Consumer medicine information

Sporanox Oral Solution

Itraconazole

BRAND INFORMATION

Brand name

Sporanox Oral Solution

Active ingredient

Itraconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sporanox Oral Solution.

What is in this leaflet

This leaflet answers some common questions about SPORANOX Oral Solution. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking SPORANOX Oral Solution against the benefits this medicine is expected to have for you.

If you have any concerns about taking SPORANOX Oral Solution, ask your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What SPORANOX Oral Solution is used for

SPORANOX Oral Solution is a medicine used for:

  • the treatment of candida (yeast) infections of the mouth, throat and/or gullet in patients who have a lowered resistance to disease.
  • the prevention of fungal infections in certain patients who may have a lowered resistance.

SPORANOX works by killing or stopping the growth of the fungus that causes the infection.

Your doctor may have prescribed SPORANOX Oral Solution for another reason. Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you take SPORANOX Oral Solution

When you must not take it

Do not take SPORANOX Oral Solution if:

  • you are pregnant or may become pregnant;
  • you have a condition called heart failure (also called congestive heart failure or CHF), SPORANOX could make it worse. If your doctor decides that you need to take SPORANOX even if you have this condition, be sure to get immediate medical help if you have shortness of breath, unexpected weight gain, swelling of the legs, unusual fatigue, or begin to wake up at night.
  • you have an allergy to SPORANOX Oral Solution or any of the ingredients. See Product Description at the end of this leaflet.

SPORANOX Oral Solution must not be taken with certain medicines. Please refer to the section 'Before you start to take it, Taking other medicines.' for a list of these medicines.

Do not take SPORANOX Oral Solution if the packaging is torn or shows signs of tampering.

Do not take SPORANOX Oral Solution beyond the expiry date (month and year) printed on the pack.

Before you start to take it

You must tell your doctor if:

  • you are breast feeding or wish to breastfeed;
  • you have had an allergic reaction to other medicines used to treat fungal infections;
  • you have or have had any liver problems;
  • you have or have had any kidney problems;
  • you have a heart problem;
  • you suffer from cystic fibrosis.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given SPORANOX Oral Solution.

Your doctor will advise whether or not to take SPORANOX Oral Solution or if you need to adjust the dose or adapt your treatment.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop.

In particular, SPORANOX Oral Solution must not be taken with the following medicines:

  • terfenadine, astemizole or mizolastine (used for allergy or hayfever);
  • bepridil, felodipine, nisoldipine, lercanidipine, ivabradine, ranolazine, eplerenone (used to treat angina (crushing chest pain) or high blood pressure);
  • cisapride (used for certain digestive problems);
  • midazolam (oral) or triazolam (used to produce calmness or to help you sleep);
  • simvastatin, lomitapide or lovastatin (used to lower your cholesterol);
  • lurasidone, pimozide or sertindole (used to treat mental disorders);
  • disopyramide, dronedarone, quinidine or dofetilide (used to treat irregular heartbeats);
  • levacetylmethadol, methadone (used for severe pain and to manage opioid-dependency);
  • ticagrelor (used for the prevention of heart attack or stroke);
  • dihydroergotamine and ergotamine (used to treat migraine);
  • ergomatrine or methylergometrine (used to control bleeding and maintain uterine contraction after child birth);
  • halofantrine (used to treat malaria);
  • irinotecan, mobocertinib (used to treat cancer);
  • domperidone (used to treat nausea and vomiting);
  • isavuconazole (used to treat fungal infections);
  • naloxegol (used to treat constipation caused by taking opioid painkillers);
  • avanafil (used to treat erectile dysfunction);
  • dapoxetine (used to treat premature ejaculation);
  • eliglustat (if you know you do not break down drugs that are broken down by the enzyme known as CYP2D6, you should check with your doctor if you can take this medicine).
  • finerenone (used to treat kidney problems in patients with type 2 diabetes);
  • voclosporin (used to treat lupusrelated kidney problems).

Medicines that must never be taken while you are taking SPORANOX Oral Solution, if you have kidney or liver problems:

  • colchicine (used to treat gout);
  • fesoterodine or solifenacin, when used to control irritated urinary bladder;
  • telithromycin (an antibiotic).

If you have chronic lymphocytic leukemia/small lymphocytic lymphoma and you want to newly start this medicine or are making dose adjustments:

  • venetoclax (used to treat certain cancers).

Wait at least 2 weeks after stopping SPORANOX Oral Solution before taking any of these medicines.

Certain medicines are not recommended because they may be affected by SPORANOX Oral Solution or may affect how well SPORANOX Oral Solution works. Your doctor may need to adjust the dose or adapt your treatment for these medicines:

  • phenytoin, phenobarbital or carbamazepine (used to treat fits);
  • bedaquiline, delamanid, rifampicin, rifabutin or isoniazid (used to treat tuberculosis);
  • certain medicines used to treat HIV/AIDS, such as cobicistat, efavirenz, indinavir, maraviroc, nevirapine, saquinavir, ritonavir, boosted darunavir, boosted elvitegravir, ritonavir-boosted fosamprenavir, tenofovir disoproxil fumerate (TDF);
  • boosted asunaprevir, boceprevir, daclatasvir, vaniprevir, elbasvir/grazoprevir, glecaprevir /pibrentasvir, ombitasvir /paritaprevir/ritonavir with or without dasabuvir (used to treat hepatitis C);
  • certain antineoplastics such as axitinib, bosutinib, bortezomib, brentuximab vedotin, busulphan, cabazitaxel, cabozanitinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, entrectinib, erlotinib, gefitinib, glasdegib, ibrutinib, idelalisib, imatinib, ixabepilone, lapatinib, nilotinib, nintedanib, olaparib, panobinostat, pazopanib, pemigatinib, ponatinib, regorafenib, ruxolitinib, sunitinib, sonidegib, talazoparib, trabectedin, trastuzumab emtansine, tretinoin (oral), vandetanib, vinca alkaloids (used to treat certain cancers);
  • aliskiren, diltiazem (to treat hypertension);
  • bosentan, digoxin, nadolol, riociguat, and certain calcium channel blockers including dihydropyridines (e.g. amlodipine, nifedipine) and verapamil (used to treat heart or blood pressure problems);
  • vorapaxar (used to treat heart attacks or strokes);
  • atorvastatin (used to lower cholesterol);
  • anticoagulants such as apixaban, edoxaban, coumarins & coumarin-like medicines (e.g. warfarin), cilostazol, dabigatran, rivaroxaban (used to slow blood clotting);
  • alfuzosin, dutasteride, silodosin (used to treat Benign Prostatic enlargement);
  • sildenafil (used to treat erectile dysfunction or pulmonary hypertension);
  • tadalafil, udenafil, vardenafil (used to treat erectile dysfunction);
  • colchicine (used to treat gout);
  • conivaptan, tolvaptan (used to treat low blood sodium levels);
  • mozavaptan; to treat low blood sodium;
  • fentanyl, a strong medicine for pain;
  • alfentanil, buprenorphine, oxycodone, sufentanil (used in surgery for pain relief and to help anaesthesia);
  • meloxicam, to treat joint inflammation and pain;
  • salmeterol (to improve breathing)
  • darifenacin, fesoterodine, imidafenacin, oxybutynin, tolterodine (used to treat urinary incontinence);
  • tamsulosin (used to treat male urinary incontinence)
  • ciprofloxacin, clarithromycin, erythromycin, telithromycin (antibiotics);
  • methylprednisolone, budesonide, ciclesonide, fluticasone and dexamethasone (often used for conditions such as inflammations, asthma and allergies);
  • bilastine, ebastine, rupatadine (used to treat allergies);
  • everolimus (given after an organ transplant)
  • cyclosporin, rapamycin (also known as sirolimus), tacrolimus, temsirolimus (used to help prevent organ transplant rejection or to treat certain problems with the immune system);
  • trimetrexate (used to treat certain type of pneumonia);
  • buspirone, perospirone, ramelteon, midazolam IV, alprazolam, brotizolam (used to treat anxiety or help you sleep);
  • aripiprazole, cariprazine, haloperidol, quetiapine, risperidone to treat psychosis;
  • medicines taken for diabetes (in particular repaglinide and saxagliptin);
  • aprepitant, netupitant (used for nausea and vomiting during cancer treatment)
  • artemether-lumefantrine, quinine (used to treat malaria);
  • praziquantel, (used to treat fluke and tapeworms);
  • some contraceptive pills (birth control pills), such as dienogest, ulipristal;
  • reboxetine, venlafaxine (used to treat depression and anxiety);
  • cinacalcet, to treat an over active parathyroid;
  • alitretinoin (oral formulation), to treat eczema;
  • eletriptan (used to treat migraine);
  • Saccharomyces boulardii, loperamide (used to treat diarrhea);
  • lumacaftor/ ivacaftor (used to treat Cystic Fibrosis);
  • guanfacine (used to treat Attention Deficit Hyperactivity Disorder);
  • suvorexant, zopiclone (used to treat insomnia);
  • cabergoline (used to treat Parkinsons Disease;
  • cannabinoids (used to treat nausea and vomiting, weight loss for patients with immune system problems and muscle spasms in patients with Multiple Sclerosis;
  • Valbenazine (used to treat movements of the mouth, tongue, jaw, and sometimes limbs, which cannot be controlled (tardive dyskinesia));
  • galantamine (used to treat Alzheimer's disease).

If you know you break down drugs that are handled/broken down by the enzyme CYP2D6 very quickly, you should check with your doctor if you can take this medicine as it may require a dose change:

  • eliglustat

Medicines not recommended while you are on SPORANOX Oral Solution, when you are on a stable dose of this medicine for chronic lymphocytic leukemia/small lymphocytic lymphoma, or at any time of treatment for acute myeloid leukemia:

  • venetoclax

This is not a complete list of medicines. Therefore, tell your doctor about all medicines you take. Wait at least 2 weeks after stopping SPORANOX Oral Solution before starting this medicine unless your doctor feels it is necessary.

Taking SPORANOX Oral Solution

How much to take

Adults

The usual doses are shown below, but your doctor may decide to adjust them to your individual needs:

Treatment of yeast infections in the mouth or throat

  • two measuring cups (200 mg or 20 mL) once a day or
  • one measuring cup (100 mg or 10 mL) twice a day (morning and afternoon).
  • continue for 1 week

Treatment of yeast infections in the foodpipe (oesophagus)

  • one measuring cup (100 mg or 10 mL) once a day
  • continue for a minimum of 3 weeks

If necessary, your doctor may decide to double the dose or prolong the treatment period.

Prevention of fungal infections

  • the dose will depend on your body weight. Your doctor will tell you how much and how often you should take SPORANOX Oral Solution.
  • SPORANOX Oral Solution is usually taken up to 8 weeks.

Children and Elderly

SPORANOX Oral Solution is not recommended for use in children and in the elderly.

How to take it

  • You should always take SPORANOX Oral Solution on an empty stomach, at least one hour before a meal.
  • If you are taking SPORANOX Oral Solution for the treatment of yeast infections in the mouth or throat, you should swish the solution around the mouth for about 20 seconds before swallowing. DO NOT RINSE your mouth after swallowing.

Directions for opening the bottle

The bottle comes with a child-resistant cap, and should be opened by pushing the plastic screw cap down while turning it anti-clockwise.

If you forget to take it

  • Take the dose you missed as soon as you remember, and then continue to take it as you would normally.
  • If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.
  • Do not take a double dose to make up for the dose you missed.

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you have taken too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre for advice, or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Poisons Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Keep these telephone numbers handy.

While you are taking SPORANOX Oral Solution

Things you must do

  • Always follow your doctor's instructions carefully.
  • If you have to take SPORANOX Oral Solution continuously for more than 1 month, your doctor may ask you to have your blood checked regularly. This is to make sure that your liver is not affected.
  • If there is any chance of you becoming pregnant, talk to your doctor about the need for highly effective contraception. Once you have finished taking SPORANOX Oral Solution, you should continue using highly effective contraception until you have had your next period. Tell your doctor immediately if you do become pregnant while taking SPORANOX Oral Solution.
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking SPORANOX Oral Solution.
  • Always complete the treatment as directed by your doctor, even if the signs of infection have gone.

Things you must not do

  • Do not take SPORANOX Oral Solution to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if his or her symptoms seem similar to yours.

Things to be careful of

Be careful driving or operating machinery. You may feel dizzy while taking SPORANOX Oral Solution. If you experience this or similar effects, you should avoid driving and using machines.

Make sure you know how you react to SPORANOX Oral Solution before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or lightheaded.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following:

  • upset stomach, excess gas in stomach, stomach cramps, nausea, vomiting, diarrhoea, constipation, an unpleasant taste in your mouth.
  • shortness of breath, headache, dizziness, fever.
  • cough, chills, cold or flu-like symptoms
  • a change in menstrual pattern.
  • unusual hair loss or thinning.
  • erectile dysfunction.
  • muscle weakness or pain, painful joints.
  • confusion
  • tremor
  • sleepiness
  • excessive sweating
  • high or low blood pressure
  • inflammation of sinus or nose

Tell your doctor immediately if you notice any of the following as you may need urgent medical care:

  • tingling, numbness or weakness in the hands or feet.
  • increased heart rate
  • chest pain
  • swelling of hands, ankles, feet, the legs or the abdomen.
  • shortness of breath, unexpected weight gain, unusual fatigue, or begin to wake up at night (heart failure).
  • oversensitivity to sunlight.
  • blurry or double vision, ringing in the ears.
  • lose the ability to control your bladder or urinate much more than usual.

STOP taking SPORANOX Oral Solution and tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen:

  • abnormal tiredness, loss of appetite, nausea, vomiting, abdominal pain, dark urine, pale stools, yellowing of the skin or eyes (liver disorder).
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
  • a severe skin disorder (widespread rashes with peeling skin and blisters in the mouth, eyes and genitals, or rashes with small pustules or blisters).
  • you experience any hearing loss symptoms. In very rare cases, patients taking SPORANOX have reported temporary or permanent hearing loss.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other effects.

After taking SPORANOX Oral Solution

Storage

  • Keep SPORANOX Oral Solution in the bottle until it is time to take it.
  • Keep your SPORANOX Oral Solution in a cool, dry place where the temperature is below 25°C.
  • Keep your medicines where children cannot reach it. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.
  • Do not store SPORANOX Oral Solution, or any medicine, in the bathroom or near a sink. Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking SPORANOX Oral Solution, or your medicine has passed its expiry date, ask your pharmacist what to do with any medicine which may be left over.

Product Description

What it looks like

SPORANOX Oral Solution is a yellow to slightly amber clear solution.

It is supplied in 150 mL amber glass bottle with a child-resistant screw cap. A 10 mL measuring cup is provided in the pack.

Ingredients

The active ingredient in SPORANOX Oral Solution is 100 mg/10 mL of itraconazole.

Other ingredients include hydroxypropylbetadex, sorbitol solution (70%, non-crystallising), propylene glycol, hydrochloric acid, 654536 cherry flavour, 654595 cherry flavour, caramel flavour, saccharin sodium, sodium hydroxide and purified water.

SPORANOX Oral Solution contains saccharin; sorbitol (7.92 g in 40 mL of solution). Products containing sorbitol may have a laxative effect or cause diarrhoea.

SPORANOX Oral Solution does not contain lactose or gluten.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: (09) 523 8700 or 0800 800 806

Australian Registration Number: AUST R 62008

This leaflet was prepared in July 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Sporanox Oral Solution

Active ingredient

Itraconazole

Schedule

S4

 

1 Name of Medicine

Itraconazole.

2 Qualitative and Quantitative Composition

Sporanox oral solution contains itraconazole 10 mg/mL.

Excipients with known effect.

Saccharin; sorbitol (7.92 g in 40 mL of solution). Products containing sorbitol may have a laxative effect or cause diarrhoea.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Oral liquid, solution.
Sporanox oral solution is clear, slightly amber to yellow solution, with a cherry odour.

4 Clinical Particulars

4.1 Therapeutic Indications

Sporanox oral solution is indicated for:
the treatment of oral and/or oesophageal candidiasis in HIV positive or other immunocompromised patients;
prophylaxis of fungal infections in neutropenic patients.

4.2 Dose and Method of Administration

Sporanox oral solution should be taken on an empty stomach at least 1 hour before food.

Treatment of oral candidiasis.

200 mg (2 measuring cups or 20 mL) once a day or 100 mg (1 measuring cup or 10 mL) twice a day for 1 week. If there is no response after 1 week, treatment should be continued for another week.

Treatment of oesophageal candidiasis.

100 mg (1 measuring cup, i.e. 10 mL) daily for a minimum treatment of three weeks. Treatment should continue for 2 weeks following resolution of symptoms. Doses up to 200 mg (2 measuring cups, i.e. 20 mL) per day may be used based on the clinical response of the patient.

Treatment of fluconazole resistant oral and/or oesophageal candidiasis.

200 mg (2 measuring cups, 20 mL) daily in one or two intakes for 2 weeks. If there is no response after 2 weeks the dose should be increased to 400 mg/day for a further 2 weeks.

Prophylaxis of fungal infections.

5 mg/kg per day administered as a twice daily dose until recovery of neutrophils, for up to 8 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Antifungal prophylaxis in neutropenia).

Instructions for use.

The bottle comes with a child resistant cap and should be opened by pushing the plastic screw cap down whilst turning it counterclockwise.

Dosage adjustment.

Elderly.

Clinical data on the use of Sporanox oral solution in elderly patients are limited. It is advised to use Sporanox oral solution 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. See Section 4.4 Special Warnings and Precautions for Use.

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 Section 4.4 Special Warnings and Precautions for Use.

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. See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Co-administration of a number of CYP3A4 substrates is contraindicated with Sporanox capsules. Increased plasma concentration of these drugs, caused by co-administration with itraconazole, may increase or prolong both therapeutic and adverse effect to such an extent that a potentially serious situation may occur. Increased plasma concentrations of some of these drugs can lead to QT prolongation. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Table 1 for some specific examples).
Co-administration of the following drugs is contraindicated with Sporanox oral solution: terfenadine, astemizole, mizolastine, bepridil, felodipine, lercanidipine, nisoldipine, cisapride, domperidone, disopyramide, dofetilide, dronedarone, quinidine, levacetylmethadol (levomethadyl), methadone, pimozide, sertindole, lurasidone, ticagrelor, halofantrine, isavuconazole, naloxegol, lomitapide, avanafil, dapoxetine, eliglustat, irinotecan, ivabradine, ranolazine, eplerenone, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin, oral midazolam, triazolam and ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine), fesoterodine (in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment), solifenacin (in subjects with severe renal impairment or moderate to severe hepatic impairment), colchicine (in subjects with renal or hepatic impairment), telithromycin (in subjects with severe renal impairment or severe hepatic impairment) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Table 1 for specific examples).
Sporanox oral solution is contraindicated in patients with a known hypersensitivity to the drug or its excipients. There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing itraconazole to patients with hypersensitivity to other azoles.
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 for Use).
Itraconazole is contraindicated in pregnant women except for the treatment of life threatening cases of systemic mycoses, where the potential benefits outweigh the potential harm to the foetus. Highly effective contraceptive precautions should be taken by women of childbearing potential throughout itraconazole therapy, and continued until the next menstrual period following the completion of itraconazole therapy.

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

Peripheral neuropathy.

Isolated cases of peripheral neuropathy have also been reported, predominantly during long-term treatment with itraconazole. If neuropathy occurs that may be attributable to itraconazole, the treatment should be discontinued.

Other azole antifungal agents.

There is limited 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.

Use in patients with congestive heart failure.

In a study with Sporanox IV in healthy volunteers a transient asymptomatic decrease of the left ventricular ejection fraction, which resolved before the next infusion, was observed. The clinical relevance of these findings to the oral formulations is not known.
Itraconazole has been shown to have a negative inotropic effect. 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. The risk benefit assessment should consider factors such as the severity of the indication, the dosing regimen (e.g. total daily dose) and individual risk factors for congestive heart failure. 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 oedematous disorders. Patients with these risk factors, who are being treated with Sporanox, should be informed of the signs and symptoms of congestive heart failure. Caution should be exercised, and the patient monitored for the signs and symptoms of congestive heart failure. Sporanox should be discontinued if such symptoms occur during treatment.
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 used when coadministering itraconazole and calcium channel blockers due to an increased risk of CHF.

Use in patients with cystic fibrosis.

Variability in therapeutic levels of itraconazole was observed and the therapeutic levels of itraconazole were not achieved in some patients. If a patient does not respond to Sporanox oral solution, consideration should be given to switching to alternative therapy.

Treatment of severely neutropenic patients.

Sporanox oral solution as treatment for oral and/or oesophageal candidiasis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties, Sporanox oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis.

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 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Cross resistance.

In systemic candidiasis, if fluconazole resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence, it is recommended to have their sensitivity tested before the start of itraconazole therapy.

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 the drug is given.

Use in patients with hepatic impairment.

Itraconazole is predominantly metabolised in the liver. Patient with impaired hepatic function should be carefully monitored when taking itraconazole and when deciding to initiate therapy with other medications metabolised by CYP3A4. Dose adjustments may be considered in these patients (see Section 5.2 Pharmacokinetic Properties, Special population).
Patients with pre-existing abnormalities of hepatic function (raised liver enzymes, an active liver disease or patients who have experienced liver toxicity with other drugs) who require itraconazole should be monitored, regardless of the duration of therapy.
Rare cases of cholestatic jaundice and very rare cases of hepatitis have been reported. Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Sporanox. 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 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.
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 such cases liver enzyme monitoring is necessary.

Use in patients with 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.

Use in the elderly.

Clinical data on the use of Sporanox oral solution in elderly patients is limited. Use Sporanox oral solution in these patients only if the potential benefits outweigh 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.

Paediatric use.

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.
Limited safety experience is available with a dose of 5 mg/kg per day. The incidence of adverse events such as nausea, diarrhoea, abdominal pain, vomiting, fever, rash, pyrexia, hypertension, cough and mucositis was higher than in adults.
Toxicological studies have shown that itraconazole, when administered to rats, can produce bone toxicity. While such toxicity has not been reported in adult patients, the long-term effect of itraconazole in children is unknown (see Toxicology).

Instructions to the patient.

Patients should be instructed to take Sporanox oral solution at least one hour before food. For the treatment of oral and/or oesophageal candidiasis, the solution should be swished around the oral cavity (approximately 20 seconds) and swallowed. There should be no rinsing after swallowing.
Patients should be instructed to report any signs and symptoms that may suggest liver dysfunction so that the appropriate laboratory testing can be done. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine or pale stool. See Section 4.8 Adverse Effects (Undesirable Effects).

Toxicology.

(See Section 5.3 Preclinical Safety Data, Toxicology).

Effects on laboratory test.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Itraconazole is a drug with a high interaction potential. The various types of interaction and associated general recommendations are described below. In addition, Table 1 is provided listing examples of drugs that may interact with itraconazole, organized per drug family for easy reference.
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Coadministration of itraconazole with moderate or potent CYP3A4 inducers may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Coadministration with moderate or potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole, which may result in increased or prolonged pharmacologic effects of itraconazole.
Itraconazole and its major metabolite, hydroxy-itraconazole are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Itraconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein and/or BCRP, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. For some drugs, coadministration with itraconazole may result in decreased plasma concentrations of the drug or of the active moiety of the drug. This may result in reduced efficacy of the drug.
Following cessation of medical treatment with itraconazole, plasma concentrations decrease below the detection limit within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the plasma concentrations decline slower. This is particularly important for consideration when initiating therapy with drugs whose metabolism is affected by itraconazole.
The following general recommendations apply, unless stated differently in Table 1.
Contraindicated: under no circumstances is the drug to be coadministered with itraconazole. This applies to:
CYP3A4 substrates for which increased plasma concentrations may increase or prolong therapeutic and/or adverse effects to such an extent that a potentially serious situation may occur (see Section 4.3 Contraindications).
Not recommended: it is recommended that the use of the drug be avoided, unless the benefits outweigh the potentially increased risks. If coadministration cannot be avoided, clinical monitoring is recommended, and the dosage of itraconazole and/or the coadministered drug adapted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. This applies to:
moderate or potent CYP3A4 inducers: not recommended from 2 weeks before and during treatment with itraconazole;
CYP3A4/P-gp/BCRP substrates for which increased or decreased plasma concentrations result in significant risk: not recommended during and up to 2 weeks after treatment with itraconazole.
Use with caution: careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely and the dosage of itraconazole and/or the coadministered drug adapted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. This applies to:
drugs that reduce gastric acidity (Sporanox capsules only);
moderate or potent inhibitors of CYP3A4;
CYP3A4/P-gp/BCRP substrates for which increased or decreased plasma concentrations result in a clinically relevant risk.
The list of examples of interacting drugs in Table 1 is not comprehensive and therefore the label of each drug that is co-administered with itraconazole should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration. The drugs listed in Table 1 are based on either drug interaction studies or case reports, or potential interactions based on the mechanism of interaction.

Potential interactions that have been excluded.

In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethazine.
No interaction of itraconazole with zidovudine (AZT) and fluvastatin has been observed. The results of a study in which eight HIV infected patients were treated with zidovudine 8 ± 0.4 mg/kg/day, with or without itraconazole 100 mg b.i.d., showed that the pharmacokinetics of zidovudine are not significantly affected during co-administration with itraconazole.
No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed.
Absorption from Sporanox oral solution is not affected by co-administration of H2-antagonists, in contrast to the effect seen with Sporanox capsules.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 5.3 Preclinical Safety Data, Genotoxicity, carcinogenicity and effects on fertility.
(Category B3)

Teratogenic effects.

Itraconazole was found to cause a dosage related increase in maternal toxicity, embryotoxicity and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day and in mice at dosage levels of approximately 80 mg/kg/day. In rats, the teratogenicity consisted of major skeletal defects and in mice it consisted of encephaloceles and/or macroglossia.
Sporanox oral solution is contraindicated in pregnancy except in life threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see Section 4.3 Contraindications).
There is limited information on the use of Sporanox during pregnancy. During postmarketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with Sporanox has not been established.
Epidemiological data on exposure to Sporanox during the first trimester of pregnancy (mostly in patients receiving short-term treatment for vulvovaginal candidiasis) did not show an increased risk of malformations as compared to control subjects not exposed to any known teratogens. Itraconazole has been shown to cross the placenta in a rat model.
Women of childbearing potential taking Sporanox oral solution should use contraceptive precautions. Highly effective contraception should be continued until the menstrual period following the end of Sporanox therapy.
Based on the determination of itraconazole concentration in the breast milk of lactating mothers who received a single daily dose of 400 mg itraconazole (200 mg b.i.d.), it was calculated that the exposure in the infant to itraconazole would be around 450 times lower than in the mother. The expected benefits of Sporanox therapy should therefore be weighed against the potential risk of breastfeeding. In case of doubt, the patient should not breastfeed.

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 effects such as dizziness, visual disturbances and hearing loss, which may occur in some instances, must be taken into account. See Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

With the use of Sporanox oral solution, the most frequently reported adverse effects were of gastrointestinal origin, such as diarrhoea, nausea, abdominal pain and vomiting. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, dizziness and allergic reactions (such as pruritus, rash, urticaria and angioedema).
Adverse experiences reported in association with the use of Sporanox 100 mg capsules:

Common (> 1%).

Body as a whole.

Dizziness, headache.

Hepatobiliary disorders.

Reversible increases in hepatic enzymes.

Gastrointestinal disorders.

Nausea, vomiting, diarrhoea, abdominal pain, constipation, dyspepsia.

Uncommon (< 1%).

Infections and infestations.

Sinusitis, upper respiratory tract infection, rhinitis.

Gastrointestinal disorders.

Flatulence.

Hepatobiliary disorders.

Hepatic function abnormal.

Renal and urinary disorders.

Pollakiuria.

Reproductive system and breast disorders.

Erectile dysfunction.

Rare (< 0.1%).

Body as a whole.

Allergic reactions such as pruritus, rash, urticaria and angioedema.

Endocrine disorders.

Menstrual disorder.

Very rare (< 0.01%).

Hepatobiliary disorders.

Hepatitis (especially during prolonged treatment).
The following is a list of additional adverse effects associated with itraconazole that have been reported in clinical trials of Sporanox oral solution and/or Sporanox IV. The adverse effects are related to the active substance and are not specifically formulation dependent.

Blood and lymphatic system disorders.

Granulocytopenia, thrombocytopenia.

Immune system disorders.

Anaphylactoid reaction.

Metabolism and nutrition disorders.

Hyperglycaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia.

Psychiatric disorders.

Confusional state.

Nervous system disorders.

Neuropathy peripheral, dizziness, somnolence.

Cardiac disorders.

Cardiac failure, left ventricular failure, tachycardia.

Vascular disorders.

Hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders.

Pulmonary oedema, dysphonia, cough.

Gastrointestinal disorders.

Gastrointestinal disorder.

Hepatobiliary disorders.

Hepatic failure, hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

Rash erythematous, hyperhidrosis.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia.

Renal and urinary disorders.

Renal impairment, urinary incontinence.

General disorders and administration site conditions.

Generalized oedema, face oedema, chest pain, pyrexia, pain, fatigue, chills.

Investigations.

Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, hepatic enzyme increased, urine analysis abnormal.

Postmarketing data.

Adverse drug effects from spontaneous reports during the worldwide postmarketing experience with Sporanox (all formulations) that meet threshold criteria are included below. The adverse drug effects are ranked by frequency, using the following convention. Very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1,000 and < 1/100); rare (≥ 1/10,000 and < 1/1,000); very rare (< 1/10,000), including isolated reports.
The frequencies below reflect reporting rates for adverse drug effects from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Blood and lymphatic system disorders.

Very rare: leukopenia and neutropenia, thrombocytopenia.

Immune system disorders.

Very rare: serum sickness, angioneurotic oedema, anaphylactic, anaphylactoid and allergic reactions.

Endocrine disorder.

Very rare: pseudoaldosteronism.

Metabolism and nutrition disorders.

Very rare: hypertriglyceridemia, hypokalaemia.

Nervous system disorders.

Very rare: peripheral neuropathy, paraesthesia, hypoaesthesia, headache, dizziness, tremor.

Eye disorders.

Very rare: visual disturbances, including vision blurred and diplopia.

Ear and labyrinth disorder.

Very rare: tinnitus, transient or permanent hearing loss.

Cardiac disorders.

Very rare: congestive heart failure.

Respiratory, thoracic and mediastinal disorders.

Very rare: pulmonary oedema, dyspnoea.

Gastrointestinal disorders.

Very rare: pancreatitis, abdominal pain, vomiting, dyspepsia, nausea, diarrhoea, constipation, dysgeusia.

Hepatobiliary disorders.

Very rare: serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes.

Skin and subcutaneous tissue disorders.

Very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity, rash, pruritus.

Musculoskeletal and connective tissue disorders.

Very rare: myalgia, arthralgia.

Renal and urinary disorders.

Very rare: pollakiuria, urinary incontinence.

Reproductive system and breast disorders.

Very rare: menstrual disorders, erectile dysfunction.

General disorders and administration site conditions.

Very rare: oedema, pyrexia.

Investigations.

Very rare: blood creatine phosphokinase increased.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

In general, adverse effects reported with overdose have been consistent with those reported for itraconazole use (see Section 4.8 Adverse Effects (Undesirable Effects)).

Treatment.

Itraconazole is not removed by dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450 dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Microbiology.

In vitro susceptibility tests, dilution or diffusion techniques.

Either quantitative (MIC) or breakpoint, should be used following a regulatory updated, recognised and standardised method (e.g. Clinical and Laboratory Standard Institute [CLSI formerly NCCLS]). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
For itraconazole, breakpoints have only been established for Candida spp. from superficial mycotic infections (CLSI M27-A2, using laboratory controlled Candida parapsilosis ATCC 22019, Candida krusei ATCC 6258). The proposed MIC breakpoints are as follows:
Susceptible: A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antifungal compound in the blood reaches the concentrations usually achievable.
Susceptibility that is "dose- or delivery-dependent" (S-DD): This category implies possible clinical applicability in body sites where the medicine is physiologically concentrated or in situations where high dosage of medicine can be used.
Note that itraconazole MIC values for Candida species; Cryptococcus neoformans; Blastomyces dermatitidis; Coccidioides immitis; Histoplasma capsulatum; and Geotricum species were reported as ≤ 1 microgram/mL.
Itraconazole MIC values for Aspergillus flavus, Aspergillus fumigatus, Trichosporon species, Fonsecaea pedrosoi, and Trichophyton species were reported as ≤ 1 microgram/mL, although interpretive breakpoints have not been established for the filamentous fungi.
Resistant: A report of "resistant" indicates that the pathogen is not likely to be inhibited if the antifungal compound in the blood reaches the concentrations usually achievable; other therapy should be select.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.
The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole resistant strains of Aspergillus fumigatus have been reported.

Correlation between in vitro MIC results and clinical outcomes.

Susceptibility of a microorganism in vitro does not predict successful therapy. Host factors are often more important than susceptibility test results in determining clinical outcomes, and resistance in vitro should often predict therapeutic failure. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.

Clinical trials.

Oral candidiasis.

Two randomised double blind studies using fluconazole as a comparator were conducted in group IV HIV positive adults with culture proven oral candidiasis. In one study, itraconazole 100 mg b.i.d. (n = 135) was compared to fluconazole 100 mg o.d. (n = 132), each given for 7 days. Maintenance therapy of itraconazole 100 mg b.i.d. or fluconazole 100 mg o.d. one day per week was given for 12 weeks. At day 7, 86% of evaluable patients (n = 124) receiving itraconazole had a global evaluation of cured or markedly improved, 41% had a negative culture and 64% had a negative microscopic result. For evaluable patients receiving fluconazole (n = 112) the results were 87%, 32% and 49%, respectively. The median time to relapse in the maintenance period using the Kaplan-Meier analysis of survival was greater than 108 and 94 days, respectively. The global evaluation and time to relapse for itraconazole 100 mg b.i.d. and fluconazole 100 mg o.d. were equivalent. In the other double blind study, itraconazole 100 mg b.i.d. (n = 68 evaluable patients) for 7 days was compared to itraconazole 100 mg b.i.d. (n = 68 evaluable patients) and fluconazole 100 mg o.d. (n = 78 evaluable patients), each for 14 days. A therapeutic response of 84%, 91% and 91% at day 15 was observed. The time to relapse and the relapse rate were similar. The mean symptom scores for soreness and burning, dysphagia, plaques, erythema and extent of lesions were almost identical.

Oesophageal (with and without oral) candidiasis.

Two randomised, double blind, double dummy studies comparing itraconazole oral solution with fluconazole in the treatment of oesophageal candidiasis with or without oral candidiasis were conducted. The first study compared itraconazole 100 mg b.i.d. (n = 58 evaluable patients) with fluconazole 50 mg for 7 days (n = 55 evaluable patients) in patients with AIDS. Pulse therapy of either itraconazole 100 mg b.i.d. or fluconazole 50 mg once weekly was continued for a further 12 weeks. In patients with oesophagitis, a clinical response was seen in 93% of patients receiving itraconazole and 89% receiving fluconazole, while in patients with oral candidiasis, a clinical response was seen in 88% and 89%, respectively. The median time to relapse was greater than 3 months by the Kaplan-Meier survival curve.
In the other study, 126 immunocompromised patients (92% HIV positive) with endoscopy confirmed oesophageal candidiasis and a positive fungal culture were treated with either 100 mg itraconazole or fluconazole for 7 days after which treatment could be increased to 200 mg. All patients were given a 200 mg dose of either drug on the first day followed by 100 mg daily thereafter. Patients continued treatment for 2 weeks following resolution of symptoms and were then followed for a further 4 weeks. A total of 18 (16%) patients (6 itraconazole, 12 fluconazole) had their dose increased to 200 mg daily due to lack of clinical response. Clinical response was seen in 94% of 53 evaluable patients receiving itraconazole and 91% of 57 evaluable patients receiving fluconazole. Mycological cures were obtained in 92% of evaluable itraconazole patients and 78% of evaluable fluconazole patients. The median time to relapse was comparable for the 2 groups, around 26 days. In these two studies, itraconazole oral solution and fluconazole capsules were demonstrated to be equivalent in the treatment of oesophageal candidiasis.

Oral and oesophageal candidiasis resistant to fluconazole.

Three open label studies were conducted in patients with either oral or oesophageal candidiasis not responding to fluconazole. In the first study, 60 patients, of whom 40 were evaluable for efficacy, received itraconazole 100 mg b.i.d. for 14 days and 200 mg b.i.d. for a further 14 days if sufficient improvement had not occurred. A global assessment of cure at day 14 was seen in 60% of patients. Clinical cure at day 14 was 68% overall and 52% by intent to treat analysis. In the second study 83 patients (65 evaluated for efficacy) received itraconazole 100 mg q.i.d. for 14 days. In patients who responded at 7 days the dose was reduced to itraconazole 200 mg for another 7 days. A maintenance phase of itraconazole 200 mg daily or 200 mg 3 times weekly was then continued for up to 6 months. Clinical response (cure or improved) at day 14 was 83% and 70% at study endpoint. Relapse occurred in 36% of patients at a mean time of 216 days. In the third study, adult HIV positive patients (n = 74) with oral candidiasis resistant to fluconazole received itraconazole 100 mg b.i.d. for 14 days and if not cured, then treatment was continued for another 14 days. Follow-up was for 6 weeks. Clinical improvement at the end of treatment was seen in 74% of evaluable patients and 70% by intent to treat analysis. The mean time to relapse was 13 days.

Antifungal prophylaxis in neutropenia.

Data on antifungal prophylaxis in neutropenia with itraconazole oral solution is currently limited to patients with haematological malignancy undergoing treatment with chemotherapy or allogeneic stem cell transplant. Commencement of prophylaxis treatment should be prior to the development of neutropenia.
The prophylactic antifungal activity of itraconazole 5 mg/kg was studied in 3 main randomised trials on neutropenic patients with haematological malignancy. In the pivotal double blind, placebo controlled trial, patients received itraconazole 2.5 mg/kg b.i.d. (n = 201) or placebo (n = 204). Oral itraconazole solution was started together with chemotherapy, except for bone marrow transplant patients in whom prophylaxis was commenced between 7 days prior to and 3 days after re-infusion of marrow until neutrophil count was restored to > 1.0 x 109/L for a maximum of 8 weeks. Treatment was continued for a maximum of 8 weeks until neutrophil recovery or until another trial endpoint (e.g. deep fungal infections, superficial fungal infections, rescue IV amphotericin B) was reached. All patients also received both nystatin (500,000 IU q.i.d.) and ciprofloxacin (500 mg b.i.d.). Incidence of all fungal infections was significantly lower in the itraconazole group (23.9% vs 33.3%). Incidence of proven deep fungal infections including aspergillosis was 5 in the itraconazole group and 9 in the placebo group (p = 0.291, one tailed analysis). There was no statistical difference between treatments in the use of IV amphotericin B as rescue medication.
The second double blind double dummy trial compared itraconazole 2.5 mg/kg b.i.d. (n = 281) to oral amphotericin B 500 mg q.i.d. (n = 276). Prophylaxis treatment with itraconazole oral solution was commenced on the first day of chemotherapy. Treatment was continued for a maximum of 8 weeks until neutrophil recovery or until another trial endpoint was reached. There were no differences between itraconazole and amphotericin B treatments in the incidence of invasive aspergillosis or proven deep fungal infections. No difference between treatments was observed in the usage of rescue antifungal medications. The third open label study compared itraconazole 2.5 mg/kg b.i.d. (n = 218, with 288 episodes of neutropenia) with fluconazole 100 mg o.d. (n = 227, with 293 episodes of neutropenia). Prophylaxis treatment with itraconazole oral solution commenced on the first day of chemotherapy. Treatment was continued until neutrophil recovery or until another endpoint was reached. Although not statistically significant, 4 cases of aspergillosis (primary parameter) occurred in the fluconazole group compared to none in the itraconazole group. The number of breakthrough deep Candida infections was 2 and 1, and the number of breakthrough superficial infections was 4 and 11, for the itraconazole and the fluconazole groups, respectively.

5.2 Pharmacokinetic Properties

Absorption.

The oral bioavailability of Sporanox oral solution is maximal when it is taken without food. During chronic administration, steady state is reached after 1-2 weeks. Peak plasma levels are observed 2 hours (fasting) to 5 hours (with food) following oral solution administration. After repeated administration of Sporanox oral solution, at a dosage of 200 mg once a day in fasting condition, steady-state plasma concentrations of itraconazole fluctuate between 1 and 2 microgram/mL (trough to peak). When Sporanox oral solution is taken with food, steady-state plasma concentrations of itraconazole are about 25% lower.
The bioavailability of Sporanox oral solution taken in a fasting condition is approximately 60% higher than the bioavailability of the capsule taken with a meal.
The bioavailability of Sporanox oral solution in HIV patients is reduced by around 20% compared to normal volunteers. The bioavailability is not altered by the stage of infection. The recommended dosage has been shown to be effective in HIV patients.
The plasma protein binding of itraconazole is 99.8%. Concentrations of itraconazole in whole blood are 60% of those in plasma.

Distribution.

Itraconazole is extensively distributed into most tissues that are prone to fungal invasion but only minimally into CSF or ocular fluid. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than the corresponding plasma concentration.

Metabolism.

Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the metabolites is hydroxyitraconazole, which has a comparable antifungal activity in vitro to itraconazole. Plasma levels of hydroxyitraconazole are about two times higher than those of itraconazole.

Excretion.

After repeated oral administration, elimination of itraconazole from plasma is biphasic with a terminal half-life of 1.5 to 2 days. Faecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 35% of the dose is excreted as metabolites in the urine within 1 week.

Special population.

Hepatic impairment.

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 mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. Patients with impaired hepatic functions should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in hepatic impairment patients (37.2 ± 17 h) should be considered when deciding to initiate therapy with other medications metabolised by CYP3A4 (see Section 4.4 Special Warnings and Precautions for Use, Use in patients with hepatic impairment).

Renal impairment.

A pharmacokinetic study using a single 200 mg dose of itraconazole (four 50 mg capsules) was conducted in three groups of patients with renal impairment (uremic: n = 7; haemodialysis: n = 7 and continuous ambulatory peritoneal dialysis: n = 5). In uremic/ haemodialysis and continuous ambulatory peritoneal dialysis subjects, Cmax were reduced compared with normal population parameters and listed below.
Cmax 132-417 (normal)/ 50.9-505 nanogram.hour/mL (uremic).
Cmax 18.2-341 (haemodialysis)/ 51.7-111 nanogram.hour/mL (continuous ambulatory peritoneal dialysis).
Plasma concentration versus time profiles showed wide intersubject variation in all three groups.

5.3 Preclinical Safety Data

Genotoxicity, carcinogenicity and effects on fertility.

Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels of up to 80 mg/kg/day. Male rats treated with 25 mg/kg/day had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolaemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.
Itraconazole produced no mutagenic effects when assayed in appropriate bacterial, nonmammalian and mammalian test systems.
Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day even though parental toxicity was present at this dosage level.
Separate studies on the vehicle, hydroxypropyl betadex, have shown that this carrier molecule is not mutagenic. It did not have carcinogenic activity in mice at dietary dose levels up to 5 g/kg/day, but caused the development of pancreatic exocrine adenomas and adenocarcinomas in rats at dietary dose levels of 0.5 to 5 g/kg/day. Pancreatic exocrine tumours in rats may be due to a nongenotoxic mechanism involving stimulation of cholecystokinin release as a result of complexation of bile salts by hydroxypropyl betadex in the intestinal lumen. However, there is only indirect evidence for this hypothesis and its relevance in humans is not known.
Hydroxypropyl betadex had no effect on fertility when administered to male and female rats at dietary doses up to 5 g/kg/day or IV doses up to 400 mg/kg/day.

Toxicology.

In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day. The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones and increased bone fragility. At a dosage level of 80 mg/kg/day over one year or 160 mg/kg/day for six months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.
Increased relative adrenal weights and swollen adrenals (reversible) were seen in rats and dogs where plasma levels were comparable to those of human therapeutic doses. Adrenocortical function was not affected in studies in humans after the recommended daily doses; with higher doses (600 mg/day for 3 months), adrenal cortex response to ACTH stimulation was reduced in 1 of 8 patients, but returned to normal when the dosage was reduced.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hydroxypropyl betadex, sorbitol solution (70 per cent) (non-crystallising), propylene glycol, hydrochloric acid, 654536 Cherry Flavour (ARTG PI No. 107587), 654595 Cherry Flavour (ARTG PI No. 107586), caramel, saccharin sodium, sodium hydroxide, purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Sporanox 10 mg/mL oral solution (150 mL) is supplied in Type I amber glass bottles with a polypropylene child-resistant cap.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Itraconazole is a synthetic triazole antifungal agent. It has three chiral centres and is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs).

Chemical structure.


C35H38Cl2N8O4.

CAS number.

84625-61-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes