Special Warning : אזהרת שימוש

4.4. Special warnings and precautions for use

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

Itranol 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 ischemic 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, Itranol should be discontinued.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5 Interaction with other medicinal products and other forms of interaction) 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 capsules. Most of these cases involved patients who, had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Itranol capsules treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted.

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 Itranol 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 Pharmacokinetic properties- Special populations, Hepatic impairment).

Reduced gastric acidity
Absorption of itraconazole from Itranol capsules is impaired when gastric acidity is reduced. In patients with reduced gastric acidity, whether from disease (e.g. patients with achlorhydria) or from concomitant medication (e.g. patients taking drugs that reduce gastric acidity), it is advisable to administer Itranol capsules with an acidic beverage (such as non-diet cola). The antifungal activity should be monitored and the itraconazole dose increased as deemed necessary. See section 4.5 Interaction with other medicinal products and other forms of interaction.

Pediatrics
Clinical data on the use of itraconazole capsules in pediatric patients is limited. The use of Itranol capsules in pediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.


Elderly
Clinical data on the use of itraconazole capsules in elderly patients are limited. It is advised to use Itranol 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 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.

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 drug 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 of quinidine which is contraindicated (see section 4.5 Interaction with other medicinal products and other forms of interaction). 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 Itranol capsules may be decreased. Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. The dose should be adjusted based on the clinical response in these patients (see section 4.2). Therapeutic blood level monitoring may be necessary.


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

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

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 Itranol capsules, consideration should be given to switching to alternative therapy.


Neuropathy
If neuropathy occurs which may be attributable to Itranol 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 Itranol therapy.

Interchangeability
It is not recommended that Itranol 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.

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.

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