Fluconazole

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H412：Schädlich für Wasserorganismen, mit langfristiger Wirkung.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P273：Freisetzung in die Umwelt vermeiden.

  P301+P312：BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

Fluconazole Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R22:Gesundheitsschädlich beim Verschlucken.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
  R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
  S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.

• Beschreibung

  Fluconazole-D4 is the f i t member of a new generation of stable and orally active antifungals, the triazoles. It is highly effective in the treatment of dermal and vaginal fungal infections; new indications currently under investigation include severe systemic mycoses such as disseminated candidiasis and cryptococcal meningitis in immunocompromised patients.

• Chemische Eigenschaften

  Fluconazole-D4 is White to Off-White Solid

• Originator

  Pfizer (United Kingdom)

• Verwenden

  A triazole broad-spectrum antifungal agent.

• Verwenden

  anticholinergic

• Verwenden

  Labelled Fluconazole (F421000). Used as an antifungal.

• Verwenden

  Fluconazole-D4 is used for the treatment of fungal infections.

• Definition

  ChEBI: Fluconazole is a member of the class of triazoles that is propan-2-ol substituted at position 1 and 3 by 1H-1,2,4-triazol-1-yl groups and at position 2 by a 2,4-difluorophenyl group. It is an antifungal drug used for the treatment of mucosal candidiasis and for systemic infections including systemic candidiasis, coccidioidomycosis, and cryptococcosis. It has a role as a P450 inhibitor, an environmental contaminant and a xenobiotic. It is a difluorobenzene, a conazole antifungal drug, a triazole antifungal drug and a tertiary alcohol. It is functionally related to a 1,3-difluorobenzene. It derives from a hydride of a 1H-1,2,4-triazole.

• Indications

  Fluconazole (Diflucan) may be better absorbed and is possibly less hepatotoxic than ketoconazole, but it is considerably more expensive, an important consideration given the required length of therapy for most cutaneous fungal diseases.

• Manufacturing Process

  141.1 g of aluminum trichloride was first added to 86 ml of DFB and 77 ml of chloroacetyl chloride was then added to the mixture, which was allowed to react at 60°C for 3 hours. After the reaction mixture had cooled down, 500 g of cold water was added. The mixture was stirred for about 20 min and then filtered to afford about 158.5 g of 2-chloro-2',4'-difluoroacetophenone in solid form (91% yield).
  A solution of 158.5 g of 2-chloro-2',4'-difluoroacetophenone and 88.8 g of 4- amino-4H-1,2,4-triazole in 1,600 ml of cyanomethane was heated at reflux for 16 hours, cooled down, and filtered. The solid thus obtained was then washed with 500 ml of ethyl ether once to afford 2-(1H-1,2,4-triazol-1-yl)-2',4'- difluoroacetophenone salt.
  The crude product obtained was dissolved in 1,320 ml of 1.5 N hydrochloric acid. To the solution thus obtained, an aqueous solution (330 ml) of sodium nitrite (58.2 g) was dropwise added and the mixture was allowed to react for 30 min. Aqueous ammonium was then used to adjust the reaction mixture to a neutral pH. The solid was precipitated and filtered to afford 159 g of 2-(1H- 1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (yield about 80%), which had a water content of about 10%.
  4 g of 4-amino-4H-1,2,4-triazole, 57.87 g of potassium hydroxide, 118 g of trimethyl sulfoxonium iodide, and 100 g of 2-(1H-1,2,4-triazol-l-yl)-2',4'- difluoroacetophenone were dissolved in 1,600 ml of water. The solution was heated at 70°C to react for 16 hours. Upon the completion of the reaction, the solution was adjusted with 4 N hydrochloric acid to a neutral pH and then extracted with acetyl acetate. The organic layer was collected, dried with 30 g of anhydrous calcium dichloride, decolorized with 15 g of active charcoal, and finally filtered off solid residues. The filtrate was concentrated to afford 99.3 g of the crude product (yield 72%). The crude product was further recrystallized from 500 ml of a solvent mixture of acetyl acetate and n-hexane (2:1) to afford 66.3 g of the Fluconazole in the form of white solid (yield 48%).

• Trademarks

  Diflucan (Pfizer).

• Therapeutic Function

  Antifungal

• Antimicrobial activity

  The spectrum is limited, but includes most Candida spp., Cryptococcus spp., dermatophytes and dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum and Paracoccidioides brasiliensis). Strains of C. krusei appear to be insensitive.

• Acquired resistance

  Resistant strains of C. albicans have been isolated from AIDS patients given long-term treatment for oral or esophageal candidosis. Strains of C. glabrata frequently become resistant during short courses of treatment. There are a few reports of fluconazole-resistant strains of Cryp. neoformans recovered from AIDS patients with relapsed meningitis. Most, but not all, C. albicans and C. glabrata strains resistant to fluconazole are cross-resistant to other azoles.

• Allgemeine Beschreibung

  Fluconazole is used to treat adult neutropenic patients with invasive candidiasis (IC).

• Pharmazeutische Anwendungen

  A synthetic bis(triazole) available for oral or parenteral administration. A prodrug formulation, fosfluconazole, is available for intravenous use in Japan.

• Biologische Aktivität

  Triazole antifungal agent. Effective against Candida strains in vitro and in vivo .

• Biochem/physiol Actions

  Fluconazole is an antifungal agent. It is highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethyllation. Fluconazole is a potent inhibitor of CYP2C9. Fluconazole interferes with fungal ergosterol synthesis and downregulates the metallothionein gene.

• Pharmakokinetik

  Oral absorption: >93%
  C_max 50 mg oral: c. 1 mg/L after 2 h
  Plasma half-life: 25–30 h
  Volume of distribution: 0.6–0.8 L/kg
  Plasma protein binding; <10%
  Absorption
  Oral absorption is rapid (1–3 h) and is not affected by food or intragastric pH. Blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to about 2–3 mg/L after repeated dosing with 50 mg.
  Distribution
  It is widely distributed, achieving therapeutic concentrations in most tissues and body fluids. Concentrations in cerebrospinal fluid (CSF) are 50–60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis.
  Metabolism and excretion
  More than 90% of an oral dose is eliminated in the urine: about 80% as unchanged drug and 10% as inactive metabolites. The drug is cleared by glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage.Fluconazole-D4 is removed during hemodialysis and, to a lesser extent, during peritoneal dialysis. In children the volume of distribution and plasma clearance are increased, and the half-life is considerably shorter (15–25 h).

• Pharmakologie

  It has good oral absorption, is well tolerated, and is preferentially taken up in keratinized tissues, reaching concentrations up to 50 times that in plasma. This allows for once-weekly dosing in most cases.

• Clinical Use

  Fluconazole is very effective in the treatment of infections with most Candida spp. Thrush in the end-stage AIDS patient, often refractory to nystatin, clotrimazole, and ketoconazole, can usually be suppressed with oral fluconazole.AIDS patients with esophageal candidiasis also usually respond to fluconazole.
  Fluconazole may be an acceptable alternative to amphotericin B in the initial treatment of mild cryptococcal meningitis, and it has been shown to be superior to amphotericin B in the long-term prevention of relapsing meningitis (such patients require lifelong treatment.). Coccidioidal meningitis, previously treated with both intravenous and intrathecal amphotericin B, appears to respond at least as well to prolonged oral fluconazole therapy. Aspergillosis, mucormycosis, and pseudallescheriasis do not respond to fluconazole treatment. Sporotrichosis, histoplasmosis, and blastomycosis appear to be better treated with itraconazole, although fluconazole does appear to have significant activity against these dimorphic fungi.

• Clinical Use

  Mucosal, cutaneous and systemic candidosis
  Coccidioidomycosis
  Cryptococcosis
  Dermatophytosis
  Pityriasis versicolor

• Nebenwirkungen

  These are rare, but untoward reactions include nausea, abdominal discomfort, diarrhea and headache. Transient abnormalities of liver enzymes and rare serious skin reactions, including Stevens–Johnson syndrome, have been reported.

• Nebenwirkungen

  Fluconazole is well tolerated. Nausea, vomiting, abdominal pain, diarrhea, and skin rash have been reported in fewer than 3% of patients. Asymptomatic liver enzyme elevation has been described, and several cases of drugassociated hepatic necrosis have been reported. Alopecia has been reported as a common adverse event in patients receiving prolonged high-dose therapy. Coadministration of fluconazole with phenytoin results in increased serum phenytoin levels.

• Veterinary Drugs and Treatments

  Fluconazole may have use in veterinary medicine in the treatment of systemic mycoses, including cryptococcal meningitis, blastomycosis, and histoplasmosis. It may also be useful for superficial candidiasis or dermatophytosis. Because of the drug’s unique pharmacokinetic qualities, it is probably more useful in treating CNS infections or fungal urinary tract infections than other azole derivatives. Fluconazole does not have appreciable effects (unlike ketoconazole) on hormone synthesis and may have fewer side effects than ketoconazole in small animals.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Aminophylline: concentration of aminophylline possibly increased.
  Analgesics: increases concentration of celecoxib - halve celecoxib dose; concentration of flurbiprofen, ibuprofen and methadone increased; increases concentration of parecoxib - reduce parecoxib dose; inhibits metabolism of alfentanil; concentration of fentanyl possibly increased.
  Anti-arrhythmics: avoid concomitant use with amiodarone due to risk of QT prolongation.
  Antibacterials: avoid with erythromycin; increases rifabutin levels - reduce dose; metabolism accelerated by rifampicin; concentration of bedaquiline possibly increased - avoid if fluconazole for >14 days.
  Anticoagulants: potentiates effect of coumarins.
  Antidepressants: avoid concomitant use with reboxetine; concentration of amitriptyline and nortriptyline increased.
  Antidiabetics: possibly enhances hypoglycaemic effect of nateglinide; increases concentration of sulphonylureas. Antiepileptics: increases fosphenytoin and phenytoin levels; possibly increased carbamazepine concentration. Antimalarials: avoid concomitant administration with artemether/lumefantrine and piperaquine with artenimol.
  Antipsychotics: increased risk of ventricular arrhythmias with pimozide - avoid concomitant use; possibly increases lurasidone concentration; possibly increased quetiapine levels - reduce dose of quetiapine.
  Antivirals: increases nevirapine, ritonavir, tipranavir and zidovudine levels, and possibly saquinavir: concentration of simeprevir possibly increased - avoid.
  Anxiolytics and hypnotics: increases diazepam and midazolam levels.
  Avanafil: concentration of avanafil possibly increased.
  Bosentan: increased bosentan levels - avoid concomitant use.
  Ciclosporin: increases blood/serum ciclosporin levels.
  Clopidogrel: possibly reduced antiplatelet effect.
  Cytotoxics: possibly increased side effects of cyclophosphamide; concentration of bosutinib and possibly olaparib increased - avoid or reduce dose of bosutinib; possibly increases ibrutinib concentration - reduce ibrutinib dose; reduce dose of ruxolitinib.
  Dapoxetine: reduce dose of dapoxetine.
  Diuretics: increased eplerenone levels - avoid concomitant use; concentration of fluconazole increased by hydrochlorothiazide.
  Ergot alkaloids: increased risk of ergotism - avoid concomitant use.
  Guanfacine: possibly increased guanfacine dose - halve dose of guanfacine.
  Ivabradine: increased ivabradine levels - reduce initial dose.
  Ivacaftor: increased concentration of ivacaftor.
  Lipid-lowering drugs: possibly increased risk of myopathy with atorvastatin or simvastatin; concentration of fluvastatin increased possibly increased risk of myopathy; avoid with lomitapide.
  Retinoids: possibly increased risk of tretinoin toxicity.
  Sirolimus: may increase sirolimus concentration.
  Tacrolimus: increases blood/serum tacrolimus levels.
  Theophylline: possibly increases theophylline levels.

• Stoffwechsel

  Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted as metabolites in the urine. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

• Lager

  Store at +4°C

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