Special Warning : אזהרת שימוש

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 SPORANOX Oral Solution to patients with hypersensitivity to other azoles.

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

Itraconazole has been shown to have a negative inotropic effect and SPORANOX 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.

SPORANOX 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, SPORANOX 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 SPORANOX. 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 SPORANOX 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 SPORANOX Oral Solution in paediatric patients are limited. The use of SPORANOX 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 SPORANOX Oral Solution in elderly patients is limited, it is advised to use SPORANOX 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 SPORANOX 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 SPORANOX Oral Solution in these circumstances.

Treatment of severely neutropenic patients
SPORANOX 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), SPORANOX 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 SPORANOX oral solution, consideration should be given to switching to SPORANOX IV or to alternative therapy.

Neuropathy
If neuropathy occurs that may be attributable to SPORANOX 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 SPORANOX Capsules and SPORANOX 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 of SPORANOX Oral Solution
SPORANOX Oral Solution contains 7 920 mg sorbitol in each 40 mL dose which is equivalent to 198 mg/mL. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered. 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. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

SPORANOX Oral Solution contains less than 1 mmol sodium (23 mg) per 40 mL dose, that is to say essentially ‘sodium-free’.

SPORANOX Oral Solution contains 0.2 mg of alcohol (ethanol) in each 40 mL dose which is equivalent to 0.005 mg/mL. The amount in 40 mL of this medicine is equivalent to less than 1 mL beer or 1 mL wine. The small amount of alcohol in this medicine will not have any noticeable effects.

SPORANOX Oral Solution contains 16 000 mg cyclodextrin(s) in each 40 mL dose which is equivalent to 400 mg/mL. Cyclodextrins may cause digestive problems such as diarrhoea. There is insufficient information on the effects of cyclodextrin in children <2 years old. Therefore, a case by case judgement should be made regarding the risk/benefit for the patient with SPORANOX Oral Solution (see section 4.2).

SPORANOX Oral Solution contains 4.2 g propylene glycol in each 40 mL dose which is equivalent to 104 mg/mL and 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). SPORANOX Oral Solution must not be used during lactation (see section 4.6). Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old. Monitoring is required in patients with hepatic or renal impairment because adverse events attributed to propylene glycol have been reported, such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

Effects on Driving

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.