Consumer medicine information

Sporanox Capsules

Itraconazole

BRAND INFORMATION

Brand name

Sporanox Capsules

Active ingredient

Itraconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sporanox Capsules.

What is in this leaflet

This leaflet answers some common questions about SPORANOX capsules. 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 capsules against the benefits this medicine is expected to have for you.

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

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

What SPORANOX capsules are used for

SPORANOX capsules are used to treat certain fungal infections which include the following:

  • persistent infections of the nails, skin, hands, feet or groin;
  • persistent candida (yeast) infections of the vagina;
  • eye infections which have not responded to other treatment or which may be affecting vision;
  • candida (yeast) infections of the mouth or throat in patients with lower resistance to disease;
  • generalised infections.

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

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

Before you take SPORANOX capsules

When you must not take it

Do not take SPORANOX capsules if:

  • you are pregnant or may become pregnant.
    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, 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.
  • 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 capsules or any of the ingredients. See Product Description at the end of this leaflet.

Do not take SPORANOX capsules with any of the following:

  • terfenadine, astemizole or mizolastine (used for allergy or hayfever);
  • bepridil, felodipine, lercanidipine, ivabradine, ranolazine, eplerenone and nisoldipine (used to treat angina (crushing check pain) or high blood pressure);
  • domperidone (used to treat nausea and vomiting);
  • ticagrelor (used for the prevention of heart attack or stroke);
  • cisapride (used for certain digestive problems);
  • certain medicines used to produce calmness or to help you sleep (midazolam (oral) or triazolam);
  • 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 or to manage opioid-dependency);
  • dihydroergotamine and ergotamine (used to treat migraine);
  • ergometrine or methylergometrine (used to control bleeding and maintain uterine contraction after child birth);
  • halofantrine (used to treat malaria);
  • irinotecan, an anti-cancer medicine;
  • 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).

If you have kidney or liver problems, do not take SPORANOX capsules with any of the following:

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

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

Do not take SPORANOX capsules 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 heart problems
  • you are a neutropenic, AIDS or an organ transplant patient.
  • you are a cystic fibrosis patient.

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

Your doctor will advise whether or not to take SPORANOX 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 capsules must not be taken with some medicines. Examples are:

  • 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);
  • certain medicines used to produce calmness or to help you sleep (midazolam (oral) or triazolam);
  • 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, an anti-cancer medicine;
  • 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).

Medicines that must never be taken while you are taking SPORANOX capsules, 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).

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

Certain medicines are not recommended because they may be affected by SPORANOX capsules or may affect how well SPORANOX capsules work. Your doctor may need to adjust the dose or adapt your treatment.

Examples of these medicines are:

  • 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, boosted elvitegravir, efavirenz, indinavir, maraviroc, nevirapine, saquinavir and ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, tenofovir disoproxil fumerate (TDF);
  • simeprevir, boosted asunaprevir, boceprevir, daclatasvir, telaprevir, vaniprevir (used to treat hepatitis C);
  • certain antineoplastics such as axitinib, bosutinib, bortezomib, brentuximab vedotin, busulphan, carbazitaxel, cabozanitinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, erlotinib, ibrutinib, idelalisib, ixabepilone, lapatinib, nilotinib, nintedanib, olaparib, panobinstat, pazopanib, ponatinib, regorafenib, ruxolitinib, sonidegib, trabectedin, trastuzumab emtansine, vandetanib, vinca alkaloids (used to treat certain cancers);
  • sunitinib (used to treat certain types of stomach, bowel, or esophagus tumor and kidney or pancreatic cancer);
  • gefitinib (used to treat breast, lung and other cancers);
  • imatinib (used to treat lung cancer);
  • aliskiren, diltiazem (to treat hypertension);
  • bosentan, digoxin, nadolol, riociguat, and certain calcium channel blockers including amlodpine besylate, nifedipine, nimodipine, other dihydropyridines 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, coumarins & coumarin-like medicines (e.g. warfarin), cilostazol, dabigatran, rivaroxaban (used to slow blood clotting);
  • alfuzosin, dutasteride, soldosin (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)
  • 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);
  • medicines which neutralize stomach acid or suppress the production of stomach acid (such as antacids, cimetidine, ranitidine, omeprazole);
  • Saccharolmyces 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);
  • artemether-lumefantrine, quinine (used to treat malaria);
  • galantamine (used to treat Alzheimer's disease)
  • glecaprevir/pibrentasvir; elbasvir/grazoprevir; ombitasvir/paritaprevir/ritonavir (with or without dasabuvir) combinations, to treat Hepatitis C

Taking SPORANOX capsules

How much to take

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

Tinea of body & groin:
1 capsule (100 mg) daily for 2 weeks.

Tinea of hands & feet:
1 capsule (100 mg) daily for 4 weeks.

Other skin infections:
2 capsules (200 mg) daily for 1 week.

Eye infections:
2 capsules (200 mg) daily for 3 weeks.

Vaginal infections:
2 capsules (200 mg) morning & evening for 1 day, or 2 capsules (200 mg) daily for 3 days.

Mouth infections:
1 to 2 capsules (100 mg to 200 mg) daily for 4 weeks.

Systemic infections:
1 to 2 capsules (100 mg to 200 mg) once or twice daily for 3 weeks to 8 months, depending on the condition.

Nail infections:

Continuous nail therapy

2 capsules (200 mg) once daily for 3 months.

Cyclic (pulse) nail therapy

2 capsules twice daily for 1 week. After that, stop taking SPORANOX for 3 weeks. Then the cycle is repeated, once for fingernails and twice for toenail infections (with or without fingernail infections). (See below).

Fingernails only
Week 1: Take 2 capsules twice daily.
Week 2, 3, 4: No SPORANOX.
Week 5: Take 2 capsules twice daily.
Week 6: Stop.
Toenails with or without fingernails
Week 1: Take 2 capsules twice daily.
Week 2, 3, 4: No SPORANOX.
Week 5: Take 2 capsules twice daily.
Week 6, 7, 8: No SPORANOX.
Week 9: Take 2 capsules twice daily.
Week 10: Stop.

Children and Elderly

SPORANOX capsules are not recommended for use in children and in the elderly.

How to take it

  • Always take SPORANOX capsules after a meal. The capsules must be swallowed whole.
  • Do not take medicines that neutralise stomach acid within 2 hours of taking SPORANOX capsules. This is because sufficient stomach acid is required to ensure that SPORANOX capsule is properly absorbed by the body. If you take medicines that suppress the production of stomach acid, you should take your SPORANOX capsules with an acidic drink, such as a cola beverage.

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 one 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 capsules

Things you must do

  • Always follow your doctor's instructions carefully.
  • If you have to take SPORANOX capsules 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, 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.
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking SPORANOX capsules.
  • 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 capsules 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 capsules. If you experience this or similar effects, you should avoid driving and using machines.

Make sure you know how you react to SPORANOX capsules 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, stomach pain or discomfort, bloating, 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, tremors.
  • Inflammation of the pancreas.

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
  • swelling of hands ankles, feet, legs or abdomen.
  • shortness of breath, unexpected weight gain, unusual fatigue, or begin to wake up at night.
  • 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 capsules 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, dark urine, pale stools, yellowing of the skin or eyes.
  • 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 or difficulty breathing, 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 using SPORANOX capsules

Storage

  • Keep SPORANOX capsules in the pack until it is time to take them.
  • Keep SPORANOX capsules in a cool dry place where the temperature is below 25°C.
  • Keep your medicines where young children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is good place to store medicines.
  • Do not store SPORANOX capsules, or any other 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 capsules or your medicines 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 capsules are pink and blue. They are supplied in a blister pack, containing:

  • 15 capsules - Australia and New Zealand;
  • 28 or 60 capsules - Australia only.

Ingredients

The active ingredient in each SPORANOX capsule is 100 milligrams of itraconazole. Other ingredients include non-pareil beads, macrogol, and hypromellose. The capsule is made of gelatin and also contains titanium dioxide, indigo carmine and erythrosine.

SPORANOX capsules contains sugars.

SPORANOX capsules do 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 47012

This leaflet was prepared in June 2021

Published by MIMS July 2021

BRAND INFORMATION

Brand name

Sporanox Capsules

Active ingredient

Itraconazole

Schedule

S4

 

1 Name of Medicine

Itraconazole.

2 Qualitative and Quantitative Composition

Each capsule contains 100 mg of itraconazole.

Excipients with known effect.

Sucrose.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule.
Blue opaque cap and pink transparent body containing beads.

4 Clinical Particulars

4.1 Therapeutic Indications

Sporanox is indicated for use in adults for the treatment of:
Superficial dermatomycoses not responding to topical treatment;
Fungal keratitis which has failed to respond to topical treatment or where the disease is either progressing rapidly or is immediately sight threatening;
Pityriasis versicolor not responding to any other treatment;
Vulvovaginal candidiasis not responding to topical treatment;
Oral candidiasis in immunocompromised patients;
Onychomycosis caused by dermatophytes.
Systemic mycoses, only in the following fungal infections:
systemic aspergillosis, histoplasmosis, lymphocutaneous/cutaneous sporotrichosis;
treatment and maintenance therapy in AIDS patients with disseminated or chronic pulmonary histoplasmosis infection;
treatment of oropharyngeal and/or oesophageal candidiasis when first line systemic antifungal therapy is inappropriate or has proven ineffective;
treatment of noninvasive candidiasis in non-neutropenic patients when first line systemic antifungal therapy is inappropriate or has proven ineffective. This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity.

4.2 Dose and Method of Administration

It is essential that Sporanox Capsules are taken immediately after a meal for maximal absorption. The capsules must be swallowed whole. Treatment schedules are as follows.

Superficial dermatomycoses.

Tinea corporis, tinea cruris.

1 capsule (100 mg) daily for 2 weeks.

Tinea pedis, tinea manus.

1 capsule (100 mg) daily for 4 weeks.

Fungal keratitis.

2 capsules (200 mg) once daily for 3 weeks.

Pityriasis versicolor.

2 capsules (200 mg) once daily for 1 week.

Vulvovaginal candidiasis.

2 capsules (200 mg) morning and evening for 1 day or 2 capsules (200 mg) once daily for 3 days.

Oral candidiasis in immunocompromised patients.

1 capsule (100 mg) or 2 capsules (200 mg) daily for 4 weeks. (See Section 4.4, Immunocompromised patients).

Onychomycosis.

2 capsules (200 mg) once daily for 3 months; or pulse therapy (see Table 1).
A pulse treatment consists of two capsules twice daily (200 mg twice daily) for one week. Two pulse treatments are recommended for fingernail infections, three pulse treatments for toenail infections. Pulse treatments are always separated by a 3 week drug free interval. Clinical response will become evident as the nail regrows, following discontinuation of the treatment.

Systemic mycoses.

(Dosage recommendations vary according to the infection treated.) See Table 2.

Special populations.

Elderly.

Clinical data on the use of Sporanox Capsules in elderly patients are limited. It is advised to use Sporanox Capsules 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 insufficiency. 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.

4.3 Contraindications

Coadministration of a number of CYP3A4 substrates is contraindicated with Sporanox Capsules. Increased plasma concentration of these drugs, caused by coadministration 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 and ventricular tachyarrhythmias including occurances of Torsades de Pointes, a potentially fatal arrhythmia. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Table 3, for specific examples).
Coadministration of the following drugs is contraindicated with Sporanox Capsules: 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 3, for specific examples).
Sporanox Capsules are contraindicated in patients with a known hypersensitivity to the drug or its excipients.
Sporanox Capsules 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.

Decreased gastric acidity.

Absorption of itraconazole from Sporanox Capsules is impaired when the gastric acidity is decreased. In patients also receiving acid neutralising medicines (e.g. aluminium hydroxide), these should be administered at least 2 hours after the intake of itraconazole. In patients with achlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H2-antagonists, proton pump inhibitors), it is advisable to administer Sporanox Capsules with a cola beverage (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 Capsules 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 hepatic impairment.

Itraconazole is predominantly metabolised in the liver. Patients 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 populations).
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.

Immunocompromised patients.

In some immunocompromised patients (e.g. neutropenic, AIDS or organ transplant patients) the oral bioavailability of Sporanox Capsules may be decreased.

Patients with immediately life threatening systemic fungal infections.

Due to the pharmacokinetic properties, Sporanox Capsules are not recommended for initiation of treatment in patients with immediately life threatening systemic fungal infections.

Patients with AIDS.

In patients with AIDS who have received treatment for a systemic fungal infection with Sporanox Capsules and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Cystic fibrosis.

In cystic fibrosis patients, variability in therapeutic levels of itraconazole was observed with steady state dosing of itraconazole oral solution using 2.5 mg/kg bid. Steady state concentrations of > 250 nanogram/mL were achieved in approximately 50% of subjects greater than 16 years of age, but in none of the patients less than 16 years of age. If a patient does not respond to Sporanox Capsules, consideration should be given to switching to alternative therapy.

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 the elderly.

Clinical data on the use of Sporanox Capsules in elderly patients is limited. Use Sporanox Capsules 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 therapy.

Paediatric use.

The efficacy and safety of itraconazole have not been established in children. Since clinical data on the use of itraconazole in children is limited, Sporanox Capsules should not be used in these patients unless the potential benefit outweighs the potential risks.
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 Capsules with food. The capsules must be swallowed whole.
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, a table is provided listing examples of drugs that may interact with itraconazole, organized per drug family for easy reference. This list of examples is not comprehensive and therefore the Product Information of each drug that is coadministered 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 coadministration.
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.
Absorption of itraconazole from the capsule formulation is reduced in subjects with reduced gastric acidity. Drugs that reduce gastric acidity impair the absorption of itraconazole from itraconazole capsules. To counteract this effect it is recommended to administer itraconazole capsules with an acidic beverage (such as non-diet cola) upon coadministration with drugs that reduce gastric acidity (see Section 4.4 Special Warnings and Precautions for Use).
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 3.
'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.
Examples of interacting drugs are listed in Table 3. The drugs listed in this table 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 AZT (zidovudine) and fluvastatin has been observed.
The results from a study in which eight HIV infected individuals 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 concomitant administration of itraconazole.
No inducing effects of itraconazole on the metabolism of ethinylestradiol and norethisterone were observed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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.
(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 Capsules are 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 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 Capsules 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 or 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)

In clinical studies involving short periods of treatment with itraconazole, the overall incidence of adverse experiences is about 7%. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse experiences was higher (about 15%).

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 edema, 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 edema, face edema, 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.

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 disorders.

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. In the event of accidental overdosage, supportive measures should be employed.
For information on the management of overdose, contact the Poison 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 sp. 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 dermatidis; Coccidioides immitis; Histroplasma 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 selected.
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.

Histoplasmosis.

In five open label, noncomparative studies in patients (n = 136) with histoplasmosis exposed to treatment and maintenance therapy with itraconazole: sixty one patients (45%) were HIV infected and 8 patients (6%) had other causes of immunosuppression. Ninety eight patients (72%) had disseminated disease and 42 patients (31%) had other forms of histoplasmosis. Overall, 135 of the 136 patients (approx. 100%) responded. Five patients (4%) relapsed while on treatment. Efficacy was demonstrated for the oral treatment and maintenance therapy of histoplasmosis, both in immunocompromised and nonimmunocompromised patients, at the recommended dose of 200-400 mg/day for 8 months.

Onychomycosis.

In three double blind, placebo controlled studies (n = 214 total) conducted in the US, patients with onychomycosis of the toenails received 200 mg once daily for 12 consecutive weeks. Results of these studies demonstrated mycological cure in 54% of patients, defined as simultaneous occurrence of negative KOH test plus negative culture. Thirty-five (35) percent of patients were considered an overall success (mycological cure plus clear or minimal nail involvement with significantly decreased signs); 14% of patients demonstrated mycological cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one (21) percent of the overall success group has a relapse (worsening of the global score or conversion of KOH test or culture from negative to positive).

Intermittent (pulse) treatment of onychomycosis.

Onychomycosis of the toe nail.

In a double blind study (n = 129 total) there was no significant difference in clinical and mycological success and overall response between itraconazole 200 mg b.i.d. one week per month (pulse) for 3 months and continuous treatment of itraconazole 200 mg o.d. for 3 months. In an open study (n = 50 total) there was no significant difference in clinical and mycological success and overall response between a 3 pulse and 4 pulse regimen.

Onychomycosis of the fingernail.

In a double blind, placebo controlled study (n = 71 total) a treatment of itraconazole 200 mg b.i.d. one week per month was more effective than placebo. The clinical and mycological success for itraconazole pulse treatment in compliant patients was 77% and 73% respectively and for placebo was nil and 12%. In an open study 84% of patients receiving 2 pulse treatments (n = 48) and 91% receiving 3 pulse treatments (n = 68) showed a clinical success and 77% and 85% respectively showed a mycological cure at endpoint.

Aspergillosis.

In nine open label studies of patients (n = 719) with systemic aspergillosis and treated with itraconazole, an overall response rate of 63% was observed. This varied according to the clinical syndrome, e.g. pulmonary aspergilloma (60%), bronchopulmonary (78%), invasive (62%) and extrapulmonary (62%). In eight patients with cerebral aspergillosis, the response rate was 13%. In a randomised, double blind comparator trial against amphotericin B in patients with proven or highly suspected aspergillosis, 6 of 8 patients receiving itraconazole responded and 2 of 5 patients responded on amphotericin B. The numbers are too small to assert any difference between treatments. The recommended dose for systemic aspergillosis is 200 mg/day for 2-5 months, with a dose of 200 mg twice daily for invasive or disseminated disease.

Sporotrichosis.

In four open label noncomparative studies of patients (n = 124) with sporotrichosis, 115 of 124 patients (93%) treated with itraconazole demonstrated a complete or marked remission rate. The recommended dosage is 100-200 mg/day for 3 months. Treatment duration may be longer in patients with lymphatic/ lymphocutaneous and extracutaneous sporotrichosis.

Candidiasis.

In three open label studies of patients (n = 143) with systemic candidiasis and treated with itraconazole, patients with urinary and pulmonary candidiasis responded with high efficacy, although the numbers with these conditions were small. An 85% response rate was observed in patients with oral and oesophageal candidiasis who had underlying cancer and were receiving chemotherapy and/or antibiotics or who had HIV/AIDS. In non-neutropenic patients with noninvasive candidiasis the response rate was 76%. The recommended dose is 100-200 mg/day for 3 weeks to 7 months.

5.2 Pharmacokinetic Properties

Absorption.

The oral bioavailability of Sporanox Capsules is maximal and appears to be more consistent when they are taken immediately after a meal. However, there is a marked intersubject variability. The observed absolute oral bioavailability of itraconazole was 55%. If administered in the fasting state, Cmax and AUC are about 30-40% lower than after a meal. Peak plasma levels are reached 3 to 5 hours following an oral dose. Elimination from plasma is biphasic with a terminal half-life of 1.5 to 2 days. During chronic administration, steady state is reached after 10-14 days. Mean steady-state plasma concentrations of itraconazole 3-4 hours after drug intake are 0.4 microgram/mL (100 mg o.d.), 1.1 microgram/mL (200 mg o.d.) and 2.0 microgram/mL (200 mg b.i.d.).
The plasma protein binding of itraconazole is 99.8%. Concentrations of itraconazole in whole blood are 60% of those in plasma. Steady-state itraconazole levels in the skin vary according to the distribution of sebaceous glands, ranging from one-third of plasma levels in the skin of the palms to double plasma levels in the skin of the back. Itraconazole is eliminated from keratinous tissues by the shedding of cells during normal regeneration. Itraconazole is undetectable in the plasma within 7 days of stopping therapy, but levels at or above the MIC90 for dermatophytes persist in the skin for one or two weeks after discontinuation of a 4 week treatment. Itraconazole is present at high concentrations in sebum but levels in sweat are negligible.

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. Serum antifungal drug levels measured by bioassay were about 3 times those of itraconazole assayed by high performance liquid chromatograph.

Excretion.

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 a 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; hemodialysis: n = 7 and continuous ambulatory peritoneal dialysis: n = 5). In uremic/ hemodialysis 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.h/mL (uremic).
Cmax 18.2-341 (hemodialysis/ 51.7-111 nanogram.h/mL (continuous ambulatory peritoneal dialysis).
Plasma concentration versus time profiles showed wide intersubject variation in all three groups.

5.3 Preclinical Safety Data

Genotoxicity.

Itraconazole produced no mutagenic effects when assayed in appropriate bacterial, nonmammalian and mammalian test systems.

Carcinogenicity.

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.

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

Non-pareil beads (ARTG PI No. 1064), hypromellose, macrogol 20000.
The capsule shell consists of gelatin, erythrosine, indigo carmine, titanium dioxide.

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 Capsules are supplied in unit-dose blister packs (PVC/LDPE/PVDC/Al blisters or Aclar blisters) of 4, 6, 15, 28 or 60 capsules.
Not all pack sizes may be marketed.

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.


CAS number.

84625-61-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes