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Fluconazole

Fluconazole is an antifungal medication used for a number of fungal infections.[3] This includes candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor.[3] It is also used to prevent candidiasis in those who are at high risk such as following organ transplantation, low birth weight babies, and those with low blood neutrophil counts.[3] It is given either by mouth or by injection into a vein.[3]

Fluconazole
Clinical data
Trade namesDiflucan, others
AHFS/Drugs.comMonograph
MedlinePlusa690002
License data
Pregnancy
category
  • AU: D
Routes of
administration
By mouth, intravenous, topical
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only) / S4
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only[1]
Pharmacokinetic data
Bioavailability>90% (oral)
Protein binding11–12%
Metabolismliver 11%
Elimination half-life30 hours (range 20–50 hours)
Excretionkidney 61–88%
Identifiers
  • 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
CAS Number
  • 86386-73-4 Y
PubChem CID
  • 3365
DrugBank
  • DB00196 Y
ChemSpider
  • 3248 Y
UNII
  • 8VZV102JFY
KEGG
  • D00322 Y
  • C07002 Y
ChEBI
  • CHEBI:46081 Y
ChEMBL
  • ChEMBL106 Y
CompTox Dashboard (EPA)
  • DTXSID3020627
ECHA InfoCard100.156.133
Chemical and physical data
FormulaC13H12F2N6O
Molar mass306.277 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point139[2] °C (282 °F)
  • OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
  • InChI=1S/C13H12F2N6O/c14-10-1-2-11(12(15)3-10)13(22,4-20-8-16-6-18-20)5-21-9-17-7-19-21/h1-3,6-9,22H,4-5H2 Y
  • Key:RFHAOTPXVQNOHP-UHFFFAOYSA-N Y
  (verify)

Common side effects include vomiting, diarrhea, rash, and increased liver enzymes.[3] Serious side effects may include liver problems, QT prolongation, and seizures.[3] During pregnancy it may increase the risk of miscarriage while large doses may cause birth defects.[4][3] Fluconazole is in the azole antifungal family of medication.[3] It is believed to work by affecting the fungal cellular membrane.[3]

Fluconazole was patented in 1981 and came into commercial use in 1988.[5] It is on the World Health Organization's List of Essential Medicines.[6] Fluconazole is available as a generic medication.[3] In 2020, it was the 174th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8]

Medical uses Edit

Fluconazole is a first-generation triazole antifungal medication. It differs from earlier azole antifungals (such as ketoconazole) in that its structure contains a triazole ring instead of an imidazole ring. While the imidazole antifungals are mainly used topically, fluconazole and certain other triazole antifungals are preferred when systemic treatment is required because of their improved safety and predictable absorption when administered orally.[9]

Fluconazole's spectrum of activity includes most Candida species (but not Candida krusei or Candida glabrata), Cryptococcus neoformans, some dimorphic fungi, and dermatophytes, among others. Common uses include:[9][10][11][12][13]

  • The treatment of non-systemic Candida infections of the vagina ("yeast infections"), throat, and mouth.
  • Certain systemic Candida infections in people with healthy immune systems, including infections of the bloodstream, kidney, or joints. Other antifungals are usually preferred when the infection is in the heart or central nervous system, and for the treatment of active infections in people with weak immune systems.
  • The prevention of Candida infections in people with weak immune systems, such as those neutropenic due to cancer chemotherapy, those with advanced HIV infections, transplant patients, and premature infants.
  • As a second-line agent for the treatment of cryptococcal meningoencephalitis, a fungal infection of the central nervous system.

Resistance Edit

Antifungal resistance to drugs in the azole class tends to occur gradually over the course of prolonged drug therapy, resulting in clinical failure in immunocompromised patients (e.g., patients with advanced HIV receiving treatment for thrush or esophageal Candida infection).[14]

In C. albicans, resistance occurs by way of mutations in the ERG11 gene, which codes for 14α-demethylase. These mutations prevent the azole drug from binding, while still allowing binding of the enzyme's natural substrate, lanosterol. Development of resistance to one azole in this way will confer resistance to all drugs in the class. Another resistance mechanism employed by both C. albicans and C. glabrata is increasing the rate of efflux of the azole drug from the cell, by both ATP-binding cassette and major facilitator superfamily transporters. Other gene mutations are also known to contribute to development of resistance.[14] C. glabrata develops resistance by up regulating CDR genes, and resistance in C. krusei is mediated by reduced sensitivity of the target enzyme to inhibition by the agent.[15]

The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the TOKU-E's product data sheet.[16] According to the United States Centers for Disease Control, fluconazole resistance among Candida strains in the U.S. is about 7%.[17]

Contraindications Edit

Fluconazole is contraindicated in patients who:[13]

  • Drink alcohol
  • have known hypersensitivity to other azole medicines such as ketoconazole;
  • are taking terfenadine, if 400 mg per day multidose of fluconazole is administered;
  • concomitant administration of fluconazole and quinidine, especially when fluconazole is administered in high dosages;
  • take SSRIs such as fluoxetine or sertraline.

Side effects Edit

Adverse drug reactions associated with fluconazole therapy include:[13]

If taken during pregnancy it may result in harm.[19][20] These cases of harm, however, were only in women who took large doses for most of the first trimester.[19]

Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of fluconazole in lactating mothers is not recommended.[21]

Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus, it is used with caution in patients with risk factors for prolonged QT interval, such as electrolyte imbalance or use of other drugs that may prolong the QT interval (particularly cisapride and pimozide).[22]

Fluconazole has also rarely been associated with severe or lethal hepatotoxicity, so liver function tests are usually performed regularly during prolonged fluconazole therapy. In addition, it is used with caution in patients with pre-existing liver disease.[23]

Some people are allergic to azoles, so those allergic to other azole drugs might be allergic to fluconazole.[24] That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. [25]

Fluconazole taken at low doses is in FDA pregnancy category C. However, high doses have been associated with a rare and distinct set of birth defects in infants. If taken at these doses, the pregnancy category is changed from category C to category D. Pregnancy category D means there is positive evidence of human fetal risk based on human data. In some cases, the potential benefits from use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks. Fluconazole should not be taken during pregnancy or if one could become pregnant during treatment without first consulting a doctor.[26] Oral fluconazole is not associated with a significantly increased risk of birth defects overall, although it does increase the odds ratio of tetralogy of Fallot, but the absolute risk is still low.[27] Women using fluconazole during pregnancy have a 50% higher risk of spontaneous abortion.[28]

Fluconazole should not be taken with cisapride (Propulsid) due to the possibility of serious, even fatal, heart problems.[22] In rare cases, severe allergic reactions including anaphylaxis may occur.[29]

Powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption or sucrase-isomaltase deficiency. Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption [30]

Interactions Edit

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C19 (CYP3A4 and CYP2C9 to lesser extent) [31] In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes. In addition, its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval. Berberine has been shown to exert synergistic effects with fluconazole even in drug-resistant Candida albicans infections.[32] Fluconazole may increase the serum concentration of Erythromycin (Risk X: avoid combination).[31]

Pharmacology Edit

Pharmacodynamics Edit

Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols.[23] Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus.[33]

Pharmacokinetics Edit

Following oral dosing, fluconazole is almost completely absorbed within two hours.[34] Bioavailability is not significantly affected by the absence of stomach acid. Concentrations measured in the urine, tears, and skin are approximately 10 times the plasma concentration, whereas saliva, sputum, and vaginal fluid concentrations are approximately equal to the plasma concentration, following a standard dose range of between 100 mg and 400 mg per day.[35] The elimination half-life of fluconazole follows zero order, and only 10% of elimination is due to metabolism, the remainder being excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose.[22]

In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol.[36]

History Edit

Fluconazole was patented by Pfizer in 1981 in the United Kingdom and came into commercial use in 1988.[5] Patent expirations occurred in 2004 and 2005.[37]

References Edit

  1. ^ "Active substance: Fluconazole" (PDF). List of nationally authorised medicinal products. European Medicines Agency. 12 November 2020.
  2. ^ Surov AO, Voronin AP, Vasilev NA, Churakov AV, Perlovich GL (20 December 2019). "Cocrystals of Fluconazole with Aromatic Carboxylic Acids: Competition between Anhydrous and Hydrated Solid Forms". Crystal Growth & Design. 20 (2): 1218–1228. doi:10.1021/acs.cgd.9b01490. S2CID 213008181.
  3. ^ a b c d e f g h i j "Fluconazole". The American Society of Health-System Pharmacists. from the original on 20 December 2016. Retrieved 8 December 2016.
  4. ^ "Fluconazole (Diflucan): Drug Safety Communication - FDA Evaluating Study Examining Use of Oral Fluconazole (Diflucan) in Pregnancy". FDA. 26 April 2016. Retrieved 29 April 2016.
  5. ^ a b Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 503. ISBN 9783527607495. from the original on 10 September 2017.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  8. ^ "Fluconazole - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  9. ^ a b "US Pharmacist". from the original on 10 February 2015. Retrieved 28 January 2015.
  10. ^ "US Prescribing Information" (PDF). (PDF) from the original on 18 January 2017. Retrieved 28 January 2015.
  11. ^ . Archived from the original on 3 February 2015. Retrieved 28 January 2015.
  12. ^ . Archived from the original on 3 February 2015. Retrieved 28 January 2015.
  13. ^ a b c Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  14. ^ a b Bennett JE (2011). . In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). Archived from the original on 31 December 2013. Retrieved 22 May 2012.
  15. ^ "DIFLUCAN® (fluconazole)". Pfizer. March 2013. from the original on 4 March 2016. Retrieved 22 March 2016.
  16. ^ (PDF). Archived from the original (PDF) on 14 March 2016.
  17. ^ "Antifungal Resistance | Fungal Disease | CDC". 25 January 2019. from the original on 19 May 2017.
  18. ^ "FDA Alert: Diflucan (fluconazole): Drug Safety Communication - Long-term, High-dose Use During Pregnancy May be Associated with Birth Defects". from the original on 28 September 2011. Retrieved 4 August 2011.
  19. ^ a b "Fluconazole". Monograph. The American Society of Health-System Pharmacists. from the original on 27 September 2014. Retrieved 27 September 2014.
  20. ^ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. from the original on 8 April 2014. Retrieved 22 April 2014.
  21. ^ (PDF). Archived from the original (PDF) on 17 January 2010.
  22. ^ a b c Brunton LL, Knollmann BC, Hilal-Dandan R, eds. (2018). Goodman & Gilman's : the Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education LLC. ISBN 978-1-259-58473-2. OCLC 1075550900.
  23. ^ a b Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.
  24. ^ Pinto A, Chan RC (April 2009). "Lack of allergic cross-reactivity between fluconazole and voriconazole" (PDF). Antimicrobial Agents and Chemotherapy. 53 (4): 1715–1716. doi:10.1128/AAC.01500-08. PMC 2663085. PMID 19164151. (PDF) from the original on 11 June 2011. Retrieved 20 October 2009.
  25. ^ Kragie L, Turner SD, Patten CJ, Crespi CL, Stresser DM (August 2002). "Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay". Endocrine Research. 28 (3): 129–140. doi:10.1081/ERC-120015045. PMID 12489563. S2CID 8282678.
  26. ^ . PubMed Health. U.S. National Library of Medicine. Archived from the original on 5 December 2012.
  27. ^ Mølgaard-Nielsen D, Pasternak B, Hviid A (August 2013). "Use of oral fluconazole during pregnancy and the risk of birth defects". The New England Journal of Medicine. 369 (9): 830–839. doi:10.1056/NEJMoa1301066. PMID 23984730.
  28. ^ Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B (January 2016). "Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth". JAMA. 315 (1): 58–67. doi:10.1001/jama.2015.17844. PMID 26746458.
  29. ^ Rang HP. Rang & Dale's pharmacology. ISBN 978-0-7020-5362-7. OCLC 942814866.
  30. ^ . reference.medscape.com. Archived from the original on 23 April 2014.
  31. ^ a b "Login". from the original on 21 December 2016. Retrieved 21 December 2016.
  32. ^ Xu Y, Wang Y, Yan L, Liang RM, Dai BD, Tang RJ, et al. (November 2009). "Proteomic analysis reveals a synergistic mechanism of fluconazole and berberine against fluconazole-resistant Candida albicans: endogenous ROS augmentation". Journal of Proteome Research. 8 (11): 5296–5304. doi:10.1021/pr9005074. PMID 19754040.
  33. ^ Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, et al. (December 2008). "Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda". Clinical Infectious Diseases. 47 (12): 1556–1561. doi:10.1086/593194. PMID 18990067.
  34. ^ Katzung BG (30 November 2017). Basic & clinical pharmacology. ISBN 978-1-259-64115-2. OCLC 1035129378.
  35. ^ Whalen K, Feild C, Radhakrishnan R (21 September 2018). Whalen K, Feild C, Radhakrishnan R (eds.). Lippincott Illustrated Reviews Pharmacology. ISBN 978-1-4963-8413-3. OCLC 1114483879.
  36. ^ . MP Biomedicals. Archived from the original on 16 January 2009.
  37. ^ "Pfizer to Expand Fluconazole Donation Program to More than 50 Developing Nations". Kaiser Health News. 7 June 2001. Retrieved 18 June 2019.

Further reading Edit

  • Popp C, Ramírez-Zavala B, Schwanfelder S, Krüger I, Morschhäuser J (February 2019). "Evolution of Fluconazole-Resistant Candida albicans Strains by Drug-Induced Mating Competence and Parasexual Recombination". mBio. 10 (1). doi:10.1128/mBio.02740-18. PMC 6428756. PMID 30723130.

External links Edit

  • "Fluconazole". Drug Information Portal. U.S. National Library of Medicine.

fluconazole, antifungal, medication, used, number, fungal, infections, this, includes, candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, tinea, versicolor, also, used, prevent, candidiasis, those, high, risk, such. Fluconazole is an antifungal medication used for a number of fungal infections 3 This includes candidiasis blastomycosis coccidioidomycosis cryptococcosis histoplasmosis dermatophytosis and tinea versicolor 3 It is also used to prevent candidiasis in those who are at high risk such as following organ transplantation low birth weight babies and those with low blood neutrophil counts 3 It is given either by mouth or by injection into a vein 3 FluconazoleClinical dataTrade namesDiflucan othersAHFS Drugs comMonographMedlinePlusa690002License dataEU EMA by INN US DailyMed Fluconazole US FDA FluconazolePregnancycategoryAU DRoutes ofadministrationBy mouth intravenous topicalATC codeD01AC15 WHO J02AC01 WHO J01RA07 WHO Legal statusLegal statusAU S3 Pharmacist only S4 UK POM Prescription only US only EU Rx only 1 Pharmacokinetic dataBioavailability gt 90 oral Protein binding11 12 Metabolismliver 11 Elimination half life30 hours range 20 50 hours Excretionkidney 61 88 IdentifiersIUPAC name 2 2 4 Difluorophenyl 1 3 bis 1H 1 2 4 triazol 1 yl propan 2 olCAS Number86386 73 4 YPubChem CID3365DrugBankDB00196 YChemSpider3248 YUNII8VZV102JFYKEGGD00322 YC07002 YChEBICHEBI 46081 YChEMBLChEMBL106 YCompTox Dashboard EPA DTXSID3020627ECHA InfoCard100 156 133Chemical and physical dataFormulaC 13H 12F 2N 6OMolar mass306 277 g mol 13D model JSmol Interactive imageMelting point139 2 C 282 F SMILES OC Cn1cncn1 Cn1cncn1 c1ccc F cc1FInChI InChI 1S C13H12F2N6O c14 10 1 2 11 12 15 3 10 13 22 4 20 8 16 6 18 20 5 21 9 17 7 19 21 h1 3 6 9 22H 4 5H2 YKey RFHAOTPXVQNOHP UHFFFAOYSA N Y verify Common side effects include vomiting diarrhea rash and increased liver enzymes 3 Serious side effects may include liver problems QT prolongation and seizures 3 During pregnancy it may increase the risk of miscarriage while large doses may cause birth defects 4 3 Fluconazole is in the azole antifungal family of medication 3 It is believed to work by affecting the fungal cellular membrane 3 Fluconazole was patented in 1981 and came into commercial use in 1988 5 It is on the World Health Organization s List of Essential Medicines 6 Fluconazole is available as a generic medication 3 In 2020 it was the 174th most commonly prescribed medication in the United States with more than 3 million prescriptions 7 8 Contents 1 Medical uses 1 1 Resistance 2 Contraindications 3 Side effects 4 Interactions 5 Pharmacology 5 1 Pharmacodynamics 5 2 Pharmacokinetics 6 History 7 References 8 Further reading 9 External linksMedical uses EditFluconazole is a first generation triazole antifungal medication It differs from earlier azole antifungals such as ketoconazole in that its structure contains a triazole ring instead of an imidazole ring While the imidazole antifungals are mainly used topically fluconazole and certain other triazole antifungals are preferred when systemic treatment is required because of their improved safety and predictable absorption when administered orally 9 Fluconazole s spectrum of activity includes most Candida species but not Candida krusei or Candida glabrata Cryptococcus neoformans some dimorphic fungi and dermatophytes among others Common uses include 9 10 11 12 13 The treatment of non systemic Candida infections of the vagina yeast infections throat and mouth Certain systemic Candida infections in people with healthy immune systems including infections of the bloodstream kidney or joints Other antifungals are usually preferred when the infection is in the heart or central nervous system and for the treatment of active infections in people with weak immune systems The prevention of Candida infections in people with weak immune systems such as those neutropenic due to cancer chemotherapy those with advanced HIV infections transplant patients and premature infants As a second line agent for the treatment of cryptococcal meningoencephalitis a fungal infection of the central nervous system Resistance Edit Antifungal resistance to drugs in the azole class tends to occur gradually over the course of prolonged drug therapy resulting in clinical failure in immunocompromised patients e g patients with advanced HIV receiving treatment for thrush or esophageal Candida infection 14 In C albicans resistance occurs by way of mutations in the ERG11 gene which codes for 14a demethylase These mutations prevent the azole drug from binding while still allowing binding of the enzyme s natural substrate lanosterol Development of resistance to one azole in this way will confer resistance to all drugs in the class Another resistance mechanism employed by both C albicans and C glabrata is increasing the rate of efflux of the azole drug from the cell by both ATP binding cassette and major facilitator superfamily transporters Other gene mutations are also known to contribute to development of resistance 14 C glabrata develops resistance by up regulating CDR genes and resistance in C krusei is mediated by reduced sensitivity of the target enzyme to inhibition by the agent 15 The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the TOKU E s product data sheet 16 According to the United States Centers for Disease Control fluconazole resistance among Candida strains in the U S is about 7 17 Contraindications EditFluconazole is contraindicated in patients who 13 Drink alcohol have known hypersensitivity to other azole medicines such as ketoconazole are taking terfenadine if 400 mg per day multidose of fluconazole is administered concomitant administration of fluconazole and quinidine especially when fluconazole is administered in high dosages take SSRIs such as fluoxetine or sertraline Side effects EditAdverse drug reactions associated with fluconazole therapy include 13 Common 1 of patients rash headache dizziness nausea vomiting abdominal pain diarrhea and or elevated liver enzymes Infrequent 0 1 1 of patients anorexia fatigue constipation Rare lt 0 1 of patients oliguria hypokalaemia paraesthesia seizures alopecia Stevens Johnson syndrome thrombocytopenia other blood dyscrasias serious hepatotoxicity including liver failure anaphylactic anaphylactoid reactions Very rare prolonged QT interval torsades de pointes FDA is now saying treatment with chronic high doses of fluconazole during the first trimester of pregnancy may be associated with a rare and distinct set of birth defects in infants 18 If taken during pregnancy it may result in harm 19 20 These cases of harm however were only in women who took large doses for most of the first trimester 19 Fluconazole is secreted in human milk at concentrations similar to plasma Therefore the use of fluconazole in lactating mothers is not recommended 21 Fluconazole therapy has been associated with QT interval prolongation which may lead to serious cardiac arrhythmias Thus it is used with caution in patients with risk factors for prolonged QT interval such as electrolyte imbalance or use of other drugs that may prolong the QT interval particularly cisapride and pimozide 22 Fluconazole has also rarely been associated with severe or lethal hepatotoxicity so liver function tests are usually performed regularly during prolonged fluconazole therapy In addition it is used with caution in patients with pre existing liver disease 23 Some people are allergic to azoles so those allergic to other azole drugs might be allergic to fluconazole 24 That is some azole drugs have adverse side effects Some azole drugs may disrupt estrogen production in pregnancy affecting pregnancy outcome 25 Fluconazole taken at low doses is in FDA pregnancy category C However high doses have been associated with a rare and distinct set of birth defects in infants If taken at these doses the pregnancy category is changed from category C to category D Pregnancy category D means there is positive evidence of human fetal risk based on human data In some cases the potential benefits from use of the drug in pregnant women with serious or life threatening conditions may be acceptable despite its risks Fluconazole should not be taken during pregnancy or if one could become pregnant during treatment without first consulting a doctor 26 Oral fluconazole is not associated with a significantly increased risk of birth defects overall although it does increase the odds ratio of tetralogy of Fallot but the absolute risk is still low 27 Women using fluconazole during pregnancy have a 50 higher risk of spontaneous abortion 28 Fluconazole should not be taken with cisapride Propulsid due to the possibility of serious even fatal heart problems 22 In rare cases severe allergic reactions including anaphylaxis may occur 29 Powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose glucose galactose malabsorption or sucrase isomaltase deficiency Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance Lapp lactase deficiency or glucose galactose malabsorption 30 Interactions EditFluconazole is an inhibitor of the human cytochrome P450 system particularly the isozyme CYP2C19 CYP3A4 and CYP2C9 to lesser extent 31 In theory therefore fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes In addition its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval Berberine has been shown to exert synergistic effects with fluconazole even in drug resistant Candida albicans infections 32 Fluconazole may increase the serum concentration of Erythromycin Risk X avoid combination 31 Pharmacology EditPharmacodynamics Edit Like other imidazole and triazole class antifungals fluconazole inhibits the fungal cytochrome P450 enzyme 14a demethylase Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase This inhibition prevents the conversion of lanosterol to ergosterol an essential component of the fungal cytoplasmic membrane and subsequent accumulation of 14a methyl sterols 23 Fluconazole is primarily fungistatic however it may be fungicidal against certain organisms in a dose dependent manner specifically Cryptococcus 33 Pharmacokinetics Edit Following oral dosing fluconazole is almost completely absorbed within two hours 34 Bioavailability is not significantly affected by the absence of stomach acid Concentrations measured in the urine tears and skin are approximately 10 times the plasma concentration whereas saliva sputum and vaginal fluid concentrations are approximately equal to the plasma concentration following a standard dose range of between 100 mg and 400 mg per day 35 The elimination half life of fluconazole follows zero order and only 10 of elimination is due to metabolism the remainder being excreted in urine and sweat Patients with impaired renal function will be at risk of overdose 22 In a bulk powder form it appears as a white crystalline powder and it is very slightly soluble in water and soluble in alcohol 36 History EditFluconazole was patented by Pfizer in 1981 in the United Kingdom and came into commercial use in 1988 5 Patent expirations occurred in 2004 and 2005 37 References Edit Active substance Fluconazole PDF List of nationally authorised medicinal products European Medicines Agency 12 November 2020 Surov AO Voronin AP Vasilev NA Churakov AV Perlovich GL 20 December 2019 Cocrystals of Fluconazole with Aromatic Carboxylic Acids Competition between Anhydrous and Hydrated Solid Forms Crystal Growth amp Design 20 2 1218 1228 doi 10 1021 acs cgd 9b01490 S2CID 213008181 a b c d e f g h i j Fluconazole The American Society of Health System Pharmacists Archived from the original on 20 December 2016 Retrieved 8 December 2016 Fluconazole Diflucan Drug Safety Communication FDA Evaluating Study Examining Use of Oral Fluconazole Diflucan in Pregnancy FDA 26 April 2016 Retrieved 29 April 2016 a b Fischer J Ganellin CR 2006 Analogue based Drug Discovery John Wiley amp Sons p 503 ISBN 9783527607495 Archived from the original on 10 September 2017 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO The Top 300 of 2020 ClinCalc Retrieved 7 October 2022 Fluconazole Drug Usage Statistics ClinCalc Retrieved 7 October 2022 a b US Pharmacist Archived from the original on 10 February 2015 Retrieved 28 January 2015 US Prescribing Information PDF Archived PDF from the original on 18 January 2017 Retrieved 28 January 2015 IDSA Guidelines Candida Infections Archived from the original on 3 February 2015 Retrieved 28 January 2015 IDSA Guidelines Cryptococcal Infections Archived from the original on 3 February 2015 Retrieved 28 January 2015 a b c Rossi S editor Australian Medicines Handbook 2006 Adelaide Australian Medicines Handbook 2006 ISBN 0 9757919 2 3 a b Bennett JE 2011 Chapter 57 Antifungal Agents In Brunton LL Chabner BA Knollmann BC eds Goodman amp Gilman s The Pharmacological Basis of Therapeutics 12th ed Archived from the original on 31 December 2013 Retrieved 22 May 2012 DIFLUCAN fluconazole Pfizer March 2013 Archived from the original on 4 March 2016 Retrieved 22 March 2016 Spectrum of fungal susptibility and resistance to fluconazole PDF Archived from the original PDF on 14 March 2016 Antifungal Resistance Fungal Disease CDC 25 January 2019 Archived from the original on 19 May 2017 FDA Alert Diflucan fluconazole Drug Safety Communication Long term High dose Use During Pregnancy May be Associated with Birth Defects Archived from the original on 28 September 2011 Retrieved 4 August 2011 a b Fluconazole Monograph The American Society of Health System Pharmacists Archived from the original on 27 September 2014 Retrieved 27 September 2014 Prescribing medicines in pregnancy database Australian Government 3 March 2014 Archived from the original on 8 April 2014 Retrieved 22 April 2014 Product information from Pfizer Inc PDF Archived from the original PDF on 17 January 2010 a b c Brunton LL Knollmann BC Hilal Dandan R eds 2018 Goodman amp Gilman s the Pharmacological Basis of Therapeutics 13th ed McGraw Hill Education LLC ISBN 978 1 259 58473 2 OCLC 1075550900 a b Pfizer Australia Pty Ltd Diflucan Australian Approved Product Information West Ryde NSW Pfizer Australia 2004 Pinto A Chan RC April 2009 Lack of allergic cross reactivity between fluconazole and voriconazole PDF Antimicrobial Agents and Chemotherapy 53 4 1715 1716 doi 10 1128 AAC 01500 08 PMC 2663085 PMID 19164151 Archived PDF from the original on 11 June 2011 Retrieved 20 October 2009 Kragie L Turner SD Patten CJ Crespi CL Stresser DM August 2002 Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay Endocrine Research 28 3 129 140 doi 10 1081 ERC 120015045 PMID 12489563 S2CID 8282678 Fluconazole PubMed Health U S 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resistant Candida albicans endogenous ROS augmentation Journal of Proteome Research 8 11 5296 5304 doi 10 1021 pr9005074 PMID 19754040 Longley N Muzoora C Taseera K Mwesigye J Rwebembera J Chakera A et al December 2008 Dose response effect of high dose fluconazole for HIV associated cryptococcal meningitis in southwestern Uganda Clinical Infectious Diseases 47 12 1556 1561 doi 10 1086 593194 PMID 18990067 Katzung BG 30 November 2017 Basic amp clinical pharmacology ISBN 978 1 259 64115 2 OCLC 1035129378 Whalen K Feild C Radhakrishnan R 21 September 2018 Whalen K Feild C Radhakrishnan R eds Lippincott Illustrated Reviews Pharmacology ISBN 978 1 4963 8413 3 OCLC 1114483879 Fluconazole MP Biomedicals Archived from the original on 16 January 2009 Pfizer to Expand Fluconazole Donation Program to More than 50 Developing Nations Kaiser Health News 7 June 2001 Retrieved 18 June 2019 Further reading EditPopp C Ramirez Zavala B Schwanfelder S Kruger I Morschhauser J February 2019 Evolution of Fluconazole Resistant Candida albicans Strains by Drug Induced Mating Competence and Parasexual Recombination mBio 10 1 doi 10 1128 mBio 02740 18 PMC 6428756 PMID 30723130 External links Edit Fluconazole Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Fluconazole amp oldid 1178776794, wikipedia, wiki, book, books, library,

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