4.1. Therapeutic indications

Itraconazole oral solution is indicated:

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

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

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

4.2. Posology and method of administration

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

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

Treatment of oral and/or oesophageal candidosis:

200mg (20ml) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.

Treatment of fluconazole resistant oral and/or oesophageal candidosis:

100 to 200mg (10-20ml) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400mg (40ml) daily dose should not be used for longer than 14 days if there are no signs of improvement.

Prophylaxis of fungal infections:

5mg/kg (0.5ml/kg) per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Almost all proven deep fungal infections occurred in patients reaching neutrophil counts below 100 cells/µl. Treatment was continued until recovery of neutrophils (i.e. > 1000 cells/µl).

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

Use in patients with gastro-intestinal motility impairment

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

Paediatric population

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

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

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5mg/kg (0.5ml/kg) per day administered in two intakes (see section 4.8).

Use in elderly

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

Use in patients with hepatic impairment

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

Use in patients with renal impairment

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

4.3. Contraindications

• Itraconazole oral solution is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients.

• Itraconazole oral solution should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections (see section 4.4).

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

• Co-administration of a number of CYP3A4 substrates is contraindicated with Itraconazole oral solution (see sections 4.4 and 4.5). These include:

Analgesics; Anaesthetics

Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine)

Anti-bacterials for Systemic Use; Anti-mycobacterials; Antimycotics for Systemic Use

Isavuconazole

Anthelmintics; Antiprotozoals

Halofantrine

Antihistamines for Systemic Use

Astemizole

Mizolastine

Terfenadine

Antineoplastic Agents

Irinotecan

Venetoclax (in patients With chronic lymphocytic leukaemia during initiation and dose titration phase of venetoclax)

Antithrombotic Agents

Dabigatran

Ticagrelor

Antivirals for Systemic Use

Ombitasvir/Paritaprevir/Ritonavir (with or without Dasabuvir)

Cardiovascular System (Agents Acting on the Renin-Angiotensin System; Antihypertensives; Beta Blocking Agents; Calcium Channel Blockers; Cardiac Therapy; Diuretics)

Aliskiren

Eplerenone

Quinidine

Bepridil

Finerenone

Ranolazine

Disopyramide

Ivabradine

Sildenafil (pulmonary hypertension)

Dofetilide

Lercanidipine

Dronedarone

Nisoldipine

Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti-inflammatory/Anti-infective Agents; Antiemetics and Antinauseants; Drugs for Constipation; Drugs for Functional Gastrointestinal Disorders

Cisapride

Domperidone

Naloxegol

Immunosuppresants

Voclosporin

Lipid Modifying Agents

Lovastatin

Lomitapide

Simvastatin

Psychoanaleptics; Psycholeptics (eg, antipsychotics, anxiolytics, and hypnotics)

Lurasidone

Pimozide

Sertindole

Midazolam (oral)

Quetiapine

Triazolam

Urologicals

Avanafil

Darifenacin

Solifenacin (in patients with severe renal impairment or moderate to severe hepatic impairment)

Dapoxetine

Fesoterodine (in patients with moderate or severe renal or hepatic impairment).

Vardenafil (in patients older than 75 years).

Miscellaneous Drugs and Other Substances

Colchicine (in patients with renal or hepatic impairment)

Eliglustat (in patients that are CYP2D6 poor metabolisers (PM), CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) that are taking a strong or moderate CYP2D6 inhibitor).

4.4. Special warnings and precautions for use

Use in patients with gastro-intestinal motility impairment

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

Cross-hypersensitivity

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

Cardiac effects

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

Itraconazole has been shown to have a negative inotropic effect and Itraconazole has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400mg (40ml) 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. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dose and duration of treatment, and individual risk factors for congestive heart failure. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, 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.

Paediatric population

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

Use in elderly

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

Hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolised by CYP3A4.

In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with 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 section 5.2).

Renal impairment

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

Prophylaxis in neutropenic patients

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

Treatment of severely neutropenic patients

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

Hearing Loss

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

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 Itraconazole oral solution, consideration should be given to switching to Itraconazole IV or to alternative therapy.

Neuropathy

If neuropathy occurs that may be attributable to Itraconazole oral solution, the treatment should be discontinued.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of itraconazole therapy.

Interaction potential

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

Interchangeability

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

Excipients Warnings

Sorbitol (E420): This medicinal product contains 6878.76 mg sorbitol in each 40 ml dose which is equivalent to 171.97 mg/ml. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Sodium: This medicinal product contains 1.2mmol (or 28.45mg) sodium per 40 ml, equivalent to 1.43% of the WHO recommended maximum daily intake of 2g sodium for an adult.

Cyclodextrins (E459): This medicinal product contains 16000 mg cyclodextrin(s) in each 40 ml dose which is equivalent to 400 mg/ml. Cyclodextrins (CDs) are excipients which can influence the properties (such as toxicity or skin penetration) of the active substance and other medicines. Safety aspects of CDs have been considered during the development and safety assessment of the drug product, and are clearly stated in the SmPC. Cyclodextrins may cause digestive problems such as diarrhoea.

Propylene glycol (E1520): This medicinal product contains 1636.8mg propylene glycol in each 40 ml dose which is equivalent to 40.92mg/ml.

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. 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 list of

examples of interacting drugs in the tables below is not comprehensive and therefore the product information of each drug that is co-administered with itraconazole should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.

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

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

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

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

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

Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. (see section 5.2)

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

Medicinal products (Per Orale [PO] Single Dose unless otherwise stated) within class

Expected/Potential effect on itraconazole levels (↑ = increase; ↔ = no change; ↓ = decrease)

Clinical comment (see above for additional info and also sections 4.3 and 4.4)

Anti-bacterials for Systemic Use; Anti-mycobacterials

Isoniazid

Although not studied directly, isoniazid is likely to decrease the concentrations of itraconazole.

Not recommended

Rifampicin PO 600 mg OD

Itraconazole AUC ↓

Not recommended

Rifabutin PO 300 mg OD

Itraconazole Cmax ↓ 71%, AUC ↓ 74%

Not recommended

Ciprofloxacin PO 500 mg BID

Itraconazole Cmax ↑ 53%, AUC ↑ 82%

Use with caution

Erythromycin 1 g

Itraconazole Cmax ↑ 44%, AUC ↑ 36%

Use with caution

Clarithromycin PO 500 mg BID

Itraconazole Cmax ↑ 90%, AUC ↑ 92%

Use with caution

Antiepileptics

Carbamazepine, Phenobarbital

Although not studied directly, these drugs are likely to decrease concentrations of itraconazole.

Not recommended

Phenytoin PO 300 mg OD

Itraconazole Cmax ↓ 83%, AUC ↓ 93% Hydroxyitraconazole Cmax ↓ 84%, AUC ↓ 95%

Not recommended

Antineoplastics Agents

Idelalisib

Although not studied directly, idelalisib is likely to increase the concentrations of itraconazole.

Use with caution

Antivirals for Systemic Use

Ombitasvir/Paritaprevir/Ritonavir (with or without Dasabuvir)

Although not studied directly, these drugs are expected to increase the concentrations of itraconazole.

Contraindicated

Efavirenz 600 mg

Itraconazole Cmax ↓ 37%, AUC ↓ 39%; Hydroxyitraconazole Cmax ↓ 35%, AUC ↓ 37%

Not recommended

Nevirapine PO 200 mg OD

Itraconazole Cmax ↓ 38%, AUC ↓ 62%

Not recommended

Cobicistat, Darunavir (boosted), Elvitegravir (ritonavir-boosted), Fosamprenavir (ritonavir-boosted), Ritonavir, Saquinavir (ritonavir-boosted)

Although not studied directly, these drugs are expected to increase the concentrations of itraconazole.

Use with caution

Indinavir PO 800 mg TID

Itraconazole concentration ↑

Use with caution

Calcium Channel Blockers

Diltiazem

Although not studied directly, diltiazem is likely to increase the concentration of itraconazole.

Use with caution

Drugs for Acid Related Disorders

Antacids (aluminium, calcium, magnesium, or sodium bicarbonate), H2-receptor antagonists (e.g., cimetidine, ranitidine), Proton pump inhibitors (e.g., lansoprazole, omeprazole, rabeprazole)

Itraconazole Cmax ↓, AUC ↓

Use with caution

Respiratory System: Other Respiratory System Products

Lumacaftor/Ivacaftor PO 200/250 mg BID

Itraconazole concentration ↓

Not recommended

Miscellaneous

St. John's Wort (Hypericum perforatum)

Although not studied directly, St. John's Wort is likely to decrease the concentration of itraconazole.

Not recommended

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

Medicinal products (PO Single Dose unless otherwise stated) within class

Expected/Potential effect on drug levels

Clinical comment

(↑ = increase; ↔ = no change; ↓ = decrease)

(see above for additional info and also sections 4.3 and 4.4)

Analgesics; Anaesthetics

Ergot alkaloids (e.g., dihydroergotamine, ergometrine, ergotamine, methylergometrine)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Eletriptan, Fentanyl

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Not recommended

Alfentanil, Buprenorphine (IV and sublingual), Cannabinoids, Methadone, Sufentanil

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Oxycodone PO 10 mg,

Oxycodone PO: Cmax ↑ 45%, AUC ↑ 2.4-fold

Use with caution

Oxycodone IV 0.1 mg/kg

Oxycodone IV: AUC ↑ 51%

Use with caution

Anti-bacterials for Systemic Use; Anti-mycobacterials; Antimycotics for Systemic Use

Isavuconazole

Although not studied directly, itraconazole is likely to increase the concentrations of isavuconazole.

Contraindicated

Bedaquiline

Although not studied directly, itraconazole is likely to increase the concentrations of bedaquiline.

Not recommended

Rifabutin PO 300 mg OD

Rifabutin concentration ↑ (extent unknown)

Not recommended

Clarithromycin PO 500 mg BID

Clarithromycin concentration ↑

Use with caution

Delamanid

Although not studied directly, itraconazole is likely to increase the concentrations of delamanid.

Use with caution

Antiepileptics

Carbamazepine

Although not studied directly, itraconazole is likely to increase the concentrations of carbamazepine.

Not recommended

Anti-inflammatory and Antirheumatic Products

Meloxicam 15 mg

Meloxicam Cmax ↓ 64%, AUC ↓ 37%

Use with caution

Anthelmintics; Antiprotozoals

Halofantrine

Although not studied directly, itraconazole is likely to increase the concentrations of halofantrine.

Contraindicated

Artemether-lumefantrine, Praziquantel

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Quinine 300 mg

Quinine Cmax ↔, AUC ↑ 96%

Use with caution

Antihistamines for Systemic Use

Astemizole, Mizolastine, Terfenadine

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Ebastine 20 mg

Ebastine Cmax ↑ 2.5-fold, AUC ↑ 6.2-fold Carebastine Cmax ↔, AUC ↑ 3.1-fold

Not recommended

Bilastine, Rupatadine

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Antineoplastic Agents

Irinotecan

Although not studied directly, itraconazole is likely to increase the concentrations of irinotecan and its active metabolite.

Contraindicated

Venetoclax

Although not studied directly, itraconazole is likely to increase

The concentrations of venetoclax.

Contraindicated in Patients with chronic Lymphocytic leukaemia During initiation and dose Titration phase of venetoclax. Otherwise, not recommended unless the benefits outweigh the risks. Refer to the venetoclax prescribing information.

Axitinib, Bosutinib, Cabazitaxel, Cabozantinib, Ceritinib, Crizotinib, Dabrafenib, Dasatinib, Docetaxel, Everolimus, Glasdegib, Ibrutinib, Lapatinib, Nilotinib, Pazopanib, Regorafenib, Sunitinib, Temsirolimus, Trabectedin, Trastuzumab emtansine, Vinca alkaloids (e.g., vinflunine, vinorelbine)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs except for cabazitaxel and regorafenib. No statistically significant change in cabazitaxel exposure, but a high variability in the results was observed. Regorafenib AUC is expected to decrease (by estimation of active moiety)

Not recommended

Cobimetinib 10 mg

Cobimetinib Cmax ↑ 3.2-fold, AUC ↑ 6.7-fold

Not recommended

Entrectinib

Entrectinib Cmax ↑ 73%, AUC ↑ 6.0‑fold

Not recommended

Olaparib 100 mg

Olaparib Cmax ↑ 40%, AUC ↑ 2.7-fold

Not recommended

Talazoparib

Talazoparib Cmax ↑ 40%, AUC ↑ 56%

Not recommended

Alitretinoin (oral), Bortezomib, Brentuximab vedotin, Erlotinib, Idelalisib, Imatinib, Nintedanib, Panobinostat, Ponatinib, Ruxolitinib, Sonidegib, Tretinoin (oral)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs

Use with caution

Busulfan 1 mg/kg Q6h

Busulfan Cmax ↑, AUC ↑

Use with caution

Gefitinib 250 mg

Gefitinib 250 mg Cmax ↑, AUC ↑ 78%

Use with caution

Pemigatinib

Pemigatinib Cmax ↑ 17%, AUC ↑ 91%

Use with caution

Antithrombotic Agents

Dabigatran, Ticagrelor

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Apixaban, Edoxaban, Rivaroxaban, Vorapaxar

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Not recommended

Cilostazol, Coumarins (e.g., warfarin)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs

Use with caution

Antivirals for Systemic Use

Ombitasvir/Paritaprevir/Ritonavir (with or without Dasabuvir)

Itraconazole may increase paritaprevir concentrations.

Contraindicated

Elbasvir/Grazoprevir, Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Not recommended

Cobicistat, Elvitegravir (ritonavir-boosted), Glecaprevir/Pibrentasvir, Maraviroc, Ritonavir, Saquinavir

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Indinavir PO 800 mg TID

Indinavir Cmax ↔, AUC ↑

Use with caution

Cardiovascular System (Agents Acting on the Renin-Angiotensin System; Antihypertensives; Beta Blocking Agents; Calcium Channel Blockers; Cardiac Therapy; Diuretics)

Bepridil, Disopyramide, Dofetilide, Dronedarone, Eplerenone, Finerenone, Ivabradine, Lercanidipine, Nisoldipine, Ranolazine, Sildenafil (pulmonary hypertension)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Aliskiren 150 mg

Aliskiren Cmax ↑ 5.8-fold, AUC ↑ 6.5-fold

Contraindicated

Quinidine 100 mg

Quinidine Cmax ↑ 59%, AUC ↑ 2.4-fold

Contraindicated

Felodipine 5 mg

Felodipine Cmax ↑ 7.8-fold, AUC ↑ 6.3-fold

Not recommended

Riociguat, Tadalafil (pulmonary hypertension)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Not recommended

Bosentan, Diltiazem, Guanfacine, Other Dihydropyridines (e.g., amlodipine, isradipine, nifedipine, nimodipine), Verapamil

Although not studied directly, itraconazole is likely to increase the concentrations of bosentan.

Use with caution

Digoxin 0.5 mg

Digoxin Cmax ↑ 34%, AUC ↑ 68%

Use with caution

Nadolol 30 mg

Nadolol Cmax ↑ 4.7-fold, AUC ↑ 2.2-fold

Use with caution

Corticosteroids for Systemic Use; Drugs for Obstructive Airway Diseases

Ciclesonide, Salmeterol

Although not studied directly, itraconazole is likely to increase the concentrations of salmeterol and the active metabolite of ciclesonide.

Not recommended

Budesonide INH 1 mg SD

Budesonide INH Cmax ↑ 65%, AUC ↑ 4.2-fold; Budesonide (other formulations) concentration ↑

Use with caution

Dexamethasone IV 5 mg Dexamethasone PO 4.5 mg

Dexamethasone IV: Cmax ↔, AUC ↑ 3.3-fold Dexamethasone PO: Cmax ↑ 69%, AUC ↑ 3.7-fold

Use with caution

Fluticasone INH 1 mg BID

Fluticasone INH concentration ↑

Use with caution

Methylprednisolone 16 mg

Methylprednisolone PO Cmax ↑ 92%, AUC ↑ 3.9-fold Methylprednisolone IV AUC ↑ 2.6-fold

Use with caution

Fluticasone nasal

Although not studied directly, itraconazole is likely to increase the concentrations of nasally-administered fluticasone.

Use with caution

Drugs Used in Diabetes

Repaglinide 0.25 mg

Repaglinide Cmax ↑ 47%, AUC ↑ 41%

Use with caution

Saxagliptin

Although not studied directly, itraconazole is likely to increase the concentrations of saxagliptin.

Use with caution

Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti-inflammatory/Anti-infective Agents; Antiemetics and Antinauseants; Drugs for Constipation; Drugs for Functional Gastrointestinal Disorders

Cisapride, Naloxegol

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Domperidone 20 mg

Domperidone Cmax ↑ 2.7-fold, AUC ↑ 3.2-fold

Contraindicated

Aprepitant, Loperamide, Netupitant

Although not studied directly, itraconazole is likely to increase the concentrations of aprepitant.

Use with caution

Immunosuppressants

Voclosporin

Although not studied directly, itraconazole is likely to increase

The concentrations of voclosporin.

Contraindicated

Sirolimus (rapamycin)

Although not studied directly, itraconazole is likely to increase the concentrations of sirolimus.

Not recommended

Cyclosporine, Tacrolimus

Although not studied directly, itraconazole is likely to increase the concentrations of cyclosporine.

Use with caution

Tacrolimus IV 0.03 mg/kg OD

Tacrolimus IV concentration ↑

Use with caution

Lipid Modifying Agents

Lomitapide

Although not studied directly, itraconazole is likely to increase the concentrations of lomitapide.

Contraindicated

Lovastatin 40 mg,

Lovastatin Cmax ↑ 14.5->20-fold, AUC ↑ > 14.8 - >20-fold Lovastatin acid Cmax ↑ 11.5-13-fold, AUC ↑ 15.4-20-fold

Contraindicated

Simvastatin 40 mg

Simvastatin acid Cmax ↑ 17-fold, AUC ↑ 19-fold

Contraindicated

Atorvastatin

Atorvastatin acid: Cmax ↔ to ↑2.5-fold, AUC ↑ 40% to 3-fold

Not recommended

Psychoanaleptics; Psycholeptics (e.g., antipsychotics, anxiolytics, and hypnotics)

Lurasidone, Pimozide, Quetiapine, Sertindole

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Midazolam (oral) 7.5 mg

Midazolam (oral) Cmax ↑ 2.5 to 3.4-fold, AUC ↑ 6.6 to 10.8-fold

Contraindicated

Triazolam 0.25 mg

Triazolam Cmax ↑, AUC ↑

Contraindicated

Alprazolam 0.8 mg

Alprazolam Cmax ↔, AUC ↑ 2.8-fold

Use with caution

Aripiprazole 3 mg

Aripiprazole Cmax ↑ 19%, AUC ↑ 48%

Use with caution

Brotizolam 0.5 mg

Brotizolam Cmax ↔, AUC ↑ 2.6-fold

Use with caution

Buspirone 10 mg

Buspirone Cmax ↑ 13.4-fold, AUC ↑ 19.2-fold

Use with caution

Midazolam (iv) 7.5 mg

Midazolam (iv) 7.5 mg: concentration ↑; Although not studied directly, itraconazole is likely to increase the concentrations of midazolam following oromucosal administration.

Use with caution

Risperidone 2-8 mg/day

Risperidone and active metabolite concentration ↑

Use with caution

Zopiclone 7.5 mg

Zopiclone Cmax ↑ 30%, AUC ↑ 70%

Use with caution

Cariprazine, Galantamine, Haloperidol, Reboxetine, Venlafaxine

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Respiratory System: Other Respiratory System Products

Lumacaftor/Ivacaftor PO 200/250 mg BID

Ivacaftor Cmax ↑ 3.6-fold, AUC ↑ 4.3-fold Lumacaftor Cmax ↔, AUC ↔

Not recommended

Ivacaftor

Although not studied directly, itraconazole is likely to increase the concentrations of ivacaftor.

Use with caution

Sex Hormones and Modulators of the Genital System; Other Gynaecologicals

Cabergoline, Dienogest, Ulipristal

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Urologicals

Avanafil, Dapoxetine, Darifenacin

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Contraindicated

Fesoterodine

Although not studied directly, itraconazole is likely to increase the concentrations of the active metabolites, 5-hydroxymethyl tolterodine.

Moderate or severe renal or hepatic impairment: Contraindicated Mild renal or hepatic impairment: Concomitant use should be avoided Normal renal or hepatic function: Use with caution with a maximum fesoterodine dose of 4 mg.

Solifenacin

Although not studied directly, itraconazole is likely to increase the concentrations of solifenacin.

Severe renal impairment: Contraindicated Moderate or severe hepatic impairment: Contraindicated Use with caution in all other patients with a maximum solifenacin dose of 5 mg.

Vardenafil

Although not studied directly, itraconazole is likely to increase the concentrations of vardenafil.

Contraindicated in patients older than 75 years; otherwise not recommended.

Alfuzosin, Silodosin, Tadalafil (erectile dysfunction and benign prostatic hyperplasia), Tamsulosin, Tolterodine

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Not recommended

Dutasteride, Imidafenacin, Sildenafil (erectile dysfunction)

Although not studied directly, itraconazole is likely to increase the concentrations of these drugs.

Use with caution

Oxybutynin 5 mg

Oxybutynin Cmax ↑ 2-fold, AUC ↑ 2-fold N-desethyloxybutynin Cmax ↔, AUC ↔ Following transdermal administration: Although not studied directly, itraconazole is likely to increase the concentrations of oxybutynin following transdermal administration.

Use with caution

Miscellaneous Drugs and Other Substances

Colchicine

Although not studied directly, itraconazole is likely to increase the concentrations of colchicine

Contraindicated in patients with renal or hepatic impairment. Not recommended in other patients.

Eliglustat

Although not directly studied, itraconazole is expected to increase the concentrations of eliglustat.

Contraindicated in CYP2D6 poor metabolisers (PM). Contraindicated in CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate CYP2D6 inhibitor. Use with caution in CYP2D6 IMs and EMs. In CYP2D6 EMs with mild hepatic impairment, an eliglustat dose of 84 mg/day should be considered.

Cinacalcet

Although not studied directly, itraconazole is likely to increase the concentrations of cinacalcet.

Use with caution

4.6. Fertility, pregnancy and lactation

Pregnancy

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

In animal studies itraconazole has shown 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.

Women of childbearing potential

Women of childbearing potential taking Itraconazole oral solution should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itraconazole therapy.

Breast-feeding

A very small amount of itraconazole is excreted in human milk. Itraconazole oral solution 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 Itraconazole oral solution treatment identified from clinical trials and/or from spontaneous reporting were dizziness, headache, dysgeusia, dyspnoea, cough, abdominal pain, diarrhoea, vomiting, nausea, dyspepsia, rash, and pyrexia. The most serious ADRs were serious allergic reactions, cardiac failure/congestive heart failure/pulmonary oedema, pancreatitis, serious hepatotoxicity (including some cases of fatal acute liver failure), and serious skin reactions. Refer to subsection Tabulated list of adverse reactions for the frequencies and for other observed ADRs. Refer to section 4.4 (Special warnings and precautions for use) for additional information on other serious effects.

Tabulated list of adverse reactions

The ADRs in the table below were derived from double-blind and open-label clinical trials with Itraconazole oral solution involving 889 patients for the treatment of oropharyngeal and esophageal candidiasis, and from spontaneous reporting.

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

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

Adverse Drug Reactions

Blood and lymphatic system disorders

Uncommon

Leukopenia, Thrombocytopenia

Immune system disorders

Uncommon

Hypersensitivity*

Not Known

Serum sickness, Angioneurotic oedema, Anaphylactic reaction

Endocrine disorders

Not known

Pseudoaldosteronism

Metabolism and nutrition disorders

Uncommon

Hypokalaemia

Not Known

Hypertriglyceridaemia

Nervous system disorders

Common

Dizziness, Headache, Dysgeusia

Uncommon

Peripheral neuropathy*, Paraesthesia, Hypoaesthesia

Eye disorders

Uncommon

Visual disturbances (including diplopia and blurred vision)

Ear and labyrinth disorders

Uncommon

Tinnitus

Not Known

Transient or permanent hearing loss*

Cardiac disorders

Uncommon

Cardiac failure

Not Known

Congestive heart failure*, Bradycardia

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea, Cough

Gastrointestinal disorders

Common

Abdominal pain, Diarrhoea, Vomiting, Nausea, Dyspepsia

Uncommon

Constipation

Not Known

Pancreatitis

Hepatobiliary disorders

Uncommon

Hepatic failure*, Hyperbilirubinaemia

Not Known

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

Skin and subcutaneous tissue disorders

Common

Rash

Uncommon

Urticaria, Pruritus

Not Known

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

Musculoskeletal and connective tissue disorders

Uncommon

Myalgia, Arthralgia

Reproductive system and breast disorders

Uncommon

Menstrual disorders

General disorders and administration site conditions

Common

Pyrexia

Uncommon

Oedema

Investigations

Not Known

Blood creatine phosphokinase 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 Capsules and Itraconazole IV, excluding the ADR term “Injection site inflammation”, which is specific to the injection route of administration.

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

Blood and lymphatic system disorders: Granulocytopenia

Immune system disorders: Anaphylactoid reaction

Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypomagnesaemia

Psychiatric disorders: Confusional state

Nervous system disorders: Somnolence, Tremor

Cardiac disorders: Left ventricular failure, Tachycardia

Vascular disorders: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders: Pulmonary oedema, Dysphonia

Gastrointestinal disorders: Gastrointestinal disorder, Flatulence

Hepatobiliary disorders: Hepatitis, Jaundice, Hepatic function abnormal

Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis

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

Reproductive system and breast disorders: Erectile dysfunction

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

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

Paediatric Population

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

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

Reporting of suspected adverse reactions

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

Treatment

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