Zoloder - 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: Fluconazole

Zoloder 100 mg hard capsules
Zoloder 150 mg hard capsules
Zoloder 200 mg hard capsules

Why is Zoloder used? What is it for?

Zoloder belongs to a group of medicines called 'antifungals'. The active ingredient is fluconazole.

Zoloder is used to treat yeast infections and can be used to prevent candida infections. The most common cause of yeast infections is a yeast called Candida.

Adults

Your doctor may prescribe this medicine to treat the following fungal infections:

  • cryptococcal meningitis
  • a "fungal infection of the brain;
  • coccidioidomycosis
  • a disease of the bronchopulmonary system;
  • infections caused by Candida and found in the bloodstream, organs (e.g. heart, lungs) or urinary tract;
  • mucosal candidiasis
  • oral mucosal infection, throat infection and dental prosthetic mouth inflammation;
  • genital candidiasis
  • infection of the vagina or penis;
  • skin infections
  • for example athlete's foot, ringworm, itching in the genital area, nail infections.

Zoloder can be prescribed to you for:

  • prevent the recurrence of cryptococcal meningitis;
  • prevent the reappearance of mucosal candidiasis;
  • decrease recurrences of vaginal candidiasis;
  • prevent Candida infections (if your immune system is weak or not working properly).

Children and adolescents (0 to 17 years)

Your doctor may prescribe this medicine to treat the following fungal infections:

  • mucosal candidiasis
  • oral mucosal infection, throat infection;
  • infections caused by Candida and found in the bloodstream, organs (e.g. heart, lungs) or urinary tract;
  • cryptococcal meningitis
  • a "fungal infection of the brain.

Zoloder can be prescribed to you for:

  • prevent Candida infections (if your immune system is weak or not working properly);
  • prevent the recurrence of cryptococcal meningitis.

Contraindications When Zoloder should not be used

Do not take Zoloder if you

  • you are allergic to fluconazole, to other medicines that you used to treat fungal infections or to any of the other ingredients of this medicine (listed in section 6). Symptoms could be itching, redness of the skin or difficulty in breathing.
  • you are taking astemizole, terfenadine (antihistamine medicines used to treat allergies);
  • you are taking cisapride (used to treat stomach disorders);
  • take pimozide (used to treat mental disorders);
  • take quinidine (used to treat heart arrhythmias);
  • you are taking erythromycin (an antibiotic used to treat bacterial infections).

Precautions for use What you need to know before taking Zoloder

Talk to your doctor or pharmacist before taking Zoloder.

Tell your doctor especially if

  • have liver or kidney problems;
  • suffer from heart disease, including cardiac arrhythmia;
  • have abnormal levels of potassium, calcium or magnesium in the blood;
  • severe skin reactions (itching, redness of the skin or difficulty in breathing) appear.

Interactions Which drugs or foods can modify the effect of Zoloder

Tell your doctor immediately if you are taking astemizole, terfenadine (antihistamine used to treat allergies) or cisapride (used to treat stomach ailments) or pimozide (used to treat mental disorders) or quinidine (used to treat cardiac arrhythmias) or erythromycin (antibiotic used to treat bacterial infections), as they cannot be taken with Zoloder (see section: "" Do not take Zoloder if you ").

There are some medicines that can interact with Zoloder. Tell your doctor if you are taking any of the following medicines:

  • rifampicin or rifabutin (antibiotics to treat bacterial infections);
  • alfentanil, fentanyl (anesthetics);
  • amitriptyline, nortriptyline (antidepressants);
  • amphotericin B, voriconazole (antifungals);
  • medicines that thin the blood to prevent clots (warfarin or similar medicines);
  • benzodiazepines (midazolam, triazolam or similar medicines) used to help you sleep or for anxiety;
  • carbamazepine, phenytoin (used to treat seizures);
  • nifedipine, isradipine, amlodipine, felodipine and losartan (used to treat hypertension
  • high blood pressure);
  • cyclosporine, everolimus, sirolimus or tacrolimus (used to prevent transplant rejection);
  • cyclophosphamide, vinca alkaloids (vincristine, vinblastine or similar medicines) used for the treatment of cancer;
  • halofantrine (used to treat malaria);
  • statins (atorvastatin, simvastatin, fluvastatin and similar medicines) used to reduce high cholesterol levels;
  • methadone (used to treat pain);
  • celecoxib, flurbiprofen, naproxen, ibuprofen, lornoxicam, meloxicam, diclofenac (non-steroidal anti-inflammatory drugs - NSAIDs);
  • oral contraceptives;
  • prednisone (steroid);
  • zidovudine, also known as AZT; saquinavir (used in HIV patients);
  • medicines for diabetes such as chlorpromamide, glibenclamide, glipizide or tolbutamide;
  • theophylline (used to control asthma);
  • vitamin A (food supplement).

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

Zoloder with food and drink

You can take the medicine with or without food.

Warnings It is important to know that:

Pregnancy and breastfeeding

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.

You should not take Zoloder if you are pregnant or breastfeeding unless your doctor has prescribed it for you.

Driving and using machines

It should be borne in mind that dizziness or convulsions may occur while driving or operating machinery.

Zoloder contains lactose

This medicine contains a small amount of lactose (milk sugar). If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicinal product.

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

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

Swallow the capsule whole with a glass of water. It is best to take the capsules at the same time each day.

The recommended doses of this medicine to be taken depending on the infection are listed below:

Adults

Indications Dosage Duration of treatment Cryptococcosis - treatment of cryptococcal meningitis Loading dose: 400 mg on day 1 Generally 6 to 8 weeks. In life-threatening infections the dose can be increased up to 800 mg Subsequent dose: 200 mg to 400 mg / day Coccidioidomycosis From 200 mg to 400 mg 11 months up to 24 months or more, depending on the patients. 800 mg / day may be considered for some infections and especially meningitis - maintenance therapy to prevent relapse of cryptococcal meningitis in patients at high risk of relapse 200 mg / day Indefinitely at a daily dose of 200 mg Invasive candidiasis Loading dose: 800 mg on day 1 Typically, the recommended duration of therapy for candidemia is 2 weeks after first negative blood culture results and resolution of signs and symptoms attributable to candidemia. Subsequent dose: 400 mg / day Treatment of mucosal candidiasis - Oropharyngeal candidiasis Loading dose: 200 mg to 400 mg on day 1 7 to 21 days (until oropharyngeal candidiasis is in remission). Longer periods can be used in patients with severe immune impairment Subsequent dose: 100 mg to 200 mg / day - Esophageal candidiasis Loading dose: 200 mg to 400 mg on day 1 14 to 30 days (until esophageal candidiasis is in remission). Longer periods can be used in patients with severe immune impairment Subsequent dose: 100 mg to 200 mg / day - Candiduria From 200 mg to 400 mg / day 7 to 21 days. Longer periods can be used in patients with severe immune impairment - Chronic atrophic candidiasis 50 mg / day 14 days - Chronic mucocutaneous candidiasis From 50 mg to 100 mg / day Up to 28 days. Longer periods based on both the severity of the infection and the immunocompromised or underlying infection. Prevention of recurrence of mucosal candidiasis in HIV-infected patients who are at high risk of recurrence - Oropharyngeal candidiasis 100 mg to 200 mg / day or 200 mg 3 times a week Indefinite period for chronic immunocompromised patients. - Esophageal candidiasis 100 mg to 200 mg / day or 200 mg 3 times a week Indefinite period for chronic immunocompromised patients. Genital candidiasis - Acute vaginal candidiasis - Balanitis from Candida 150 mg Single dose - Treatment and prophylaxis of relapses of vaginal candidiasis (4 or more episodes per year) 150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by a maintenance dose of 150 mg once weekly Maintenance dose: 6 months. Dermatomycosis - tinea pedis, 150 mg once a week or 50 mg once a day From 2 to 4 weeks, the tinea pedis it may take up to 6 weeks of treatment. - tinea corporis, - tinea cruris, - infections with Candidia - tinea versicolor 300 mg to 400 mg once a week 1 to 3 weeks. 50 mg once a day 2 to 4 weeks. - tinea unguium (onychomycosis) 150 mg once a week The treatment should be continued until the infected nail is replaced (the healthy nail grows back). Regrowth of finger and toe nails normally takes 3 to 6 months and 6 to 12 months, respectively. However, the rate of growth can vary greatly according to individual and age. After successful treatment of long-term chronic infections, nails may remain impaired. Prophylaxis of Candida in patients with prolonged neutropenia From 200 mg to 400 mg Treatment should begin several days before the expected onset of neutropenia and continue for 7 days after recovery from neutropenia after the neutrophil count has risen above 1000 cells per mm3.

Use in adolescents aged 12 to 17 years

Always take the dose prescribed by your doctor (either the adult dose or the children's dose).

Use in children up to 11 years

The maximum dose in children is 400 mg per day.

The dose will be based on the child's weight in kilograms

Indication Dosage Recommendations - Candidiasis of the mucous membranes Initial dose: 6 mg / kg The starting dose can be used on the first day to reach the levels more quickly steady -state. Subsequent dose: 3 mg / kg / day - Invasive candidiasis - Cryptococcal meningitis Dose: 6 to 12 mg / kg / day Based on the severity of the disease - Maintenance therapy for the prevention of relapse of cryptococcal meningitis in children at high risk of relapse. Dose: 6 mg / kg / day Based on the severity of the disease - Prophylaxis of Candida in immunocompromised patients Dose: 3 to 12 mg / kg / day Based on the extent and duration of induced neutropenia (see posology in adults)

Use in children aged 0 to 4 weeks

Use in children aged 3 to 4 weeks:

The same dosage as described above but given once every 2 days. The maximum dose is 12 mg per kg of body weight every 48 hours.

Use in infants less than 2 weeks of age:

The same dosage as described above but given once every 3 days. The maximum dose is 12 mg per kg of body weight every 72 hours.

Your doctor may sometimes prescribe doses other than these. Always take your medicine as directed by your doctor. If you are unsure, ask your doctor or pharmacist.

Use in the elderly

The same dose as for adults should be used unless you have kidney problems.

Use in patients with kidney problems

Your doctor may adjust the dosage based on your kidney function.

Overdose What to do if you have taken too much Zoloder

If you take more Zoloder than you should

Taking too many capsules at once could cause you problems. Contact your doctor immediately or go to the nearest hospital. In the event of an accidental overdose, symptoms may include hearing, seeing, feeling and thinking things that are not real (hallucinations and paranoid behavior). Symptomatic treatment (with adequate supportive measures and possibly gastric lavage) may be appropriate.

If you forget to take Zoloder

Do not take a double dose to make up for any forgotten doses. If you forget to take a dose, take it as soon as possible. If it is time for your next dose, skip the missed dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Zoloder

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

Some people experience allergic reactions although severe allergic reactions occur rarely. If you experience any of the following symptoms tell your doctor immediately.

  • sudden wheezing, difficulty in breathing or tightness in the chest;
  • swelling of the eyelids, face or lips;
  • itching all over the body, red skin or itchy red patches;
  • skin rashes;
  • severe skin reactions, such as a rash that causes blisters (may affect the mouth and tongue).

Zoloder can affect the liver. Symptoms of liver problems include:

  • tiredness;
  • loss of appetite;
  • He retched;
  • yellowing of the skin and whites of the eyes (jaundice).

If you get any of these symptoms, stop taking Zoloder and tell your doctor immediately.

Other side effects:

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

  • headache;
  • stomach upset, diarrhea, nausea, vomiting;
  • increases in liver function values ​​in blood tests;
  • skin rashes.

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

  • reduction in red blood cells which can cause paleness, weakness or breathlessness;
  • decreased appetite;
  • insomnia, drowsiness;
  • seizures, dizziness, sensation of vertigo, tingling, pricking or numbness;
  • change in taste;
  • constipation, difficulty in digestion, flatulence, dry mouth;
  • muscular pain;
  • liver damage and yellowing of the skin and eyes (jaundice);
  • swelling, blistering (hives), itching, increased sweating;
  • fatigue, general malaise, fever.

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

  • lower than normal levels of white blood cells, which help defend against infection, and platelets, which make it possible for blood to clot;
  • change in skin discolouration (red or purple) which may be caused by a reduction in platelets, other changes in blood cells;
  • changes in the chemical composition of the blood (high levels of cholesterol, fat);
  • low levels of potassium in the blood;
  • chills;
  • altered electrocardiogram (ECG), change in heart rhythm and rate;
  • liver failure;
  • allergic reactions (sometimes severe), including rash with widespread blistering and peeling of the skin, severe skin reactions, swelling of the lips and face;
  • hair loss.

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. You can also report side effects directly via 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 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 label after EXP. The expiry date refers to the last day of that month. Do not store above 30 ° 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 Zoloder contains

  • The active ingredient is fluconazole. Each hard capsule contains fluconazole 100 mg, 150 mg or 200 mg.
  • The other ingredients are: Capsule contents: lactose monohydrate, pregelatinised starch, magnesium stearate, colloidal anhydrous silica, sodium lauryl sulfate. Capsule caps contents: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172) (only in 100 mg capsules).

What Zoloder looks like and contents of the pack

Zoloder 100 mg hard capsules are yellow. Box containing 10 capsules of 100 mg.

Zoloder 150 mg hard capsules are white. Box containing 2 capsules of 150 mg.

Zoloder 200 mg hard capsules are white. Box containing 7 capsules of 200 mg

Not all pack sizes may be marketed

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 Zoloder 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

ZOLODER HARD CAPSULES

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 100 mg fluconazole

Excipients: Each hard capsule also contains 115 mg lactose monohydrate

Each hard capsule contains 150 mg fluconazole

Excipients: Each hard capsule also contains 172.5 mg lactose monohydrate

Each hard capsule contains 200 mg fluconazole

Excipients: Each hard capsule also contains 230 mg lactose monohydrate

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Hard capsule.

The 100 mg hard gelatin capsule is yellow. The capsule size is n. 2.

The 150 mg hard gelatin capsule is white. The capsule size is n. 0.

The 200 mg hard gelatin capsule is white. The capsule size is n. 0.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

ZOLODER is indicated in the following fungal infections (see section 5.1).

ZOLODER is indicated in adults for the treatment of:

• Cryptococcal meningitis (see section 4.4).

• Coccidioidomycosis (see section 4.4).

• Invasive candidiasis.

• Mucosal candidiasis, including oropharyngeal candidiasis, esophageal candidiasis, candiduria and chronic mucocutaneous candidiasis.

• Chronic atrophic oral candidiasis (dental prosthesis stomatitis), when dental hygiene and topical treatment are insufficient.

• Vaginal candidiasis, acute or recurrent, when local therapy is not appropriate.

• Balanitis from Candida, when local therapy is not appropriate.

• Dermatomycosis, including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and skin infections from Candida, when systemic therapy is indicated.

• Tinea unguinium (onychomycosis), when other treatments are not considered appropriate.

ZOLODER is indicated in adults for the prophylaxis of:

• Recurrence of cryptococcal meningitis in patients at high risk of relapse.

• Recurrence of oropharyngeal or esophageal candidiasis in HIV infected patients at high risk of relapse.

• To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes per year).

• Prophylaxis of candidemia in patients with prolonged neutropenia (eg patients with malignant haematological diseases undergoing chemotherapy or patients receiving hematopoietic stem cell transplantation (see section 5.1)).

ZOLODER is indicated in full-term newborns, infants, infants, children and adolescents from 0 to 17 years:

ZOLODER is used in the treatment of mucosal candidiasis (or pharyngeal and esophageal), invasive candidiasis, cryptococcal meningitis and in the prophylaxis of candidiasis in immunocompromised patients.

ZOLODER can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children at high risk of relapse (see section 4.4).

Therapy can be instituted before culture or other laboratory test results are known, but when results become available, anti-infective therapy should be adjusted accordingly.

Official guidelines for the appropriate use of antifungals should be considered.


04.2 Posology and method of administration

Dosage

Dosage should be based on the nature and severity of the fungal infection. Treatment of infections requiring multiple dosing should continue until clinical parameters or other laboratory tests demonstrate that the active fungal infection has cleared. An inadequate treatment period could lead to recurrence of the active infection.

Adults

Indications Dosage Duration of treatment Cryptococcosis - treatment of cryptococcal meningitis Loading dose: 400 mg on day 1 Generally 6 to 8 weeks. In life-threatening infections the dose can be increased up to 800 mg Subsequent dose: 200 mg to 400 mg / day Coccidioidomycosis From 200 mg to 400 mg 11 months up to 24 months or more, depending on the patients. 800 mg / day may be considered for some infections and especially meningitis - maintenance therapy to prevent relapse of cryptococcal meningitis in patients at high risk of relapse 200 mg / day Indefinitely at a daily dose of 200 mg Invasive candidiasis Loading dose: 800 mg on day 1 Typically, the recommended duration of therapy for candidemia is 2 weeks after first negative blood culture results and resolution of signs and symptoms attributable to candidemia. Subsequent dose: 400 mg / day Treatment of mucosal candidiasis - Oropharyngeal candidiasis Loading dose: 200 mg to 400 mg on day 1 7 to 21 days (until oropharyngeal candidiasis is in remission). Longer periods can be used in patients with severe immune impairment Subsequent dose: 100 mg to 200 mg / day - Esophageal candidiasis Loading dose: 200 mg to 400 mg on day 1 14 to 30 days (until esophageal candidiasis is in remission). Longer periods can be used in patients with severe immune impairment Subsequent dose: 100 mg to 200 mg / day - Candiduria From 200 mg to 400 mg / day 7 to 21 days. Longer periods can be used in patients with severe immune impairment - Chronic atrophic candidiasis 50 mg / day 14 days - Chronic mucocutaneous candidiasis From 50 mg to 100 mg / day Up to 28 days. Longer periods based on both the severity of the infection and the immunocompromised or underlying infection. Prevention of recurrence of mucosal candidiasis in HIV-infected patients who are at high risk of recurrence - Oropharyngeal candidiasis 100 mg to 200 mg / day or 200 mg 3 times a week Indefinite period for chronic immunocompromised patients. - Esophageal candidiasis 100 mg to 200 mg / day or 200 mg 3 times a week Indefinite period for chronic immunocompromised patients. Genital candidiasis - Acute vaginal candidiasis - Balanitis from Candida 150 mg Single dose - Treatment and prophylaxis of relapses of vaginal candidiasis (4 or more episodes per year) 150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by a maintenance dose of 150 mg once weekly Maintenance dose: 6 months. Dermatomycosis - tinea pedis, 150 mg once a week or 50 mg once a day From 2 to 4 weeks, the tinea pedis it may take up to 6 weeks of treatment. - tinea corporis, - tinea cruris, - infections with Candidia - tinea versicolor 300 mg to 400 mg once a week 1 to 3 weeks. 50 mg once a day 2 to 4 weeks. - tinea unguium (onychomycosis) 150 mg once a week The treatment should be continued until the infected nail is replaced (the healthy nail grows back). Regrowth of finger and toe nails normally takes 3 to 6 months and 6 to 12 months, respectively. However, the rate of growth can vary greatly according to individual and age. After successful treatment of long-term chronic infections, nails may remain impaired. Prophylaxis of Candida in patients with prolonged neutropenia From 200 mg to 400 mg Treatment should begin several days before the expected onset of neutropenia and continue for 7 days after recovery from neutropenia after the neutrophil count has risen above 1000 cells per mm3.

Special populations

Senior citizens

Dosage should be adjusted based on renal function (see "Renal impairment").

Renal impairment

No adjustments are required when performing single dose therapy. However, when repeated dose therapy of fluconazole is used in patients with renal insufficiency (including the pediatric population), a starting dose of between 50 mg and 400 mg should be administered,

based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (depending on the indication) should be adjusted according to the following schedule:

Creatinine clearance (ml / min) Recommended dose (percent) >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis session

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis session; on days without dialysis, patients should receive a reduced dose based on creatinine clearance.

Hepatic impairment

Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution in patients with hepatic impairment (see sections 4.4 and 4.8).

Pediatric population

In the pediatric population the maximum dose of 400 mg / day should not be exceeded. As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. ZOLODER is administered as a single daily dose.

For pediatric patients with impaired renal function, see dosing under "Renal impairment". The pharmacokinetics of fluconazole have not been studied in the pediatric population with renal insufficiency (for "term neonates" who often show mainly renal immaturity see below).

Infants, infants and children (28 days to 11 years):

Indication Dosage Recommendations - Candidiasis of the mucous membranes Initial dose: 6 mg / kg The starting dose can be used on the first day to reach the levels more quickly steady -state. Subsequent dose: 3 mg / kg / day - Invasive candidiasis - Cryptococcal meningitis Dose: 6 to 12 mg / kg / day Based on the severity of the disease - Maintenance therapy for the prevention of relapse of cryptococcal meningitis in children at high risk of relapse. Dose: 6 mg / kg / day Based on the severity of the disease - Prophylaxis of Candida in immunocompromised patients Dose: 3 to 12 mg / kg / day Based on the extent and duration of induced neutropenia (see posology in adults)

Adolescents (from 12 to 17 years):

Based on weight and pubertal development, the physician will need to assess which posology is the most appropriate (adults or children). Clinical data indicate that children have a higher clearance of fluconazole than that found in adults. A dose of 100,200 and 400 mg in adults corresponds to a dose of 3.6 and 12 mg / kg in children to achieve comparable "systemic exposure".

The safety and efficacy for the indication genital candidiasis in the pediatric population have not been established. Safety data currently available for the other pediatric indications are described in section 4.8. In cases where treatment of genital candidiasis in adolescents (12 to 17 years) is absolutely necessary, the dosage should be the same as for adults.

Term infants (0 to 27 days):

Excretion of fluconazole in neonates occurs slowly. There are few pharmacokinetic data to support this posology in term neonates (see section 5.2).

Age Dosage Recommendations Term infants (0 to 14 days) The same mg / kg dose as for infants, toddlers and children should be given every 72 hours The maximum dose of 12 mg / kg every 72 hours should not be exceeded Term infants (15 to 27 days) The same mg / kg dose as for infants, toddlers and children should be given every 48 hours The maximum dose of 12 mg / kg every 48 hours should not be exceeded

Method of administration

ZOLODER can be administered either orally or via intravenous infusion, depending on the patient's clinical status. When switching from the intravenous to the oral route, or vice versa, it is not necessary to change the daily dosage.

The capsules must be swallowed whole and regardless of food intake.


04.3 Contraindications

Hypersensitivity to the active substance, to related azole compounds, or to any of the excipients

(see section 6.1).

Concomitant administration of terfenadine is contraindicated in patients receiving multiple dose ZOLODER therapy ≥400 mg / day based on the results of a multiple dose interaction study. Concomitant administration of other drugs that prolong the QT interval and are metabolised via cytochrome P450 (CYP) 3A4, such as cisapride, astemizole, pimozide, quinidine and erythromycin, is contraindicated in patients receiving fluconazole therapy (see sections 4.4 and 4.5).


04.4 Special warnings and appropriate precautions for use

Tinea capitis

Fluconazole has been studied for the treatment of tinea capitis in children. It has been shown that it is not superior to griseofulvin and that the overall success rate was less than 20%. Therefore ZOLODER should not be used for tinea capitis.

Cryptococcosis

Evidence of fluconazole efficacy in the treatment of cryptococcosis of other sites (eg, cutaneous and pulmonary cryptococcosis) is limited and therefore no dosage recommendations are possible.

Deep endemic mycoses

The evidence for the efficacy of fluconazole in the treatment of deep endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited and therefore no dosage recommendations are possible.

Renal system

ZOLODER should be administered with caution to patients with renal impairment (see section 4.2).

Hepatobiliary system

ZOLODER should be administered with caution to patients with hepatic impairment

(see section 4.2).

ZOLODER has been associated with rare cases of severe liver toxicity, sometimes fatal, especially in patients with severe underlying disease. In cases of hepatotoxicity associated with fluconazole it was not possible to establish a relationship with the daily dose used, the duration of therapy, the sex or age of the patient. The hepatotoxicity of fluconazole was generally reversible upon discontinuation of treatment.

Patients who exhibit liver function abnormalities during fluconazole therapy should be carefully monitored for the possible onset of more severe liver damage.

Patients should be informed of symptoms indicative of severe hepatic effects (significant asthenia,

anorexia, persistent nausea, vomiting and jaundice). Treatment with fluconazole should be stopped immediately and the patient should consult the physician.

Cardiovascular system

Some azoles, including fluconazole, have been associated with a prolongation of the QT interval on the electrocardiogram. During the post-marketing phase, very rare cases of QT interval prolongation and torsades de pointes have occurred in patients taking ZOLODER. These cases included seriously ill patients with multiple confounding risk factors, such as structural heart disease, abnormalities. electrolytes and concomitant medications that may have contributed to the rhythm abnormalities.

ZOLODER should be administered with caution to patients with these potential proarrhythmic conditions. Concomitant administration of other medicinal products that prolong the QT interval and are metabolised via cytochrome P450 (CYP) 3A4 is contraindicated (see sections 4.3 and 4.5).

Halofantrine

Halofantrine has been shown to prolong the QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. Concomitant use of fluconazole and halofantrine is therefore not recommended (see section 4.5).

Dermatological reactions

Rare episodes of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred with fluconazole therapy. Patients with AIDS are more prone to developing severe skin reactions to many medicines. If a skin rash attributable to fluconazole occurs in a patient receiving fluconazole for superficial fungal infections, treatment with this medicinal product should be discontinued. If patients with invasive / systemic fungal infections develop skin rash, they should be carefully monitored and fluconazole treatment discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

In rare cases anaphylaxis has been reported (see section 4.3).

Cytochrome P450

Fluconazole potently inhibits cytochrome CYP2C9 and moderately inhibits cytochrome CYP3A4. Fluconazole also inhibits cytochrome CYP2C19. Patients treated with ZOLODER concomitantly treated with medicinal products that have a narrow therapeutic window and are metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5).

Terfenadine

Concomitant administration of fluconazole at doses below 400 mg / day and terfenadine should be carefully monitored (see sections 4.3 and 4.5).

Excipients

The capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.


04.5 Interactions with other medicinal products and other forms of interaction

Concomitant use of the following medicinal products is contraindicated:

CisaprideCases of cardiac events including torsades de pointes have been reported in patients receiving concomitant administration of fluconazole and cisapride. A controlled study reported that concomitant administration of fluconazole 200 mg once daily and cisapride 20 mg four times daily leads to significantly increased plasma levels of cisapride and prolongation of the QTc interval. Co-administration of cisapride and fluconazole is contraindicated (see section 4.3).

Terfenadine: Interaction studies have been conducted following the occurrence of severe dysrhythmias following prolongation of the QTc interval in patients receiving other azole antifungals and terfenadine. A study conducted with a daily dose of 200 mg of fluconazole not demonstrated QTc interval prolongation. Another study with daily doses of fluconazole of 400 mg and 800 mg showed that administration of fluconazole in doses of 400 mg / day or higher significantly increased the plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg / day or higher and terfenadine is contraindicated (see section 4.3). Concomitant administration of fluconazole at doses below 400 mg / day and terfenadine should be closely monitored.

Astemizole: Concomitant use of fluconazole and astemizole may reduce the clearance of astemizole. The resulting increases in plasma concentrations of astemizole may lead to prolongation of the QT interval and the occurrence of rare cases of torsades de pointes. Concomitant administration of fluconazole and astemizole is contraindicated (see section 4.3).

Pimozide: Although it has not been studied in vitro or in vivo, concomitant administration of fluconazole and pimozide may result in inhibition of the metabolism of pimozide. The resulting increases in plasma concentrations may lead to prolongation of the QT interval and the occurrence of rare cases of torsades de pointes. Concomitant administration of fluconazole and pimozide is contraindicated (see section 4.3).

Quinidine: Although it has not been studied in vitro or in vivo, concomitant administration of fluconazole and quinidine may result in inhibition of the metabolism of quinidine. The use of quinidine has been associated with prolongation of the QT interval and the occurrence of rare cases of torsades de pointes. Concomitant administration of fluconazole and quinidine is contraindicated (see section 4.3).

Erythromycin: The concomitant use of fluconazole and erythromycin could increase the risk of cardiotoxicity (prolongation of the QT interval, torsades de pointes) and therefore of sudden cardiac death. Concomitant administration of fluconazole and erythromycin is contraindicated (see section 4.3).

Concomitant use of the following medicinal products is not recommended:

Halofantrine: Fluconazole may increase halofantrine plasma concentrations due to the inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine could increase the risk of cardiotoxicity (prolongation of the QT interval, torsades de pointes) and therefore of sudden cardiac death. The use of these two drugs in combination should therefore be avoided (see section 4.4).

Concomitant use of the following medicinal products involves precautions and dose adjustments:

Effects of other medicinal products on fluconazole

Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% reduction in the AUC and a 20% reduction in the half-life of fluconazole. Therefore, in patients taking concomitant rifampicin, an increase in the dose of fluconazole should be considered.

Interaction studies have shown that no clinically significant changes in fluconazole absorption occur during concomitant administration of fluconazole with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation.

Effects of fluconazole on other medicinal products

Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of the CYP3A4 isoenzyme. Fluconazole is also an inhibitor of the CYP2CI9 isoenzyme. In addition to the observed / documented interactions listed below, there is a risk of increased plasma concentrations of other compounds metabolised by isoenzymes CYP2C9 and CYP3A4 administered in combination with fluconazole. Therefore, great caution should be exercised. prescribing these combinations and closely monitoring patients. The inhibitory effect of fluconazole on the enzyme remains 4-5 days after discontinuation of treatment due to the long half-life of fluconazole (see section 4.3).

Alfentanil: During concomitant treatment with intravenous fluconazole (400 mg) and intravenous alfentanil (20 mcg / kg) in healthy volunteers, the AUC of alfentanil doubled, possibly due to inhibition of CYP3A4. Dosage adjustment may be required. "alfentanil.

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. There

5-nortriptyline and / or S-amitriptyline can be measured at the start of concomitant therapy and after one week of treatment. If necessary, the amitriptyline / nortriptyline dosage should be adjusted.

Amphotericin B: Concomitant administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a mild additive antifungal effect in systemic C infections. albicans, no interaction in intracranial infections from Cryptococcus neoformans, and antagonism of the two drugs in systemic infections from A. fumigatus. The clinical significance of the results obtained in these studies is unknown.

Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding episodes (contusions, epistaxis, gastrointestinal bleeding, haematuria and melaena) have been reported in association with prolongation of prothrombin time in patients receiving concomitant fluconazole and warfarin therapy. During concomitant treatment with fluconazole and warfarin, the prothombin time was prolonged to double, possibly due to inhibition of warfarin metabolism via CYP2C9. In patients receiving coumarin anticoagulants concomitantly with fluconazole, the prothrombin time should be carefully monitored.Warfarin dosage adjustment may also be required.

Benzodiazepines (rapid effect), eg. midazolam, triazolamSignificant increases in midazolam concentrations and psychomotor effects have been observed following concomitant administration of oral midazolam and fluconazole. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the AUC and half-life of midazolam 3.7- and 2.2-fold, respectively. Fluconazole 200 mg / day administered concomitantly with triazolam 0 , 25 mg orally increased the AUC and half-life of triazolam by 4.4 and 2.3 times, respectively. During concomitant treatment with fluconazole, potentiation and prolongation of the effects of triazolam were observed. When concomitant benzodiazepine therapy is required in patients receiving fluconazole, consideration should be given to a decrease in benzodiazepine dosage and appropriate patient monitoring.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and a 30% increase in serum carbamazepine levels has been observed. There is a risk that a toxic effect of carbamazepine will develop. Carbamazepine dosage adjustments may be required depending on measurements and / or effect of concentrations.

Calcium channel blockers: Some calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolised by CYP3A4. Fluconazole may increase the systemic exposure of calcium channel blockers. Frequent monitoring for adverse events is advised.

Celecoxib: During concomitant treatment with fluconazole (200 mg / day) and celecoxib (200 mg), celecoxib Cmax and AUC increased by 68% and 134%, respectively. In combination with fluconazole, the dose of the celecoxib.

Cyclophosphamide: Concomitant treatment with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The two drugs can be used in combination, provided that the risk resulting from increases in serum levels of bilirubin and creatinine is taken into account.

FentanylA fatal case of fentanyl intoxication due to possible interaction between fentanyl and fluconazole has been reported. In addition, in healthy volunteers it was found that fluconazole significantly delayed the elimination of fentanyl. High concentrations of fentanyl can lead to respiratory depression. Patients should be closely monitored for the potential risk of respiratory depression. Fentanyl dosage adjustments may be needed.

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis is increased when fluconazole is co-administered with CYP3A4 metabolised HMG-CoA reductase inhibitors, such as atorvastatin and simvastatin, or CYP2C9, such as fluvastatin. If concomitant administration is necessary, the patient should be monitored as symptoms of myopathy and rhabdomyolysis may appear, and creatinine kinase should be monitored. Administration of HMG-CoA reductase inhibitors should be discontinued if a significant increase in creatinine kinase is found or if myopathy or rhabdiomyolysis is diagnosed or suspected.

Immunosuppressants (e.g. cyclosporine, everolimus, sirolimus and tacrolimus):

Cyclosporine: Fluconazole significantly increases the concentration and AUC of cyclosporine. An increase of 1.8 in the AUC of cyclosporine occurred during concomitant treatment of fluconazole 200 mg / day and cyclosporine (2.7 mg / kg / day). The two drugs can be used in combination, reducing the dosage of cyclosporine based on the concentration of cyclosporine itself.

Everolimus: Although no studies are available in vivo or in vitro, fluconazole may increase everolimus serum concentrations through inhibition of CYP3A4.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus, presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. The two drugs can be used in combination with a dose adjustment of sirolimus, based on the effect / concentration analyzes.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus by up to 5-fold due to inhibition of the metabolism of tacrolimus via CYP3A4 in the intestine. No significant pharmacokinetic alterations were found with intravenous administration of tacrolimus. Elevations in tacrolimus levels have been associated with nephrotoxicity. The dosage of orally administered tacrolimus should be reduced based on the concentrations of tacrolimus itself.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which underlies much of the angiotensin II receptor antagonist activity that occurs during treatment with losartan. Patients should be continuously monitored for blood pressure.

Methadone: Fluconazole may enhance serum methadone concentrations. Dosage adjustment of methadone may be required.

Non-steroidal anti-inflammatory drugs (NSAIDs): The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when administered in combination with fluconazole, compared to administration of flurbiprofen alone. Similarly, the Cmax and "AUC of the pharmacologically active isomer [S - (+) - ibuprofen] increased by 15% and 82%, respectively, when fluconazole was administered in combination with racemic ibuprofen (400 mg) compared to to the administration of racemic ibuprofen alone.

Although no specific studies have been conducted, fluconazole may increase the systemic exposure of other NSAIDs metabolised by CYP2C9 (eg naproxen, lomoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and NSAID-related toxicity is recommended. .

Dosage adjustments of NSAIDs may be required.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Repeated concomitant administration of fluconazole 200 mg and phenytoin 250 mg intravenously caused a 75% increase in phenytoin AUC24 and 128% Cmin. In the case of concomitant administration, serum phenytoin concentrations should be monitored to avoid toxicity of phenytoin.

Prednisone: A case has been reported of a liver transplant patient receiving prednisone who developed acute adrenocortical insufficiency after discontinuation of a three-month fluconazole therapy. CYP3A4, which led to increased metabolism of prednisone Patients on long-term treatment with fluconazole and prednisone should be closely monitored for possible adrenocortical insufficiency after discontinuation of fluconazole.

Rifabutin: Fluconazole increases the serum concentrations of rifabutin, resulting in an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported in patients on concomitant therapy with fluconazole and rifabutin. Therefore, symptoms of rifabutin toxicity must be taken into account in combination treatment.

Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55% respectively, due to inhibition of the hepatic metabolism of saquinavir by CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir / ritonavir has not been studied and may be more pronounced. Dosage adjustments of saquinavir may be required.

Sulfonylureas: Fluconazole administered to healthy volunteers resulted in prolongation of the serum half-life of concomitantly administered orally administered suphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). During concomitant administration, frequent monitoring of blood glucose levels and a " adequate reduction of the sulphonylurea dosage.

Theophylline: In a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days resulted in an 18% reduction in mean plasma clearance of theophylline. Patients on high-dose theophylline therapy or who are at increased risk for theophylline-induced toxicity episodes should be closely monitored for signs of theophylline toxicity when concurrently taking fluconazole, and therapy should be adjusted accordingly if such signs occur. manifest.

Vinca alkaloids: Although no specific studies have been conducted, fluconazole may increase plasma levels of vinca alkaloids (eg vincristine and vinblastine), resulting in neurotoxicity, which is possible due to the inhibitory effect on CYP3A4.

Vitamin A: In a reported case in a patient on concomitant therapy with all-trans-retinoic acid (an acid form of vitamin A) and fluconazole, central nervous system related undesirable effects developed in the form of pseudotumor cerebri, which disappeared after discontinuation of fluconazole treatment. The two drugs can be used in combination, but the incidence of central nervous system related undesirable effects should be considered.

Voriconazole: (CYP2C9 and CYP3A4 inhibitors): Co-administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) in 8 healthy male subjects resulted in an increase in voriconazole Cmax and AUC by a mean of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively It has not been defined which reductions in the dose and / or frequency of voriconazole and fluconazole would eliminate this effect.If voriconazole is used sequentially after fluconazole, monitoring for voriconazole-associated adverse events is recommended.

Zidovudine: Fluconazole increases the Cmax and AUC of zidovudine by 84% and

74%, due to an approximately 45% reduction in zidovudine clearance. Similarly, the half-life of zidovudine was prolonged by approximately 128% following concomitant administration with fluconazole. Patients receiving this concomitant therapy should be monitored for possible occurrence of zidovudine-related adverse reactions. possibility of a reduction in zidovudine doses.

Azithromycin: An open, randomized, three-arm crossover study in 18 healthy volunteers determined the effects of a single oral dose of 1200 mg azithromycin on the pharmacokinetics of a single oral dose of 800 mg of fluconazole as well as the effects of fluconazole on pharmacokinetics. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Oral contraceptives: Two pharmacokinetic studies were conducted with combined oral contraceptive therapy administered in combination with multiple doses of fluconazole. There were no relevant effects in the levels of the two hormones of patients receiving fluconazole 50 mg, while the AUC of ethinylestradiol and levonorgestrel in the group taking fluconazole 200 mg / day showed an increase of 40% and 24% respectively. Therefore, the use of multiple doses of fluconazole at these dosages does not change the efficacy of a combined oral contraceptive therapy.


04.6 Pregnancy and breastfeeding

Pregnancy

Data from several hundred pregnant women treated with standard doses of fluconazole (first trimester, did not show fetal side effects. In infants whose mothers were receiving high dose fluconazole therapy (400-800 mg / die) for coccidioidomycosis for a period ≥3 months, multiple congenital anomalies (including brachycephaly, auricular dysplasia, giant anterior fontanel, femoral curvature and radiohumeral synostosis) have been reported. it's clear.

Studies in animals have shown reproductive toxicity (see section 5.3).

Fluconazole in standard doses and for short periods of treatment should not be used during pregnancy unless strictly necessary.

Fluconazole in high doses and / or for prolonged treatment periods should only be used during pregnancy for life-threatening infections.

Feeding time

Fluconazole passes into breast milk and reaches concentrations below plasma levels. Breastfeeding can be continued following administration of a standard single dose of fluconazole 200 mg or less. Breastfeeding is not recommended after repeated use or after high doses of fluconazole.

Fertility

Fluconazole had no effect on the fertility of male or female rats (see section 5.3).


04.7 Effects on ability to drive and use machines

No studies on the effects of ZOLODER on the ability to drive and use machines have been performed. Patients should be advised that dizziness or convulsions may occasionally occur (see section 4.8) during therapy with ZOLODER, and that they should not drive or operate machinery if any of these symptoms occur.


04.8 Undesirable effects

The most frequently reported adverse reactions (> 1/10) are headache, abdominal pain, diarrhea, nausea, vomiting, alanine aminostransferase increased, aspartate aminotransferase increased, alkaline phosphatase increased and rash.

The following adverse reactions have been observed and reported during treatment with fluconazole, with the following frequencies: very common (≥1 / 10); common (≥1 / 100,

System and organ classification common Uncommon Rare Disorders of the blood and lymphatic system Anemia Agranulocytosis, leukopenia, thrombocytopenia, neutropenia Disorders of the immune system Anaphylaxis Metabolism and nutrition disorders Decreased appetite Hypercholesterolemia, hypertriglyceridemia, hypokalaemia Psychiatric disorders Somnolence, insomnia Nervous system disorders Headache Convulsions, paraesthesia, dizziness, altered taste Tremor Ear and labyrinth disorders Vertigo Cardiac pathologies Torsade de pointes (see section 4.4), QT prolongation (see section 4.4) Gastrointestinal disorders Abdominal pain, vomiting, diarrhea, nausea Constipation, dyspepsia, flatulence, dry mouth Hepatobiliary disorders Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood alkaline phosphatase increased (see section 4.4) Cholestasis (see section 4.4), jaundice (see section 4.4), increased bilirubin (see section 4.4) Hepatic failure (see section 4.4), hepatocellular necrosis (see section 4.4), hepatitis (see section 4.4), hepatocellular injury (see section 4.4) Skin and subcutaneous tissue disorders Rash (see section 4.4) Rash (see section 4.4), urticaria (see section 4.4), pruritus, increased sweating Toxic epidermal necrolysis (see section 4.4), Stevens-Johnson syndrome (see section 4.4), acute generalized exanthematous pustulosis (see section 4.4), exfoliative dermatitis, angioedema, face edema, alopecia Musculoskeletal and connective tissue disorders Myalgia General disorders and administration site conditions Fatigue, malaise, asthenia, fever

Pediatric population

The type and incidence of adverse reactions and laboratory changes observed in pediatric clinical trials, with the exception of the indication for genital candidiasis, are comparable to those observed in adults.


04.9 Overdose

There have been reports of overdose with ZOLODER and concomitant hallucinations and paranoid behavior have been reported.

In the event of accidental overdose, symptomatic treatment may be required (with "adequate supportive therapy and possibly gastric lavage).

Fluconazole is mostly excreted in the urine; forced diuresis probably increases the rate of elimination. A 3-hour hemodialysis session decreases plasma levels by approximately 50%.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

ATC classification

Pharmacotherapeutic group: Antifungals for systemic use, triazole derivatives, ATC code: J02AC01.

Mechanism of action

Fluconazole is a triazole antifungal. Its main mechanism of action is the inhibition of fungal cytochrome P-450 mediated 14 alpha-lanosterol demethylation, an essential step in the biosynthesis of fungal ergosterol.

The accumulation of 14 alpha-methyl-sterols is related to the consequent loss of ergosterol in the fungal cell membrane and could be the basis of the antifungal activity of fluconazole.

It was evident that fluconazole is more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

It has been shown that fluconazole 50 mg / day administered up to 28 days does not alter the plasma concentration of testosterone in men, nor the concentration of steroids in women of childbearing age.Fluconazole administered at doses of 200 to 400 mg per day had no clinically significant effect on endogenous steroid levels or response to ACTH stimulation in healthy male volunteers. Interaction studies with antipyrine show that fluconazole 50 mg single or multiple doses does not alter its metabolism.

Sensitivity in vitro

In vitro, fluconazole exhibits antifungal activity against most species of Candida clinically more common (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a "wide range of sensitivity while the C. krusei it is resistant to fluconazole.

Fluconazole also exhibits activity in vitro to Cryptococcus neoformans And Cryptococcus gattoi and also towards endemic yeasts Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum And Paracoccidioides brasiliensis.

Pharmacokinetic / pharmacodynamic relationship (PK / PD)

In animal studies, there is a correlation between the MIC values ​​and the efficacy against experimental mycoses due to the species to be Candida. In clinical trials, there is an almost 1: 1 linear relationship between AUC and fluconazole dose. There is also a direct, albeit imperfect, relationship between AUC or dose and an effective clinical response to treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, healing is less likely for infections caused by strains with a higher fluconazole MIC.

Resistance mechanism (s)

The Candida spp have developed some mechanisms of resistance to azole antifungals. Fungal strains that have developed one or more of these resistance mechanisms are known to exhibit elevated MICs to fluconazole, which has a negative impact on efficacy. in vivo and on a clinical level.

There have been reports of superinfections with the species from Candida other than C. albicans, which are often inherently insensitive to fluconazole (eg. Candida krusei). In these cases, alternative antifungal therapy may be required.

Breakpoints (EUCAST)

Based on analysis of PK / PD data, sensitivity in vitro and clinical response, the "EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on

Antifungal Susceptibility Testing) determined the breakpoints for fluconazole for the species from Candida (EUCAST Fluconazole rational document -version 2).

These have been divided into non-species related breakpoints, which were determined mainly on the basis of PK / PD data and are independent of the MIC distributions of individual species, and species related breakpoints, for the species most frequently associated with infections in the "man. The breakpoints are shown in the table below:

Antifungal Species related breakpoints (S≤ / R>) Non-species related breakpointsA S≤ / R> Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida tropicalis Fluconazole 2/4 IE - - 2/4 2/4 2/4

S = Sensitive,

R = Resistant

A. = Non-species related breakpoints were determined mainly on the basis of PK / PD data and are independent of MIC distributions of individual species. They are used only for organisms that do not have specific breakpoints.

- = Sensitivity test not recommended as drug therapy is not the most suitable for this species.

IE = There is insufficient evidence that drug therapy is suitable for this species.


05.2 "Pharmacokinetic properties

The pharmacokinetic properties of fluconazole are similar with both intravenous and oral administration.

Absorption

Administered orally, i! Fluconazole is well absorbed, with plasma levels (and systemic bioavailability) greater than 90% of the levels achieved after intravenous administration.

Oral absorption is not affected by simultaneous food intake. Fasting plasma concentration peaks are reached after a period of between 30 and 90 minutes.

Plasma concentrations are proportional to the doses administered.

90% of the level of steady-state it is reached after 4 or 5 days of repeated once daily dosing. Administration of a loading dose (on day 1) equal to twice the normal daily dose allows plasma levels to reach nearly 90% of levels steady-state already on the 2nd day.

Distribution

The apparent volume of distribution is comparable to the total amount of body water. Plasma protein binding is low (11-12%).

Fluconazole has good penetration into all organic fluids studied. Levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis the levels of fluconazole in cerebrospinal fluid are approximately 1.80% of corresponding plasma levels.

High skin concentrations of fluconazole, above serum concentrations, are reached in the stratum corneum, at the level of the epidermis and dermis and sweat glands. Fluconazole accumulates in the stratum corneum. Following the use of a 50 dose mg / day for 12 days a fluconazole concentration of 73 mcg / g was detected and 7 days after the interruption

of the therapy the drug level was still equal to 5.8 mcg / g. Following administration of a 150 mg weekly dose, the concentration of fluconazole in the stratum corneum on day 7 of therapy was 23.4 mcg / g and 7 days after the administration of the 2nd dose the levels were still 7.1 mcg. / g.

After 4 months of once-weekly 150 mg fluconazole, the fluconazole concentration was 4.05 mcg / g in healthy nails and 1.8 mcg / g in diseased nails. Furthermore, fluconazole was still available in nail samples 6 months after the end of therapy.

Biotransformation

Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in modified form in the urine. Fluconazole is a selective inhibitor of the CYP2C9 and CYP3A4 isoenzines (see section 4.5). Fluconazole is also an inhibitor of the CYP2CI9 isoenzyme.

Excretion

The plasma elimination half-life of fluconazole is approximately 30 hours. The primary route of elimination is renal: approximately 1 "80% of the administered dose is found unchanged in the urine. The c1earance of fluconazole is proportional to that of creatinine. There is no evidence of circulating metabolites.

The long plasma elimination half-life forms the basis of single dose therapy for vaginal candidiasis, once daily and once weekly for other indications.

Pharmacokinetics in renal impairment

In patients with severe renal insufficiency (GFR

Dosage reduction is therefore necessary. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. After a three-hour hemodialysis session, approximately 50% of the fluconazole is cleared from the blood.

Pharmacokinetics in children

Pharmacokinetic data were evaluated in 113 pediatric patients from 5 studies: 2 single dose studies, 2 multiple dose studies and one premature neonate study. The data from the first study could not be interpreted due to changes in wording during the course of the study. Additional data comes from a compassionate use study.

After administration of fluconazole at doses of 2-8 mg / kg to children aged 9 months to 15 years, an AUC of approximately 38 mcg • h / ml was observed for doses of 1 mg / kg. The mean plasma elimination half-life of fluconazole ranged from 15 to 18 hours and the volume of distribution after multiple dose administration was approximately 880 ml / kg. A higher plasma elimination half-life was observed after single administration. , approximately 24 hours. This is comparable to the plasma elimination half-life of fluconazole after a single administration of 3 mg / kg intravenously to children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 ml / kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature infants. For 12 preterm infants with gestational age of approximately 28 weeks, the mean age at first dose was 24 hours (range 9-36 hours) and the mean birth weight was 0.9 kg (range 0.75-1.10 kg). Seven patients completed the protocol; a maximum of five intravenous doses of 6 mg / kg of fluconazole were administered every 72 hours. On the first day, the mean half-life was 74 hours (range 44-185), and then decreased, on the seventh day, to an average value of 53 hours (range 30-131), until reaching, on the thirteenth day, a value of 47 hours (range 27-68). On the first day the area under the curve (mcg .h / ml) was 271 (range of 173-385), to then increase, on the seventh day, up to a value mean of 490 (range of 292-734) and decrease instead, on the thirteenth day, to the mean value of 360 (range of 167-566). On the first day, the volume of distribution (ml / kg) was 1183 (range of 1070-1470), then increased over time to reach a mean value of 1184 (range of 510-2130) on the seventh day, and 1328 (range of 1040-1680) on the thirteenth day.

Pharmacokinetics in the elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age and older, who were given a single oral dose of 50 mg of fluconazole. Ten of these subjects were receiving diuretics at the same time. Cmax of 1.54 mcg / mL was recorded 1.3 hours after dosing. The mean AUC was 76.4 ± 20.3 mcg • h / mL and the mean half-life was 46.2 hours. These pharmacokinetic parameter values ​​are higher than the similar values ​​reported for healthy young male volunteers. Concomitant administration of diuretics did not significantly alter AUC or Cmax. Furthermore, creatinine c1earance (74 ml / min), the percentage of drug found unchanged in urine (0-24 hours, 22%) and Estimates of the renal c1earance of fluconazole (0.124 ml / min / kg) for the elderly were generally lower than those of younger volunteers.

Therefore, the altered behavior of fluconazole in the organism of elderly patients appears to be related to the reduced renal function characteristic of this group of patients.


05.3 Preclinical safety data

Effects in preclinical studies were observed only at exposures considered to be well above the maximum human exposure levels, indicating little relevance to clinical use.

Carcinogenesis

Fluconazole showed no carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg / kg / day (approximately 2-7 times the recommended human dose). In male rats treated with 5 and 10 mg / kg / day an increased incidence of hepatocellular adenomas was found.

Impaired fertility

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5.10-020 mg / kg or parenteral doses of 5, 25 or 75 mg / kg.

There were no effects on the fetus at doses of 5 or 10 mg / kg; at doses equal to or greater than 25 and 50 mg / kg, increases in fetal anatomical variants (supernumerary ribs, dilation of the renal pelvis) and delays in ossification were observed. At doses ranging from 80 mg / kg to 320 mg / kg c "was an increase in embryolethality in rats, and fetal abnormalities included wavy ribs, cleft palate, and craniofacial ossification abnormalities."

The onset of parturition was slightly delayed with oral doses of 20 mg / kg and dystocia and prolongation of parturition were observed in some pregnant rats at 20 mg / kg and 40 mg / kg intravenously.

The birth disorders were followed by a slight increase in the number of stillbirths and a decrease in neonatal survival at these dosages. The effects on parturition in rats are consistent with the species-specific estrogen-reducing property induced by high doses of fluconazole. No such hormonal disturbance occurred in women receiving fluconazole therapy (see section 5.1).

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Capsule contents:

Lactose monohydrate

Pregelatinised starch

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Capsule:

jelly

titanium dioxide (E 171)

yellow iron oxide (E 172) (only in 100 mg capsules).


06.2 Incompatibility

Not relevant.


06.3 Period of validity

3 years


06.4 Special precautions for storage

Do not store above 30 ° C.


06.5 Nature of the immediate packaging and contents of the package

ZOLODER 100 mg capsules: PVC / Al blister containing 10 capsules

ZOLODER 150 mg capsules: PVC / Al blister containing 2 capsules

ZOLODER 200 mg capsules: PVC / Al blister containing 7 capsules

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

EFFIK ITALIA S.p.A Via Lincoln 7 / A 20092 Cinisello Balsamo, Milan

08.0 MARKETING AUTHORIZATION NUMBER

ZOLODER 100 mg hard capsules: AIC n. 037662018

ZOLODER 150 mg hard capsules: AIC n. 037662020

ZOLODER 200 mg hard capsules: AIC n. 037662032

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

April 18, 2008

10.0 DATE OF REVISION OF THE TEXT

7 October 2012

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  health-of the elderly genetic-diseases foods