1.  Vulvovaginal candidosis

2.  Pityriasis versicolor

3.  Dermatophytoses caused by organisms susceptible to itraconazole

4.  Oral candidosis

5.  Fungal keratitis

6.  Systemic mycoses

7.  Onychomycosis

ITRAZOL® is for oral administration and must be taken immediately after a meal for maximal absorption. The capsules must be swallowed whole.

Treatment schedules in adults for each indication are as follows:

Short-Term Usage

Indication	Dose
Vulvovaginal candidosis	200 mg twice daily for 1 day or 200 mg once daily for 3 days.
Pityriasis versicolor	200 mg once daily for 7 days
Tinea corporis, tinea cruris	100 mg once daily for 2 weeks or 200 mg once daily for 7 days
Tinea pedis, tinea manuum	100 mg once daily for 4 weeks
Oral candidosis	100 mg once daily for 2 weeks
Fungal keratitis	200 mg once daily for 3 weeks

Treatment should not exceed 4 weeks.

Long Term Usage

Dosage recommendations vary according to the infection treated.

Indication	Dose	Median Duration
Onychomycosis	200 mg od	3 months
Aspergillosis	200 mg od	2-5 months
Candidosis	100-200 mg od	3 weeks - 7 months
Non-meningeal cryptococcosis	200 mg od	1-6 months
Cryptococcal meningitis	200 mg bid	2 months - 1 year
Histoplasmosis	200 mg od - 200 mg bid	8 months
Sporotrichosis	100 mg od	3 months
Paracoccidioidomycosis	100 mg od	6 months
Chromomycosis	100-200 mg od	6 months
Blastomycosis	100 mg od - 200 mg bid	6 months

Use in Children (below 12 years):

 

Clinical data on the use of ITRAZOL® capsules in paediatric patients are limited. ITRAZOL® capsules should not be used in children unless the potential benefit outweighs the potential risks. (See Section 4.4)

Use in Elderly:

As for use in children

Use in patients with 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.

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).

ITRAZOL® capsules are contra-indicated in patients with known hypersensitivity to itraconazole or to any of the excipients. Coadministration of a number of CYP3A4 substrates is contraindicated with ITRAZOL® Capsules (see sections 4.4 and 4.5). These include: Analgesics; Anaesthetics Methadone 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 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) Felodipine* Finerenone Aliskiren Dronedarone Nisoldipine Bepridil Eplerenone Quinidine Disopyramide Ivabradine Ranolazine Dofetilide Lercanidipine Sildenafil (pulmonary hypertension) Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti- inflammatory/Anti-infective Agents; Antiemetics and Antinauseants; Drugs for Constipation; Drugs for Functional Gastrointestinal Disorders Cisapride Domperidone Naloxegol Lipid Modifying Agents Lovastatin Lomitapide Simvastatin Immunosuppressants Voclosporin 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) *Based on clinical drug interaction information with itraconazole 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 ITRAZOL® capsules 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 ITRAZOL® capsules must not be used during pregnancy (except for life-threatening cases). See section 4.6. Women of childbearing potential taking ITRAZOL® should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of ITRAZOL® therapy. Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome.

Cross-hypersensitivity

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

 

Cardiac effects

In a healthy volunteer study with ITRAZOL® 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 ITRAZOL® 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.

ITRAZOL® should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g. total daily dose), and individual risk factors for congestive heart failure. These risk factors include cardiac disease, such as 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, ITRAZOL® 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 used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF (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 ITRAZOL®. 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 ITRAZOL® 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 ITRAZOL® capsules is impaired when 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 ITRAZOL® capsules. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (eg H2-antagonists, proton pump inhibitors), it is advisable to administer ITRAZOL® capsules with a cola beverage.

Use in children

 

Clinical data on the use of ITRAZOL® capsules in paediatric patients is limited. ITRAZOL® 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 ITRAZOL® capsules in elderly patients is limited. ITRAZOL® 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 Section 4.3 Contraindications and 4.5 Interaction with other medicinal products and other forms of interaction, 3.Effect of itraconazole on the metabolism of other drugs). 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 ITRAZOL® capsules may be decreased.

Patients with immediately life-threatening systemic fungal infections

Due to the pharmacokinetic properties (see section 5.2), ITRAZOL® capsules are not recommended for initiation of treatment 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 and 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 that may be attributable to ITRAZOL® capsules, 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 itraconazole therapy.

Interaction potential

 

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in section 4.3 Contraindications and section 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 interactions described in these tables are categorised as contraindicated, not recommended or to be used with caution with itraconazole taking into account the extent of the concentration increase and the safety profile of the interacting drug (see also sections 4.3 and 4.4 for further information). The interaction potential of the listed drugs was evaluated based on human pharmacokinetic studies with itraconazole, and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g. ketoconazole) and/or in vitro data:

 

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

•                     Not recommended’: The use of the drug should be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the concomitantly administered drug is recommended, and its dosage be reduced or

•                      interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.

•          ‘Use with caution’: Careful monitoring is recommended when the drug is co-administered with itraconazole. Upon 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 Oral [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/Rit onavir (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 (ritonavirboosted),	Although not studied directly, these drugs are expected to increase the concentrations of itraconazole	Use with caution

 

Ritonavir, Saquinavir (ritonavir- boosted)
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
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 islikely 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 (↑ = increase; ↔ = no change; ↓ = decrease)	Clinical comment (see above for additional info and also sections 4.3 and 4.4)
Analgesics; Anaesthetics
Ergot alkaloids (eg, 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	Potential for an increased risk of tumor lysis syndrome	Contraindicated during the dose initiation and ramp-up phase in patients with CLL/SLL. Refer to the venetoclax prescribing information for dosing and safety monitoring instructions

 

Axitinib, Bosutinib, Cabazitaxel, Cabozantinib, Ceritinib, Crizotinib, Dabrafenib, Dasatinib, Docetaxel, Everolimus, Ibrutinib, Lapatinib, Nilotinib, Pazopanib, Regorafenib, Sunitinib, Temsirolimus, Trabectedin, Trastuzumab emtansine, Vinca alkaloids (eg, 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
Olaparib 100 mg	Olaparib Cmax ↑ 40%, AUC ↑ 2.7- fold	Not recommended
Alitretinoin (oral), Bortezomib, Brentuximab vedotin, Erlotinib, Idelalisib, Imatinib, Nintedanib, Panobinostat, Ponatinib, Ruxolitinib, Sonidegib	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
Mobocertinib*
Entrectinib*
Pemigatinib*
Immunosuppressants
Voclosporin
Antithrombotic Agents
Dabigatran, Ticagrelor	Although not studied directly, itraconazole is likely to increase the concentrations of these drugs	Contraindicated
Apixaban, Rivaroxaban, Vorapaxar	Although not studied directly, itraconazole is likely to increase the concentrations of these drugs	Not recommended
Cilostazol, Coumarins (eg, warfarin)	Although not studied directly, itraconazole is likely to increase the concentrations of these drugs	Use with caution
Antivirals for Systemic Use
Ombitasvir/Paritaprevir/Rit onavir (with or without Dasabuvir)	Itraconazole may increase paritaprevir concentrations	Contraindicated
Elbasvir/Grazoprevir, Simeprevir, 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), lecaprevir/Pibrentasvir,	Although not studied directly, itraconazole is likely to increase the concentrations of these drugs	Use with caution

 

Maraviroc, Ritonavir, Saquinavi
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, 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 (eg, 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
Finerenone
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 nasallyadministered fluticasone	Use with caution
Drugs Used in Diabetes
Repaglinide 0.25 mg	Repaglinide Cmax ↑ 47%, AUC ↑	Use with caution

 

		41%
Saxagliptin		Although not studied directly, itraconazole is likely to increase the concentrations of saxagliptin	Use with caution
Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti-inflammatory/Antiinfective 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
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 (eg, 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 impairment: 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	Although not studied directly, itraconazole is likely to increase the concentrations of these drugs		Not recommended

 

prostatic hyperplasia), Tamsulosin, Tolterodine
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

 

* Based on clinical drug interaction information with itraconazole.

Pregnancy

ITRAZOL® 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). There is limited information on the use of ITRAZOL® 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 ITRAZOL® has not been established.

Epidemiological data on exposure to ITRAZOL® 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 childbearing potential

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

Lactation

A very small amount of itraconazole is excreted in human milk. The expected benefits of ITRAZOL® therapy should be weighed against the risks of breast feeding. In case of doubt, the patient should not breast feed.

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.

a)      Tabulated list of AE:

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

In double-blind, controlled clinical trials involving 2104 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 category, 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).

 

MedDRA System Organ Class	Adverse reactions / Frequency
	Very common	Common	Uncommon	Rare	Very rare	Not known

 

Blood and lymphatic system disorders				Leukopenia		Neutropenia, Thrombocytopenia
Immune system disorders			Hypersensitivity*			Anaphylactic Reaction, Anaphylactoid Reaction, Angioneurotic Oedema, Serum Sickness
Metabolism and nutrition disorders						Hypokalemia, Hypertriglyceridem ia
Nervous system disorders			Headache, Dizziness,	Hypoaesthesia		Peripheral Neuropathy*

 

			Paraesthesia
Eye disorders				Visual Disturbance		Vision Blurred and Diplopia
Ear and labyrinth disorder				Tinnitus		Transient or permanent Hearing Loss*
Cardiac disorders						Congestive Heart Failure*
Respiratory,tho racic and mediastinal disorders				Dyspnoea		Pulmonary Oedema
Gastrointestinal disorders		Abdomin al Pain, Nausea	Vomiting, Diarrhoea, Constipation, Dyspepsia, Dysgeusia, Flatulence	Pancreatitis
Hepato-biliary disorders			Hyperbilirubinae mia, Alanine Aminotransferase Increased, Aspartate Aminotransferase Increased	Hepatic Enzyme Increased		Fatal Acute Hepatic Failure*, Hepatitis, Hepatotoxicity*
Skin and subcutaneous tissue disorders		Rash	Urticaria, Alopecia, Pruritus			Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Acute generalised exanthematous pustulosis , Erythema Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis, Photosensitivity
Musculoskeletal and connective						Myalgia, Arthralgia

 

tissue disorders
Renal and urinary disorders				Pollakiuria		Urinary Incontinence
Reproductive system and breast disorders			Menstrual Disorders			Erectile Dysfunction
General disorders and administration site conditions			Oedema	Pyrexia

*see section 4.4

 

b)      Other special population:

Use in Children (below 12 years):

Clinical data on the use of ITRAZOL® capsules in paediatric patients are limited. ITRAZOL® capsules should not be used in children unless the potential benefit outweighs the potential risks. (See Section 4.4 )

Use in Elderly :

As for use in children

Use in patients with 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 .

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).

 

To report any side effect (s):

Saudi Arabia:

 

Other GCC states and other countries:

 

No data are available.

In the event of an overdose, 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.

 

Pharmacotherapeutic classification

Antimycotic 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 >1 µg/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 μg/ml. These include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp.; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides immitis; Pseudallescheria boydii; Penicillium marneffei; and various other yeasts and fungi.

Candida krusei, Candida glabrata and Candida tropicalis 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 spp. and Scopulariopsis spp.

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

General pharmacokinetic characteristics:

 

The pharmacokinetics of itraconazole has been investigated in healthy subjects, special populations and patients after single and multiple dosing. In general, itraconazole is well absorbed. Peak plasma concentrations are reached within 2 to 5 hours following administration of the oral solution. Itraconazole undergoes extensive hepatic metabolism to give numerous metabolites. The main metabolite is hydroxy- itraconazole, with plasma concentrations about twice those of the unchanged drug. The terminal half-life of itraconazole is about 40 hours after repeated dosing. The pharmacokinetics of itraconazole is characterised by non-linearity and, consequently, shows accumulation in plasma after multiple dose administration. Steady-state concentrations are reached within 15 days, with Cmax values of about 2 μg/ml after oral administration of 200 mg once daily. Itraconazole clearance decreases at higher doses due to a saturable mechanism of its hepatic metabolism. Itraconazole is excreted as inactive metabolites in urine (~35%) and in faeces (~54%). Absorption:

Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral dose. The observed absolute bioavailability of itraconazole under fed conditions is about 55% Oral bioavailability is maximal when the capsules are taken immediately after a full meal.

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. Brain to plasma ratios were about 1.

The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma.

Metabolism:

Itraconazole is extensively metabolised by the liver into a large number of metabolites. The main metabolite is hydroxy-itraconazole which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-metabolite are about twice those of itraconazole.

As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Excretion:

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with faeces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas faecal excretion of unchanged drug varies between 3-18% of the dose.

As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.

 

Special Populations

Hepatic impairment

Itraconazole is predominantly metabolised in the liver. A single oral dose (100 mg capsule) was administered to 12 patients with cirrhosis and six healthy control subjects; Cmax, AUC and terminal half-life of itraconazole were measured and compared between groups. Mean itraconazole Cmax was reduced significantly (by 47%) in patients with cirrhosis. Mean elimination half-life was prolonged compared to that found in subjects without hepatic impairment (37 vs. 16 hours, respectively). Overall exposure to itraconazole, based on AUC was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See sections 4.2 Posology and method of administration, and 4.4 Special warnings and special precautions for use.)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when the drug is administered in this patient population.

Itraconazole:

Itraconazole has been tested in a standard battery of non-clinical safety studies. Acute toxicity studies with itraconazole in mice, rats, guinea pigs and dogs indicate a wide safety margin. Sub (chronic) oral toxicity studies in rats and dogs revealed several target organs or tissues: adrenal cortex, liver and mononuclear phagocyte system as well as disorders of the lipid metabolism presenting as xanthoma cells in various organs.

At high doses, histological investigations of adrenal cortex showed a reversible swelling with cellular hypertrophy of the zona reticularis and fasciculata, which was sometimes associated with a thinning of the zona glomerulosa. Reversible hepatic changes were found at high doses. Slight changes were observed in the sinusoidal cells and vacuolation of the hepatocytes, the latter indicating cellular dysfunction, but without visible hepatitis or hepatocellular necrosis. Histological changes of the mononuclear phagosystem were mainly characterised by macrophages with increased proteinaceous material in various parenchymal tissues.

There are no indications of a mutagenic potential of itraconazole.

Itraconazole is not a primary carcinogen in rats or mice. In male rats, however, there was a higher incidence of soft-tissue sarcoma, which is attributed to the increase in non-neoplastic, chronic inflammatory reactions of the connective tissue as a consequence of raised cholesterol levels and cholesterosis in connective tissue.

There is no evidence of a primary influence on fertility under treatment with itraconazole. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats and mice at high doses. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia.

A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration.

In three toxicology studies using rats, itraconazole induced bone defects. The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.

The inactive ingredients of the capsules are hypromellose, poloxamer, sucrose, and maize starch.

Not applicable

2 years.

Store below 25°C.

 

Forming Ultraprotect PVC-PE-PVDC-PE-PVC / Aluminium blister pack.

Packs with either 4 or 15 capsules.

 

No special requirements.