Sporanox^® 10 mg/ml Oral Solution.

1 ml Sporanox oral solution contains 10mg itraconazole.

Sorbitol E420 (190 microlitre per ml).

For a full list of excipients, see section 6.1.

Oral solution.

Sporanox oral solution is clear, yellow to slightly amber solution with an odour of cherry.

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Sporanox oral solution is indicated:

− For the treatment of oral and/or oesophageal candidosis in HIV-positive or other immunocompromised patients.

− As prophylaxis of deep fungal infections anticipated to be susceptible to itraconazole, when standard therapy is considered inappropriate, in patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (ie < 500 cells/µl). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.

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

For optimal absorption, Sporanox oral solution should be taken without food (patients are advised to refrain from eating for at least 1 hour after intake).

For the treatment of oral and/or oesophageal candidosis, the liquid should be swished around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after swallowing.

Treatment of oral and/or oesophageal candidosis: 200 mg (2 measuring cups) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.

Treatment of fluconazole resistant oral and/or oesophageal candidosis: 100 to 200 mg (1-2 measuring cups) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400mg daily dose should not be used for longer than 14 days if there are no signs of improvement.

Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Almost all proven deep fungal infections occurred in patients reaching neutrophil counts below 100 cells/µl. Treatment was continued until recovery of neutrophils (ie > 1000 cells/µl).

Pharmacokinetic parameters from clinical studies in neutropenic patients demonstrate considerable intersubject variation. Blood level monitoring should be considered particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of Sporanox oral solution.

Use in children:

Since clinical data on the use of Sporanox oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks. See section 4.4 Special warnings and special precautions for use.

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes (see section 4.8 Undesirable effects).

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. See section 4.4 Special warnings and special precautions for use.

Use 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 this drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Use in patients with renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Sporanox oral solution is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients.

Co-administration of the following drugs is contraindicated with Sporanox oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):

- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Sporanox oral solution. Co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

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

- Triazolam and oral midazolam

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

- Eletriptan

- Nisoldipine

- Sporanox oral solution should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. (see section 4. 4 Special warnings and precautions)

Sporanox oral solution should not be used during pregnancy for non life-threatening indications (see section 4.6 Pregnancy and lactation).

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 400mg total daily dose than among those of lower total daily doses, suggesting that the rsik of heart failure might increase with the total daily dose of itraconazole.

Sporanox oral solution 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 the 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 oral solution should be discontinued.

Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5. Interaction with other medicinal products).

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 oral solution in paediatric patients is limited, its use in children is not recommended unless 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.

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. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

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 esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), 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.

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

Sporanox Oral Solution 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.

Sporanox oral solution contains sorbitol and should not be given to patients with rare hereditary problems of fructose intolerance.

4.5.1. 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 this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.

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

4.5.2.1 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 levels decline gradually, depending on the dose and duration of treatment (See Section 5.2. Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of itraconazole on comedicated drugs is considered.

-The following drugs are contraindicated with itraconazole:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl),mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Sporanox oral solution since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

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

- 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 busulfan, docetaxel, trimetrexate and vinca alkaloids;

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

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

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

• Digoxin (via inhibiton of P-glycoprotein)

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

4.5.2.2

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

4.5.3. 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 oral solution 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 4.3 Contraindications).

In animal studies itraconazole has shown reproduction toxicity (see 5.3 Preclinical safety data).

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 childbearing potential taking Sporanox oral solution should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Sporanox therapy.

Lactation:

A very small amount of itraconazole is excreted in human milk. Sporanox Oral Solution must not be used during lactation.

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 Undesirable effects), which may occur in some instances, must be taken into account.

Approximately 9% of patients can be expected to experience adverse reactions while taking itraconazole. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological 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.

Paediatric Population

The safety of Sporanox 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 Sporanox oral solution for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.

Symptoms:

There are limited data on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of Sporanox oral solution or up to 3000 mg of Sporanox capsules, the adverse event profile was similar to that observed at recommended doses.

Treatment:

In the event of an overdose, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.

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.

Paediatric Population

The tolerability and safety of itraconazole oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of itraconazole oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to itraconazole were vomiting, abnormal liver function, and abdominal pain.

General pharmacokinetic characteristics

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

Absorption

Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of the unchanged drug are reached within 2.5 hours following an oral dose under fasting conditions. The observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30 % when the oral solution is taken in fasting conditions.

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

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. Plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.

As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Elimination

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with feces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas fecal excretion of unchanged drug varies between 3 – 18% of the dose. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Linearity/non-linearity

As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. The mean elimination half-life of itraconazole is about 40 hours after repeated dosing.

Special Populations

Hepatic Insufficiency: A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in average C_max (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects.

Data are not available in cirrhotic patients during long-term use of itraconazole.

Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when the drug is administered in this patient population.

Paediatric Population:

Two pharmacokinetic studies have been conducted in neutropenic children aged 6 months to 14 years in which itraconazole oral solution was administered 5 mg/kg once or twice daily. The exposure to itraconazole was somewhat higher in older children (6 to 14 years) compared to younger children. In all children, effective plasma concentrations of itraconazole were reached within 3 to 5 days after initiation of treatment and maintained throughout treatment.

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.

Hydroxypropyl-β-cyclodextrin, sorbitol E420, propylene glycol, cherry flavour 1 (contains 1,2-propylene glycol E1520 and acetic acid E260), cherry flavour 2 (contains 1,2-propylene glycol E1520 and lactic acid E270), caramel, sodium saccharin, hydrochloric acid and sodium hydroxide (for pH adjustment), purified water.

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

24months as packaged for sale.

1 month after first opening the container.

Do not store above 25°C.

150 ml amber glass bottle, with child resistant polypropylene screw cap and LDPE liner ring.

A measuring cup graduated to indicate 10 ml is provided.

Sporanox oral solution is supplied in bottles with a child-proof cap, and should be opened as follows: push the plastic screw cap down while turning it counter clockwise.

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

00242/0307

26 April 1996/26 April 2006

2 July 2011

POM.