Consumer medicine information

Itracap

Itraconazole

BRAND INFORMATION

Brand name

Itracap

Active ingredient

Itraconazole

Schedule

What is in this leaflet

This leaflet answers some common questions about ITRACAP Itraconazole 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 benefits and risks. Your doctor has weighed the risks of you taking ITRACAP against the benefits expected for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What ITRACAP is used for

ITRACAP 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 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.

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

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

Before you take ITRACAP

When you must not take it

Do not take ITRACAP if you have an allergy to:

any medicine containing itraconazole
any of the ingredients listed at the end of this leaflet. See Product Description at the end of this leaflet.
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 this medicine, 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 this medicine
you have a condition called heart failure (also called congestive heart failure or CHF), this medicine could make it worse. If your doctor decides that you need to take this medicine 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.

Some of the symptoms of an allergic reaction may include

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin
add any other specific reactions listed in the PI.
Tell your doctor immediately if you do become pregnant while taking ITRACAP.

Do not take this medicine if you are pregnant or may become pregnant. It may affect your developing baby if you take it during pregnancy.

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 itraconazole, 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 ITRACAP.

Do not take this medicine if you have heart failure (also called congestive heart failure or CHF). ITRACAP could make it worse. If your doctor decides that you need to take ITRACAP 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.

Do not take ITRACAP with any of the following medicines:

terfenadine, astemizole or mizolastine (used for allergy or hay fever);
bepridril felodipine, lercanidipine, ivabradine, ranolazine, eplerenone and nisoldipine (used to treat angina (crushing chest pain) and 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 traizolam);
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 to treat 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).
finerenone (used to treat kidney problems in patients with type 2 diabetes);
voclosporin (used to treat lupusrelated kidney problems).
If you have kidney or liver problems, do not take ITRACAP capsules with any of the following:
colchicine (used to treat gout);
fesoterodine or solifenacin (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 ITRACAP capsules before taking any of these medicines.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you:

you are breastfeeding or wish to breastfeed;
you have had allergic reactions to other medicines used to treat fungal infections;
any liver problems;
any kidney problems;
heart problems;
neutropenia or AIDS
organ transplant patient
cystic fibrosis

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

If you have not told your doctor or pharmacist about any of the above, tell him/her before you start taking ITRACAP capsules.

Your doctor will advise whether or not to take ITRACAP 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 any that you get without a prescription from a pharmacy, supermarket or health food shop.

In particular, ITRACAP capsules must not be taken with some medicines. Examples are:

terfenadine, astemizole or mizolastine (used for allergy or hay fever);
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 traizolam);
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 to treat severe pain and to manage opioid-dependency);
ticagrelor (used for the prevention of heart attack or stroke);
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;
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).

Certain medicines are not recommended because they may be affected by ITRACAP capsules or may affect how well ITRACAP 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);
boosted asunaprevir, bocoeprevir, daclatasvir, telaprevir, vaniprevir as HCV protease inhibitors (used to treat hepatitis C);
glecaprevir/ pibrentasvir, elbasvir/grazoprevir; ombitasvir/paritaprevir/ritonavir (with or without dasabuvir) combinations, to treat Hepatitis C
certain antineoplastics such as axitinib, bosutinib, bortezomib, brentuximab vedotin, busulphan, carbazitaxel, cabozanitinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, erlotinib, gefitinib, glasdegib, ibrutinib, idelalisib, imatinib, ixabepilone, lapatinib, nilotinib, nintedanib, Olaparib, panobinstat, pazopanib, ponatinib, regorafenib, ruxolitinib, sunitinib, sonidegib, talazoparib, trabectedin, trastuzumab emtansine, tretinoin (oral), vandetanib, vinca alkaloids (used to treat certain cancers); or docetaxel)
sunitinib, used to treat certain types of bowel, stomach, or oesophagus tumours and kidney or pancreatic cancer
gefitinib, used to treat breast, lung and other cancers
imatinib, used to treat lung cancer
conivaptan, tolvaptan or mozavaptan, used to treat low blood sodium levels
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);
varopaxar (used to treat heart attacks or strokes);
atorvastatin (used to lower cholesterol);
anticoagulant medicines such as apixaban coumarins & coumarin-like medicines (e.g. warfarin), cilostazol, dabigatran, rivaroxaban (used to slow blood clotting);
simeprevir and telaprevir as HCV protease inhibitors (used to treat hepatitis C);
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);
tolvaptan (used to treat low blood sodium levels);
conivaptan, colchicine (used to treat gout);
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 join 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, ciclesondiate, 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)
ciclosporin, 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)

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 ITRACAP capsules, when you are on a stable dose of this medicine:

venetoclax

Wait at least 2 weeks after stopping ITRACAP capsules before starting this medicine unless your doctor feels it is necessary. Taking ITRACAP capsules.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take ITRACAP

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

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 and groin
1 capsule (100 mg) daily for 2 weeks.

Tinea of hands and 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 and evening for 1 day, or 2 capsules (200 mg) daily for 3 days.

Mouth infections
1 to 2 capsules (100 mg - 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 (200 mg) twice daily for 1 week. After that, stop taking ITRACAP 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 ITRACAP.

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 ITRACAP.

Week 5: Take 2 capsules twice daily.
Week 6, 7, 8: No ITRACAP.

Week 9: Take 2 capsules twice daily.
Week 10: Stop.

Children and Elderly
ITRACAP capsules are not recommended for use in children and in the elderly.

How to take it

Always take ITRACAP after a meal.

The capsules must be swallowed whole.

Do not take medicines that neutralise stomach acid within 2 hours of taking ITRACAP capsules. This is because sufficient stomach acid is required to ensure that ITRACAP capsule is properly absorbed by the body. If you take medicine that suppress the production of stomach acid, you should take your ITRACAP 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 taking your medicine 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 you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much ITRACAP. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking ITRACAP

Things you must do

Always follow your doctor's instructions carefully.

If you have to take ITRACAP capsules continuously for more than 1 month, your doctor may ask you to have your blood checked regularly to make sure that your liver is not affected.

If you become pregnant while taking this medicine, tell your doctor immediately.

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 ITRACAP, you should continue using adequate contraception until you have had your next period.

If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking ITRACAP.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

Ask your doctor or pharmacist if you're not sure whether the treatment is working.

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 ITRACAP capsules to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if his or her symptoms seem similar to yours.

Do not stop taking your medicine or change the dosage without checking with your doctor.

Things to be careful of

You may feel dizzy while taking ITRACAP capsules. If you experience this or similar effects, you should avoid driving and using machines.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ITRACAP.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist if you experience any of the following:

upset stomach, stomach pain or discomfort, nausea, vomiting, diarrhoea, constipation, an unpleasant taste in your mouth.
shortness of breath, headache, dizziness, fever.
confusion
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.
High or low blood pressure
Sleepiness
Excessive sweating
inflammation of the pancreas.

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

tingling, numbness or weakness in the hands or feet.
swelling of hands ankles, feet, legs or abdomen.
Increased heart rate
Chest pain
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.

If any of the following happen, STOP taking ITRACAP and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

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 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 itraconazole 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 are other effects.

After taking ITRACAP

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store ITRACAP or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

ITRACAP capsules are a size "0el" hard gelatin white opaque capsules filled with off-white to cream coloured pellets and imprinting with 'ITR' on cap and '100' on body

They are supplied in a PVC/PE/PVDC/Al blister pack of 4, 6, 15, 28 and 60 capsules.

Not all pack sizes are available.

Ingredients

ITRACAP capsules contains 100 mg of itraconazole as the active ingredient.

It also contains the following inactive ingredients:

hypromellose
macrogol 20,000
sucrose
maize starch
gelatin
TekPrint SW-9008 Black Ink

This medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

ITRACAP capsule contains sugars and sulfites. This medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

Sponsor

Arrotex Pharmaceutical Pty Ltd
15 - 17 Chapel Street
Cremorne, VIC 3121
www.arrotex.com.au

Distributor

ITRACAP is distributed in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone 1800 274 276

Australian registration numbers:

ITRACAP itraconazole capsule blister pack 100 mg: AUST R 244472

This leaflet was prepared in September 2023.

ITRACAP® is a Viatris company trade mark

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Itracap

Active ingredient

Itraconazole

Schedule

1 Name of Medicine

Itraconazole.

2 Qualitative and Quantitative Composition

Itracap capsules contain itraconazole 100 mg.

Excipients with known effect.

Sugars and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Itracap is available as size 0el hard gelatin white opaque capsules filled with off-white to cream colored pellets and imprinting with ITR on cap and 100 on body.

4 Clinical Particulars

4.1 Therapeutic Indications

Itracap 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 non-invasive 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 Itracap 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 Special Warnings and Precautions for Use, 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 b.i.d.) 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.

See Table 2.

Special populations.

Elderly.

Clinical data on the use of itraconazole capsules in elderly patients are limited. It is advised to use Itracap 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 itraconazole 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 occurrences 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 itraconazole capsule: 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).
Itraconazole capsules are contraindicated in patients with a known hypersensitivity to the drug or its excipients.
Itraconazole 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 itraconazole 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 itraconazole 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 itraconazole capsules to patients with hypersensitivity to other azoles.

Use in patients with congestive heart failure.

In a study with itraconazole 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. Itraconazole 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.
Itraconazole 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 itraconazole, 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. Itraconazole 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 itraconazole. 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 itraconazole 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 itraconazole capsules may be decreased.

Patients with immediately life-threatening systemic fungal infections.

Due to the pharmacokinetic properties itraconazole capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.

Patients with AIDS.

In patients with AIDS having received treatment for a systemic fungal infection with itraconazole 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 itraconazole 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 candidosis, 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 itraconazole capsules and itraconazole 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.
* Itraconazole oral solution is unavailable in this brand however is available in other brands.

Use in the elderly.

Clinical data on the use of itraconazole capsules in elderly patients is limited. Use itraconazole capsules in these patients only if the potential benefits outweigh the potential risks. In general, it is recommended that the dose section 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, itraconazole 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 Section 5.3 Preclinical Safety Data, Toxicology).

Instructions to the patient.

Patients should be instructed to take itraconazole 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 tests.

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 label 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 (BRCP). 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 (itraconazole 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.
Itraconazole 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 itraconazole 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 itraconazole has not been established.
Epidemiological data on exposure to itraconazole 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 itraconazole oral solution should use contraceptive precautions. Highly effective contraception should be continued until the menstrual period following the end of itraconazole 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 itraconazole capsules therapy should therefore be weighed against the potential risk of breast-feeding. In case of doubt, the patient should not breast-feed.

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 reactions 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%). See Table 4.
Table 5 is a list of additional adverse effects associated with itraconazole that have been reported in clinical trials of itraconazole oral solution and/or itraconazole IV. The adverse effects are related to the active substance and are not specifically formulation dependent.

Postmarketing data.

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with itraconazole (all formulations) that meet threshold criteria are included in Table 6. The adverse drug reactions 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 < 1/1000); very rare (< 1/10,000), including isolated reports.
The frequencies below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

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 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 Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antimycotic for systemic use, triazole and tetrazole derivatives, ATC code: J02AC02.

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 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, non-comparative 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 non-immunocompromised 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 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 or culture from negative to positive).
Intermittent (pulse) treatment of onychomycosis.

Onychomycosis of the toenail.

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 extra-pulmonary (62%). In eight patients with cerebral aspergillosis the response rate was 13%. In a randomised, double-blind, comparator trial against amphotericin B (amphotericin) 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, non-comparative 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 non-invasive 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 itraconazole 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, C_max 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 micrograms/mL (200 mg o.d.) and 2.0 micrograms/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 hydroxy-itraconazole, 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.