PRODUCT SUMMARY

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.

Treatment schedules in adults are as follows:

Indication	Dose	Remarks
Tinea pedis and/or tinea	1 pulse treatment	A pulse treatment consists
manuum		of 200 mg bd. for 7 days.
Onychomycosis -	2 pulse treatments	Pulse treatments are
fingernails		separated by a 3-week
Onychomycosis - toenails	3 pulse treatments	drug-free interval

Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases, blood level monitoring is indicated.

Use in children

Not recommended. See 4.4 Special warnings and special precautions for use.

In Elderly

Not recommended. See 4.4 Special warnings and special precautions for use.

Use in patients with renal impairment

The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. A dose adjustment may be considered. See 4.4 Special warnings and special precautions for use.

Use in patients with hepatic impairment

Itraconazole is predominantly metabolised by the liver. The terminal half-life of itraconazole in cirrhotic patients is somewhat prolonged. The oral bioavailability in cirrhotic patients is somewhat decreased. A dose adjustment may be considered. See 4.4 Special warnings and special precautions for use.

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. 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. 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

Special warnings and precautions for use.

•    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 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; 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 dose and duration of treatment (e.g. total daily dose), and individual risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, 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 4.5) 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 capsules. 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 capsules treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In such cases liver enzyme monitoring is necessary.

Reduced gastric acidity

Absorption of itraconazole from Sporanox-Pulse is impaired when the gastric acidity is reduced. In patients also receiving acid neutralising medicines (eg aluminium hydroxide), these should be administered at least 2 hours after the intake of Sporanox-Pulse. In patients with achlorhydria such as certain AIDS patients and patients on secretion suppressors (eg H2-antagonists, proton-pump inhibitors), it is advisable to administer Sporanox-Pulse with a cola beverage.

Use in children

Clinical data on the use of Sporanox-Pulse capsules in paediatric patients is limited. Sporanox-Pulse capsules should not be used in paediatric patients unless the potential benefit outweighs the potential risks.

Use in elderly

Clinical data on the use of Sporanox-Pulse capsules in elderly patients is limited. Sporanox-Pulse capsules should not be used in these patients unless the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See Section 5.2)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adaptation may be considered.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see 4.3 and 4.5). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Immunocompromised patients

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Sporanox-Pulse capsules may be decreased.

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

Patients with AIDS

In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Neuropathy

If neuropathy occurs which may be attributable to Sporanox-Pulse, the 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.

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

Sporanox-Pulse 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.

4.5 Interaction with other medicinal products and other forms of interaction

Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.

Drugs that may decrease itraconazole plasma concentrations

Drugs that reduce the gastric acidity (e.g. acid neutralising medicines such as aluminum hydroxide, or acid secretion suppressors such as H₂-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules:

It is recommended that itraconazole be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.

It is recommended that acid neutralising medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of Sporanox-Pulse.

Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.

Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be largely reduced. Examples include:

Antibacterials: isoniazid, rifabutin (see also under Drugs that may have their plasma concentrations increased by itraconazole), rifampicin.

Anticonvulsants: carbamazepine, (see also under Drugs that may have their plasma concentrations increased by itraconazole), phenobarbital, phenytoin.

Antivirals: efavirenz, nevirapine.

Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.

Drugs that may increase itraconazole _plasma concentrations

Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:

Antibacterials: ciprofloxacin, clarithromycin, erythromycin,

Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under Drugs that may have their plasma concentrations increased by itraconazole), ritonavir (see also under Drugs that may have their plasma concentrations increased by itraconazole),

It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma concentrations be measured.

Drugs that may have their plasma concentrations increased by itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolised by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolised drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. 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.

The interacting drugs are categorized as follows:

•    ‘Contraindicated’: Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.

•    ‘Not recommended’: It is recommended that 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 coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended,

and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

• ‘Use with caution’: Careful monitoring is recommended when the drug is coadministered 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 be measured.

Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:

Drug Class	Contraindicated	Not Recommended	Use with Caution
Alpha Blockers		tamsulosin
Analgesics	levacetylmethadol (levomethadyl), methadone	fentanyl	alfentanil, buprenorphine IV and sublingual, oxycodone
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin
Antibacterials		rifabutin3
Anticoagulants and Antiplatelet Drugs		rivaroxaban	coumarins, cilostazol, dabigatran
Anticonvulsants		carbamazepinea
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals	halofantrine		praziquantel
Antihistamines	astemizole, mizolastine, terfenadine		ebastine
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan
Antineoplastics	irinotecan	dasatinib, nilotinib, trabectedin	bortezomib, busulphan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids

Drug Class	Contraindicated	Not Recommended	Use with Caution
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, sertindole, triazolam		alprazolam, aripiprazole, brotizolam, buspirone, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone
Antivirals			maraviroc, indinavirb, ritonavirb, saquinavir
Beta Blockers			nadolol
Calcium Channel Blockers	bepridil, felodipine, lercanidipine, nisoldipine		other dihydropyridines, including verapamil
Cardiovascular Drugs, Miscellaneous	ivabradine, ranolazine	aliskiren
Diuretics	eplerenone
Gastrointestinal Drugs	cisapride,		aprepitant, domperidone
Immunosuppressants		everolimus	budesonide, ciclesonide, ciclosporin, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus, temsirolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin
Respiratory Drugs		salmeterol
SSRIs, Tricyclics and Related Antidepressants			reboxetine
Urological Drugs		vardenafil	fesoterodine. imidafenacin, sildenafil, solifenacin, tadalafil,

Drug Class	Contraindicated	Not Recommended	Use with Caution
			tolterodine
Other	colchicine, in subjects with renal or hepatic impairment	colchicine	alitretinoin (oral formulation), cinacalcet, mozavaptan, tolvaptan

a See also under Drugs that may decrease itraconazole plasma concentrations b See also under Drugs that may increase itraconazole plasma concentrations

Drugs that may have their plasma concentrations decreased by itraconazole

Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentrations of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adapted if necessary.

Paediatric Population

Interaction studies have only been performed in adults.

4.6 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.

Women of child bearing potential

Women of childbearing potential taking Sporanox-Pulse capsules should use contraceptive precautions. Effective contraception should be continued until the next 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

Undesirable effects listed below have been reported in clinical trials with Sporanox-Pulse and/or from spontaneous reports from post-marketing experience for all Sporanox formulations.

In open-label and₌double-blind clinical trials involving 8499 itraconazole-treated patients in the treatment of dermatomycoses or onychomycosis, the most frequently reported adverse experiences in clinical trials were of gastrointestinal, dermatological, and hepatic origin.

The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:

Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (> 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

Adverse Drug Reactions

Blood and lymphatic system disorders
Rare	Leukopenia,
Not Known	Neutropenia, Thrombocytopenia

Immune system disorders

Uncommon	Hypersensitivity*
Not Known	Anaphylactic Reaction, Anaphylactoid Reaction, Angioneurotic Oedema, Serum Sickness

Metabolism and nutrition disorders

Not Known Hypokalemia, Hypertriglyceridemia

Nervous system disorders
Uncommon	Headache, Dizziness, Paraesthesia
Rare	Hypoaesthesia
Not Known	Peripheral Neuropathy*
Eye disorders
Rare	Visual Disturbance
Not Known	Vision Blurred and Diplopia
Ear and labyrinth disorder
Rare	Tinnitus
Not Known	Transient or permanent Hearing Loss*
Cardiac disorders
Not Known	Congestive Heart Failure*
Respiratory, thoracic and mediastinal disorders
Rare	Dyspnoea
Not Known	Pulmonary Oedema
Gastrointestinal disorders
Common	Abdominal Pain, Nausea
Uncommon	Vomiting, Diarrhoea, Constipation, Dyspepsia, Dysgeusia; Flatulence
Not Known	Pancreatitis
Hepatobiliary disorders
Uncommon	Hyperbilirubinaemia, Alanine Aminotransferase Increased, Aspartate Aminotransferase Increased
Rare	Hepatic Enzyme Increased
Not Known	Acute Hepatic Failure*, Hepatitis, Hepatotoxicity*
Skin and su	bcutaneous tissue disorders
Common	Rash
Uncommon	Urticaria, Alopecia, Pruritus
Not Known	Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Acute generalised exanthematous pustulosis, Erythema Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis, Photosensitivity
Musculoskeletal and connective tissue disorders
Not Known	Myalgia, Arthralgia
Renal and urinary disorders
Rare	Pollakiuria,
Unknown	Urinary Incontinence
Reproductive system and breast disorders
Uncommon	Menstrual disorder
Unknown	Erectile Dysfunction

General disorders and administration site conditions

Uncommon	Oedema
Rare	Pyrexia

*see section 4.4

4.9 Overdose

No data are available.

In the event of overdosage, supportive measures should be employed Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis.

No specific antidote is available.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic classification: (Antimycotics for systemic use, triazole 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.

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

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

dermatophytes (Trichophyton spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis and C. parapsilosis), Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Blastomyces dermatitidis; and various other yeasts and fungi.

Candida glabrata and Candida krusei 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 14a-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 pg/ml, 1.1 pg/ml and 2.0 pg/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 H2-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. x 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 (Tmax, Cmax, and AUC0-8h). 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, Cmax and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.

5.3 Preclinical safety data

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

6.    PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Sugar spheres Hypromellose 2910 5mPa.s Macrogol 20000

Capsule shell:

Titanium dioxide E171 Indigotin carmine E132 Gelatin.

Incompatibilities

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

Pack size: 28 capsules.

6.6.    Instructions for use handling, (and disposal)

Not applicable.

No Data Held

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.

26 March 1997.

DATE OF REVISION OF THE TEXT

16/04/2013