4.1. Therapeutic indications

Itraconazole is indicated for the treatment of histoplasmosis.

Itraconazole is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. (This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity).

Treatment of aspergillosis, candidosis and cryptococcosis (including cryptococcal meningitis): in immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system.

Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.

4.2. Posology and method of administration

Posology

Itraconazole is given on the first two days in a loading dose twice daily, followed by once daily dosing.

Day 1 and 2 of the treatment: 1-hour infusion of 200 mg (60 ml of the admixed solution) Itraconazole twice daily (see section 6.6).

From day 3 on: one 1-hour infusion of 200 mg (60 ml of the admixed solution) Itraconazole each day. Safety for periods longer than 14 days has not been established.

Paediatric population

Clinical data on the use of itraconazole IV in paediatric patients are limited. The use of itraconazole IV in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks (see section 4.4).

Elderly

Since clinical data of the use of itraconazole in elderly patients are limited, it is advised to use itraconazole 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).

Renal impairment

Limited data are available on the use of intravenous itraconazole in patients with renal impairment.

Hydroxypropyl-β-cyclodextrin, a required component of itraconazole intravenous formulation, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 ml/min the use of itraconazole IV is contraindicated (see section 4.3).

In patients with mild and moderate renal impairment, itraconazole IV should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation (see sections 4.4. and 5.2).

Hepatic impairment

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

Method of administration

Intravenous use.

This product is supplied with an extension line with a 2-way stopcock and 0.2 μm in-line filter. The dedicated extension line including the in-line filter must be used to ensure the correct administration of the product (see section 6.6).

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

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Itraconazole cannot be used when administration of Sodium Chloride injection is contraindicated.

The excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration. Therefore, Itraconazole is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 ml/min) see sections 4.4 and 5.2).

Co-administration of a number of CYP3A4 substrates is contraindicated with itraconazole IV (see sections 4.4 and 4.5).

Itraconazole must not be used during pregnancy for non life-threatening indications (see section 4.6).

4.4. Special warnings and precautions for use

Cross hypersensitivity

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

Cardiac effects

In a healthy volunteer study with itraconazole, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. A similar investigation was not performed in the target patient population.

Itraconazole has been shown to have a negative inotropic effect and itraconazole has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.

Itraconazole should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk.

Physicians should carefully review the risks and benefits of itraconazole therapy for patients with known risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischaemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other oedematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment. If such signs or symptoms do occur during treatment, itraconazole should be discontinued.

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 itraconazole. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving itraconazole treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs.

Elderly

Since clinical data of the use of itraconazole in elderly patients are limited, it is advised to use itraconazole 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

Studies have not been conducted with intravenous itraconazole 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 the drug is administered to 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 metabolized 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 itraconazole 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 sections 4.2 and 5.2.).

Renal impairment

Hydroxypropyl-β-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 ml/min itraconazole is contraindicated (see sections 4.3 and 5.2).

Itraconazole IV should be used with caution in patients with a lesser degree of renal failure. In patients with mild or moderate renal impairment, serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation (see section 4.4).

Hearing Loss

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

Neuropathy

If neuropathy occurs that may be attributable to itraconazole, 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 section 4.5.

Paediatric population

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

Excipients

This medicinal product contains approximately 177 mg sodium per dose, equivalent to 9 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicine contains 26 mg propylene glycol per 10 mg/ml of Itraconazole Concentrate for Solution for Infusion.

Various adverse events, such as hyperosmolality, lactic acidosis; renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity (arrhythmia, hypotension); central nervous system disorders (depression, coma, seizures); respiratory depression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) and haemoglobinuria; or multisystem organ dysfunction, have been reported with high doses or prolonged use of propylene glycol.

Adverse events usually reverse following weaning off of propylene glycol, and in more severe cases following hemodialysis. Medical monitoring is required.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old and serious adverse effects in neonates. Doses higher than 500 mg/kg/day propylene glycol may be administered in children > 5 years old but will have to be considered case by case.

While propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis.

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. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a strong 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

Co-administration of itraconazole with strong enzyme inducers of CYP3A4 may decrease the exposure of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be 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.

- Herbal medicine: Hypericum perforatum (St John's Wort).

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

Drugs that may increase itraconazole plasma concentrations

Strong inhibitors of CYP3A4 may increase the exposure 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') and telaprevir.

It is recommended that these drugs be used with caution when co-administered with itraconazole IV. It is recommended that patients who must take itraconazole concomitantly with strong inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and 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. The full inhibitory effect of itraconazole is obtained after steady state in plasma is reached (see section 5.2). The effects of itraconazole in increasing the AUC of other drugs can be as high as 11-fold, as seen with oral midazolam (a sensitive CYP3A4 substrate) when co-administered with itraconazole 200 mg/d. These elevated plasma concentrations are likely to increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized 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. Full inhibitory effect is not obtained until itraconazole steady state has been reached which takes approximately 2-4 days for itraconazole IV (see section 5.2). 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 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. 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': 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 co-administration 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 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 be measured.

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

Drug Class

Contraindicated

Not Recommended

Use with Caution

Alpha Blockers

tamsulosin

Analgesics

fentanyl

alfentanil, buprenorphine IV and sublingual, oxycodone, methadonec, sufentanil

Antiarrhythmics

disopyramide, dofetilide, dronedarone, quinidine

digoxin

Antibacterials

telithromycin, in subjects with severe renal impairment or severe hepatic impairment

rifabutina

telithromycin

Anticoagulants and Antiplatelet Drugs

dabigatran, ticagrelor

apixaban, rivaroxaban

coumarins, cilostazol

Anticonvulsants

carbamazepinea

Antidiabetics

repaglinide, saxagliptin

Antihelmintics and Antiprotozoals

halofantrine

praziquantel

Antihistamines

mizolastine, terfenadine

ebastine

bilastine

Antimigraine Drugs

ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)

eletriptan

Antineoplastics

irinotecan

axitinib, dabrafenib, dasatinib, ibrutinib, lapatinib, nilotinib, sunitinib, trabectedin

bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, ponatinib, trimetrexate, vinca alkaloids

Antipsychotics, Anxiolytics and Hypnotics

lurasidone, oral midazolam, pimozide, quetiapine, sertindole, triazolam

alprazolam, aripiprazole, brotizolam, buspirone, haloperidol, midazolam IV, perospirone, risperidone

Antivirals

simeprevir

maraviroc, indinavirb, ritonavirb, saquinavir

Beta Blockers

nadolol

Calcium Channel Blockers

bepridil, lercanidipine, nisoldipine

felodipine

other dihydropyridines, verapamil

Cardiovascular Drugs, Miscellaneous

aliskiren, ivabradine, ranolazine

riociguat

bosentan

Diuretics

eplerenone

Gastrointestinal Drugs

cisapride, domperidone

aprepitant

Immunosuppressants

ciclesonide, everolimus, temsirolimus

budesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus

Lipid Regulating Drugs

lovastatin, simvastatin

atorvastatin

Respiratory Drugs

salmeterol

SSRIs, Tricyclics and Related Antidepressants

reboxetine

Urological Drugs

darifenacin, fesoterodine, in patients with moderate to severe renal or moderate to severe hepatic impairment, sildenafil, when indicated for pulmonary arterial hypertension, solifenacin, in patients with severe renal or moderate to severe hepatic impairment, vardenafil, in men older than 75 years of age

tolterodine, vardenafil, in men 75 years of age and younger

fesoterodine, oxybutynin, sildenafil, when indicated for erectile dysfunction, solifenacin, tadalafil

Other

colchicine, in patients with renal or hepatic impairment

colchicine

alitretinoin (oral formulation), cinacalcet, tolvaptan

a See also under 'Drugs that may decrease itraconazole plasma concentrations'

b See also under 'Drugs that may increase itraconazole plasma concentrations'

c Torsade de pointes has been reported

Drugs that may have their plasma concentrations decreased by itraconazole

Co-administration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when co-administered with itraconazole, including monitoring for any reduction in efficacy of meloxicam with adjustments to the dose as necessary.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Itraconazole 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 and 4.4).

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

Epidemiological data on exposure to Itraconazole during the first trimester of pregnancy – mostly in patients receiving short-term treatment for vulvovaginal candidosis – did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens. Itraconazole has been shown to cross the placenta in a rat model.

Fertility

Women of childbearing potential receiving itraconazole should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of itraconazole therapy.

Breast-feeding

A very small amount of itraconazole is excreted in human milk and must not be administered to lactating women. Breast-feeding is to be discontinued prior to taking itraconazole.

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 itraconazole intravenous treatment identified from clinical trials and/or from spontaneous reporting were cough, diarrhoea, vomiting, nausea, rash, and oedema (including generalised oedema and face oedema). 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 for additional information on other serious effects.

Tabulated list of adverse reactions

The ADRs in the table below were derived from one randomized, active controlled, open-label clinical trial with itraconazole intravenous involving 192 patients for empirical therapy of febrile neutropenia, 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).

Adverse Drug Reactions

Blood and lymphatic system disorders

Common

Granulocytopenia

Uncommon

Thrombocytopenia

Immune system disorders

Common

Anaphylactoid reaction, Hypersensitivity*

Not known

Serum sickness, Angioneurotic oedema, Anaphylactic reaction

Metabolism and nutrition disorders

Common

Hyperglycaemia, Hypomagnesaemia

Uncommon

Hyperkalaemia

Not known

Hypertriglyceridaemia

Psychiatric disorders

Common

Confusional state

Nervous system disorders

Common

Dizziness, Headache, Somnolence, Tremor

Uncommon

Hypoaesthesia, Dysgeusia

Eye disorders

Common

Visual disturbances, (including diplopia and blurred vision)

Ear and labyrinth disorders

Uncommon

Transient or permanent hearing loss*

Cardiac disorders

Common

Cardiac failure, Tachycardia

Uncommon

Left ventricular failure

Not known

Congestive heart failure*

Vascular disorders

Common

Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Common

Pulmonary oedema, Dyspnoea

Uncommon

Dysphonia

Gastrointestinal disorders

Very common

Diarrhoea, Vomiting, Nausea

Common

Constipation, Abdominal pain, Dyspepsia, Gastrointestinal disorder

Not known

Pancreatitis

Hepatobiliary disorders

Common

Hepatitis, Jaundice, Hyperbilirubinaemia

Not known

Serious hepatotoxicity (including some cases of fatal acute liver failure)*

Skin and subcutaneous tissue disorders

Very common

Rash

Common

Urticaria, Rash erythematous, Pruritus, Alopecia, Hyperhidrosis

Not known

Toxic epidermal necrolysis, Stevens-Johnson syndrome, Acute generalised exanthematous pustulosis, Erythema multiforme, Exfoliative dermatitis, Leukocytoclastic vasculitis, Photosensitivity

Musculoskeletal and connective tissue disorders

Common

Myalgia

Renal and urinary disorders

Common

Renal impairment, Urinary incontinence

General disorders and administration site conditions

Very common

Oedema (including generalised oedema and face oedema)

Common

Chest pain, Injection site inflammation, Pyrexia, Pain, Fatigue, Chills

Endocrine Disorders

Not known

Pseudoaldosteronism

Investigations

Common

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

Uncommon

Blood creatine phosphokinase increased, Hepatic enzyme increased

* 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 itraconazole oral solution and itraconazole capsules.

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

Blood and lymphatic system disorders: Leukopenia

Metabolism and nutrition disorders: Hypokalaemia

Nervous system disorders: Peripheral neuropathy*, Paraesthesia

Ear and labyrinth disorders: Tinnitus

Gastrointestinal disorders: Flatulence

Hepatobiliary disorders: Hepatic failure*, Hepatic function abnormal

Musculoskeletal and connective tissue disorders: Arthralgia

Renal and urinary disorders: Pollakiuria

Reproductive system and breast disorders: Erectile dysfunction, Menstrual disorder

Paediatric population

The safety of itraconazole IV was evaluated in 36 paediatric patients aged 6 months to 17 years who participated in 3 open-label clinical trials. These patients received at least one dose of itraconazole IV for prevention or treatment of fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the very commonly reported adverse drug reactions (ADRs) in paediatric patients were pyrexia (16.7 %) and vomiting (11.1 %). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but in general, the incidence is higher in the adult subjects.

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 at www.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

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

Management

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