 µg/ml and 2.0 µg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. 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 oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral capsule dose. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H_2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see section 4.4 Special Warnings and Precautions for use, and section 4.5 Interactions). Absorption of itraconazole under fasted conditions in these subjects is increased when Sporanox-Pulse is administered with an acidic beverage (such as a non-diet cola). When Sporanox capsules were administered as a single 200 mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H_2-receptor antagonist, itraconazole absorption was comparable to that observed when Sporanox capsules were administered alone. (See section 4.5 Interactions.)

Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (See section 4.4 Special Warnings and Precautions for use.)

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, is up to four times higher than in plasma. 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 the hydroxy-itraconazole are about twice those of itraconazole.

Excretion

Itraconazole is mainly excreted as inactive metabolites in urine (35%) and 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 varies between 3 – 18% of the dose.

Special Populations

Hepatic Impairment:

Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in average Cmax (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. 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 section 4.2 Dosage and Administration, and section 4.4 Special warnings and precautions for use.)

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 (uremia: n=7; hemodialysis: 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 hemodialysis 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 also section 4.2 Dosage and Administration, and section 4.4 Special warnings and precautions for use.)

Paediatrics:

Limited pharmacokinetic data are available on the use of itraconazole in the paediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, C_max and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.

5.3 Preclinical safety data

Itraconazole

Acute oral toxicity studies with itraconazole in mice, rats, guinea-pigs and dogs indicate a wide safety margin (4 to 16 fold of Maximum Recommended Human Dose [MRHD] of 400 mg/day based on mg/m2/day)

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. 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, (no toxicity was observed up to 20 mg/kg/day (24-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.

Reproductive toxicology

Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at 40 and 160 mg/kg/day (1- and 4-fold of MRHD based on mg/m²/day) and mice at 80 and 160 mg/kg/day (1 and 2-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).

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sugar spheres

Hypromellose 2910 5mPa.s

Macrogol 20000

Capsule shell:

Titanium dioxide E171

Indigotin carmine E132

Gelatin PhEur.

Erythrosine E127

6.2. Incompatibilities

None known.

6.3. Shelf life

36 months.

6.4. Special Precautions for Storage

Do not store above 30°C.

Store in the original container.

6.5. Nature and content of container

Tristar blister - plastic foil consisting of 3 layers

• polyvinylchloride on the outside
• low density polyethylene in the middle
• polyvinylidene chloride on the inside

Aluminium foil (thickness 20 µm) coated on the inner side with colourless heatseal lacquer: PVC mixed polymers with acrylates 6 g/m²

or:

PVC blister consisting of:

Polyvinylchloride “genotherm” glass clear, thickness 250 μm Aluminium foil (thickness 20 µm) coated on the inner side with a colourless heatseal lacquer: PVC mixed polymers with acylates 6 g/m²

Pack size: 28 capsules.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. MARKETING AUTHORISATION NUMBER(S)

PL: 00242/0334.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26 March 1997.

10 DATE OF REVISION OF THE TEXT

08/11/2023