Sporanox^® I.V. 10 mg/ml concentrate and solvent for solution for infusion.

Each ml of the Sporanox IV concentrate contains 10 mg itraconazole.

One ampoule with 25 ml contains 250 mg itraconazole (itraconazole trihydrochloride salt formed in situ).

Each ml of the admixed solution contains 3.33 mg itraconazole.

One single dose of 200 mg itraconazole corresponds to 60 ml of the admixed solution.

For a full list of excipients, see section 6.1.

Concentrate and solvent for solution for infusion.

Sporanox IV 10 mg/ml concentrate and solvent (0.9% Sodium Chloride Injection) for solution for infusion is presented in a procedure pack consisting of:

(a) 25ml of Sporanox IV 10 mg/ml concentrate for infusion, a colourless solution presented in a glass ampoule.

(b) 50ml of 0.9 % Sodium Chloride Injection solvent for solution for infusion, a colourless solution presented in a polypropylene bag.

(c) Extension line with 2-way stopcock and in-line filter

Sporanox I.V. is indicated for the treatment of histoplasmosis.

Sporanox I.V. is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. (This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity).

Treatment of aspergillosis, candidosis and cryptococcosis (including cryptococcal meningitis): in immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system.

Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.

This product is supplied with an extension line with a 2-way stopcock and 0.2 μm in-line filter. The dedicated extension line including the in-line filter must be used to ensure the correct administration of the product (see section 6.6).

Sporanox I.V. is given on the first two days in a loading dose twice daily, followed by once daily dosing.

Day 1 and 2 of the treatment: 1-hour infusion of 200 mg (60 ml of the admixed solution) Sporanox I.V. twice daily. (See section 6.6).

From day 3 on: one 1-hour infusion of 200 mg (60 ml of the admixed solution) Sporanox I.V. each day. Safety for periods longer than 14 days has not been established.

Use in children: Since clinical data on the use of Sporanox I.V. in paediatric patients are unavailable, Sporanox I.V. should not be used in children unless the potential benefit outweighs the potential risk. (See section 4.4).

Use in elderly: Since clinical data of the use of Sporanox I.V. in elderly patients are limited, it is advised to use Sporanox I.V. in these patients only if the potential benefit outweighs the potential risk. (See section 4.4).

Use in patients with renal impairment: Limited data are available on the use of intravenous itraconazole in patients with renal impairment.

Hydroxypropyl-β-cyclodextrin, a required component of Sporanox intravenous formulation, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 ml/min the use of Sporanox IV is contraindicated. (See section 4.3).

In patients with mild and moderate renal impairment, Sporanox IV should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation. (See sections 4.4. and 5.2).

Use in patients with hepatic impairment: Limited data are available on the use of itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See section 5.2).

− Sporanox I.V. is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients.

− Sporanox I.V. cannot be used when administration of Sodium Chloride Injection is contraindicated.

− The excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration. Therefore, Sporanox I.V. is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 ml/min). (See section 4.4 and section 5.2).

− Coadministration of the following drugs is contraindicated with Sporanox I.V. (see section 4.5):

• CYP3A4 metabolised substrates that can prolong the QT-interval e.g., terfenadine, astemizole, bepridil, mizolastine, cisapride, dofetilide, levacetylmethadol (levomethadyl), quinidine, sertindole or pimozide coadministration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes.

• CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin

• Triazolam and oral midazolam

• Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

• Eletriptan

• Nisoldipine

− Sporanox I.V. must not be used during pregnancy for non life-threatening indications (see section 4.6 ).

Cross hypersensitivity

There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Sporanox IV 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; this resolved before the next infusion. A similar investigation was not performed in the target patient population.

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.

Physicians should carefully review the risks and benefits of Sporanox therapy for patients with known 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 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, 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. 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 patients with impaired hepatic function liver enzyme should be carefully monitored when taking itraconazole.

Use in children

Since clinical data on the use of Sporanox I.V. in paediatric patients are unavailable, Sporanox I.V. should not be used in children unless the potential benefit outweighs the potential risk.

Use in elderly

Since clinical data of the use of Sporanox I.V. in elderly patients are limited, it is advised to use Sporanox I.V. in these patients only if the potential benefit outweighs the potential risk.

Hepatic impairment

Studies have not been conducted with intravenous itraconazole 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 the drug is administered to this patient population. (See Section 4.2 and 5.2).

Renal impairment

Hydroxypropyl-β-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with renal impairment defined as creatinine clearance below 30 ml/min Sporanox IV is contraindicated (see sections 4.3 and 5.2).

Sporanox I.V. should be used with caution in patients with a lesser degree of renal failure. In patients with mild and moderate renal impairment, serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation. (See section 4.4).

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.

Neuropathy

If neuropathy occurs that may be attributable to Sporanox I.V., 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

Sporanox has a potential for clinically important drug interactions (see section 4.5).

Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure.

1. Drugs affecting the metabolism of itraconazole:

Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John's Wort), phenobarbital and isoniazid but similar effects should be anticipated.

Potent inhibitors of CYP3A4 such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.

2. Effect of itraconazole on the metabolism of other drugs:

Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or a prolongation of their effects, including side effects. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism. After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment (see section 5.2). This should be taken into account when the inhibitory effect of itraconazole on co-medicated drugs is considered.

Drugs which are contraindicated with itraconazole:

• Terfenadine, astemizole, bepridil, mizolastine, levacetylmethadol (levomethadyl), cisapride, dofetilide, quinidine, sertindole or pimozide are contraindicated with Sporanox I.V. since coadministration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).

• CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin.

• Triazolam and oral midazolam.

• Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

• Eletriptan.

• Nisoldipine

Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

The following drugs should be used with caution and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with itraconazole, should be reduced if necessary:

− Oral anticoagulants;

− HIV Protease Inhibitors such as ritonavir, indinavir, saquinavir;

− Certain antineoplastic agents such as vinca alkaloids, busulfan, docetaxel and trimetrexate;

− CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;

− Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as cerivastatin (see also drugs which are contraindicated with itraconazole);

− Certain immunosuppressive agents: cyclosporine, tacrolimus, rapamycin (also known as sirolimus);

− Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;

− Digoxin: (via inhibition of P-glycoprotein);

− Others: carbamazepine, cilostazol, buspirone, alfentanil, alprazolam, brotizolam, midazolam I.V., rifabutin, disopyramide ebastine, fentanyl, halofantrine, repaglinide and reboxetine. The importance of the concentration increase and clinical relevance of these changes during co-administration with itraconazole remain to be established.

No interaction of itraconazole with zidovudine (AZT) and fluvastatine has been observed.

No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed.

3. Effect on protein binding:

In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine.

Pregnancy

Sporanox IV 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 shows reproduction toxicity (see section 5.3).

Epidemiological data on exposure to Sporanox 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 child bearing potential

Women of child-bearing potential receiving Sporanox IV should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Sporanox IV therapy.

Lactation

A very small amount of itraconazole is excreted in human milk and must not be administered to lactating women. Breast-feeding is to be discontinued prior to taking itraconazole.

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.

In clinical trials with intravenous itraconazole, the most frequently reported adverse experiences were of gastrointestinal, metabolic and nutritional, and hepatobiliary 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, 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).

* see section 4.4.

In the event of overdose, supportive measures should be employed. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivatives

ATC code: J02A C02

Mode of action

Itraconazole inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi.

PK/PD relationship

The PK/PD relationship for itraconazole, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.

Mechanism(s) of resistance

Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are:

• Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme)

• Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for itraconazole

• Drug-transporter over-expression resulting in increased efflux of itraconazole from fungal cells (i.e., removal of itraconazole from its target)

• Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles.

Breakpoints

Breakpoints for itraconazole have not yet been established for fungi using EUCAST methods.

Using CLSI methods, breakpoints for itraconazole have only been established for Candida species from superficial mycotic infections. The CLSI breakpoints are: susceptible 0.125 mg/L and resistant 1 mg/L.

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

The in vitro susceptibility of fungi to itraconazole depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of itraconazole may vary widely. Susceptibility in the table below is based on MIC₉₀ < 1 mg itraconazole/L. There is no correlation between in vitro susceptibility and clinical efficacy.

¹ These organisms may be encountered in patients who have returned from travel outside-Europe.

² Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

³ Natural intermediate susceptibility.

General pharmacokinetic characteristics

The pharmacokinetics of intravenously administered itraconazole has been investigated in healthy subjects, and patients after single and multiple dosing and in special populations after single doses.

Peak plasma concentrations of itraconazole are reached at the end of the intravenous infusion, declining thereafter. Peak plasma concentrations of hydroxyl-itraconazole (see Biotransformation below) are reached within 3 hours of beginning of a one-hour infusion, declining thereafter.

Each 200 mg intravenous dose of itraconazole contains 8g hydroxypropyl-β-cyclodextrin to increase the solubility of itraconazole. The pharmacokinetic profiles of each are described below. (See Itraconazole; see Special populations-Renal Impairment, Hydroxypropyl-β-cyclodextrin.)

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, and the uptake into keratinous tissues, skin in particular, up to four times higher. Brain to plasma ratios were about 1 as measured in beagle dogs.

Biotransformation

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

As shown in in-vitro studies, CYP3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Elimination

Itraconazole total plasma clearance following intravenous administration is on average 381 ml/min. Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and about 54% with feces. Renal excretion of the itraconazole and the active metabolite hydroxy-itraconazole account for less than 1%of an intravenous dose. Based on an oral dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral dose.

Linearity/non-linearity

As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. In a multiple-dose pharmacokinetic study, itraconazole IV was administered as a 1-hour infusion of 200 mg itraconazole twice daily on days 1 and 2 of treatment, followed by a 1-hour infusion of 200 mg once daily from day 3 to 7. Steady-state concentrations were reached after the fourth dose of itraconazole IV and by the seventh dose for hydroxy-itraconazole. Mean C_max and C_min values after 4 doses of 200 mg itraconazole IV in healthy subjects were 3055 ng/ml and 687 ng/ml respectively, while mean values for hydroxy-itraconazole at the same time points were 1058 ng/ml and 1263 ng/ml respectively. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. The mean elimination half-life of itraconazole is about 32.5 hours after repeated dosing.

Special Populations

Studies have not been conducted with intravenous itraconazole in patients with 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). Data are not available in cirrhotic patients during long-term use of itraconazole.

Renal Impairment

A small fraction (<1%) of an intravenous dose of itraconazole is excreted unchanged in urine.

After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (CrCl 50-79 ml/min), moderate (CrCl 20-49 ml/min), and severe renal impairment (CrCl <20 ml/min) were similar to that in healthy subjects, (range of means 42-49 hr vs 48 hr in renally impaired patients and healthy subjects, respectively.) Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.

Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole.

Hydroxypropyl-ß-Cyclodextrin

In patients with normal renal function, the pharmacokinetic profile of hydroxypropyl- ß–cyclodextrin, an ingredient of Sporanox intravenous formulation, has a short half-life of 1 to 2 hours, and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority of an 8 g dose of hydroxypropyl-ß-cyclodextrin is eliminated in the urine. Following a single intravenous dose of itraconazole 200 mg, clearance of hydroxypropyl-ß-cyclodextrin was reduced in subjects with renal impairment, resulting in higher exposure to hydroxypropyl-ß-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-ß-cyclodextrin until steady state is reached. Hydroxypropyl- ß-cyclodextrin is removed by hemodialysis.

Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.

Itraconazole has the potential to precipitate when Sporanox I.V. is diluted in solutions other than the 50ml 0.9% sodium chloride injection supplied.

Sporanox I.V.:

Shelf life as packaged:

2 years

0.9% Sodium Chloride Injection:

3 years

Admixed Solution:

24 hours.

Sporanox I.V.:

Do not store above 25°C. Store in the original container.

0.9% Sodium Chloride Injection:

Do not store above 25°C. Do not freeze.

Admixed solution:

Protect from direct sunlight.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution of the admixture has taken place in controlled and validated aseptic conditions.

Sporanox I.V.:

25 ml siliconised type I colourless glass ampoule with 25 ml containing 250 mg itraconazole.

0.9% Sodium Chloride:

Flexible 75ml polypropylene infusion bag, equipped with a flexible inlet and outlet port, and containing 52 to 56ml of 0.9% Sodium Chloride Injection.

Extension Line:

Polyvinylchloride tubing with 2-way stopcock and in-line filter.

Sporanox I.V.:

Sporanox I.V. should be prepared for administration according to the following instructions:

Opening ampoule:

− Break the ampoule as shown:

Opening sodium chloride bag:

Tear outer wrap at notch and remove infusion bag.

Flush procedure before the infusion

Before the infusion, the catheter should be flushed to avoid compatibility problems between residual amounts of other drugs and itraconazole.

- Fill the extension line provided with the kit containing the 0.2 μm in-line filter with sterile 0.9% sodium chloride solution and connect directly to the indwelling intravenous catheter.

- Flush the extension line provided with the kit and indwelling intravenous catheter with sterile 0.9% sodium chloride solution.

Admixing Sporanox I.V. Concentrate and 0.9% Sodium Chloride Injection:

− Each component must be at room temperature.

Admix only in the infusion bag provided. Using aseptic technique and an additive delivery needle of appropriate length (not supplied with the kit), draw up all the concentrate from the ampoule and subsequently add the Sporanox I.V. concentrate to the infusion bag by puncturing the resealable additive port and inject.

− Add the entire volume (25 ml) of Sporanox I.V. concentrate to the bag in a slow single action (up to 60 seconds). During the admixing process some opalescence may appear. This is a normal phenomenon for the product and will disappear after the full content of the 25 ml of Sporanox IV has been diluted into the Sodium Chloride infusion bag and after gentle mixing.. Withdraw needle after injecting the Sporanox IV concentrate into the bag.

− Gently mix the content of the bag once the Sporanox I.V. concentrate is completely transferred to the bag. The admixture will become clear but product intrinsic aggregates (described as fibrous to flake-like, non-crystalline, white particles) may be observed. These aggregates do not affect the quality of the product.

The admixture should be used immediately and should be protected from direct sunlight. During administration, exposure to normal room light is acceptable: (see sections 6.3 and 6.4).

Infusion:

− The admixed solution is intended for single-dose infusion only. No administration should occur if the solution is a milky white colour that does not disappear after gentle mixing, or contains foreign matter, or if the infusion bag is damaged.

− The infusion bag should now contain 25 ml Sporanox I.V. concentrate and 50 ml 0.9% Sodium Chloride Injection.

− Note: An infusion line with drip chamber is not supplied with the kit. Close the flow control device (e.g. rotary clamp) on the infusion line. Remove the breakable part of the outlet port. Using aseptic technique, push the pin of the infusion line in the flexible port of the infusion bag.

− Slowly release the flow control device and fill the drip chamber to half full by squeezing (pumping) it.

− Open the flow control device until all the air has been expelled from the infusion line.

− Connect the infusion line to the two-way stop cock of the extension line.

− The Sporanox infusion is now ready for intravenous infusion to the patient.

− Adjust the infusion rate to 1 ml/min (approximately 25 drops/min) by means of a flow control device (e.g. rotary clamp or infusion pump).

− Administer 60 ml of the solution to the patient over approximately one hour.

− Stop the infusion when 60 ml is administered.

− Note that 200 mg of itraconazole has been administered.

− Flush the line as per the flushing procedure described below.

Flush procedure after the infusion:

− After the infusion a complete flush procedure must be started to clean the catheter. This is done to avoid compatibility problems between residual amounts of itraconazole and other drugs which later could be administered through the same catheter.

− Flush the extension line and catheter with 15 – 20 ml of sterile 0.9% sodium chloride solution at the level of the 2-way stop cock, just before the 0.2 μm in-line filter.

− Perform the flush in a continuous run of 30 seconds to 15 minutes.

− After flushing, disconnect and discard the bag, the infusion line and the extension line.

− Do not re-sterilise or re-use the Sporanox infusion set.

1. Sodium chloride infusion bag

2. Sporanox IV ampoule

3. Infusion line with drip chamber (not provided)

4. & 5. Extension line with 2-way stopcock and in-line filter.

Janssen-Cilag Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 0242/0344

22 July 1999 / 21^st July 2009

2 July 2011