ITRACONAZOLE

g. with neutropenia, AIDS or after organ transplantation, the bioavailability of itraconazole may be lowered. Doubling the dose may be indicated. Itraconazole remains substantially longer in the skin than in the blood. Optimal healing is thus achieved 2-4 weeks after withdrawing Itraconazole in case of mycoses of the skin.

Systemic mycoses Indication Dosage Duration of treatment1) Notes Aspergillosis 2 capsules once daily (equivalent to 200 mg itraconazole) 2-5 months In invasive or disseminated disease, increase to 2 capsules twice daily (in the morning and in the evening) (equivalent to 400 mg itraconazole) Candidiasis 1-2 capsules once daily (equivalent to 100-200 mg itraconazole) 3 weeks- 7 months In invasive or disseminated disease, increase to 2 capsules twice daily (in the morning and in the evening) (equivalent to 400 mg itraconazole) Histoplasmosis 2 capsules once daily up to twice 8 months daily (in the morning and in the evening) (equivalent to 200-400 mg itraconazole) 1) The duration of treatment should be adjusted depending on clinical efficacy.

4). Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. 8). 4). Use in patients with impaired renal function The oral bioavailability of itraconazole may be reduced in patients with renal insufficiency.

4). Use in patients with impaired hepatic function Itraconazole is predominantly metabolized in the liver. In patients with hepatocirrhosis, the terminal half-life of itraconazole is somewhat prolonged and the oral bioavailability of itraconazole somewhat reduced.

4). Method of administration The capsules are to be taken without chewing with some liquid directly after a meal in order to achieve maximum absorption.

Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) with itraconazole capsules treatment identified from clinical trials and/or from spontaneous reporting were headache, abdominal pain, and nausea.

The most serious ADRs were serious allergic reactions, cardiac failure/congestive heart failure/pulmonary oedema, pancreatitis, serious hepatotoxicity (including some cases of fatal acute liver failure), and serious skin reactions.

Refer to subsection “Tabulated list of adverse reactions” for the frequencies and for other observed ADRs. 4 for additional information on other serious effects. Tabulated list of adverse reactions The ADRs in the table below were derived from open-label and double-blind clinical trials with itraconazole capsules involving 8499 patients in the treatment of dermatomycoses or onychomycosis, and from spontaneous reporting.

The table below presents ADRs by System Organ Class. 4. Description of selected adverse reactions The following is a list of ADRs associated with itraconazole that have been reported in clinical trials of itraconazole oral solution and intravenous itraconazole, excluding the ADR term “Injection site inflammation”, which is specific to the injection route of administration.

Blood and lymphatic system disorders Granulocytopenia, thrombocytopenia Immune system disorders Anaphylactoid reaction Metabolism and nutrition disorders Hyperglycaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia Psychiatric disorders Confusional state Nervous system disorders Peripheral neuropathy*, dizziness, somnolence, tremor Cardiac disorders Cardiac failure, left ventricular failure, tachycardia Vascular disorders Hypertension, hypotension Respiratory, thoracic and mediastinal disorders Pulmonary oedema, dysphonia, cough Gastrointestinal disorders Gastrointestinal disorder Hepatobiliary disorders Hepatic failure*, hepatitis, jaundice Skin and subcutaneous tissue disorders Rash erythematous, hyperhidrosis Musculoskeletal and connective tissue disorders Myalgia, arthralgia Renal and urinary disorders Renal impairment, urinary incontinence General disorders and administration site conditions Generalised oedema, face oedema, chest pain, pyrexia, pain, fatigue, chills Investigations Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, hepatic enzyme increased, urine analysis abnormal Paediatric population The safety of 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. 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. uk/yellowcard.

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

Cardiac effects In a healthy volunteer study with intravenous itraconazole, 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 has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.

Itraconazole should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. , total daily dose), and individual risk factors for congestive heart failure.

These risk factors include cardiac disease, such as ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, itraconazole 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. 5) due to an increased risk of congestive heart failure.

Hepatic effects Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. 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 medicinal products.

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 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.

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the medicinal product 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 medicinal products, treatment with itraconazole is strongly discouraged unless there is a serious or life- threatening situation where the expected benefit exceeds the risk.

2). Reduced gastric acidity Absorption of itraconazole from itraconazole capsules is impaired when gastric acidity is reduced. g. g. patients taking medicinal products that reduce gastric acidity), it is advisable to administer itraconazole capsules with an acidic beverage (such as non-diet cola).

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

Use in older patients Clinical data on the use of itraconazole capsules in older patients is limited. It is advised to use itraconazole capsules 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 older patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or therapy with other medicinal products.

Renal impairment Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal Insufficiency. Caution should be exercised when this medicinal product is administered in this patient population and adjusting the dose may be considered.

Hearing loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration […]

1. Co-administration of a number of CYP3A4 substrates is contraindicated with itraconazole. Increased plasma concentrations of these active ingredients, 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 active ingredients can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. 5. 4). 6). • Women of childbearing potential taking itraconazole should use contraceptive precautions.

Effective contraception should be continued until the menstrual period following the end of itraconazole therapy.