Package leaflet: Information for the patient

Trioxal, 100 mg, hard capsules
Itraconazolum
Please read this leaflet carefully before using the medicine, as it contains
important information for the patient.

Keep this leaflet for future reference.
If you have any questions, consult your doctor or pharmacist.
This medicine has been prescribed for a specific individual. Do not pass it on to others. The medicine may harm someone else, even if their symptoms are the same.
If the patient experiences any adverse reactions, including any not listed in this leaflet, inform the doctor or pharmacist. See section 4.

Table of contents

What Trioxal is and what it is used for
Important information before taking Trioxal
How to take Trioxal
Possible side effects
How to store Trioxal
Contents of the pack and other information

1. What Trioxal is and what it is used for

Trioxal contains as its active substance itraconazole, belonging to the group of triazole derivatives, which is
a broad-spectrum antifungal agent.
Trioxal is indicated for the treatment of:

Genital tract infections: vaginal and vulval candidiasis;
Skin, mucous membrane or eye infections: dermatomycoses, pityriasis versicolor, severe or recurrent seborrhoeic dermatitis, oral candidiasis, fungal keratitis;
Fungal nail infections caused by dermatophytes and (or) yeasts;
Systemic fungal infections (fungal infections of various organs and tissues): systemic aspergillosis and systemic candidiasis, cryptococcosis, including cryptococcal meningitis, in patients with cryptococcosis and impaired immunity, as well as in all patients with central nervous system cryptococcosis (Trioxal is indicated only when first-line treatment is ineffective), histoplasmosis, blastomycosis, sporotrichosis, paracoccidioidomycosis, and other rare systemic or tropical fungal infections.

2. Important information before using Trioxal

When not to use Trioxal:

if the patient is allergic to itraconazole or any of the other ingredients of this medicine (listed in section 6);
if the patient currently has or has previously had heart problems, such as congestive heart failure, except in the treatment of life-threatening or other serious infections; symptoms of congestive heart failure include: shortness of breath, unexpected weight gain, swelling of the limbs or abdomen, severe fatigue, or waking up at night due to breathlessness;
if the patient is pregnant (except in life-threatening cases); if the patient is of childbearing age, she should use effective contraceptive methods until the first menstrual period after discontinuation of Trioxal.

During treatment with Trioxal, the concomitant use of certain other medicines is contraindicated (see section "Trioxal and other medicines").

Warnings and precautions
Before starting Trioxal, discuss with the doctor if any of the following situations apply to the patient.

The patient has kidney disease. Dose adjustment of this medicine may be necessary.
The patient has liver disease. Dose adjustment of this medicine may be necessary. The doctor may recommend monitoring liver function in patients receiving Trioxal, as this medicine may very rarely cause severe liver damage.
The patient has heart disease.
The patient has previously experienced an allergic reaction to another antifungal medicine.
The patient has a weakened immune system, e.g. due to neutropenia, AIDS, or organ transplantation. Dose adjustment of this medicine may be necessary.
The patient is taking other medicines.

If any of the symptoms described below occur during treatment with Trioxal, the patient should inform the doctor immediately.

Symptoms suggesting hepatitis (liver inflammation): loss of appetite, nausea, vomiting, fatigue, abdominal pain, yellowing of the skin or eyes, pale stools, or dark urine – discontinue the medicine and contact the doctor immediately.
Symptoms of congestive heart failure: shortness of breath, unexplained weight gain, leg swelling, unusual fatigue, waking up at night due to breathlessness – discontinue the medicine and contact the doctor immediately.
Symptoms of a severe allergic reaction: rash, itching, hives, difficulty breathing and/or facial swelling – discontinue the medicine and contact the doctor immediately.
Photosensitivity.
Severe skin reactions, such as: widespread rash with skin peeling and blisters in the mouth, eyes, or genital area, or rash with small blisters or pustules – discontinue the medicine and contact the doctor immediately.
Symptoms of neuropathy (nerve damage), such as: tingling, sensory disturbances, reduced sensation, muscle weakness in the limbs, headache, dizziness – discontinue the medicine and contact the doctor immediately.
Symptoms of hearing loss.
Blurred or double vision, ringing in the ears, urinary incontinence, or frequent urination.

Trioxal and other medicines
Inform the doctor or pharmacist about all medicines currently used, recently used, or planned to be used.

Medicines that must not be used with Trioxal:

certain antihistamines used in allergies: terfenadine, astemizole, mizolastine;
certain medicines used in angina pectoris (coronary artery disease) or high blood pressure: bepridil, felodipine, nisoldipine, lercanidipine, ivabradine, ranolazine, eplerenone;
cisapride, a medicine used for gastrointestinal motility disorders;
certain cholesterol-lowering medicines: simvastatin, lovastatin;
certain sedatives: midazolam (oral), triazolam;
certain antipsychotics: lurasidone, pimozide, sertindole;
colchicine, a medicine used in gout, when administered to patients with impaired kidney or liver function;
certain medicines used for severe pain or addiction: levacetylmethadol (i.e. levomethadyl), methadone;
halofantrine, a medicine used in malaria treatment;
irinotecan, an anticancer medicine;
ergot alkaloids used in migraine treatment: dihydroergotamine or ergotamine;
ergot alkaloids used to control bleeding and maintain uterine contraction after childbirth: ergometrine (i.e. ergonovine) or methylergometrine (i.e. methylergonovine);
certain antiarrhythmics: disopyramide, dronedarone, quinidine, dofetilide.

If the patient is taking any of these medicines, Trioxal must not be used. If the patient is taking Trioxal, these medicines may be started no earlier than at least 2 weeks after discontinuation of Trioxal.

Medicines that should not be used with Trioxal unless the doctor considers it necessary:

certain anticancer medicines: dasatinib, nilotinib, trabectedin;
aliskiren, a medicine used in hypertension;
rifabutin, an antituberculosis medicine;
carbamazepine, an antiepileptic medicine;
colchicine, a medicine used in gout;
everolimus, a medicine used after organ transplantation;
fentanyl, a strong painkiller;
rivaroxaban, an anticoagulant;
salmeterol, a medicine used in bronchial asthma;
tamsulosin, a medicine used in treating urinary incontinence in men;
vardenafil, a medicine used in erectile dysfunction. These medicines may be started no earlier than at least 2 weeks after discontinuation of Trioxal.

Other medicines that interact with Trioxal:

certain antibiotics: ciprofloxacin, clarithromycin, erythromycin;
certain medicines acting on the heart or blood vessels: digoxin, nadolol, certain calcium channel blockers, including verapamil;
medicines affecting blood coagulation: coumarins, cilostazol, dabigatran;
methylprednisolone, budesonide, ciclesonide, fluticasone, or dexamethasone, administered orally, by injection, or by inhalation in the treatment of inflammatory conditions, asthma, and allergies;
cyclosporine, tacrolimus, temsirolimus, sirolimus (i.e. rapamycin), usually administered after organ transplantation;
certain medicines used in HIV (AIDS) treatment: maraviroc, protease inhibitors, including indinavir, ritonavir, darunavir, fosamprenavir, saquinavir;
certain anticancer medicines: bortezomib, busulfan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids;
certain medicines used for anxiety or sleep: buspirone, perospirone, ramelteon, midazolam (intravenous), alprazolam, brotizolam;
certain strong painkillers: alfentanil, buprenorphine, oxycodone;
certain medicines used in diabetes: repaglinide, saxagliptin;
certain antipsychotics: aripiprazole, haloperidol, quetiapine, risperidone;
certain medicines used for nausea and vomiting: aprepitant, domperidone;
certain medicines used in bladder inflammation: fesoterodine, imidafenacin, solifenacin, tolterodine;
certain medicines used in erectile dysfunction: sildenafil, tadalafil;
praziquantel, an antiparasitic medicine;
ebastine, an antihistamine;
reboxetine, an antidepressant;
atorvastatin, a cholesterol-lowering medicine;
meloxicam, a medicine used in joint inflammation and pain;
cinacalcet, a medicine used in hyperparathyroidism;
certain medicines used in hyponatremia: mozavaptan, tolvaptan;
alitretinoin (oral), a medicine used in eczema treatment;
eletriptan, a medicine used in migraine treatment.

If the patient is taking any of these medicines, dose adjustment of either Trioxal or the concomitant medicine may be necessary.

Medicines affecting itraconazole absorption
Medicines that reduce gastric acidity may impair the absorption of itraconazole released from Trioxal capsules. Therefore, antacids should be taken at least 1 hour before or at least 2 hours after taking Trioxal. For the same reason, if the patient is taking medicines that reduce gastric acid secretion, Trioxal should be taken with a cola-type beverage (non-diet).

If in doubt, consult the doctor or pharmacist.

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult the doctor or pharmacist before using this medicine.

Trioxal should not be used during pregnancy, except in life-threatening cases where, in the doctor's opinion, the potential benefits of treatment outweigh the possible risks to the fetus.

Women of childbearing age taking Trioxal should use effective contraceptive methods until the first menstrual period after discontinuation of Trioxal.

Itraconazole passes into human milk in very small amounts. The doctor will decide whether the expected benefits of using Trioxal during breastfeeding outweigh the risks to the infant. In case of any doubts, the patient should not breastfeed.

Driving and operating machinery
Trioxal may occasionally cause dizziness, blurred or double vision, or hearing loss. If the patient experiences any of these symptoms, he or she should not drive or operate machinery.

Trioxal contains sucrose
Each hard capsule contains 265.3 mg of sucrose in granules, which contain 80.0–91.5% sucrose. If the patient has previously been diagnosed with intolerance to certain sugars, he or she should consult the doctor before taking the medicine.

3. How to use Trioxal

This medicine should always be taken exactly as directed by the physician or pharmacist. If in doubt,
consult your doctor or pharmacist.
Trioxal is administered orally, immediately after a full meal. The capsules should be swallowed whole.
Dosage for adults

Genital infections
Indication	Dosage	Duration of treatment
Vulvovaginal candidiasis	200 mg twice daily or 200 mg once daily	1 day or 3 days
Skin, mucous membrane or eye infections
Indication	Dosage	Duration of treatment
Skin mycosis	200 mg once daily or 100 mg once daily	7 days or 15 days
Infections in areas with increased keratinization, such as tinea pedis and tinea manuum	200 mg twice daily or 100 mg once daily	7 days or 30 days
Pityriasis versicolor	200 mg once daily	7 days
Seborrheic dermatitis (severe or recurrent)	200 mg once daily	7 days#
Seborrheic dermatitis (severe or recurrent)	# one month after initial treatment, as maintenance therapy, itraconazole 200 mg daily for the first two days of subsequent months may be used; treatment duration depends on patient response
Oral candidiasis	100 mg once daily	15 days
In some immunocompromised patients (e.g. patients with neutropenia, AIDS or after organ transplantation), the physician may recommend doubling the dose.
Fungal keratitis	200 mg once daily	21 days Treatment duration depends on patient response

Onychomycosis caused by dermatophytes and (or) yeasts
Intermittent treatment
Consists of taking two capsules twice daily (200 mg twice daily) for one week. For fingernail onychomycosis, two cycles are used. For toenail onychomycosis, three cycles are used. The treatment periods (cycles) are separated by a three-week break during which the drug is not taken. The response to treatment becomes evident after completion of therapy and regrowth of the nails.
Location of nail infection	Week 1.	Week 2.	Week 3.	Week 4.	Week 5.	Week 6.	Week 7.	Week 8.	Week 9.
Toenails or toenails and fingernails	Cycle 1.	Break in itraconazole administration			Cycle 2.	Break in itraconazole administration			Cycle 3.
Fingernails only	Cycle 1.	Break in itraconazole administration			Cycle 2.

Continuous treatment
Site of nail fungus	Dosage	Duration of treatment
Only toenails or together with fingernails	200 mg once daily	3 months

Elimination of itraconazole from the skin and nails is slower than from plasma. Optimal treatment outcomes in terms of clinical symptoms and mycological test results are achieved within 2 to 4 weeks after completion of treatment for skin infections and 6 to 9 months after completion of treatment for nail infections.

Systemic fungal infections
Indication	Dosage	Mean duration of treatment¹	Notes
Aspergillosis	200 mg once daily	2 to 5 months	The physician may increase the dose to 200 mg twice daily if lesions are deep or disseminated
Candidiasis	100 mg to 200 mg once daily	3 weeks to 7 months	The physician may increase the dose to 200 mg twice daily if lesions are deep or disseminated
Cryptococcosis (without meningitis)	200 mg once daily	2 months to 1 year
Cryptococcal meningitis	200 mg twice daily	2 months to 1 year	The physician may consider continuation of maintenance therapy
Histoplasmosis	from 200 mg once daily to 200 mg twice daily	8 months
Blastomycosis	from 100 mg once daily to 200 mg twice daily	6 months
Lymphocutaneous and cutaneous sporotrichosis	100 mg once daily	3 months
Paracoccidioidomycosis	100 mg once daily	6 months	Lack of data on efficacy of Trioxal capsules in treatment of paracoccidioidomycosis in AIDS patients
Chromoblastomycosis	100 to 200 mg once daily	6 months
¹ The physician will adjust the treatment duration according to the patient's response to therapy

Use in children
Trioxal may be used in children only if the doctor decides that the expected benefits outweigh the risk.
Taking a higher than recommended dose of Trioxal
If a higher than recommended dose of the medicine has been taken, consult a doctor immediately.
Missed dose of Trioxal
Do not take a double dose to make up for a missed dose.
Stopping Trioxal treatment
Continue taking Trioxal for as long as your doctor recommends. Do not stop treatment on your own, even if the patient notices improvement.
If you have any further questions regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
In clinical trials involving 8499 patients receiving itraconazole, adverse reactions occurred in at least 1 in 100 patients, such as: headache, nausea, and abdominal pain.
During these clinical trials, the following adverse reactions occurred less frequently than in 1 in 100 patients receiving itraconazole: rhinitis, sinusitis, upper respiratory tract infections, low white blood cell count, hypersensitivity, taste disturbances, hypoaesthesia, paraesthesia (sensory disturbances, tingling, numbness, burning sensation on the skin), tinnitus, constipation, diarrhoea, indigestion, flatulence, vomiting, abnormal liver function, elevated bilirubin levels in blood, itching, rash, urticaria, polyuria, erectile dysfunction, menstrual disorders, and oedema.
Adverse reactions identified for the first time after itraconazole was introduced into the market, across all pharmaceutical forms, are listed below.
Very rare adverse reactions (may occur in less than 1 in 10,000 patients):

serum sickness-like reaction (a type of systemic allergic reaction), angioedema (swelling most commonly affecting the face or throat, possibly impairing breathing), anaphylactic reaction (allergic reaction);
hypertriglyceridaemia (high levels of fats in the blood);
visual disturbances (including double and blurred vision);
transient or permanent hearing loss;
congestive heart failure (characterized by symptoms such as shortness of breath, unexpected weight gain, swelling of limbs or abdomen, severe fatigue, or waking up at night with breathlessness);
dyspnoea;
pancreatitis;
severe hepatotoxicity (severe liver damage, including several cases of death due to acute liver failure);
severe skin reactions with desquamation (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis), acute generalised exanthematous pustulosis, leukocytoclastic vasculitis (inflammation of small skin vessels), alopecia, photosensitivity;
increased blood levels of creatine phosphokinase enzyme.

Additional adverse reactions in children and adolescents
In clinical trials conducted in children and adolescents (aged 1 to 17 years), the following adverse reactions were observed in more than 1 in 100 patients: headache, vomiting, abdominal pain, diarrhoea, liver function abnormalities, hypotension, nausea, and urticaria.
Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website:
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Trioxal

Keep the medicine out of sight and reach of children.
Store below 30°C.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the stated month.
The marking on the packaging following the abbreviation EXP indicates the expiry date, and following the abbreviation Lot/LOT indicates the batch number.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Trioxal contains

The active substance is itraconazole. Each capsule contains 100 mg of itraconazole.
The other ingredients are: saccharose granules (sucrose, corn starch, purified water), poloxamer 188, hypromellose, micronized poloxamer 188; capsule shell composition: indigo carmine (E132), quinoline yellow (E104), titanium dioxide (E171), gelatin, purified water.

What Trioxal looks like and contents of the pack
Trioxal is in the form of hard gelatin capsules (size 0), filled with yellowish-brown spherical microgranules. The cap and body are opaque, green in colour.
Aluminium/aluminium blisters, in a cardboard box.
The pack contains 4, 14, 15, 28 or 84 capsules.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Zakłady Farmaceutyczne POLPHARMA S.A.
ul. Pelplińska 19, 83-200 Starogard Gdański
tel. + 48 22 364 61 01

Manufacturer
Zakłady Farmaceutyczne POLPHARMA S.A.
ul. Pelplińska 19, 83-200 Starogard Gdański
LICONSA SA
Avda. Miralcampo, No 7, E-19200 Azuqueca de Henares (Guadalajara)
Spain