TRIASPORIN - PACKAGE LEAFLET - LEAFLETS

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Triasporin - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Itraconazole

Triasporin 100 mg hard capsules

Why is Triasporin used? What is it for?

What is Triasporin and what is it for

Antifungal for systemic use, triazole derivatives

THERAPEUTIC INDICATIONS

Triasporin contains itraconazole which belongs to a group of medicines called "systemic antifungals" used for the following fungal infections (fungal infections):

Superficial mycoses:

vulvovaginal candidiasis (infection of the female genital tract)
pityriasis versicolor (skin infection caused by fungi characterized by light and dark spots)
dermatophytosis (superficial skin infection caused by fungi)
oral candidiasis (mouth infection)
fungal keratitis (an "inflammation of the cornea on the front of the eye"
Onychomycosis (nail infections) caused by fungi and / or yeasts.

Systemic mycoses (infections caused by fungi that spread throughout the body):

aspergillosis (infection caused by the Aspergillus fungus)
candidiasis (infection caused by the Candida-type fungus)
cryptococcosis (infection caused by the Cryptococcal type fungus), including cryptococcal meningitis (inflammation of the meninges)
histoplasmosis (infection caused by the fungus Histoplasma)
sporotrichosis (infection caused by the fungus of the genus Sporothricum)
paracoccidioidomycosis (infection caused by the fungus Paracoccidioides Brasiliensis)
blastomycosis (infection caused by the fungus Blastomyces Dermatitidis)
other rare systemic mycoses.

Talk to your doctor if you don't feel better or if you feel worse.

Contraindications When Triasporin should not be used

DO NOT use Triasporin

if you are allergic to itraconazole or any of the other ingredients of this medicine (listed in section 6)
if you are pregnant, suspect or are planning to become pregnant (see section "Pregnancy and breast-feeding")
have severe heart problems with evidence of ventricular dysfunction, for example if you have or have had congestive heart failure, unless your doctor assesses the need to treat potentially life-threatening or other serious infections

TRIASPORIN must not be given at the same time as certain drugs. There are many medicines that interact with TRIASPORIN; see section "Other medicines and Triasporin"

Precautions for use What you need to know before taking Triasporin

Talk to your doctor or pharmacist before taking Triasporin.

Stop taking Triasporin and consult your doctor immediately if you develop symptoms such as:

decreased appetite
nausea
He retched
fatigue
abdominal pain
yellowing of the skin or eyes
I made clear
dark urine. If your doctor deems it necessary to take Triasporin, he will advise you to have regular blood tests. This is in order to highlight any liver problems early on, which can occur very rarely.
problems with the peripheral nervous system (Neuropathy)
if you experience hearing loss symptoms

Tell your doctor right away or seek medical help if you have a severe allergic reaction (characterized by significant rash, itching, hives, difficulty breathing and / or swelling of the face) while taking Triasporin.

Do not take Triasporin and tell your doctor immediately if you have:

hypersensitivity to light
severe skin problems such as: - a widespread rash with peeling of the skin and blisters in the mouth, eyes and genitals - a rash with small pustules or blisters.

Contact your doctor immediately if you have:

shortness of breath
unexpected weight gain
swelling in the legs or abdomen
unusual tiredness
if he began to wake up at night

These could be symptoms of heart failure.

tingling
numbness
weakness in the limbs
other problems with the nerves in the arms or legs
blurred vision or double vision, in case of ringing in the ears, in case of loss of control of urination or in case of increased frequency of urination compared to normal.

Tell your doctor if you have or have had:

Liver problems: your dose of Triasporin may need to be adjusted
Heart problems
Kidney problems: Your dose of Triasporin may need to be adjusted
Central nervous system problems
Peripheral nervous system problems (Neuropathy)
Allergic reactions: tell your doctor if you have ever had allergic reactions to other antifungal medicines (medicines used to treat fungal infections)
Immunocompromise: Tell your doctor if you have neutropenia (reduced number of white blood cells) or AIDS or if you have had an organ transplant. Your dose of Triasporin may need to be adjusted.

Special warnings

In the treatment of skin infections, for example:

pityriasis versicolor (infection of the skin caused by fungi that occurs with the development of light and dark, slightly scaly patches mainly on the trunk),
dermatophytosis (infections of the skin caused by fungi) the doctor will evaluate the treatment with a product for local use before starting the intake of Triasporin in cases of minor and reduced extent.

Interactions Which drugs or foods may change the effect of Triasporin

Other medicines and Triasporin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Tell your doctor or pharmacist if you are taking other medicines as taking some medicines with Triasporin at the same time could be harmful or could affect the way Triasporin works.

Do not take the following medicines while being treated with Triasporin:

some antiallergic medicines (terfenadine, astemizole, mizolastine);
some medicines used to treat angina (oppressive chest pain) or high blood pressure (bepridil, felodipine, nisoldipine, lercanidipine, ivabradine, ranolazine, eplerenone, aliskiren);
a medicine used to treat some digestive disorders (cisapride);
medicines that lower cholesterol levels (atorvastatin, simvastatin and lovastatin);
some medicines to treat insomnia (midazolam, triazolam);
some medicines used for the treatment of psychotic disorders (severe alteration of the psychic balance of the individual) (lurasidone, pimozide, sertindole, quetiapine);
a medicine to treat gout (inflammation of the joints that causes pain and swelling), when used in people with kidney or liver problems (colchicine);
some medicines for severe pain or to manage drug addiction (levacetyl methadol (levomethadyl), methadone);
a medicine used in the treatment of malaria (halofantrine);
an anti-cancer medicine (irinotecan);
some medicines used to treat heart arrhythmias (irregular heartbeat) (disopyramide, dronedarone, quinidine, dofetilide);
medicines called ergot alkaloids used for migraine (headache) (dihydroergotamine or ergotamine);
a medicine used for migraine (headache) (eletriptan);
medicines called ergot alkaloids, used to control bleeding and to maintain uterine contractions after childbirth (ergometrine (ergonovine) or methylergometrine (methylergonovine)).

Wait at least 2 weeks after stopping treatment with Triasporin before taking any of these medicines.

Tell your doctor if you are taking the following medicines as they may decrease the action of Triasporin:

medicines used to treat epilepsy (carbamazepine, phenytoin, phenobarbital);
medicines for the treatment of tuberculosis (rifampicin, rifabutin, isoniazid);
St. John's wort (Hypericum perforatum);
medicines for the treatment of HIV / AIDS (efavirenz, nevirapine).

Always tell your doctor if you are taking any of these medicines so that appropriate steps can be taken.

Wait at least 2 weeks after stopping treatment with these medicines before taking Triasporin.

Do not take the following medicines unless your doctor thinks they are necessary:

some medicines used in the treatment of cancer (dasatinib, nilotinib, trabectedin);
a medicine to treat tuberculosis (rifabutin);
a medicine to treat epilepsy (carbamazepine);
a medicine to treat gout (inflammation of the joints that causes pain and swelling) (colchicine);
a medicine given after an organ transplant (everolimus);
a potent pain reliever (fentanyl);
a medicine that slows down blood clotting (rivaroxaban);
a medicine to improve your breathing (salmeterol);
a medicine to treat male urinary incontinence (tamsulosin);
a medicine to treat erectile dysfunction (vardenafil).

Wait at least 2 weeks after stopping Triasporin before starting treatment with these medicines unless your doctor considers it necessary.

Tell your doctor if you are being treated with any of the following medicines as they may require a dose adjustment:

some antibiotic medicines (ciprofloxacin, clarithromycin, erythromycin);
some medicines that affect the heart or blood vessels (digoxin, nadolol, some calcium channel blockers such as dihydropyridines and verapamil);
medicines that reduce blood clotting (coumarins, cilostazol, dabigatran);
medicines used for the treatment (oral, inhaled or parenteral) of inflammation, asthma and allergies (methylprednisolone, budesonide, ciclesonide, fluticasone or dexamethasone);
medicines routinely used after organ transplants (cyclosporine, tacrolimus, temsirolimus or rapamycin (also known as sirolimus));
some medicines used to treat HIV / AIDS (maraviroc and HIV protease inhibitors: ritonavir, indinavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir);
some medicines used in the treatment of cancer (bortezomib, busulfan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids);
some anxiolytic drugs or tranquilizers (buspirone, perospirone, ramelteon, IV midazolam, alprazolam, brotizolam);
some potent pain relievers (alfentanil, buprenorphine, oxycodone);
some medicines to treat diabetes (repaglinide, saxagliptin);
some medicines for the treatment of psychosis (severe alteration of the psychic balance of the individual) (aripiprazole, haloperidol, risperidone);
some medicines to treat nausea and vomiting (aprepitant, domperidone);
some medicines to control overactive bladder (urinary incontinence) (fesoterodine, imidafenacin, solifenacin, tolterodine);
some medicines to treat erectile dysfunction (sildenafil, tadalafil);
a medicine used to treat parasites and worms (tapeworms) (praziquantel);
a medicine to treat allergies (ebastine);
a medicine used to treat depression (reboxetine);
a medicine used to treat joint inflammation and pain (meloxicam);
a medicine to treat hyperactivity (increased activity) of the parathyroid gland (cinacalcet);
some medicines to treat low sodium levels in the blood (mozavaptan, tolvaptan);
a medicine for the treatment of eczema (itchy and non-contagious inflammatory skin reaction), in an oral formulation (alitretinoin);

Absorption of Triasporin into the body occurs in the presence of sufficient acidity in the stomach. For this reason, medicines that neutralize gastric acidity (antacid medicines) must be taken at least 1 hour before taking Triasporin or should not be taken for at least 2 hours after taking Triasporin. For the same reason, if you are taking Triasporin. use medicines that inhibit stomach acid production, Triasporin should be swallowed with a drink containing cola

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Triasporin is contraindicated in pregnancy. If you are a woman of childbearing potential you must use adequate contraceptive measures during treatment with Triasporin and maintain them until the next menstrual cycle after the end of therapy. Consult your doctor if you have started Triasporin without taking adequate contraceptive measures.

Feeding time

Avoid breast-feeding during treatment with Triasporin, as small amounts of the medicine can pass into breast milk.

Driving and using machines

Triasporin may in some cases cause dizziness, visual disturbances and hearing loss (see section "Possible side effects").

Triasporin contains sucrose

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Triasporin: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Take Triasporin immediately after one of your main meals to ensure optimal absorption. Keep in mind that:

The capsule must not be opened and must be swallowed whole.
The dose to be taken varies according to the infection to be treated.
In immunosuppressed patients, the oral bioavailability of the drug may be decreased. In such cases, therefore, the dose can be doubled.

Always carefully follow the instructions of your doctor who can adapt the treatment to your needs from time to time.

Treatment of superficial mycotic (fungal) infections

INDICATION DOSE DURATION Pityriasis versicolor 200 mg 1 time per day 7 days Dermatomycosis 200 mg 1 time per day 7 days The treatment of particularly keratinized areas, as in the plantar forms of tinea pedis and palmar forms of tinea manus, requires a dosage of 200 mg twice a day for 7 days. Onychomycosis 1 cycle = 200 mg 2 times a day for a week 2 cycles for nail infections of the hands, 3 cycles for those of the feet. Each cycle should be followed by 3 weeks of non-treatment Vulvovaginal candidiasis 200 mg once a day or 200 mg twice a day 3 days 1 day Oral candidiasis 100 mg 1 time per day 15 days In immunosuppressed patients, the oral bioavailability of the drug may be decreased. In such cases, therefore, the dose can be doubled. Fungal keratitis 200 mg 1 time per day 21 days

In skin infections, the lesions completely disappear only a few weeks after the end of treatment, simultaneously with the regeneration of healthy skin. In onychomycosis (nail infections) it is necessary to wait for the nails to grow back.

Treatment of systemic fungal infections (infections of the internal organs).

INDICATION DOSE AVERAGE DURATION OBSERVATIONS Aspergillosis 200 mg 1 time per day 2-5 months 200 mg b.i.d. in the case of invasive or disseminated infections Candidiasis 100-200 mg 1 time per day 3 weeks-7 months Non-meningeal cryptococcosis 200 mg 1 time per day 2 months - 1 year Cryptococcal meningitis 400 mg 1 time per day 2 months - 1 year Maintenance therapy: 200 mg / day See section 4.4 Special warnings and precautions for use Histoplasmosis from 200 mg once a day to 200 mg twice a day 8 months Sporotrichosis 100 mg 1 time per day 3 months Paracoccidioidomi-so 100 mg 1 time per day 6 months Chromomycosis 100-200 mg 1 time per day 6 months Blastomycosis from 100 mg once a day to 200 mg twice a day 6 months

Overdose What to do if you have taken too much Triasporin

If you take more Triasporin than you should

In case of accidental ingestion / intake of an overdose of Triasporin, notify your doctor immediately or go to the nearest hospital.

Treatment

In case of accidental ingestion / intake of an excessive dose of Triasporin, the doctor will take appropriate supportive measures. If your doctor sees fit, he may give you activated charcoal. Triasporin is not removed by hemodialysis (renal replacement therapy). There is no specific antidote.

Side Effects What are the side effects of Triasporin

Like all medicines, Triasporin can cause side effects, although not everybody gets them.

The most commonly reported undesirable effects during treatment with itraconazole capsules reported during clinical trials and / or resulting from spontaneous reporting are:

Headache
Abdominal pain
Nausea.

The most serious side effects are:

Severe allergic reaction
Heart failure and congestive heart failure (heart problems)
Pulmonary edema (swelling due to fluid retention in the lungs)
Pancreatitis (inflammation of the pancreas)
Severe hepatotoxicity (liver damaging effect), including some cases of acute fatal liver failure (liver problems)
Severe skin reactions.

Other undesirable effects found during clinical trials are listed below.

Common side effects (may affect up to 1 in 10 people) include:

Headache
Abdominal pain
Nausea

Uncommon side effects (may affect up to 1 in 100 people) include:

Sinusitis (inflammation of the paranasal mucous membranes)
Upper respiratory tract infection
Rhinitis (nasal congestion)
Allergy (Hypersensitivity) *
Dysgeusia (altered taste)
Paresthesia (change in sensation in the limbs or other parts of the body)
Confusion
Diarrhea
He retched
Constipation (constipation)
Dyspepsia (alteration of digestive functions in the stomach which occurs mainly as pain, burning)
Flatulence (gas in the stomach or intestines)
Abnormal liver function
Hyperbilirubinaemia (increased bilirubin in the blood which can cause yellow skin)
Urticaria (Rash)
Skin rash (Rash)
Itching
Alopecia (hair loss which in some cases may be permanent)
Menstrual disorders
Edema (swelling)

Rare side effects (may affect up to 1 in 1,000 people) include:

Leukopenia (reduction in white blood cells)
Serum sickness (reaction similar to an "allergy)
Angioneurotic edema (swelling of the face, mouth, lips and / or tongue)
Anaphylactic reaction (severe allergic reaction)
Hypertriglyceridaemia (high concentration of triglycerides in the blood)
Hypoesthesia (reduced sensitivity and response to a certain stimulus)
Tremor
Visual disturbances, including diplopia (double vision) and blurred vision
Transient or permanent hearing loss *
Tinnitus (Sound generated in the ear)
Congestive heart failure *
Dyspnea (difficulty in breathing including wheezing, exertional wheezing and wheezing)
Pancreatitis (inflammation of the pancreas)
Severe hepatotoxicity (liver damaging effect), including some cases of fatal acute liver failure *
Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS / TEN) (Severe drug-induced skin and / or mucosal reaction)
Acute generalized exanthematous pustulosis (AGEP) (Sudden rash manifesting as pustules)
Erythema multiforme (inflammation of the blood vessels causing an allergic reaction)
Exfoliative dermatitis, Severe and widespread skin irritation causing peeling of the skin)
Leukocytoclastic vasculitis (inflammation of small blood vessels)
Photosensitivity (abnormal and excessive skin reactivity to "solar or artificial irradiation)
Pollakiuria (high-frequency emission of small amounts of urine)
Erectile dysfunction
Fever
Increase in blood creatine phosphokinase (an enzyme found in the blood)

* see paragraph "Precautions for use"

Pediatric population

Based on safety data from clinical trials, the most commonly reported undesirable effects in pediatric patients are:

Headache
He retched
Abdominal pain
Diarrhea
Abnormal liver function
Hypotension (condition in which blood pressure values are lower than normal)
Nausea
Urticaria (Rash)

In general, undesirable effects reported in pediatric patients are similar to those seen in adult subjects, but the frequency is higher in pediatric patients. A few cases of cardiac arrest have also been reported.

Side effects reported during the marketing of Triasporin, the frequency of which is not known

Serum sickness (reaction similar to an "allergy)
Angioneurotic edema (swelling of the face, mouth, lips and / or tongue)
Anaphylactic reaction (severe allergic reaction)
Hypertriglyceridemia
Visual disturbances, including diplopia (double vision) and blurred vision
Transient or permanent hearing loss
Congestive heart failure
Dyspnea (difficulty in breathing which includes wheezing, dyspnea on exertion and wheezing)
Pancreatitis (inflammation of the pancreas)
Severe hepatotoxicity (liver damaging effect), including some cases of acute fatal liver failure
Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS / TEN) (Severe drug-induced skin and / or mucosal reaction)
Acute generalized exanthematous pustulosis (AGEP) (Sudden rash manifesting as pustules)
Erythema multiforme (inflammation of the blood vessels causing an allergic reaction)
Exfoliative dermatitis (severe and widespread skin irritation causing peeling of the skin)
Leukocytoclastic vasculitis (inflammation of small blood vessels)
Alopecia (hair loss which in some cases may be permanent)
Photosensitivity (abnormal and excessive skin reactivity to "solar or artificial irradiation)
Increase in blood creatine phosphokinase (an enzyme found in the blood)

Reporting of side effects

If you get any side effects, including any possible side effects not listed in this leaflet, contact your doctor or pharmacist. You can also report side effects directly via the national reporting system at http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package after the word EXP. The expiry date refers to the last day of that month. The expiry date refers to the unopened product which has been stored correctly.

Store below 25 ° C.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Triasporin contains

The active ingredient is itraconazole. One capsule contains 100 mg of itraconazole.
The other components are supporting sugar granules (composed of corn starch, purified water and sucrose), hypromellose, macrogol. Capsule constituents: gelatin, titanium dioxide (E171), erythrosine (E127), indigo carmine (E132).

What Triasporin looks like and contents of the pack

8 hard capsules.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Triasporin can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

TRIASPORIN 100 MG HARD CAPSULES

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains:

active ingredient: itraconazole 100 mg.

Excipients with known effects: sucrose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Hard capsules for oral use.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

TRIASPORIN is indicated for the following fungal infections:

Superficial mycoses: vulvovaginal candidiasis, pityriasis versicolor, dermatophytosis, oral candidiasis and fungal keratitis. Onychomycosis caused by dermatophytes and or yeasts.

Systemic mycoses: aspergillosis and candidiasis, cryptococcosis (including cryptococcal meningitis), histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other rare systemic mycoses.

04.2 Posology and method of administration

In order to ensure optimal absorption, it is essential to take the drug immediately after one of the main meals.

The capsule must not be opened and must be swallowed whole.

Treatment of superficial fungal infections

Since the elimination of the drug from the skin is slower than that from the plasma, optimal clinical and antifungal effects are achieved 2-4 weeks after the end of the treatment course.

In onychomycosis, the clinical response is evident with the regrowth of the nails, from 6 to 9 months after the end of the treatments.

Therapy of systemic fungal infections

The recommended treatment schedules vary according to the infection being treated.

04.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 .

• Co-administration of a number of CYP3A4 substrates is contraindicated with TRIASPORIN capsules.Increased plasma concentrations of these medicinal products, caused by co-administration with itraconazole, may increase or prolong both therapeutic effects and adverse events to the point that potentially serious situations could occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including some cases of torsades de pointes, a life-threatening arrhythmia (specific examples are listed in section 4.5).

• TRIASPORIN capsules should not be given to patients with evidence of ventricular dysfunction, for example patients who have or have had congestive heart failure, except when there is a need to treat potentially life-threatening or other serious infections. See section 4.4

• TRIASPORIN capsules must not be used during pregnancy (except in life-threatening situations) (see section 4.6).

Therefore, all women of childbearing potential must use adequate contraceptive measures during treatment with TRIASPORIN and must maintain them until the next menstrual cycle after the end of therapy.

04.4 Special warnings and appropriate precautions for use

Cross-hypersensitivity

There is limited information on cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution is warranted when prescribing TRIASPORIN capsules to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with itraconazole i.v. a transient asymptomatic reduction in left ventricular ejection fraction was observed; the event resolved before the next infusion. The clinical significance of this event with respect to the oral formulation is unknown.

Itraconazole has been shown to have a negative inotropic effect and TRIASPORIN has been associated with episodes of congestive heart failure..

Cases of heart failure were reported more frequently among patients who received a total daily dose of 400 mg compared to patients who received lower total daily doses; this suggests that the risk of heart failure may increase as the total daily dose of itraconazole increases.

TRIASPORIN should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the expected benefit clearly outweighs the risk. Individual benefit / risk assessment should consider factors such as severity of the condition, dose regimen (e.g. total daily dose) and individual risk factors for congestive heart failure. These risk factors include heart disease, such as ischemic and valvular disease; significant lung diseases such as chronic obstructive pulmonary disease; renal failure and other edematous disorders. These patients should be informed about the signs and symptoms of congestive heart failure, treated carefully and monitored during treatment for signs and symptoms of congestive heart failure. If these signs or symptoms appear during treatment, TRIASPORIN should be discontinued.

Calcium channel blockers may have negative inotropic effects which may add to those of itraconazole. Furthermore, itraconazole may inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised in co-administration of itraconazole and calcium channel blockers due to an increased risk of heart failure congestive (see section 4.5).

Hepatic effects

Very rare cases of severe hepatotoxicity, including some fatal cases of acute liver failure, have occurred with the use of TRIASPORIN. Most of these cases involved patients who had pre-existing liver disease, who had been treated for systemic indications, who had other significant concomitant medical conditions and / or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases occurred in the first month of treatment, including some cases seen during the first week. Monitoring of liver function should be considered in patients receiving TRIASPORIN. Patients should be instructed to promptly report signs and symptoms indicative of hepatitis such as anorexia, nausea, vomiting, asthenia, abdominal pain or dark urine, to their physician. in these patients, treatment should be discontinued immediately tto and liver function tests should be conducted.

Limited data are available on oral use of itraconazole in patients with hepatic impairment. Caution should be exercised when administering the medicinal product to this patient population. Close monitoring of patients with impaired hepatic function is recommended when taking itraconazole.

It is recommended that the prolonged elimination half-life observed in a clinical study with itraconazole single oral dose capsules in cirrhotic patients be taken into account, including when deciding to initiate therapy with other medicinal products metabolised by CYP3A4,

In patients with elevated or abnormal levels of liver enzymes or active liver disease or who have already experienced liver toxicity with other medicines, treatment with TRIASPORIN is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit outweighs the risks. Monitoring of liver function is recommended in patients with pre-existing liver function abnormalities or in those who have previously experienced hepatic toxicity with other medicinal products (see section 5.2).

Reduced gastric acidity

Absorption of TRIASPORIN capsules is reduced if gastric acidity decreases. In patients with reduced gastric acidity due to disease (eg patients with achlorhydria) or due to the concomitant administration of medicines (eg patients taking medicines to reduce gastric acidity) it is advisable to administer TRIASPORIN capsules with an acidic drink (such as cola antifungal activity should be monitored and the itraconazole dose increased, if deemed necessary (see sections 4.5 and 5.2).

Use in children

Clinical data on the use of TRIASPORIN capsules in pediatric patients are limited. The use of TRIASPORIN capsules is not recommended in pediatric patients unless the expected benefit outweighs the potential risk.

Use in elderly patients

Clinical data on the use of TRIASPORIN capsules in elderly patients are limited. TRIASPORIN capsules should not be used in these patients unless the expected benefit outweighs the potential risk. In general it is recommended that the choice of dose for an elderly patient should be take into account the greater frequency of decrease in hepatic, renal or cardiac function and the concomitant presence of pathologies or other pharmacological therapies.

Hepatic insufficiency

There are limited data on the use of orally administered itraconazole in patients with hepatic impairment. The drug should be administered with caution in this patient population (see section 5.2).

Kidney failure

Limited data are available on the use of orally administered itraconazole in patients with renal insufficiency. The oral bioavailability of itraconazole may be reduced in patients with renal insufficiency. The drug should be administered with caution in this patient population. In these patients it is therefore advisable to monitor the plasma levels of the drug and, if necessary, to adjust the dosage.

Loss of hearing

Transient or permanent hearing loss has been reported in patients treated with itraconazole. Many of these reports have reported co-administration of quinidine which is contraindicated (see sections 4.3 and 4.5).

Hearing loss usually resolves upon discontinuation of treatment but in some patients this loss may be permanent.

Immunocompromised patients

In some immunocompromised patients (eg patients with neutropenia or AIDS or patients undergoing an organ transplant), the oral bioavailability of TRIASPORIN capsules may be decreased.

Patients with immediate life threatening systemic mycosis

Due to its pharmacokinetic characteristics (see section 5.2) TRIASPORIN capsules are not recommended as initial antifungal therapy in immediately life-threatening patients.

Patients with AIDS

For AIDS patients, already treated for a "systemic infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal and non-meningeal) and who are considered at risk of relapse, the treating physician should consider the appropriateness of maintenance therapy." .

Cystic fibrosis

In patients with cystic fibrosis, variability in therapeutic itraconazole levels was observed with a steady state dose of itraconazole oral solution of 2.5 mg / kg twice daily. Steady state concentrations> 250 ng / mL were achieved in approximately 50% of subjects over 16 years of age, but none of patients under the age of 16. If a patient with cystic fibrosis did not respond to TRIASPORIN capsules, a switch to alternative therapy should be considered.

Neuropathy

The possible onset of a neuropathy, related to the intake of TRIASPORIN capsules, must lead to the suspension of the treatment.

Disorders of carbohydrate metabolism

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.

Cross resistance

In systemic candidiasis, if cross-resistance to fluconazole-sensitive candida species is suspected, these resistances do not necessarily occur with itraconazole, however their sensitivity should be tested before starting therapy with itraconazole.

Substitutability

Substitutability between TRIASPORIN capsules and TRIASPORIN oral solution is not recommended. This is because the exposure to the medicine is greater with the oral solution than with the capsules when the same dose of medicine is administered.

Potential interactions

Co-administration of itraconazole with specific medicinal products may lead to changes in the efficacy of itraconazole and / or concomitantly administered medicinal product, life threatening and / or sudden death. Medicines contraindicated, not recommended or recommended for use with caution in combination to itraconazole are listed in section 4.5.

Itraconazole should not be used within two weeks of stopping treatment with inducers of the CYP3A4 enzyme (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John's wort). The use of itraconazole with these drugs can lead to subtherapeutic plasma levels of itraconazole and thus to therapy failure.

04.5 Interactions with other medicinal products and other forms of interaction

Itraconazole is mainly metabolised via the cytochrome CYP3A4. Other substances that share the same metabolic pathway or that modify CYP3A4 activity may affect the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a potent inhibitor of CYP3A4 and a P-glycoprotein inhibitor. In case of concomitant use of medicinal products, it is recommended that the Summary of Product Characteristics be consulted for information on the metabolic route and the possible need for dose adjustments.

Medicinal products that may decrease the plasma concentration of itraconazole.

Medicines that reduce gastric acidity (eg acid neutralizing drugs such as aluminum hydroxide or acid suppressors such as H2 receptor antagonists and proton pump inhibitors) interfere with the absorption of itraconazole from the itraconazole capsules. It is recommended that these medicinal products are used with caution when co-administered with itraconazole capsules:

It is recommended to administer itraconazole with an acidic drink (such as a non-dietary cola) after concomitant treatment with medicinal products that reduce gastric acidity.

It is recommended that acid neutralizing medicines (eg aluminum hydroxide) be administered no later than 1 hour before or 2 hours after taking TRIASPORIN capsules.

Following co-administration, it is recommended that antifungal activity be monitored, and the itraconazole dose increased if deemed appropriate.

Co-administration of itraconazole with potent CYP3A4 enzyme inducers may decrease the bioavailability of itraconazole and hydroxy-itraconazole to an extent that may reduce efficacy. Examples include:

Antibacterials: isoniazid, rifabutin (see also Medicines whose plasma concentration can be increased by itraconazole), rifampicin.

Anticonvulsants: carbamazepine (see also Medicines whose plasma concentration can be increased by itraconazole), phenobarbital, phenytoin.

Antidepressants: St. John's wort (Hypericum perforatum).

Antivirals: efavirenz, nevirapine.

Therefore, administration of potent CYP3A4 inducers with itraconazole is not recommended. It is recommended to avoid the use of these medicinal products from two weeks before and during treatment with itraconazole, unless the benefits outweigh the risks of a potential reduction in the efficacy of itraconazole. After co-administration, it is recommended to monitor the treatment. antifungal activity and, if necessary, increase the dose of itraconazole.

Medicinal products that may increase the plasma concentration of itraconazole.

Potent CYP3A4 inhibitors may increase the bioavailability of itraconazole. Examples include:

Antibacterials: ciprofloxacin, clarithromycin, erythromycin.

Antivirals: ritonavir boosted darunavir, ritonavir boosted fosamprenavir, indinavir, ritonavir (see also Medicines whose plasma concentration may be increased by itraconazole).

It is recommended that these medicinal products are used with caution when co-administered with itraconazole capsules. It is recommended that patients taking itraconazole concomitantly with potent CYP3A4 inhibitors be closely monitored for signs or symptoms of increased or prolonged pharmacological effects of itraconazole and, if necessary, decrease the dose of itraconazole. When appropriate, it is recommended to measure the plasma concentration of itraconazole.

Medicinal products whose plasma concentration can be increased by itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, may inhibit the metabolism of medicinal products metabolised by CYP3A4 and may inhibit the transport of medicinal products by P-glycoprotein, which may result in increased plasma concentrations of these medicinal products and / or of their active metabolites when administered with itraconazole These elevated plasma concentrations may increase or prolong both the therapeutic and adverse effects of these medicinal products.

Medicinal products metabolised by CYP3A4 that prolong the QT interval may be contraindicated with itraconazole, as the combination may lead to ventricular tachyarrhythmia, including cases of torsades de pointes, a life-threatening arrhythmia. Upon termination of treatment, the plasma concentration of itraconazole decreases to an undetectable concentration within 7-14 days, depending on the dose and duration of treatment. In patients with liver cirrhosis or in subjects receiving CYP3A4 inhibitors, the decrease in plasma concentration may be more gradual. This is particularly important when therapy with medicinal products whose metabolism is affected by itraconazole is initiated.

Interacting medicinal products are classified as follows:

- "Contraindicated": in no case should the medicinal product be co-administered with itraconazole for two weeks after stopping treatment with itraconazole.

- "Not recommended": it is recommended to avoid the use of the medicine during and for two weeks after stopping treatment with itraconazole, unless the benefits outweigh the potentially increased risks of adverse events. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged therapeutic effects or adverse events of the interacting medicinal product is recommended and, if necessary, dose reduction or discontinuation of treatment. When appropriate, it is recommended to measure the plasma concentration.

- "Use with caution": Close monitoring is recommended when the medicinal product is co-administered with itraconazole. After co-administration, it is recommended to carefully monitor patients for signs or symptoms of increased or prolonged therapeutic effects or adverse events of the interacting medicinal product and, if necessary, to reduce its dose. When appropriate, it is recommended to measure the plasma concentration.

Examples of drugs whose plasma concentration can be increased by itraconazole, presented by drug class with advice regarding co-administration with itraconazole:

Pharmacological class Contraindicated Not recommended Use with caution Alpha blockers tamsulosin Analgesics levacetylmethadol (levomethadyl), methadone fentanyl alfentanil, iv and sublingual buprenorphine, oxycodone, sufentanil Antiarrhythmics disopyramide, dofetilide, dronedarone, quinidine digoxin Antibacterials rifabutinaa Anticoagulants and antiplatelet drugs apixaban rivaroxaban coumarins cilostazol dabigatran Anticonvulsants carbamazepinaa Antidiabetic repaglinide, saxagliptin Anthelmintics and Antiprotozoans halofantrine praziquantel Antihistamines astemizole, mizolastine, terfenadine bilastine, ebastine Anti-migraine drugs ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) eletriptan Antineoplastics irinotecan dasatinib, nilotinib, sunitinib trabectedin bortezomib, busulphan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids Antipsychotics, Anxiolytics and Hypnotics lurasidone, oral midazolam, pimozide, quetiapine sertindole, triazolam alprazolam, aripiprazole, brotizolam, buspirone, haloperidol, midazolam iv, perospirone, ramelteon, risperidone Antivirals simeprevir maraviroc, indinavirb, ritonavirb, saquinavir Beta blockers nadolol Calcium channel blockers bepridil, felodipine, lercanidipine, nisoldipine other dihydropyridines, verapamil Cardiovascular drugs, Various aliskiren ivabradine, ranolazine riociguat Diuretics eplerenone Gastrointestinal drugs cisapride aprepitant, domperidone Immunosuppressants everolimus budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus, temsirolimus Lipid-regulating drugs lovastatin, simvastatin atorvastatin Respiratory drugs salmeterol SSRIs, Tricyclics and Related Antidepressants reboxetine Urological drugs vardenafil fesoterodine. imidafenacin, sildenafil, solifenacin, tadalafil, tolterodine Others colchicine, in subjects with renal or hepatic insufficiency colchicine St. John's wort (Hypericum perforatum) alitretinoin (oral formulation), cinacalcet, mozavaptan, tolvaptan a See also Medicinal products that may decrease the plasma concentration of itraconazole b See also Medicinal products that may increase the plasma concentration of itraconazole

Medicines whose plasma concentration can be decreased by itraconazole

Co-administration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when co-administered with itraconazole and to monitor its effects or adverse events. It is recommended, if necessary, to adjust the dose of meloxicam when co-administered with itraconazole.

Pediatric population

Interaction studies have only been performed in adults.

04.6 Pregnancy and breastfeeding

Pregnancy

TRIASPORIN should not be used in pregnancy except in cases of life-threatening systemic mycosis where the expected benefit to the mother outweighs the potential risk to the fetus (see section 4.3).

In animal studies, itraconazole has shown reproductive toxicity and teratogenicity (see section 5.3).

Little information is available on the use of TRIASPORIN during pregnancy. In the post-marketing phase of pharmacovigilance, there have been cases of congenital anomalies, such as malformations of the skeletal muscles, genitourinary tract, cardiovascular system, eyes and also chromosomal and multiple malformations. However, a causal relationship between the appearance of these anomalies and the use of TRIASPORIN has not been defined.

Epidemiological studies on exposure to TRIASPORIN during the first trimester of pregnancy (most of the patients had undergone short treatment for vulvovaginal candidiasis) did not show an increased risk of malformations compared to subjects who have never exposed to known teratogenic drugs.

Patients of childbearing age

Women of childbearing potential should use contraceptive measures during treatment with TRIASPORIN and continue to use them until the next menstruation after the end of TRIASPORIN therapy.

Feeding time

Only a very small amount of itraconazole is excreted in breast milk. When administering TRIASPORIN to a nursing woman, the potential risk must be weighed against the expected benefit. In case of doubt, the woman should not breastfeed.

Fertility

For information on animal fertility data, see section 5.3.

04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed. While driving and using machines, the possibility of adverse reactions in certain circumstances such as dizziness, visual disturbances should be taken into consideration. , and hearing loss (see section 4.8).

04.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions (ADRs) during treatment with itaconazole capsules identified in clinical trials and / or from spontaneous reporting are headache, abdominal pain and nausea. The most serious ADRs are severe allergic reactions, heart failure, congestive heart failure, pulmonary edema, pancreatitis, severe hepatotoxicity (including some cases of fatal acute liver failure) and severe skin reactions. Refer to the subsection Summary table of adverse reactions for the frequencies and for the other ADRs observed. Refer to section 4.4 for additional information on other serious effects.

Summary table of adverse reactions

The adverse reactions listed in the table below are derived from open-label and double-blind clinical studies with itraconazole capsules involving 8499 patients in the treatment of dermatomycosis and onychomycosis and from spontaneous reporting.

The following table lists the adverse reactions classified by systems and organs.

Within each system organ class, ADRs were sorted by frequency, using the following convention:

Very common (≥1 / 10); Common (≥1 / 100,.

Adverse reactions Infections and infestations Uncommon Sinusitis, upper respiratory tract infection, rhinitis Disorders of the blood and lymphatic system Rare Leukopenia Disorders of the immune system Uncommon Hypersensitivity * Rare Serum sickness, angioneurotic edema, anaphylactic reaction Metabolism and nutrition disorders Rare Hypertriglyceridemia Nervous system disorders common Headache Uncommon Dysgeusia, paraesthesia, confusion Rare Tremor, hypoesthesia Eye disorders Rare Visual disturbances (including diplopia and blurred vision) Ear and labyrinth disorders Rare Transient or permanent hearing loss *, tinnitus Cardiac pathologies Rare Congestive heart failure * Respiratory, thoracic and mediastinal disorders Rare Dyspnea Gastrointestinal disorders common Abdominal pain, nausea Uncommon Diarrhea, vomiting, constipation, dyspepsia, flatulence, altered taste Rare Pancreatitis Hepatobiliary disorders Uncommon Abnormal liver function, hyperbilirubinaemia Rare Severe hepatotoxicity (including some cases of fatal acute liver failure) * Skin and subcutaneous tissue disorders Uncommon Hives, rash, itching, alopecia Rare Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity Renal and urinary disorders Rare Pollakiuria Diseases of the reproductive system and breast Uncommon Menstrual disorders Rare Erectile dysfunction General disorders and administration site conditions Uncommon Edema Rare Fever Diagnostic tests Rare Blood creatinine phosphokinase increased

* see section 4.4.

Description of selected adverse reactions

The following list lists the itraconazole-associated ADRs that have been reported in clinical studies with itraconazole oral solution and / or iv itraconazole, excluding the term "Injection site inflammation", which is specific to the injection route of administration.

Blood and lymphatic system disorders: granulocytopenia, thrombocytopenia

Immune system disorders: anaphylactoid reaction

Metabolism and nutrition disorders: hyperglycemia, hyperkalaemia, hypokalaemia, hypomagnesaemia

Psychiatric disorders: confusional state

Nervous system disorders: peripheral neuropathy *, dizziness, somnolence

Cardiac disorders: heart failure, left ventricular failure, tachycardia

Vascular disorders: hypertension, hypotension

Respiratory, thoracic and mediastinal disorders: pulmonary edema, dysphonia, cough, chest pain

Gastrointestinal disorders: gastrointestinal disorders

Hepatobiliary disorders: hepatic failure *, hepatitis, jaundice

Skin and subcutaneous tissue disorders: erythematous rash, hyperhidrosis

Musculoskeletal and connective tissue disorders: myalgia, arthralgia

Renal and urinary disorders: renal failure, urinary incontinence

General disorders and administration site conditions: generalized edema, face edema, pyrexia, pain, fatigue, chills

Investigations: increased levels of alanine aminotransferase, increased levels of aspartate aminotransferase, increased blood alkaline phosphatase levels, increased blood lactate dehydrogenase levels, increased blood urea levels, increased gamma-glutamyltransferase levels, increased blood liver enzymes, abnormal urinalysis.

Pediatric population

The safety of itraconazole capsules was evaluated in 165 pediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind placebo-controlled; 9 open-label; 1 study with an open-label phase followed by a double-blind phase). These patients received at least one dose of itaconazole capsules for the treatment of fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the most commonly reported adverse drug reactions (ADRs) in pediatric patients were headache (3.0%), vomiting (3.0%), abdominal pain (2 , 4%), diarrhea (2.4%), abnormal liver function (1.2%), hypotension (1.2%), nausea (1.2%) and urticaria (1.2%). In general, the nature of ADRs in pediatric patients is similar to that seen in adults, but the incidence is higher in pediatric patients.

A few cases of cardiac arrest have been reported

Post-marketing experience

The following are adverse reactions identified in post-marketing with itraconazole (all formulations)

Immune system disorders: serum sickness, angioneurotic edema, anaphylactic reaction

Metabolism and nutrition disorders: hypertriglyceridemia

Eye disorders: visual disturbances (including diplopia and blurred vision)

Ear and labyrinth disorders: transient or permanent hearing loss

Cardiac disorders: congestive heart failure

Respiratory, thoracic and mediastinal disorders: dyspnoea

Gastrointestinal disorders: pancreatitis

Hepatobiliary disorders: severe hepatotoxicity (including some cases of acute liver failure)

Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, clastic leukocyte vasculitis, alopecia, photosensitivity

Investigations: Blood creatine phosphokinase levels increased

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

Symptoms and signs

In general, the adverse reactions reported in overdose are consistent with those reported for the use of itraconazole (see section 4.8).

Treatment

In the event of an overdose, supportive measures should be taken. If deemed appropriate, activated charcoal can be administered. Itraconazole is not removed by hemodialysis.

There is no specific antidote.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antifungals for systemic use; triazole derivatives.

ATC code: J02AC02.

Itraconazole, a triazole derivative, has a broad spectrum of action.

Education in vitro showed that itraconazole inhibits ergosterol synthesis in the fungal cell. Since ergosterol is a vital component of the fungal cell membrane, inhibition of its synthesis results in an antifungal effect

For itraconazole, breakpoints derived from superficial fungal infections have been established and only for the Candida spp. (CLSI M & SUP2; 7-A2 methodology; no breakpoints are available for the EUCAST methodology). The breakpoints proposed for the CLSI methodology are: sensitive ≤0.125; sensitive dose-dependent 0.25-0.5 and resistant ≥ 1 mcg / ml. No interpretative breakpoints have been established for filamentous fungi.

Education in vitro show that itraconazole inhibits the growth of a broad spectrum of human pathogenic fungi, at concentrations usually ≤ 1 mcg / ml. These are:

- dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Candida spp., included C. albicans, C. tropicalis, C. parapsilosis, C. glabrata And C. krusei, Malassezia spp., Trichosporon. spp., Geotrichum spp.), Aspergillus spp., Histoplasma spp. included H. capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Coccidiodes immitis, Pseudallescheria boydii, Penicillium marneffei, and various other yeasts and fungi.

- Candida krusei, glabrata and tropicalis are among the species of Candida those less susceptible, with some isolated cases of unequivocal resistance to itraconazole in vitro.

The main pathogenic fungi that are not inhibited by itraconazole are: Zygomycetes (for instance Rhizopus spp., Rhizomucor spp., Mucor spp. And Absidia spp.), Fusarium spp., Scedosporium spp. And Scopulariopsis spp.

Resistance to azoles occurs slowly and is often the result of a series of genetic mutations. The mechanisms that have been described are: over-expression of the ERG11 gene, which codes for the enzyme 14a demethylase, point mutations of the ERG11 gene that cause a decrease in the affinity of the target enzyme and / or overexpression of the membrane transporters that carry to an increase in drug efflux.

For Candida spp. Cross-resistance has been observed between the different members of the azole class even though resistance to one azole does not necessarily imply that there is also resistance to the other members of the class.

Strains of Aspergillus fumigatus resistant to itraconazole.

05.2 "Pharmacokinetic properties

General pharmacokinetic characteristics

Peak plasma concentrations of itraconazole are achieved within 2-5 hours after oral administration. Due to its non-linear pharmacokinetics, itraconazole accumulates in plasma upon multiple dose administration. Steady-state concentrations are generally achieved in approximately 15 days, with Cmax values of 0.5 mcg / ml, 1, 1 mcg / ml and 2.0 mcg / ml after administration of a single oral dose of 100 mg once daily, 200 mg once daily, 200 mg bid respectively. The final half-life of itraconazole generally ranges from 16 to 28 hours after the single dose and increases to 34-42 hours with repeated doses. Upon discontinuation of treatment, plasma concentrations decrease to negligible values within 7-14 days, depending on the dose and duration of treatment. The mean total plasma elimination of itraconazole following intravenous administration is 278 ml / min. The elimination of itraconazole decreases at higher doses due to saturation of hepatic metabolism.

Absorption

Itraconazole is rapidly absorbed following oral administration.

Plasma peaks of unchanged medicinal product are reached 2-5 hours after taking a single oral capsule dose. The absolute oral bioavailability of itraconazole is approximately 55%. Oral bioavailability is maximal when the capsules are taken immediately after a meal business suit.

The absorption of itraconazole capsules is reduced in patients with reduced gastric acidity, such as those taking medicines to reduce gastric acid secretion (eg H2 receptor antagonists, proton pump inhibitors) or patients with achlorhydria caused by certain diseases (see sections 4.4 and 4.5) The absorption of itraconazole in these subjects is increased under fasting conditions when TRIASPORIN capsules are administered together with an acidic drink (such as a non-dietary cola). When TRIASPORIN capsules are administered as a single dose of 200 mg under fasting conditions with a non-dietary cola after pretreatment with ranitidine, an H2 antagonist, the absorption of itraconazole is comparable to that observed when TRIASPORIN capsules are administered alone (see paragraph 4.5).

The exposure to itraconazole is lower with the capsule formulation than with the oral solution at the same dose (see section 4.4).

Distribution

Most of itraconazole in plasma is bound to proteins (99.8%), especially albumin (99.6% for the hydroxy-metabolite). It also has a marked affinity for lipids. Only 0.2% of itraconazole is present in plasma in free form.Itraconazole is distributed in a large apparent body volume (> 700L), which suggests its wide distribution in the tissues. The concentrations in the lung, kidney, liver, bone, stomach, spleen and muscle are 2 -3 times higher than the corresponding concentrations in plasma and the distribution in keratinized tissues, particularly in the skin, is up to 4 times higher than in plasma.Cerebrospinal fluid concentrations are very low compared to plasma concentrations.

Metabolism

Itraconazole is extensively metabolised by the liver to a large number of metabolites. Studies in vitro showed that CYP3A4 is the major enzyme involved in the metabolism of itraconazole.

The major metabolite is hydroxy-itraconazole, which in vitro exhibits anti-fungal activity comparable to that of itraconazole; the plasma concentration of this metabolite is approximately double that of itraconazole.

Excretion

Itraconazole is excreted primarily as an inactive metabolite in the urine (35%) and faeces (54%) within one week of an oral solution dose.

Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on a radio-labeled oral dose, faecal excretion of unchanged drug ranges from 3% to 18% of the dose.

Since the redistribution of itraconazole from the keratinized tissues appears negligible, the elimination of itraconazole from these tissues is related to the regeneration of the epidermis. Contrary to plasma, the presence of the drug in the skin is also detected for 2-4 weeks after the interruption of a 4-week treatment and in the nail keratin - where itraconazole can be detected as early as one week after the start of treatment - for at least 6 months after the end of a 3-month treatment.

Special populations

Hepatic insufficiency

Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study was conducted in 6 healthy subjects and 12 with cirrhosis given a single dose of 100 mg of itraconazole in capsules. A statistically significant reduction in mean Cmax (47%) and a two-fold increase in the elimination half-life of itraconazole (37 ± 17 hours vs. 16 ± 5 hours) was observed in cirrhotic subjects compared to healthy subjects. Total exposure to itraconazole, based on AUC, was similar in patients with cirrhosis and in healthy subjects. No data are available in patients with cirrhosis for long-term treatment with itraconazole (see sections 4.2 and 4.4).

Kidney failure

Limited data are available on the use of oral itraconazole in patients with renal insufficiency. A single dose pharmacokinetic study of itraconazole 200 mg (4 capsules of 50 mg) was conducted in three groups of patients with renal insufficiency (uremia: n = 7; hemodialysis: n = 7; continuous ambulatory peritoneal dialysis: n = 5). clearance of mean creatinine of 13 mL / min × 1.73 m2, exposure, based on AUC, was slightly reduced compared to normal population parameters. This study demonstrated no significant effect of hemodialysis or continuous ambulatory peritoneal hemodialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8h). Plasma concentration versus time profiles showed large inter-subject variations in all three groups.

After a single intravenous dose, the mean terminal half-life of itraconazole in patients with mild (defined in this study as CrCl 50-79 mL / min), moderate (defined in this study as CrCl 20-49 mL / min) and severe renal insufficiency (defined in this study as CrCl normal renal function.

There are no data on long-term use of itraconazole in patients with renal impairment. Dialysis has no effect on half-life or clearance of itraconazole or hydroxy-itraconazole (see sections 4.2 and 4.4).

Pediatric population

Limited pharmacokinetic data are available on the use of itraconazole in the pediatric population. Clinical pharmacokinetic studies have been conducted in children and adolescents aged 5 months to 17 years with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsules and oral solution ranged from 1.5 to 12.5 mg / kg / day, administered once daily or twice daily. The intravenous formulation was administered as a single 2.5 mg / kg infusion or as an infusion. 2.5 mg / kg once or twice daily. For the same daily dose, dosing given twice daily versus single daily dose resulted in fluctuations in concentrations that were comparable to the single daily dose in adults. No significant age-related variability was observed for itraconazole AUC and total body clearance, while a weak association between age and volume of distribution of itraconazole, Cmax and terminal elimination rate. Apparent clearance of itraconazole and volume of distribution appear to be related to body weight.

05.3 Preclinical safety data

Itraconazole has been studied in a standard series of preclinical safety studies.

Acute toxicity studies with itraconazole in mice, rats, guinea pigs and dogs indicate a large margin of safety. Oral toxicity studies in rats and dogs have revealed numerous target organs or tissues: the adrenal cortex, the liver and the mononuclear phagocyte system, lipid metabolism disorders that manifest with xanthomas in various organs have also emerged. Histological studies of the adrenal cortex with high doses of itraconazole have shown a reversible swelling with cellular hypertrophy of the reticular and fasciculate area, which is sometimes associated with a thinning of the glomerular area. High dosages can cause reversible liver changes. Slight abnormalities were found in sinusoidal cells and vacuolation of hepatocytes (the latter sign of cellular dysfunction) but without evident hepatitis or hepatocellular necrosis. parenchymal tissues.

There are no indications of potential mutagenic effects of itraconazole.

Itraconazole is not a primary carcinogen in rats and mice. In male rats, however, there is "a" higher incidence of soft tissue sarcomas, which is attributable to the increase in non-neoplastic reactions, chronic connective tissue inflammation in relation to increased cholesterol and connective tissue cholesterol.

Itraconazole has no primary influence on fertility. In a rat model, itraconazole was shown to cross the placenta. There was a dose-dependent increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high concentrations. In rats, teratogenicity consists of skeletal muscle defects; in mice in the onset of encephalocele and macroglossia (section 4.6).

Lower total bone density was observed in young dogs after chronic administration of itraconazole.

In three toxicology studies in rats, itraconazole induced bone defects. These defects include decreased bone plate activity, thinning of the firmness of large bones, and increased bone fragility.