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Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals

0.4

0.63

White crystalline powder

Crystals from ethyl acetate/hexane

slightly soluble in water

Poorly soluble in water but can be dissolved in organic solvents such as chloroform, propylene glycol, and polyethoxylated castor oil (preparation for IV use but dangerous for dogs)

Slightly soluble in water and saline

1.39e+00 g/L

34.9 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Antifungal Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antifungal medicines

138-140 °C

138-140 °C

138 - 140 °C

1.76

pKa = 2.27 (1,2,4-triazole)

167.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID3020627]

156.2 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

163.9 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

163.4 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 0.5% (1 of 197) of reports.

Danger

H302 (99.5%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P263, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P308+P316, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 197 reports by companies from 33 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluconazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Concurrent use of fluconazole and short-acting benzodiazepines, such as midazolam, may increase the concentration of the benzodiazepine and increase the psychomotor effects; consider decreasing the benzodiazepine dose and monitor the patient carefully for signs of increased benzodiazepine exposure.

Concurrent use of fluconazole and/or itraconazole with tolbutamide, chlorpropamide, glyburide, or glipizide has increased the plasma concentrations of these sulfonylurea agents; hypoglycemia has been noted; blood glucose concentrations should be monitored, and the dose of the oral hypoglycemic agent may need to be reduced.

... In a small study, fluconazole was given with terfenadine and a small pharmacokinetic interaction was found; although no change in cardiac repolarization or accumulation of parent terfenadine was found, concurrent use of terfenadine with fluconazole at doses of 400 mg or greater per day is contraindicated.

Concurrent use of cisapride with fluconazole ... is contraindicated; concurrent use of this antifungal may inhibit the cytochrome P450 enzyme metabolic pathways, resulting in elevated plasma concentrations of cisapride ; this has led to ventricular arrhythmias, including torsades de pointes and QT prolongation ...

For more Interactions (Complete) data for FLUCONAZOLE (17 total), please visit the HSDB record page.

Transient mild-to-moderate elevations in serum aminotransferase levels occur in up to 5% of patients treated with fluconazole, but these abnormalities are usually asymptomatic and resolve even with continuation of the medication. ALT elevations above 8 times the upper limit of normal are reported to occur in 1% of patients taking fluconazole and to represent the most common adverse event leading to early discontinuation of treatment. Clinically apparent hepatotoxicity due to fluconazole is rare, but well described. The liver injury is typically hepatocellular, arises within the first few weeks of therapy and can be accompanied by signs of hypersensitivity such as fever, rash and eosinophilia. Fatal instances of fluconazole induced liver injury have been reported (Case 1), but most cases are self-limited, although recovery may be delayed for several weeks after stopping fluconazole and may be slow requiring 2 to 3 months.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5.3X10+4(SRC), determined from a structure estimation method(2), indicates that fluconazole is expected to be immobile in soil(SRC). Volatilization of fluconazole from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.0X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Fluconazole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-9 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5.3X10+4(SRC), determined from a structure estimation method(2), indicates that fluconazole is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.0X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3.2(SRC), from an estimated log Kow of 0.25(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fluconazole, which has an estimated vapor pressure of 3.0X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase fluconazole may be removed from the air by wet and dry deposition(SRC). Fluconazole does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

EXPERIMENTAL: Fluconazole is distributed into human milk at concentrations similar to those achieved in plasma. Administration of a single 150-mg oral dose to several nursing women resulted in peak plasma fluconazole concentrations of 2.61 ug/mL (range: 1.57-3.65 ug/mL).

In a case report, acute toxicity of fluconazole has been described with peripheral nervous system involvement. In addition, the patient developed polyneuropathy, a confusional state, acute kidney injury, and thrombotic thrombocytopenic purpura.

Fluconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Fluconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of fluconazole can be estimated to be 5.3X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that fluconazole is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Signs and symptoms of overdose may include hallucinations, paranoid behaviors, decreased motility and respiration, ptosis, urinary incontinence, and cyanosis.

/CASE REPORTS/ While results of several studies evaluating pregnancy outcomes did not indicate an increased risk for congenital malformations in infants born to women who received fluconazole during pregnancy, data from these studies indicate that there has been at least one case each of congenital dislocation of the hip, lacrimal stenosis, partial syndactyly, ventricular septum deficiency, polydactyly or syndactyly, heart defect, or spina bifida in infants born to women who received the drug during pregnancy. In addition, there have been at least 3 reports of congenital abnormalities (craniofacial, skeletal, cardiac) in infants born to women who received fluconazole (400-800 mg daily) for the treatment of coccidioidomycosis during the first trimester.

/CASE REPORTS/ Hallucinations and paranoid behavior developed in a patient with human immunodeficiency virus (HIV) infection who reportedly ingested 8.2 g of fluconazole. The patient was hospitalized, and these manifestations resolved within 48 hours.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluconazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J02AC01

D - Dermatologicals

J - Antiinfectives for systemic use

QD - Dermatologicals

QJ - Antiinfectives for systemic use

J02AC01

Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections: _Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans_ This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth as well as cell adhesion, thereby treating fungal infections and their symptoms. The fungistatic activity of fluconazole has also been shown in normal and immunocompromised animal models with both systemic and intracranial fungal infections caused by _Cryptococcus neoformans_ and for systemic infections caused by Candida albicans. It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole. This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy. **A note on steroidal effects of fluconazole** There has been some concern that fluconazole may interfere with and inactivate human steroids/hormones due to the inhibition of hepatic cytochrome enzymes. Fluconazole has demonstrated to be more selective for _fungal_ cytochrome P-450 enzymes than for a variety of mammalian cytochrome P-450 enzymes. Fluconazole 50 mg administered daily for up to 28 days in individuals of reproductive age has been show to have no effect on testosterone plasma concentrations of males and plasma concentrations of steroids in females. A 200-400 mg dose of fluconazole showed no clinically relevant effect on steroid levels or on ACTH-stimulated steroid response in healthy males, in one clinical study mentioned on the European Medicines Agency label. Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data.

Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme _lanosterol 14-α-demethylase_. This enzyme normally works to convert _lanosterol_ to _ergosterol_, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane. Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing.

Fluconazole usually is fungistatic in action. Fluconazole and other triazole-derivative antifungal agents (e.g., itraconazole, terconazole) appear to have a mechanism of action similar to that of the imidazole-derivative antifungal agents (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole). Like imidazoles, fluconazole presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (eg, amino acids, potassium), and impaired uptake of precursor molecules (eg, purine and pyrimidine precursors to DNA). Although the exact mechanism of action of fluconazole and other triazoles has not been fully determined, the drugs inhibit cytochrome P-450 14-a-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol. It appears that this may occur because a nitrogen atom (N-4) in the triazole molecule binds to the heme iron of cytochrome P-450 14-a-desmethylase in susceptible fungi. Unlike some imidazoles (eg, clotrimazole, econazole, miconazole, oxiconazole) that suppress ATP concentrations in intact cells and spheroplasts of C. albicans, fluconazole does not appear to have an appreciable effect on ATP concentrations in the organism. It is unclear whether this effect is related to the in vivo antifungal effects of the drugs. Fluconazole generally is fungistatic against Candida albicans when the organism is in either the stationary or early logarithmic phase of growth.

Fungistatic; may be fungicidal, depending on the concentration; azole antifungals interfere with cytochrome P450 enzyme activity, which is necessary for the demethylation of 14-alpha-methylsterols to ergosterol. Ergosterol, the principal sterol in the fungal cell membrane, becomes depleted. This damages the cell membrane, producing alterations in membrane functions and permeability. In Candida albicans, azole antifungals inhibit transformation of blastospores into invasive mycelial form.

The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single-dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.

The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 30 hours (range: 20-50 hours). In one study, plasma elimination half-life of the drug was 22 hours after the first day of therapy and 23.8 and 28.6 hours after 7 and 26 days of therapy, respectively.

In a limited, single-dose study in HIV-infected adults, the plasma elimination half-life of fluconazole averaged 32 hours (range: 25-42 hours) in those with absolute helper/inducer (CD4+, T4+) T-cell counts greater than 200 cu m and 50 hours (range: 32-69 hours) in those with CD4+ T-cell counts less than 200 cu m. In other single-dose studies in a limited number of HIV-infected adults with CD4+ T-cell counts less than 200 cu m, the plasma elimination half-life of the drug averaged 35-40 hours (range 22-75 hours).

The mean plasma half-life of fluconazole in children 9 months to 15 years of age has ranged from about 15-25 hours. In a limited study in premature neonates who received IV fluconazole once every 72 hours, the plasma half-life decreased over time, averaging 88 hours after the first dose and 55 hours after the fifth dose (day 13).

Fluconazole is metabolized minimally in the liver. Fluconazole is an inhibitor of CYP2C9, CYP3A4 and CYP2C19. Two metabolites were detected in the urine of healthy volunteers taking a 50 mg radiolabeled dose of fluconazole; a glucuronidated metabolite on the hydroxyl moiety (6.5%) and a fluconazole N-oxide metabolite (2%). The same study indicated that no signs of metabolic cleavage of fluconazole were observed, suggesting a difference in metabolism when compared to other agents in the same drug class, which are heavily metabolized in the liver.

Hepatic accounts for <10% of elimination

Hepatic Route of Elimination: In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Half Life: 30 hours (range 20-50 hours)

8VZV102JFY

FLUCONAZOLE

Established Pharmacologic Class [EPC] - Azole Antifungal

Chemical Structure [CS] - Azoles

Mechanisms of Action [MoA] - Cytochrome P450 2C19 Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.

Compounds that specifically inhibit STEROL 14-DEMETHYLASE. A variety of azole-derived ANTIFUNGAL AGENTS act through this mechanism.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C9.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C19.

The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached. Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours. Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole. **A note on the capsule and powder form and malabsorption syndromes** The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, _Lapp lactase enzyme_ deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and _sucrase-isomaltase_ enzyme deficiency.

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine. **A note on renal failure** The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%.

The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg. Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections. Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.

This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h). Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.

The pharmacokinetics of fluconazole are similar following IV or oral administration. The drug is rapidly and almost completely absorbed from the GI tract, and there is no evidence of first-pass metabolism. Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug generally are attained within 1-2 hours after oral administration. ... The rate and extent of GI absorption of fluconazole are not affected by food. The manufacturer states that the commercially available fluconazole suspensions are bioequivalent to the 100-mg fluconazole tablets.

Peak plasma fluconazole concentrations and AUCs increase in proportion to the dose over the oral dosage range of 50-400 mg. Steady-state plasma concentrations of fluconazole are attained within 5-10 days following oral doses of 50-400 mg given once daily. ... When fluconazole therapy is initiated with a single loading dose equal to twice the usual daily dosage and followed by the usual dosage given once daily thereafter, plasma concentrations of the drug reportedly approach steady state by the second day of therapy.

Mesh Heading: Antifungal agents

MEDICATION: Antifungal

MEDICATION (VET)

Use (kg) in Switzerland (2009): >100

For the treatment of fungal infections.

Trade names: Biozolene (Bioindustria), Diflucan (Mason, Pfizer, Roerig), Dimycon (Alkaloid), Elazor (Sigma-Tau), Flavizol (Gador), Fungata (Mack), Mutum (Raffo), Triflucan (Pfizer).

Fluconazole (DIFLUCAN) is marketed in the United States as tablets ... for oral administration, powder for oral suspension ... and iv solutions ... in saline and in dextrose solutions.

Oral: For suspension: 50 mg/5 mL Diflucan, (Pfizer), 200 mg/5 mL Diflucan, (Pfizer); Tablets: 50 mg* Diflucan (with povidone), (Pfizer), 100 mg Diflucan (with povidone), (Pfizer), 150 mg Diflucan (with povidone), (Pfizer), 200 mg Diflucan (with povidone), (Pfizer).