Consumer medicine information

Itranox Capsules

Itraconazole

BRAND INFORMATION

Brand name

Itranox

Active ingredient

Itraconazole

Schedule

SUMMARY CMI

ITRANOX Capsules

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ITRANOX?

ITRANOX contains the active ingredient itraconazole. ITRANOX is 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. For more information, see Section 1. Why am I using ITRANOX? in the full CMI.

2. What should I know before I use ITRANOX?

Do not take if you have ever had an allergic reaction to ITRANOX or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use ITRANOX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ITRANOX and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ITRANOX?

Only take as many ITRANOX capsules as you have been prescribed and ask your doctor or pharmacist if you are not sure. More instructions can be found in Section 4. How do I use ITRANOX? in the full CMI.

5. What should I know while using ITRANOX?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking ITRANOX. Complete the treatment as directed by your doctor, even if the signs of infection have gone. Call your doctor straight away if you become pregnant while taking this medicine.
Things you should not do	Do not take ITRANOX to treat any other complaint unless your doctor says so. Do not give this medicine to anyone else, even if their symptoms are similar to yours.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how ITRANOX affects you. ITRANOX may cause dizziness in some people.
Looking after your medicine	Keep ITRANOX Capsules in a cool dry place where the temperature is below 25°C.

For more information, see Section 5. What should I know while using ITRANOX? in the full CMI.

6. Are there any side effects?

Common side effects include: stomach upset/pain/discomfort, nausea, vomiting, diarrhoea, constipation, unpleasant taste in mouth, shortness of breath, headache, dizziness, fever, change in menstrual pattern, hair loss/thinning, erectile dysfunction, muscle weakness/pain, painful joints, tremors, confusion, cough, chills, high or low blood pressure. Serious side effects include: tingling/numbness/weakness in hands/feet, swelling of hands/ankles/feet/legs/abdomen, shortness of breath, weight gain, tiredness/fatigue/beginning to wake up at night, oversensitivity to sunlight, blurry/double vision, ringing in ears, loss of ability to control bladder/urinating more, loss of appetite, nausea, vomiting, dark urine, pale stools, yellowing of skin/eyes, sudden signs of allergy (rash/itching/hives on skin, swelling of the face/lips/tongue/other parts of the body, shortness of breath/trouble breathing), severe skin disorder (widespread skin rashes/peeling and blisters in mouth/eyes/genitals), any hearing loss symptoms. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

ITRANOX Capsules

Active ingredient(s): Itraconazole

Consumer Medicine Information (CMI)

This leaflet provides important information about using ITRANOX 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 ITRANOX against the benefits this medicine is expected to have for you.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ITRANOX.

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

Where to find information in this leaflet:

1. Why am I using ITRANOX?
2. What should I know before I use ITRANOX?
3. What if I am taking other medicines?
4. How do I use ITRANOX?
5. What should I know while using ITRANOX?
6. Are there any side effects?
7. Product details

1. Why am I using ITRANOX?

ITRANOX contains the active ingredient itraconazole.

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

ITRANOX is 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.

2. What should I know before I use ITRANOX?

Warnings

Do not use ITRANOX if:

you are allergic to itraconazole, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take this medicine.
you have a condition called heart failure (also called congestive heart failure or CHF), ITRANOX could make it worse.
you are pregnant or may become pregnant.

Do not take ITRANOX with any of the following medicines:

certain medicines for allergy or hay fever (e.g. terfenadine, astemizole, mizolastine);
certain medicines used to treat angina and high blood pressure (e.g. bepridil, felodipine, nisoldipine, lercanidipine, ranolazine, eplerenone) and ivabradine, a heart rate lowering agent;
anticoagulants (used to slow blood clotting), such as apixaban, rivaroxaban, dabigatran;
cisapride, a drug used to treat gastric reflux;
domperidone, an antiemetic used to treat nausea, vomiting, bloating and fullness;
levomethadyl and methadone, which are opioids;
antipsychotic medications, such as pimozide, lurasidone and sertindole;
ticagrelor, an anticoagulant;
halofantrine, a medicine used to treat malaria;
isavuconazole, an antifungal medicine;
naloxegol, a medicine used to reduce opioid constipation;
avanafil, a drug used for erectile dysfunction and dapoxetine, used for premature ejaculation;
eliglustat, used to treat Gaucher disease;
irinotecan, mobocertinib (used to treat cancer);
venetoclax (used to treat certain cancers) in patients just starting or adjusting the dose of venetoclax;
certain medicines used to produce calmness or to help you sleep (midazolam oral or triazolam);
certain medicines used to lower your cholesterol, known as HMG-CoA reductase inhibitors, (e.g. simvastatin, lomitapide, lovastatin);
dronedarone, dofetilide, quinidine or disopyramide (used to treat irregular heartbeats);
dihydroergotamine or ergotamine (used to treat migraine);
fesoterodine and solifenacin in patients with moderate to severe liver or kidney disease (these are medicines used to treat overactive bladder);
colchicine in patients with severe liver or kidney disease (medicine used to treat gout and Behcet's disease);
telithromycin in patients with severe liver or kidney disease (an antibiotic used to treat pneumonia);
ergometrine or methylergometrine (used to control bleeding);
finerenone (used to treat kidney problems in patients with type II diabetes);
voclosporin (used to treat lupus-related kidney problems).

Check with your doctor if you:

have or have had any other medical conditions, in particular:
liver or kidney problems;
allergic reaction to other medicines used to treat fungal infections;
heart problems;
neutropenia (low levels of a type of white blood cells) or AIDS or an organ transplant patient;
hearing problems;
weakness, numbness and pain from nerve damage, usually in the hands and feet;
cystic fibrosis.
take any medicines for any other condition;
you have allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

If there is a chance you may become pregnant, talk to your doctor about the need for highly effective contraception. Once you have finished ITRANOX, contraception should be continued until you have had your next period. Tell your doctor immediately, if you do become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Your doctor can discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

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

In particular, ITRANOX must not be taken with some medicines. Wait at least 2 weeks after stopping ITRANOX before taking any of these medicines. Examples are provided in section 2. “Do not take ITRANOX with any of the following medicines”.

Some medicines may be affected by ITRANOX or may interfere with ITRANOX and affect how it works. Your doctor may need to adjust the dose or adapt your treatment.

Examples of these medicines are:

alfuzosin, tamsulosin, silodosin (used to treat Benign Prostatic enlargement);
alfentanil, buprenorphine, oxycodone, sufentanil (used in surgery for pain relief and to help anaesthesia);
fentanyl, a strong medicine for pain;
digoxin (used to treat heart failure);
bedaquiline, delamanid, rifampicin, rifabutin or isoniazid (used to treat tuberculosis);
trimetrexate, used to treat a certain type of pneumonia;
anticoagulants (used to slow blood clotting), such as, edoxaban, vorapaxar, coumarins and coumarin like medicines (e.g. warfarin); phenytoin, phenobarbital or carbamazepine (used to treat fits);
medicines taken for diabetes, such as repaglinide and saxagliptin;
praziquantel, a worm medication;
artemether-lumefantrine, quinine (used to treat malaria);
bilastine, ebastine, rupatadine (used to treat allergies);
eletriptan (used to treat migraine);
certain antineoplastics such as axitinib, bosutinib, bortezomib, brentuximab vedotin, busulfan, cabazitaxel, cabozanitinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, erlotinib, entrectinib, gefitinib, glasdegib, imatinib, ibrutinib, idelalisib, ixabepilone, lapatinib, nilotinib, nintedanib, olaparib, panobinstat, pazopanib, pemigatinib, ponatinib, regorafenib, ruxolitinib, sonidegib, sunitinib, talazoparib, trabectedin, trastuzumab emtansine, tretinoin (oral), vandetanib, vinca alkaloids (used to treat certain cancers);
alprazolam, aripiprazole, brotizolam, buspirone, cariprazine, haloperidol, midazolam i.v., perospirone, quetiapine, ramelteon, risperidone, suvorexant, zopiclone, (used to treat anxiety or help you sleep);
certain medicines used to treat AIDS, such as cobicistat, darunavir (boosted), efavirenz, elvitegravir (boosted), fosamprenavir (ritonavirboosted), indinavir, maraviroc, nevirapine, saquinavir, tenofovir disoproxil fumarate, or ritonavir;
boosted asunaprevir, boceprevir, daclatasvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir, ombitasvir/paritaprevir/ritonavir (with or without dasabuvir), vaniprevir (used to treat hepatitis C);
aliskiren, bosentan, nadolol or riociguat (used to treat heart or blood pressure problems or hypertension);
sildenafil or tadalafil (used to treat erectile dysfunction or pulmonary hypertension);
certain calcium channel blockers (used to treat heart or blood pressure problems), such as diltiazem, verapamil or other dihydropyridines;
contraceptives such as, dienogest or ulipristal;
aprepitant, netupitant (used for nausea and vomiting during cancer treatment);
Saccharomyces boulardii, loperamide (used to treat diarrhoea);
budesonide, ciclesonide, cyclosporin, dexamethasone, fluticasone, methylprednisolone, sirolimus, tacrolimus, temsirolimus or everolimus (used to help prevent organ transplant rejection or to treat certain problems with the immune system);
atorvastatin (used to lower cholesterol);
meloxicam (a non-steroidal anti-inflammatory drug);
salmeterol, a respiratory drug;
reboxetine or venlafaxine (used to treat depression);
darifenacin, vardenafil, dutasteride, imidafenacin, oxybutynin, tolterodine or udenafil (used to treat urinary disorders);
cinacalcet, to treat an over active parathyroid;
alitretinoin (oral formulation), to treat eczema;
cabergoline (used to treat Parkinson's Disease);
cannabinoids (used to treat nausea and vomiting, weight loss for patients with immune system problems and muscle spasms in patients with Multiple Sclerosis);
galantamine (used to treat Alzheimer's disease);
ivacaftor, lumacaftor/ivacaftor (used to treat Cystic Fibrosis);
guanfacine (used to treat attention deficit hyperactivity disorder and high blood pressure);
conivaptan, tolvaptan, mozavaptan (used to treat low blood sodium levels);
medicines used to reduce stomach acid such as antacids, H2 antagonists (e.g. ranitidine) proton pump inhibitors (e.g. omeprazole).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ITRANOX.

4. How do I use ITRANOX?

How much to take

Adults

ITRANOX is specially designed to give higher blood levels of active ingredient than other formulations of itraconazole capsules. A 50 mg capsule of ITRANOX is therapeutically equivalent to 100 mg of other brands of itraconazole capsules but the capsules are not interchangeable.

Only take as many ITRANOX capsules as you have been prescribed and ask your doctor or pharmacist if you are not sure.

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

Tinea of body & groin:

1 capsule daily for 2 weeks.

Tinea of hands & feet:

1 capsule daily for 4 weeks.

Other skin infections:

2 capsules daily for 1 week.

Eye infections:

2 capsules daily for 3 weeks.

Vaginal infections:

2 capsules morning & evening for 1 day, or 2 capsules daily for 3 days.

Mouth infections:

1 to 2 capsules daily for 4 weeks.

Systemic infections:

1 to 2 capsules once or twice daily for 3 weeks to 8 months, depending on the condition.

Nail infections:

Continuous nail therapy: 2 capsules once daily for 3 months.

Cyclic (pulse) nail therapy: 2 capsules twice daily for 1 week. After that, stop taking ITRANOX for 3 weeks. Then the cycle is repeated, once for fingernails and twice for toenail infections (with or without fingernail infections).

Follow the instructions provided when ITRANOX was prescribed, including the number of days it should be taken.

Don't worry if you don't see an immediate improvement after your treatment.

With skin infections, the marks or spots (lesions) typically disappear a few weeks after you finish the course. Although the medicine kills the fungus, the marks don't disappear until after new skin has grown.
With nail infections, marks on the nail may take 6 to 9 months to disappear, because new nail needs to grow.

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

Children and Elderly

ITRANOX is not recommended for use in children and in the elderly.

When to take / use ITRANOX

Always take ITRANOX after a meal.

The capsules must be swallowed whole.

Do not take medicines that neutralise stomach acid within 2 hours of taking ITRANOX capsules. This is because sufficient stomach acid is required to ensure that ITRANOX capsule is properly absorbed by the body. If you take medicine that suppress the production of stomach acid, you should take your ITRANOX capsules with an acidic drink, such as a cola beverage.

How to take ITRANOX?

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

If you forget to use ITRANOX

ITRANOX should be taken regularly at the same time each day.

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 are not sure what to do, ask your doctor or pharmacist.

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

If you use too much ITRANOX

If you think that you have used too much ITRANOX, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ITRANOX?

Things you should do

Always follow your doctor's instructions carefully.

If you have to take ITRANOX 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.

Always complete the treatment as directed by your doctor, even if the signs of infection have gone.

Call your doctor straight away if you:

become pregnant while taking this medicine.

If there is any chance of you becoming pregnant, talk to your doctor about the need for adequate contraception.

Remind any doctor, dentist or pharmacist you visit that you are taking ITRANOX.

Things you should not do

Do not take ITRANOX to treat any other complaints unless your doctor tells you to.
Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ITRANOX affects you.

ITRANOX may cause dizziness in some people.

If you experience this or similar effects, you should avoid driving and using machines.

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

Looking after your medicine

Keep ITRANOX Capsules in the original pack until it is time to take them.
Keep ITRANOX Capsules in a cool dry place where the temperature is below 25°C.

Do not store ITRANOX, 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.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about 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.

Less serious side effects

Less serious side effects	What to do
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. a change in menstrual pattern unusual hair loss or thinning erectile dysfunction muscle weakness or pain, painful joints, tremors high or low blood pressure	Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
tingling, numbness or weakness in the hands or feet swelling of hands, ankles, feet, legs or abdomen shortness of breath, unexpected weight gain, unusual fatigue, or beginning to wake up at night oversensitivity to sunlight blurry or double vision, ringing in the ears loss of ability to control your bladder or urinating much more than usual	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
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) any hearing loss symptoms. In very rare cases, patients taking ITRANOX have reported temporary or permanent hearing loss	STOP taking ITRANOX and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is available with a doctor's prescription.

What ITRANOX contains

Active ingredient (main ingredient)	itraconazole
Other ingredients (inactive ingredients)	hypromellose macrogol 20,000 sucrose maize starch gelatin TekPrint SW-9008 Black Ink
Potential allergens	The capsules contain sulfites and sugars.

Do not take this medicine if you are allergic to any of these ingredients.

What ITRANOX looks like

ITRANOX 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 (AUST R 244472)

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.

Who distributes ITRANOX

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in June 2024

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Itranox

Active ingredient

Itraconazole

Schedule

1 Name of Medicine

Itraconazole.

2 Qualitative and Quantitative Composition

Itranox capsules contain itraconazole 100 mg.
Itraconazole is a synthetic triazole antifungal agent.

Excipients with known effect.

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

3 Pharmaceutical Form

Itranox 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

Itranox 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 Itranox 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.

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

Special populations.

Elderly.

Clinical data on the use of itraconazole capsules in elderly patients are limited. It is advised to use Itranox 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

Co-administration of a number of CYP3A4 substrates is contraindicated with Itranox capsules. Increased plasma concentration of these drugs, caused by co-administration with itraconazole, may increase or prolong both therapeutic and adverse effect to such an extent that a potentially serious situation may occur. Increased plasma concentrations of some of these drugs can lead to QT prolongation 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).
Co-administration of the following drugs is contraindicated with itraconazole capsule: terfenadine, astemizole, bepridil, felodipine, lercanidipine, domperidone, disopyramide, dronedarone, methadone, lurasidone, ticagrelor, halofantrine, isavuconazole, naloxegol, lomitapide, avanafil, dapoxetine, eliglustat, irinotecan, ivabradine, ranolazine, eplerenone, nisoldipine, mizolastine, cisapride, dofetilide, levacetylmethadol (levomethadyl), quinidine, pimozide, sertindole, 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 co-administering 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. Patient with impaired hepatic function should be carefully monitored when taking itraconazole and when deciding to initiate therapy with other medications metabolised by CYP3A4. Dose adjustments may be considered in these patients (see Section 5.2 Pharmacokinetic Properties, Special population).
Patients with pre-existing abnormalities of hepatic function (raised liver enzymes, an active liver disease, or patients who have experienced liver toxicity with other drugs) who require itraconazole should be monitored, regardless of the duration of therapy.
Rare cases of cholestatic jaundice and very rare cases of hepatitis have been reported. Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of 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 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 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 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 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 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, Table 3 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 (itraconazole caps 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 Table 3. The drugs listed in Table 3 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 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%).

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 angio-oedema.

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. 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.

Hyperglycemia, hyperkalemia, hypokalemia, hypomagnesemia.

Psychiatric disorders.

Confusional state.

Nervous system disorders.

Neuropathy peripheral, dizziness, somnolence.

Cardiac disorders.

Cardiac failure, left ventricular failure, tachycardia.

Vascular disorders.

Hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders.

Pulmonary oedema, dysphonia, cough.

Gastrointestinal disorders.

Gastrointestinal disorder.

Hepatobiliary disorders.

Hepatic failure, hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

Rash erythematous, hyperhidrosis.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia.

Renal and urinary disorders.

Renal impairment, urinary incontinence.

General disorders and administration site conditions.

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

Investigations.

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

Postmarketing data.

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with itraconazole (all formulations) that meet threshold criteria are included in Table 4. 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 in Table 4 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 this medicinal product is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

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 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antimycotic for systemic use, triazole and tetrazole derivatives, ATC code: J02A C02.

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, interpretive breakpoints have not been established by CLSI Candida spp. and the filamentous fungi.
EUCAST breakpoints for itraconazole have been established for Aspergillus flavus, A. fumigatus, A. nidulans and A. terreus, and are as follows: susceptible ≤ 1 mg/L, resistant > 1 mg/L. EUCAST breakpoints for itraconazole have been established for Candida albicans and C. dubliniensis, and are as follows: susceptible ≤ 0.06 mg/L, resistant > 0.06 mg/L. EUCAST breakpoints for itraconazole have been established for Candida parapsilosis and C. tropicalis and are as follows: susceptible ≤ 0.125 mg/L, resistant > 0.125 mg/L. Interpretive breakpoints have not been established by EUCAST for Candida glabrata, C. krusei, C. guilliermondii, C. lusitaniae, Cryptococcus neoformans, Aspergillus niger, and non-species related breakpoints for Candida and Aspergillus.
In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤ 1 microgram/mL. These include: Aspergillus spp, Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp., including H. capsulatum, Paracoccidioides brasiliensis, Penicillium marneffei, Sporothrix schenckii and Trichosporon spp. Itraconazole also displayed activity in vitro against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp., and various other yeasts and fungi.
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.