Fluconazole

J02A - Antimycotics for systemic use ATC J02AC01 Small molecule approved 1990 Oral Parenteral

JFDA label: Funzol 100 capsule

Mechanism of Action

Inhibitor of Lanosterol 14-alpha demethylase — Cytochrome P450 51 inhibitor

Target	Action	Gene / class
Lanosterol 14-alpha demethylase efficacy	INHIBITOR	ERG11

Indications

Off-label

Candida intertrigo
Candidiasis, empiric therapy (non-neutropenic patients in the ICU)
Coccidioidomycosis (non-HIV infected)
Cryptococcal pneumonia
Primary antifungal prophylaxis in pediatric oncology patients
Surgical prophylaxis (perioperative)

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Fungi

Organism	Activity	MIC
Candida albicans	Active	—
Candida dubliniensis	Active	—
Candida glabrata	Active	—
Candida guilliermondii	Active	—
Candida kefyr	Active	—
Candida krusei	Active	—
Candida lusitaniae	Active	—
Candida parapsilosis	Active	—
Candida tropicalis	Active	—
Cryptococcus neoformans	Active	—

Class profile

antifungalClass	Azole
targetMolecule	Lanosterol 14-alpha-demethylase (CYP51)
isFungicidal	0
spectrumCandida	S (not C.krusei/C.glabrata)
spectrumAspergillus	Resistant
spectrumCryptococcus	S
spectrumDermatophytes	Resistant
resistanceMechanisms	ERG11 mutations (Y132F/K143R/F145L),Efflux pumps (CDR1/CDR2/MDR1),Overexpression of CYP51
source	Pappas2016/Lass-Florl2011

Contraindications

Source: Curated · Lexicomp

Co-administration with QT-prolonging drugs metabolised by CYP3A4 (cisapride, astemizole) Absolute
Hypersensitivity to fluconazole or any component of the formulation (cross-reaction with other azole antifungal agents may occur, but has not been established Absolute
coadministration of terfenadine in adult patients receiving multiple doses of 400 mg or higher or with CYP3A4 substrates which may lead to QTc prolongation (eg, astemizole, cisapride, erythromycin, pimozide, or quinidine) Absolute
use caution) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Uncommon QT prolongation

Nervous system disorders (3)

Common Headache

Not Known dizziness · Headache

Hepatobiliary disorders (7)

Uncommon Elevated liver enzymes

Rare Serious hepatotoxicity (rare)

Not Known Hepatitis · increased serum alkaline phosphatase · increased serum ALT · increased serum AST · jaundice

Gastrointestinal disorders (7)

Common Nausea

Not Known abdominal pain · diarrhea · dysgeusia · dyspepsia · Nausea · vomiting

Skin and subcutaneous tissue disorders (2)

Uncommon Rash

Not Known Skin rash

Dosing

Source: Lexicomp

The daily dose of fluconazole is the same for both oral and IV administration Usual dosage range: Oral, IV: 150 mg once or Loading dose: 200 to 800 mg; maintenance: 200 to 800 mg once daily; duration and dosage depend on location and severity of infection Indication-specific dosing: Blastomycosis (off-label use): Oral: CNS disease: Consolidation: 800 mg daily for ≥12 months and until resolution of CSF abnormalities (Chapman 2008) Candidiasis: Candidemia (neutropenic and non-neutropenic patients) (off-label dose) (IDSA [Pappas 2016]): Oral, IV: Initial therapy (ie, first-line): Loading dose: 800 mg (12 mg/kg) on day 1, then 400 mg daily (6 mg/kg/day) for 14 days after first negative blood culture and resolution of signs/symptoms. Note: Not recommended as first-line therapy in patients with previous azole exposure, critical illness, or if at high risk of C. glabrata infection (elderly, diabetic, malignancy) Step down therapy (ie, after patient has responded to initial therapy): Oral: Isolates other than C. glabrata: 400 mg daily Isolates of C. glabrata (fluconazole-susceptible): 800 mg daily Duration: Continue for 14 days after first negative blood culture and resolution of signs/symptoms; step-down therapy to fluconazole (usually after 5 to 7 days in non-neutropenic patients) is recommended only in clinically stable patients with negative repeat cultures and fluconazole-susceptible isolates Chronic, disseminated (hepatosplenic) (fluconazole-susceptible isolates): Oral: 400 mg daily (6 mg/kg/day) following several weeks of initial therapy with an amphotericin B lipid formulation or an echinocandin. Continue fluconazole until lesion resolution (usually several months) (IDSA [Pappas 2016]) CNS candidiasis: Oral, IV: 400 to 800 mg daily (6 to 12 mg/kg/day) as step-down therapy following initial therapy with liposomal amphotericin B (with or without flucytosine); continue fluconazole until signs/symptoms and CSF/radiological abnormalities have resolved (IDSA [Pappas 2016]) Empiric therapy, suspected invasive candidiasis (non-neutropenic patients in the ICU) (alternative therapy) (off-label use): Oral, IV: Loading dose: 800 mg (12 mg/kg) on day 1, then 400 mg daily (6 mg/kg/day); treatment should continue for 14 days in patients with clinical improvement. Consider discontinuing after 4 to 5 days in patients with no clinical response. Note: Not recommended for patients with previous azole exposure or those colonized with azole-resistant Candida spp. (Pappas [IDSA 2016]) Endophthalmitis (with or without vitritis): Oral, IV: Loading dose: 800 mg (12 mg/kg) on day 1, then 400 to 800 mg daily (6 to 12 mg/kg/day) for at least 4 to 6 weeks until examination indicates resolution; for patients with vitritis or with macular involvement (with or without vitritis), an intravitreal injection with voriconazole or amphotericin B deoxycholate is also recommended (IDSA [Pappas 2016]) Esophageal: Oral, IV: Manufacturer’s labeling: Loading dose: 200 mg on day 1, then main

(For additional information see "Fluconazole: Pediatric drug information") The daily dose of fluconazole is the same for oral and IV administration Usual dosage range: Oral, IV: Loading dose: 6 to 12 mg/kg/dose; maintenance: 3 to 12 mg/kg/dose once daily; duration and dosage depend on location and severity of infection Indication-specific dosing: Candidiasis: Oral, IV: Esophageal: Manufacturer’s recommendation: Loading dose: 6 mg/kg/dose; maintenance: 3-12 mg/kg/dose once daily for 21 days and for at least 2 weeks following resolution of symptoms (maximum: 600 mg/day) HIV-exposed/-infected: Loading dose: 6 mg/kg/dose once on day 1; maintenance: 3 to 6 mg/kg/dose once daily for 4 to 21 days (maximum: 400 mg/day) (CDC 2009) Relapse suppression (HIV-exposed/-infected): 3 to 6 mg/kg/dose once daily (maximum: 200 mg/day) (CDC 2009) Invasive disease (alternative therapy): 5 to 6 mg/kg/dose every 12 hours for ≥28 days (maximum: 600 mg/day) (CDC 2009) Oropharyngeal: Manufacturer’s recommendation: Loading dose: 6 mg/kg/dose; maintenance: 3 mg/kg/dose once daily for ≥2 weeks (maximum: 600 mg/day) HIV-exposed/-infected: 3 to 6 mg/kg/dose once daily for 7 to 14 days (maximum: 400 mg/day) (CDC 2009) Surgical (perioperative) prophylaxis in high-risk patients undergoing liver, pancreas, kidney, or pancreas-kidney transplantation (off-label use): IV: 6 mg/kg given in the perioperative period and continued in the postoperative period for ≤28 days (maximum dose 400 mg). Time of initiation and duration varies with transplant type and operative protocol (Bratzler 2013). Coccidioidomycosis: Oral, IV: Children: Meningeal infection, or in a stable patient with diffuse pulmonary or disseminated disease (HIV-exposed/-infected): Treatment: 5 to 6 mg/kg/dose twice daily (maximum daily dose: 800 mg/day) (CDC 2009) followed by chronic suppressive therapy (see below) Relapse suppression: 6 mg/kg/dose once daily (maximum daily dose: 400 mg/day) (CDC 2009) Adolescents: Treatment, primary prophylaxis, or chronic suppressive therapy (secondary prophylaxis): Refer to adult dosing. Cryptococcosis: Oral, IV: Meningitis: Manufacturer's labeling: 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day for 10-12 weeks following negative CSF culture HIV-exposed/-infected: CNS disease (alternative therapy in patients intolerant of amphotericin B): Children: Induction: 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 800 mg/day) for ≥2 weeks (in combination with flucytosine) (CDC 2009) Consolidation: 10 to 12 mg/kg/day for 8 weeks (Perfect 2010) or 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 800 mg/day) for 8 weeks (CDC 2009) Maintenance (suppression): 6 mg/kg/day (maximum: 200 mg/day) (CDC 2009; Perfect 2010) Adolescents: Refer to adult dosing. Non-CNS disease, disseminated (including severe pulmonary disease) (alternative therapy; off-label use): Induction: 12 mg/kg/dose for 1 dose, then 6 to 12 mg/kg/day (maximum: 600 mg/day) (CDC 2009) Non-CNS disease, localized (inc

Refer to adult dosing.

Manufacturer's labeling: Note: Renal function estimated using the Cockcroft-Gault formula No adjustment for vaginal candidiasis single-dose therapy For multiple dosing in adults, administer loading dose of 50 to 400 mg, then adjust daily doses as follows (dosage reduction in children should parallel adult recommendations): CrCl >50 mL/minute: No dosage adjustment necessary CrCl ≤50 mL/minute (no dialysis): Reduce dose by 50% End-stage renal disease on intermittent hemodialysis (IHD): Manufacturer's labeling: 100% of daily dose (according to indication) after each dialysis session; on nondialysis days, patient should receive a reduced dose according to their CrCl. Alternate recommendations: Doses of 200 to 400 mg every 48 to 72 hours or 100 to 200 mg every 24 hours have been recommended. Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions (Heintz 2009). Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment: CVVH: Loading dose of 400 to 800 mg followed by 200 to 400 mg every 24 hours CVVHD/CVVHDF: Loading dose of 400 to 800 mg followed by 400 to 800 mg every 24 hours (CVVHD or CVVHDF) or 800 mg every 24 hours (CVVHDF) Note: Higher maintenance doses of 400 mg every 24 hours (CVVH), 800 mg every 24 hours (CVVHD), and 500 to 600 mg every 12 hours (CVVHDF) may be considered when treating resistant organisms and/or when employing combined ultrafiltration and dialysis flow rates of ≥2 L/hour for CVVHD/CVVHDF (Heintz 2009; Trotman 2005).

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Warnings & Precautions

Source: Lexicomp

Arrhythmias

Cases of QTc prolongation and torsade de pointes associated with fluconazole use have been reported (usually high dose or in combination with agents known to prolong the QT interval); use caution in patients with concomitant medications or conditions which are arrhythmogenic.

CNS effects

May occasionally cause dizziness or seizures; use caution driving or operating machinery.

Hepatotoxicity

Serious (and sometimes fatal) hepatic toxicity (eg, hepatitis, cholestasis, fulminant hepatic failure) has been observed. Monitor patients who develop abnormal liver function tests for the development of more severe hepatic injury; discontinue fluconazole if signs and symptoms consistent with liver disease develop.

Hypersensitivity reactions

Anaphylaxis has been reported rarely; use with caution in patients with hypersensitivity to other azoles.

Skin reactions

Rare exfoliative skin disorders have been observed; fatal outcomes have been reported in patients with serious concomitant diseases. Monitor patients with deep seated fungal infections closely for rash development and discontinue if lesions progress. In patients with superficial fungal infections who develop a rash attributable to fluconazole, treatment should also be discontinued. Disease-related concerns:

Hepatic impairment

Use with caution in patients with preexisting hepatic impairment; monitor liver function closely and discontinue if symptoms consistent with liver disease develop.

Renal impairment

Use with caution in patients with renal impairment; dosage adjustment may be necessary. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

Sucrose

Oral suspension contains sucrose; avoid use in patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.

Pregnancy & Lactation

Pregnancy

FDA category C Teratogenic

Caution

Single 150 mg dose for vaginal candidiasis generally considered acceptable (some guidelines prefer topical azoles). Avoid systemic courses > 150 mg total or prolonged treatment — use amphotericin B or topical azoles instead

Lactation

RID 5.0%

Fluconazole is present in breast milk at concentrations similar to maternal plasma concentrations (Force 1995; Schilling 1993). The relative infant dose (RID) of fluconazole is 5% to 21% when calculated using the highest breast milk concentration located and compared to an infant therapeutic dose of 3 to 12 mg/kg/day. In general, breastfeeding is considered acceptable when the RID is 25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000). The RID of fluconazole was calcula

Monitoring

Efficacy	Fungal culture and species identification; minimum inhibitory concentration (MIC) where available; clinical response (temperature, imaging for invasive fungal disease)
Toxicity	LFTs (hepatotoxicity — azoles in particular); renal function; ECG for QT prolongation (azoles); drug levels if available (itraconazole, voriconazole)
Clinical pearl	Voriconazole levels are highly variable due to CYP2C19 polymorphism — TDM recommended (target trough 2–5 mg/L). Check for drug interactions with CYP3A4 substrates.
Counseling	Report visual disturbances (voriconazole), jaundice, or rash. Take azoles with food or as directed to optimise absorption.

Chemistry & Properties

Formula	C13H12F2N6O
Molecular weight	306.28 g/mol
IUPAC name	2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol
CAS	86386-73-4
PubChem CID	3365
InChIKey	`RFHAOTPXVQNOHP-UHFFFAOYSA-N`
logP	0.74 (XLogP 0.4)
Polar surface area	81.65 Å²
H-bond acceptors / donors	7 / 1
Drug-likeness (QED)	0.75
Lipinski violations	0

SMILES

OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.22)

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Inhibitor	IC₅₀ 8.2 µM
CYP2C9	Inhibitor	IC₅₀ 23.18510067971863 µM
CYP3A4	Inhibitor	IC₅₀ 12.551116510287736 µM
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acalabrutinib	major
Acetohexamide	major
Alfentanil	major
Alprazolam	major
Amiodarone	major
Amisulpride	major
Anagrelide	major
Anisindione	major
Arsenic trioxide	major
Astemizole	major
Atorvastatin	major
Avanafil	major
Avapritinib	major
Avatrombopag	major
Bedaquiline	major
Benzhydrocodone	major
Bepridil	major
Bosutinib	major
Brexpiprazole	major
Brigatinib	major
Butorphanol	major
Cabozantinib	major
Ceritinib	major
Cerivastatin	major
Chloroquine	major
Chlorpropamide	major
Cilostazol	major
Cisapride	major
Citalopram	major
Clopidogrel	major
Clozapine	major
Cobimetinib	major
Colchicine	major
Crizotinib	major
Deflazacort	major
Dicoumarol	major
Disopyramide	major
Dofetilide	major
Dolasetron	major
Dronedarone	major

Showing 40 of 100+.

Registered Products (44)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Duracan	Capsule 150 mg	1 cap	شركة مستودع ادوية الايمان	2.910
Flucozal cap	Capsule 150 mg	1 cap	Ibn Rushd Drug Store	2.910
Oramax	Capsule 150 mg	1 cap	Professional Drug Store	2.920
Flucand 150 Capsules	Capsule 150 mg	1 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	3.520
FLUCOHEAL 150 CAPSULES	Capsule 150 mg	1 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	3.780
Fungimid Capsules	Capsule 150 mg	1 cap pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	3.890
Candivast capsule	Capsule 150 mg	1 cap	The Arab Pharmaceutical Manufacturing PSC/Salt	3.940
Diflazol Cap	Capsule 150 mg	1 cap pack varies	Hayat Pharmaceutical Industries CO.PLC/JORDAN	3.940
Flucover Tab.	Tablet 150 mg	1 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	3.940
Funzol 150 capsule	Capsule 150 mg	1 cap pack varies	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	3.940
Unizole Capsule	Capsule 150 mg	1 cap	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	3.940
DIFLUCAN CAPS	Capsule 150 mg	1 cap	Khoury Drug Store	4.150
Flucand 150 Capsules	Capsule 150 mg	2 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	6.690
FLUCOHEAL 150 CAPSULES	Capsule 150 mg	2 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	7.180
Fungimid Capsules	Capsule 150 mg	2 cap pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	7.390
Diflazol Cap	Capsule 150 mg	2 cap pack varies	Hayat Pharmaceutical Industries CO.PLC/JORDAN	7.490
Flucover Tab	Tablet 150 mg	2 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	7.490
Candivast capsule	Capsule 50 mg	7 cap	The Arab Pharmaceutical Manufacturing PSC/Salt	8.730
FLUCOHEAL 50 CAPSULES	Capsule 50 mg	7 cap	Dar Al Dawa Development and Investment Co Ltd/Jordan	8.730
Flucand 50 Capsules	Capsule 50 mg	7 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	8.730
Fungimid Capsules	Capsule 50 mg	7 cap pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	8.730
Funzol 50 capsule	Capsule 50 mg	7 cap	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	8.730
DIFLUCAN CAPS	Capsule 50 mg	7 cap	Khoury Drug Store	9.700
FLUCOHEAL 150 CAPSULES	Capsule 150 mg	4 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	12.000
Flucover Tab.	Tablet 150 mg	4 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	12.000
Diflazol Cap	Capsule 150 mg	4 cap pack varies	Hayat Pharmaceutical Industries CO.PLC/JORDAN	14.660
Funzol 100 capsule	Capsule 100 mg	7 cap	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	18.000
Fungimid Capsule	Capsule 200 mg	7 cap	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	35.470
Fungimid Capsules	Capsule 150 mg	1 cap pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	147.700
Fungimid Capsules	Capsule 50 mg	50 X 7 pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	371.030
Funzol 150 capsule	Capsule 150 mg	168 cap pack varies	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	562.630
Flucover Tab	Tablet 150 mg	500 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	1674.500
DIFLUCAN	Vial 200 mg/100 ml	1 vial	Khoury Drug Store	—
DIFLUCAN	Vial 100 mg/50 ml	1 vial	Khoury Drug Store	—
Exomax	Injection 2 mg/ml	100 ml	Khoury Drug Store	—
Flucand	Injection 2 mg/ml	200 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Flucand Infusion	Infusion 100 mg/50 ml	50 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Flucand Infusion	Infusion 200 mg/100 ml	100 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Fluconazole B.Braun	Injection 2 mg/ml	100 ml	THE ARAB DRUG STORE P.S.C	—
Flukas	Vial 100 mg/50 ml	1 vial	Al Wafi Drug Store	—
Flukas	Vial 200 mg/100 ml	1 vial	Professional Drug Store	—
Unizol 100mg/50ml Solution for Inj	Injection 2 mg/1 ml	1 Bag pack varies	MS PHARMA/JORDAN	—
Unizol 200/100ml Solution for Infusion	Infusion 2 mg/1 ml	100 ml pack varies	MS PHARMA/JORDAN	—
Unizol 400/200 ml Solution For Infusion	Infusion 2 mg/1 ml	1 bag pack varies	MS PHARMA/JORDAN	—