Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Tinea capitis
Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, Fluconazole B.Braun 2mg/ml should not be used for tinea capitis.

Cryptococcosis
The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep endemic mycoses
The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.

Renal system
Fluconazole should be administered with caution to patients with renal dysfunction (see section 4.2).

Adrenal insufficiency
Ketoconazole is known to cause adrenal insufficiency, and this could also, although rarely seen, be applicable to fluconazole. For adrenal insufficiency relating to concomitant treatment with prednisone is described in the section 4.5, ‘The effects of fluconazole on other medicinal products’.

Hepatobiliary system
Fluconazole should be administered with caution to patients with liver dysfunction.

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury.
The patient should be informed of suggestive symptoms of serious hepatic effects (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment with fluconazole should be immediately discontinued and the patient should consult a physician.
Cardiovascular system
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole.
These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsades de pointes.
Fluconazole should be administered with caution to patients with potentially pro- arrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolized via the cytochrome P450 (CYP) 3A4 is contraindicated (see sections 4.3 and 4.5).

Halofantrine
Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5).

Dermatological reactions
Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole.
Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported.
AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity
In rare cases anaphylaxis has been reported (see section 4.3).

Cytochrome P450
Fluconazole is a potent CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Fluconazole-treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5).

Terfenadine
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5).

Candidiasis
Studies have shown an increasing prevalence of infections with Candida species other than C. albicans. These are often inherently resistant (e.g. C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy secondary to treatment failure. Therefore, prescribers are advised to take into account the prevalence of resistance in various Candida species to fluconazole.

Excipients
This medicinal product contains 3.54 mg sodium per ml of solution. An infusion bottle containing 50 ml, 100 ml or 200 ml of solution contains 177 mg, 354 mg or 709 mg of sodium respectively, equivalent to 8.85%, 17.7% or 35.45% respectively of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Fluconazole B.Braun 2 mg/ml solution for infusion is considered high in sodium. This should be particularly taken into account when it is administered to patients on a low salt diet.

Effects on Driving

4.7   Effects on ability to drive and use machines
No studies have been performed on the effects of fluconazole on the ability to drive or use machines.
Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking fluconazole and should be advised not to drive or operate machines if any of these symptoms occur.