Consumer medicine information

Lozanoc 50mg Capsules

Itraconazole

BRAND INFORMATION

Brand name

Lozanoc

Active ingredient

Itraconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lozanoc 50mg Capsules.

What is in this Leaflet

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

If you have any concerns about taking LOZANOC Capsules, ask your doctor or pharmacist.

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

What LOZANOC® Capsules are used for

LOZANOC Capsules are used to treat certain fungal infections which include the following:

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

LOZANOC works by killing or stopping the growth of the 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 LOZANOC® Capsules

When you must not take it

Do not take LOZANOC Capsules if:

  • you have an allergy to LOZANOC Capsules or any of the ingredients (see Product Description at the end of this Leaflet).
  • you have a condition called heart failure (also called congestive heart failure or CHF), LOZANOC could make it worse.
  • you are pregnant or may 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 LOZANOC, contraception should be continued until you have had your next period. Tell your doctor immediately, if you do become pregnant.

Do not take LOZANOC Capsules 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;
  • 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, a chemotherapy agent for colon cancer;
  • certain medicines used to produce calmness or to help you sleep (midazolam oral or triazolam);
  • certain medicines used to lower your cholesterol, known as HMGCoA 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 Behcets disease);
  • telithromycin in patients with severe liver or kidney disease (an antibiotic used to treat pneumonia);
  • ergometrine or methylergometrine (used to control bleeding).

Do not take LOZANOC Capsules 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 have or have had any of the following medical conditions:

  • liver or kidney problems;
  • you have had an 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;
  • you have cystic fibrosis.

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

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or LOZANOC Capsules.

Taking other medicines

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

In particular, LOZANOC capsules must not be taken with some medicines. Wait at least 2 weeks after stopping LOZANOC capsules before taking any of these medicines. Examples are:

  • 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;
  • 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, a chemotherapy agent for colon cancer;
  • certain medicines used to produce calmness or to help you sleep (midazolam or triazolam);
  • certain medicines used to lower your cholesterol, known as HMGCoA 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 Behcets disease);
  • telithromycin in patients with severe liver or kidney disease (an antibiotic used to treat pneumonia);
  • ergometrine or methylergometrine (used to control bleeding).

Certain medicines are not recommended because they may be affected by LOZANOC Capsules or may affect how well LOZANOC Capsules work. 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);
  • ciprofloxacin, erythromycin, clarithromycin, (antibiotics);
  • trimetrexate, used to treat a certain type of pneumonia;
  • anticoagulants (used to slow blood clotting), such as apixaban, rivaroxaban, vorapaxar, coumarins and coumarin like medicines (eg warfarin) or dagibatran; phenytoin, phenobarbital or carbamazepine (used to treat fits);
  • medicines taken for diabetes, such as repaglinide and saxagliptan;
  • 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, carbazitaxel, cabozanitinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, erlotinib, gefitinib, imatinib, ibrutinib, idelalisib, ixabepilone, lapatinib, nilotinib, nintedanib, olaparib, panobinstat, pazopanib, ponatinib, regorafenib, ruxolitinib, sonidegib, sunitinib, trabectedin, trastuzumab emtansine, vandetanib, vinca alkaloids (used to treat certain cancers);
  • alprazolam, aripiprazole, brotizolam, buipirone, cariprazine, haloperidol, midazolam i.v., perospirone, quetiapine, ramelteon, risperidone, suvorexant, zoplicone, (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;
  • simeprevir, boosted asunaprevir, boceprevir, daclatasvir, elbasvir/ grazoprevir, glecaprevir/pibrentasvir, ombitasvir/paritaprevir/ritonavir (with or without dasabuvir), telaprevir, 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);
  • Saccharolmyces 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 (used to treat low blood sodium levels);
  • mozavaptan, used to treat low blood sodium.353672-8

How to Take LOZANOC® Capsules

How much to take

Adults

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

Only take as many LOZANOC 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 LOZANOC for 3 weeks. Then the cycle is repeated, once for fingernails and twice for toenail infections (with or without fingernail infections).

Children and Elderly

LOZANOC Capsules are not recommended for use in children and in the elderly.

How to take it

Always take LOZANOC exactly as your doctor has told you to.

Check with your doctor or pharmacist if you are not sure. LOZANOC Capsules can be taken before or after a meal.

How long to take it

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.

If you forget to take it

Take the dose you missed as soon as you remember, and then continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the one you missed.

If you 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 have taken 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 your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking LOZANOC® Capsules

Things you must do

Always follow your doctor's instructions carefully.

If you have to take LOZANOC 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 adequate contraception.

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

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 LOZANOC Capsules to treat any other complaint unless your doctor says so.

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

Things to be careful of

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

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

Side Effects

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

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

Tell your doctor if you experience any of the following:

  • upset stomach, stomach pain or discomfort, nausea, vomiting, diarrhoea, constipation, an unpleasant taste in your mouth.
  • shortness of breath, headache, dizziness, fever.
  • a change in menstrual pattern.
  • unusual hair loss or thinning.
  • erectile dysfunction.
  • muscle weakness or pain, painful joints.

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

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

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

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

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

After using LOZANOC® Capsules

Storage

Keep LOZANOC 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 LOZANOC Capsules in a cool dry place where the temperature is below 25°C.

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

Do not store LOZANOC Capsules, or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

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

Product Description

What it looks like

LOZANOC Capsules are blue opaque capsules with i-50 printed in black.

They are supplied in a blister pack or bottle pack.

Ingredients

LOZANOC Capsules contain 50 mg of itraconazole as the active ingredient. It also contains:

  • hypromellose phthalate
  • sodium starch glycollate (Type A)
  • silicon dioxide
  • magnesium stearate
  • gelatin
  • brilliant blue FCF
  • titanium dioxide
  • TekPrint SW-9008 Black Ink

LOZANOC Capsules do not contain lactose or gluten.

Sponsor

Mayne Pharma International Pty Ltd
1538 Main North Rd
Salisbury South, SA 5106

Australian Registration Number:

Blister pack AUST R 206361

Bottle pack AUST R 206360

This leaflet was prepared February 2020.

CMI Version Number: 5.0

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Lozanoc

Active ingredient

Itraconazole

Schedule

S4

 

1 Name of Medicine

Itraconazole.

6.7 Physicochemical Properties

Chemical structure.

Itraconazole has three chiral centres and is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs). The chemical structure of itraconazole is shown below:
Molecular formula: C35H38CI2N8O4.
(±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]- 1-piperazinyl]phenyl]-2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazol-3-one.

CAS number.

CAS No. 84625-61-6.
It is a white to slightly yellowish powder, with a pKa of 3.7. It is highly hydrophobic and lipophilic with a log partition coefficient of 5.66 in the n-octanol/aqueous buffer solution of pH = 8.1. Itraconazole is insoluble in water at pH 1-12, very slightly soluble in alcohol and freely soluble in dichloromethane.

2 Qualitative and Quantitative Composition

The active ingredient in Lozanoc is itraconazole. Lozanoc is available as capsules containing 50 mg of suprabioavailable itraconazole.
Itraconazole is a synthetic triazole antifungal agent.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Lozanoc are powder-filled capsules consisting of a blend of itraconazole spray-dried powder and excipients, encapsulated into hard gelatin capsules.
The capsules are light blue with i-50 printed in black on the cap.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Microbiology.

In vitro susceptibility tests, dilution or diffusion techniques.

Either quantitative (MIC) or breakpoint, should be used following a regulatory updated, recognised and standardised method (e.g. Clinical and Laboratory Standard Institute [CLSI formerly NCCLS]). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
For itraconazole, breakpoints have only been established for Candida spp. from superficial mycotic infections (CLSI M27-A2, using laboratory controlled Candida parapsilosis ATCC 22019, Candida krusei ATCC 6258). The proposed MIC breakpoints are as follows:

Susceptible.

A report of susceptible indicates that the pathogen is likely to be inhibited if the antifungal compound in the blood reaches the concentrations usually achievable.

Susceptibility that is dose or delivery dependent (S-DD).

This category implies possible clinical applicability in body sites where the medicine is physiologically concentrated or in situations where high dosage of medicine can be used.
Note that itraconazole MIC values for Candida species; Cryptococcus neoformans; Blastomyces dermatitidis; Coccidioides immitis; Histoplasma capsulatum; and Geotricum species were reported as ≤ 1 microgram/mL.
Itraconazole MIC values for Aspergillus flavus, Aspergillus fumigatus, Trichosporon species, Fonsecaea pedrosoi, and Trichophyton species were reported as ≤ 1 microgram/mL, although interpretive breakpoints have not been established for the filamentous fungi.

Resistant.

A report of resistant indicates that the pathogen is not likely to be inhibited if the antifungal compound in the blood reaches the concentrations usually achievable; other therapy should be 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. The most important parameter for itraconazole is the AUC/MIC ratio. This pharmacokinetic-pharmacodynamic parameter demonstrates that Lozanoc 50 mg achieves the AUC/MIC target ratio of greater than 25 for optimal efficacy in both the fed and fasted state for the organisms relevant to the indicated mycoses (see Section 4.1 Therapeutic Indications). Therefore, Lozanoc can be considered a therapeutic alternative (at half the dose) to the conventional itraconazole capsules, in the treatment of these indications.

Clinical trials.

A double blind placebo controlled clinical study was conducted, comparing the safety and efficacy of Lozanoc 2 x 50 mg capsules with conventional itraconazole 2 x 100 mg capsules administered once daily for 12 weeks in the treatment of onychomycosis of the toenail. The primary efficacy outcomes measured at the end of study visit, week 24, were (i) therapeutic cure, (ii) clinical cure and (iii) mycological cure.
For the primary endpoints, cure rates were consistent with results seen in previous studies using conventional itraconazole. Lozanoc was noninferior to conventional itraconazole capsules and superior to placebo for moderate-severe onychomycosis of the toenail at week 24 (see Table 8).
The following clinical trials were conducted with a conventional formulation of itraconazole. One capsule of Lozanoc 50 mg is therapeutically equivalent to one 100 mg capsule of conventional itraconazole capsules. The recommended dose for Lozanoc is therefore half the recommended dose for conventional itraconazole capsules.

Clinical trials.

Histoplasmosis.

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

Onychomycosis.

In three double blind, placebo controlled studies (n = 214 total), conducted in the US, patients with onychomycosis of the toenails received 200 mg once daily for 12 consecutive weeks. Results of these studies demonstrated mycological cure in 54% of patients, defined as simultaneous occurrence of negative KOH 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 toe nail: In a double blind study (n = 129 total) there was no significant difference in clinical and mycological success and overall response between itraconazole 200 mg b.i.d. one week per month (pulse) for 3 months and continuous treatment of itraconazole 200 mg o.d. for 3 months. In an open-label 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-label 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 in patients with proven or highly suspected aspergillosis, 6 of 8 patients receiving itraconazole responded and 2 of 5 patients responded on amphotericin B. The numbers are too small to assert any difference between treatments. The recommended dose for systemic aspergillosis is 200 mg/day for 2-5 months, with a dose of 200 mg twice daily for invasive or disseminated disease.

Sporotrichosis.

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

Candidiasis.

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

5.2 Pharmacokinetic Properties

The pharmacokinetics of itraconazole have been investigated in healthy subjects after single and multiple dosing.

Absorption.

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2-6 hours following an oral dose.
In a clinical trial comparing single doses of Lozanoc 50 mg capsules to conventional 100 mg itraconazole capsules, both taken with a full meal, the observed relative bioavailability (Frel) of itraconazole of the Lozanoc 50 mg formulation was 181%. In this trial, the Frel for the Lozanoc 50 mg capsule formulation when taken in the fasted versus the fed state was 124%, whereas for the conventional 100 mg capsule formulation the Frel was 156%.
In a replicate designed clinical trial comparing two single doses of Lozanoc 50 mg capsules to two single doses of conventional 100 mg itraconazole capsules, both taken with a full meal, within subject variability in total exposure was considerably lower for the Lozanoc 50 mg formulation than for the conventional 100 mg itraconazole formulation, with values of 27.8% and 51.2% for AUC0-tlast and 22.2% and 47.4% for AUC0-inf, respectively. There was no overlap in the 90% CI ranges obtained for the two formulations at each AUC measure, therefore the difference in within subject variability, in the order of 50%, was statistically significant at the 90% level.

Distribution.

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 seven 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 four week treatment. Itraconazole is present at high concentrations in sebum but levels in sweat are negligible.

Metabolism.

Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the main metabolites is hydroxyl-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.
As shown in in vitro studies, CYP3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Excretion.

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with faeces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas faecal excretion of unchanged drug varies between 3-18% of the dose. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. The mean elimination half-life of itraconazole is about 40 hours after repeated dosing.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels of up to 80 mg/kg/day. Male rats treated with 25 mg/kg/day had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolaemia, which is a response of rats, but not dogs or humans to chronic itraconazole administration.
Female rats treated with 50 mg/kg/day had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.

Toxicology.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Superficial mycoses.

Lozanoc is indicated - if external treatment is not effective or not appropriate - for the treatment of the following fungal infections: dermatomycoses (e.g. tinea corporis, tinea cruris, tinea pedis, tinea manus, onychomycosis) and pityriasis versicolor.

Systemic mycoses.

Lozanoc is indicated for the treatment of systemic mycoses, such as candidiasis, aspergillosis, and histoplasmosis.
Consideration should be given to official guidance on the appropriate use of antimycotic agents, and to the discussion of the pharmacodynamic properties (see Section 5.1 Pharmacodynamic Properties).

4.3 Contraindications

Co-administration of a number of CYP3A4 substrates is contraindicated with itraconazole capsules. Increased plasma concentration of these drugs, caused by co-administration with itraconazole, may increase or prolong both therapeutic and adverse effects 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 for specific examples).
Co-administration of the following drugs is contraindicated with itraconazole capsule: terfenadine, astemizole, bepridil, felodipine, lercanidipine, nisoldipine, mizolastine cisapride, domperidone, disopyramide, dofetilide, dronedarone, levacetylmethadol (levomethadyl), quinidine, 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 patients with moderate to severe renal impairment, or moderate to severe hepatic impairment), solifenacin (in patients with severe renal impairment or moderate to severe hepatic impairment), colchicine (in subjects with renal or hepatic impairment), telithromycin (in patients with severe renal impairment or severe hepatic impairment) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Table for specific examples).
Hypersensitivity to itraconazole or to any of the excipients listed see Section 6.1 List of Excipients.
Itraconazole 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

One capsule of Lozanoc 50 mg is therapeutically equivalent to one 100 mg capsule of conventional itraconazole capsules. The recommended dose for Lozanoc is therefore half the recommended dose for conventional itraconazole capsules.
Similarly, 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.
The following list of precautions is based on experience from the use of conventional itraconazole formulations and reports published in the medical literature. For “Impact of reduced gastric acidity”, in vitro dissolution studies have been performed for Lozanoc, as presented below.

Cross-hypersensitivity.

There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing itraconazole to patients with hypersensitivity to other azoles.

Cardiac effects.

In a healthy volunteer study with itraconazole IV, 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 and 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 (of conventional itraconazole formulation) 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. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dose and duration of treatment (e.g. total daily dose), and individual risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other oedematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment. If such signs or symptoms do occur during treatment, itraconazole should be discontinued.
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 exercised when coadministering itraconazole and calcium channel blockers (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) due to an increased risk of congestive heart failure.

Impact of reduced gastric acidity.

In vitro dissolution studies have demonstrated that the dissolution of itraconazole from Lozanoc is not affected by increased pH. Therefore patients taking drugs that reduce gastric acid or who are otherwise achlorhydric are unlikely to have a reduction in bioavailability of itraconazole from Lozanoc, in contrast to conventional formulations of itraconazole.

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.

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.

Immunocompromised patients.

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

Patients with immediately life-threatening systemic fungal infections.

Due to the pharmacokinetic properties (see Section 5.2 Pharmacokinetic Properties), itraconazole is 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 such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or nonmeningeal) 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.
*Itraconazole oral solution is unavailable in this brand however is available in other brands.

Cross-resistant strains.

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

Use in 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.
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 hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases were 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 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 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 consideration should be given to adjusting the dose.

Use in the elderly.

Clinical data on the use of itraconazole in elderly patients is limited. Itraconazole should not be used in these patients unless 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 therapy.

Paediatric use.

Clinical data on the use of itraconazole in paediatric patients is limited. Itraconazole should not be used in paediatric 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 5.1 Pharmacodynamic Properties, Toxicology).

Instructions to the patient.

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).

Effects on laboratory tests.

There is no information available about the effect of itraconazole on laboratory tests.

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, organised per drug family for easy reference. This list of examples is not comprehensive and therefore the Product Information of each drug that is co-administered with itraconazole should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Co-administration 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. Co-administration with moderate or potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole, which may result in increased or prolonged pharmacologic effects of itraconazole.
Itraconazole and its major metabolite, hydroxy-itraconazole are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BRCP). Itraconazole can inhibit the metabolism of drugs metabolised 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, co- administration 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.
‘Contraindicated’: Under no circumstances is the drug to be co-administered 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 co-administration cannot be avoided, clinical monitoring is recommended, and the dosage of itraconazole and/or the co- administered 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 co-administered with itraconazole. Upon co-administration, it is recommended that patients be monitored closely and the dosage of itraconazole and/or the co-administered drug adapted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. This applies to:
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 4. 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.
For the effect (middle column) the name of the parent drug is stated, even when the effect is related to the active moiety or the active metabolite of a prodrug.

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 of 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 for 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 for 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 next 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 breastfeeding. In case of doubt, the patient should not breastfeed.

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 5.
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. See Table 6.

Postmarketing experience.

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with conventional itraconazole formulations that meet threshold criteria are included in Table 7. 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 events.

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

4.2 Dose and Method of Administration

Lozanoc is for oral administration and can be taken with or without food.
One capsule of Lozanoc 50 mg is therapeutically equivalent to one 100 mg capsule of conventional itraconazole capsules. The recommended dose for Lozanoc is therefore half the recommended dose for conventional itraconazole capsules. Lozanoc 50 mg capsules and conventional itraconazole 100 mg capsules are not bioequivalent and therefore are not interchangeable.
A discussion of the relative pharmacokinetics of Lozanoc compared with conventional itraconazole hard capsules is presented below (see Section 5.2 Pharmacokinetic Properties).

Use in patients with hepatic impairment.

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population (see Section 4.4 Special Warnings and Precautions for Use).

Use in patients with renal impairment.

The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

Use in the elderly.

Clinical data on the use of itraconazole in elderly patients are limited. It is advised to use itraconazole 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.
The Lozanoc treatment schedules in adults for each indication are given in Tables 1, 2 and 3.

NB.

In some immunosuppressed patients, e.g. with neutropenia, AIDS or after organ transplantation, the bioavailability of itraconazole may be lowered. Doubling the dose may be indicated.
Itraconazole remains substantially longer in the skin than in the blood. Optimal healing is thus achieved 2-4 weeks after withdrawing itraconazole in cases of mycoses of the skin.
An alternative dosage regimen for dermatomycosis of nails (onychomycosis) is pulsed therapy. A pulse treatment consists of two capsules twice daily for one week. Two pulse treatments are recommended for fingernail infections, three pulse treatments for toenail infections. Pulse treatments are always separated by a 3 week drug free interval. Clinical response will become evident as the nail regrows, following discontinuation of the treatment.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse 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).

4.9 Overdose

In the event of overdosage, patients should be treated symptomatically with supportive measures. No specific antidote is available and itraconazole is not removed by dialysis. Itraconazole cannot be removed by haemodialysis. Activated charcoal may be given if considered appropriate. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lozanoc also contains the following inactive ingredients: hypromellose phthalate, sodium starch glycolate Type A, silicon dioxide, magnesium stearate, gelatin, Brilliant Blue FCF, titanium dioxide, TekPrint SW-9008 Black Ink (ARTG PI 2328).

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Lozanoc is supplied in bottles or blisters of 15, 28 or 60 as trade packs. Not all trade pack sizes or container types may be marketed.
A Lozanoc starter pack of 7 capsules in a bottle is also available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes