Active ingredients: Itraconazole
Sporanox 100 mg hard capsules
Indications Why is Sporanox used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antifungal for systemic use, triazole derivatives
THERAPEUTIC INDICATIONS
SPORANOX 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.
Contraindications When Sporanox should not be used
- Hypersensitivity to the active substance or to any of the excipients (see "Undesirable effects");
- Known or suspected pregnancy (see "Special warnings" - "Pregnancy and breastfeeding");
- moderate or severe liver failure;
in patients with evidence of ventricular dysfunction, for example patients who have or have had congestive heart failure, except where there is a need to treat potentially life-threatening or other serious infections.
SPORANOX should not be given at the same time as some medications. There are many medicines that interact with SPORANOX capsules; refer to the "Interactions" section
Precautions for use What you need to know before taking Sporanox
Always inform your doctor or pharmacist if you are taking other drugs as the simultaneous intake of some drugs could be harmful.
Liver Disorders: Tell your doctor if you suffer from liver disorders. The dosage of SPORANOX capsules may need to be adjusted. Stop taking SPORANOX capsules and consult your doctor immediately if you develop symptoms such as decreased appetite, nausea, vomiting, fatigue, abdominal pain, yellowing of the skin or eyes, pale stools or dark urine. "taking SPORANOX capsules, your doctor will recommend regular blood tests. This is in order to highlight any liver disorders early, a very rare but possible occurrence.
- Heart ailments: tell your doctor if you have heart problems. The patient should contact the doctor immediately in case of shortness of breath, unexpected weight gain, swelling in the legs or abdomen, unusual tiredness or if he begins to wake up at night as these could be symptoms of heart failure.
- Renal disordersi: tell your doctor if you have kidney problems.In fact, it may be necessary to adjust the dosage of the drug.
- Inform your doctor immediately if you experience tingling, numbness or weakness in the limbs or other problems with the nerves in the arms or legs.
- It is advisable to inform your doctor if you have had allergic reactions to other antifungals in the past. Inform your doctor immediately or seek medical assistance if you have a severe allergic reaction (characterized by significant rash, itching, hives, difficulty in breathing and / or swelling of the face) while taking SPORANOX capsules.
- Stop taking SPORANOX capsules and inform your doctor immediately in case of hypersensitivity to light.
- Stop taking SPORANOX capsules and inform your doctor immediately if you have severe skin disorders such as widespread rash with peeling skin and blisters in the mouth, eyes and genitals or a rash with small pustules or blisters.
- Use in immunocompromised patients: Tell your doctor if you have neutropenia or AIDS or have had an organ transplant. You may need to adjust the dosage of SPORANOX capsules.
- Use in elderly patientsi: SPORANOX must not be administered to elderly patients, unless otherwise prescribed.
- Neuropathy: the possible onset of a neuropathy must lead to the suspension of the treatment.
- Loss of hearing: If hearing loss symptoms occur, stop treatment with SPORANOX immediately and inform your doctor.
- Inform your doctor if you have blurry vision or double vision, ringing in your ears, lose control of urination, or if your urination frequency increases from normal.
Interactions Which drugs or foods may change the effect of Sporanox
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
In particular, some medications should not be taken at the same time and, if this happens, some adjustments, such as dose adjustments, should be considered.
Medicines that must never be taken during treatment with SPORANOX capsules are:
- some antiallergic drugs: terfenadine, astemizole and mizolastine;
- some medicines used to treat angina (oppressive chest pain) or high blood pressure such as bepridil, felodipine, nisoldipine, lercanidipine, ivabradine, ranolazine, eplerenone, aliskiren;
- cisapride a medicine used to treat some digestive disorders;
- some medicines that lower cholesterol levels: atorvastatin, simvastatin and lovastatin;
- some medicines to treat insomnia: midazolam and triazolam;
- some medicines used to treat psychotic disorders: lurasidone, pimozide, sertindole; quetiapine
- colchicine a medicine to treat gout, when used in people with kidney or liver impairment;
- some medicines for severe pain or to manage drug addiction: levacetyl methadol (levomethadyl), methadone
- halofantrine a medicine used in the treatment of malaria
- irinotecan an anti-cancer drug
- some drugs used to treat heart arrhythmias, such as disopyramide, dronedarone, quinidine, and dofetilide
- medicines called ergot alkaloids, such as dihydroergotamine or ergotamine used for migraines
- eletriptan used for migraine
- medicines called ergot alkaloids, such as ergometrine (ergonovine) or methylergometrine (methylergonovine) used to control bleeding and to maintain uterine contractions after childbirth
Wait at least 2 weeks after stopping SPORANOX capsules before taking any of these medicines.
Medicines that may decrease the action of SPORANOX capsules, such as:
- 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.
For this reason it is always necessary to inform your doctor if you are taking any of these drugs, so that appropriate measures can be taken.
Wait at least 2 weeks after stopping these medicines before taking SPORANOX capsules.
Medicines not recommended unless your doctor deems them necessary, such as:
- some medicines used in the treatment of cancer called dasatinib, nilotinib, trabectedin;
- rifabutin, a medicine to treat tuberculosis;
- carbamazepine, a medicine to treat epilepsy;
- colchicine, a medicine to treat gout;
- everolimus, a medicine given after an organ transplant;
- fentanyl, a strong medicine for the treatment of pain;
- rivaroxaban, a medicine that slows blood clotting;
- salmeterol, a medicine to improve breathing;
- tamsulosin, a medicine to treat male urinary incontinence;
- vardenafil, a medicine to treat erectile dysfunction.
Wait at least 2 weeks after stopping SPORANOX capsules before starting treatment with these medicines unless your doctor deems it necessary.
Medicines that may require a dose change (for both SPORANOX capsules and other medicines), such as:
- some antibiotics such as 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;
- methylprednisolone, budesonide, ciclesonide, fluticasone or dexamethasone (by mouth, inhalation or parenteral used for the treatment of inflammation, asthma and allergies);
- cyclosporine, tacrolimus, temsirolimus or rapamycin (also known as sirolimus), drugs routinely used after organ transplants;
- 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 anxiolytics or tranquilizers: buspirone, perospirone, ramelteon, midazolam IV, alprazolam, brotizolam;
- some strong medicines to treat pain: alfentanil, buprenorphine, oxycodone;
- some medicines to treat diabetes: repaglinide, saxagliptin;
- some medicines for the treatment of psychosis: aripiprazole, haloperidol, risperidone;
- some medicines to treat nausea and vomiting: aprepitant, domperidone;
- some medicines to control irritated urinary bladder: fesoterodine, imidafenacin, solifenacin, tolterodine;
- some medicines for the treatment of erectile dysfunction: sildenafil, tadalafil;
- praziquantel, a medicine used to treat parasites and tapeworms;
- ebastine, a medicine to treat allergies
- reboxetine, a medicine used to treat depression
- meloxicam, a medicine used to treat joint inflammation and pain;
- cinacalcet, a medicine for the treatment of parathyroid hyperactivity;
- some medicines to treat low blood sodium levels: mozavaptan, tolvaptan;
- alitretinoin (oral formulation), a medicine to treat eczema;
Tell your doctor if you are being treated with any of these medicines.
The absorption of SPORANOX capsules in the organism occurs properly in the presence of sufficient acidity in the stomach. For this reason, drugs that neutralize gastric acidity must be taken at least 1 hour before taking SPORANOX capsules or should not be taken for at least 2 hours after taking SPORANOX capsules. For the same reason, if you use medicines which inhibit the production of acid in the stomach, SPORANOX capsules should be swallowed with a drink containing cola.
If in doubt, consult your doctor.
Warnings It is important to know that:
In the treatment of minor and minor skin infections (eg pityriasis versicolor, dermatophytosis), it is advisable to consider the use of a product for local use before starting an oral treatment.
Pregnancy and breastfeeding
Inform your doctor or pharmacist before taking any medicine.
SPORANOX is contraindicated in pregnancy. Therefore, all women of childbearing potential must implement adequate contraceptive measures during treatment with SPORANOX and maintain them until the next menstrual cycle after the end of therapy.
You should consult your doctor if you have started therapy with SPORANOX without taking adequate contraceptive measures.
Breastfeeding should be avoided during treatment with SPORANOX, as small amounts of the drug can pass into breast milk.
Effects on ability to drive and use machines
When driving vehicles and operating machines, the possibility of adverse reactions in certain circumstances such as dizziness, visual disturbances, and hearing loss should be taken into consideration (see Undesirable Effects).
Important information about some of the ingredients
SPORANOX 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 Sporanox: Posology
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
As for skin infections, the lesions completely disappear only a few weeks after the end of the treatment, simultaneously with the regeneration of healthy skin. In onychomycosis it is necessary to wait for the regrowth of the nails.
Always follow the instructions of the attending physician who can adapt the treatment to individual needs from time to time.
Treatment of systemic fungal infections (infections of internal organs).
The recommended treatment schemes vary according to the infection being treated:
Overdose What to do if you have taken too much Sporanox
In case of accidental ingestion / intake of an excessive dose of SPORANOX, notify your doctor immediately or go to the nearest hospital.
Urgent measures
Take appropriate supportive measures.
If deemed appropriate, activated charcoal can be administered.
SPORANOX is not removed by hemodialysis; there is no specific antidote.
If you have any questions about the use of SPORANOX, ask your doctor or pharmacist.
Side Effects What are the side effects of Sporanox
Like all medicines, SPORANOX can cause side effects, although not everybody gets them.
Summary of the safety profile
The most commonly reported adverse reactions (ADRs) during treatment with SPORANOX 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 subsection Summary table of adverse reactions for frequencies and other observed ADRs.
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 SPORANOX capsules involving 8499 patients in the therapy 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,
* see section 4.4
Description of selected adverse reactions
The following list of itraconazole-associated ADRs that have been reported in clinical studies with SPORANOX oral solution and IV SPORANOX, 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, hypomegnesemia
Psychiatric disorders: confusional state
Nervous system disorders: peripheral neuropathy *, dizziness, somnolence, tremor
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 gammaglutamyltransferase levels, increased liver enzymes , abnormal urinalysis.
Pediatric population
The safety of SPORANOX capsules was evaluated in 165 pediatric patients aged 1-17 years who participated in 14 clinical studies (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 SPORANOX 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 post-marketing with SPORANOX (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: increased blood creatine phosphokinase levels Compliance with the instructions contained in this package leaflet reduces the risk of side effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine
Expiry and Retention
Expiry: see the expiry date indicated on the package. The expiry date refers to the product in intact and correctly stored packaging.
Warning: do not use the medicine after the expiry date indicated on the package.
Store below 25 ° C
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
COMPOSITION
One capsule contains:
active ingredient: itraconazole 100 mg.
Excipients: supporting sugar granules (composed of corn starch, purified water and sucrose), hypromellose, macrogol.
Capsule constituents: gelatin, titanium dioxide (E171), erythrosine (E127), indigo carmine (E132).
PHARMACEUTICAL FORM AND CONTENT
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.
01.0 NAME OF THE MEDICINAL PRODUCT
SPORANOX HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains: 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
SPORANOX 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 of the plasma, the 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 SPORANOX 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).
• SPORANOX 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.
• SPORANOX capsules must not be used during pregnancy (except in situations that are life-threatening) (see section 4.6).
Therefore, all women of childbearing potential must use adequate contraceptive measures during treatment with SPORANOX 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 no information on cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution is required when prescribing SPORANOX 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 SPORANOX 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.
SPORANOX 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, SPORANOX 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 SPORANOX. 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 SPORANOX. 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 and liver function tests should be conducted.
Limited data are available on the 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 to keep it safe. Consider the prolonged elimination half-life observed in a clinical study with itraconazole single oral dose capsules in cirrhotic patients even when a decision is made 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 SPORANOX is strongly discouraged unless there is a serious or life-threatening situation where the benefit expected 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
The absorption of SPORANOX 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 SPORANOX capsules with an acidic drink (such as a 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 SPORANOX capsules in pediatric patients are limited. The use of SPORANOX 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 SPORANOX capsules in elderly patients are limited SPORANOX 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 keep in consideration of 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 SPORANOX capsules may be decreased.
Patients with immediate life threatening systemic mycosis
Due to its pharmacokinetic characteristics (see section 5.2) SPORANOX 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 to be at risk of relapse, the treating physician should evaluate the appropriateness of maintenance therapy." .
Neuropathy
The possible onset of a neuropathy, related to the intake of SPORANOX 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 SPORANOX capsules and SPORANOX 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 given.
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 stomach acid (eg acid neutralizing drugs such as aluminum hydroxide or acid suppressants 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-diet cola) after concomitant treatment with medicines that reduce stomach acid.
• It is recommended that acid neutralizing medicines (eg aluminum hydroxide) be administered no later than 1 hour before or 2 hours after taking SPORANOX 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 it can greatly 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 are 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.
Medicines 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 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 medicine be co-administered with itraconazole for two weeks after stopping treatment with itraconazole.
• "Not recommended": It is recommended that the use of the medicine be avoided 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 this 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.
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 lactation
Pregnancy
SPORANOX 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 (see section 5.3).
Little information is available on the use of SPORANOX 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 SPORANOX has not been defined.
Epidemiological studies on exposure to SPORANOX 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 SPORANOX and continue to use them until the next menstruation after the end of SPORANOX therapy.
Feeding time
Only a small amount of itraconazole is excreted in breast milk. When administering SPORANOX to a nursing woman, the potential risk should be weighed against the expected benefit. In case of doubt, the woman should not breastfeed.
Fertility
Refer to section 5.3 for information on animal fertility data.
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 SPORANOX 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 SPORANOX capsules involving 8499 patients in the treatment of spontaneously reported dermatomycosis and onychomycosis.
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,.
* see section 4.4
Description of selected adverse reactions
The following list of itraconazole-associated ADRs that have been reported in clinical studies with SPORANOX oral solution and IV SPORANOX, 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, hypomegnesemia.
Psychiatric disorders: confusional state.
Nervous system disorders: peripheral neuropathy *, dizziness, somnolence, tremor.
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 SPORANOX capsules was evaluated in 165 pediatric patients aged 1-17 years who participated in 14 clinical studies (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 SPORANOX 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
Adverse reactions identified post-marketing with SPORANOX (all formulations) are listed below.
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 have shown 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 Candida spp (CLSI M27-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 mg / 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. AndAbsidia 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: hyper-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 different members of the azole class although resistance to one azole does not necessarily imply that there is also resistance to 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 to 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 mg / ml, 1, 1 mg / mL and 2.0 mg / mL following 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 bioavailability of itraconazole is approximately 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal. .
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 fasted conditions when SPORANOX capsules are administered together with an acidic drink (such as a non-dietary cola). When SPORANOX capsules are administered as a single 200 mg dose 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 SPORANOX 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 activity 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 or 3 times higher than the corresponding concentrations in plasma and the absorption in keratinized tissues, particularly in the skin, is up to 4 times higher than in plasma. Concentrations in CSF 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 primarily excreted 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 the 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; and 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 orclearance 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 dependence was observed for itraconazole AUC and clearance total body, while a weak association between age and volume of distribution of itraconazole, Cmax and terminal elimination rate was observed. There clearance apparent 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. Histological changes in the single-cell phagocyte system are evident mainly through the higher presence of proteinaceous material in various 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. A dose-dependent increase in maternal toxicity, embryotoxicity, and teratogenicity was found in rats and mice at high concentrations. In rats, teratogenicity consists of skeletal muscle defects; in mice in the appearance of encephalocele and macroglossia.
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.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
One capsule contains: supporting sugar granules (composed of corn starch, purified water and sucrose), hypromellose, macrogol.
Capsule constituents: gelatin, titanium dioxide (E171), erythrosine (E127), indigo carmine (E132).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store at a temperature below 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
PVC / PE / PVDC / Al blister of 8 capsules packed in lithographed cardboard boxes containing the package leaflet.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
JANSSEN-CILAG SpA - Via M. Buonarroti, 23 - 20093 Cologno Monzese (MI).
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 027808017
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First Authorization: 19.10.1992.
Renewal of the Authorization: 03.11.2007.
10.0 DATE OF REVISION OF THE TEXT
AIFA resolution of 19 June 2014.
