An Expert Monograph on Fluconazole (DB00196)

Authored by a Senior Clinical Pharmacologist

Executive Summary

Fluconazole (DrugBank ID: DB00196) is a first-generation synthetic triazole antifungal agent that represents a cornerstone in the management of both superficial and life-threatening systemic mycoses. Since its approval by the U.S. Food and Drug Administration (FDA) in 1990, it has remained a widely prescribed medication, valued for its efficacy, convenient dosing, and availability in both oral and intravenous formulations. Its mechanism of action involves the highly selective inhibition of fungal cytochrome P450-dependent enzyme lanosterol 14-α-demethylase, a critical step in the biosynthesis of ergosterol. The subsequent disruption of fungal cell membrane integrity results in a primarily fungistatic effect against a broad spectrum of yeasts and dimorphic fungi.

The clinical utility of fluconazole is profoundly influenced by its exceptional pharmacokinetic profile, characterized by near-complete oral bioavailability (>90%), low plasma protein binding (11-12%), and extensive distribution into body tissues and fluids, including remarkable penetration into the cerebrospinal fluid (CSF). This latter property revolutionized the treatment of cryptococcal meningitis, enabling a shift from toxic parenteral therapies to effective oral management. The drug's long elimination half-life of approximately 30 hours facilitates convenient once-daily dosing. Elimination is predominantly renal, with about 80% of the drug excreted unchanged in the urine, a characteristic that necessitates dose adjustments in patients with renal impairment.

Fluconazole is indicated for the treatment of various forms of candidiasis, including oropharyngeal, esophageal, and vulvovaginal disease, as well as systemic infections like candidemia. It is a primary agent for the treatment and long-term suppression of cryptococcal meningitis and serves as a crucial prophylactic agent against candidiasis in immunocompromised hosts, such as bone marrow transplant recipients.

Despite its benefits, the use of fluconazole requires a thorough understanding of its significant safety considerations. The drug carries a prominent warning for hepatotoxicity, with rare but serious cases of liver failure reported, particularly in patients with severe underlying illnesses. Another major concern is its potential to prolong the QT interval, creating a risk of life-threatening cardiac arrhythmias like Torsades de Pointes, especially in patients with pre-existing risk factors or on concomitant QT-prolonging medications. Furthermore, chronic high-dose fluconazole use during the first trimester of pregnancy is associated with a specific pattern of congenital anomalies, making its use in this population a matter of careful risk-benefit assessment. Finally, as a potent inhibitor of cytochrome P450 enzymes CYP2C9 and CYP2C19 and a moderate inhibitor of CYP3A4, fluconazole is implicated in numerous clinically significant drug-drug interactions, requiring vigilant medication review and management. Its enduring position on the World Health Organization's List of Essential Medicines underscores its global importance, balanced by the clinical diligence required for its safe and effective use.

1.0 Introduction and Drug Classification

1.1 Historical Context and Development

Fluconazole, a synthetic antifungal agent, was patented by Pfizer in 1981 and received its initial approval from the U.S. Food and Drug Administration (FDA) in 1990.[1] Its introduction represented a significant therapeutic advance in the field of medical mycology. It emerged at a time when the therapeutic options for serious fungal infections were limited and often associated with substantial toxicity, primarily dominated by parenteral amphotericin B. Fluconazole offered a novel, effective, and safer alternative for a range of fungal diseases.[3]

1.2 Classification as a First-Generation Triazole Antifungal

Fluconazole is classified as a first-generation, fluorine-substituted, bis-triazole antifungal agent.[2] This classification is based on its core chemical structure, which features a five-membered triazole ring containing three nitrogen atoms. This structure distinguishes it from the earlier class of azole antifungals, the imidazoles (e.g., ketoconazole), which contain an imidazole ring with two nitrogen atoms.[2]

This structural distinction is not merely academic; it is the basis for fluconazole's improved pharmacological profile. The triazole ring confers a higher degree of selectivity for fungal cytochrome P450 enzymes over their mammalian counterparts.[3] This enhanced selectivity translates directly into a more favorable safety profile, particularly a reduced propensity to inhibit human steroidogenesis, thereby minimizing the endocrine-related adverse effects that were a significant limitation of earlier agents like ketoconazole.[3] Furthermore, this structural class is associated with improved physicochemical properties, such as predictable and high oral absorption, which enabled reliable systemic therapy with an oral agent—a capability largely absent in the preceding imidazole class, which was mainly confined to topical applications.[2] The development of fluconazole thus marked a paradigm shift, moving the treatment of many systemic fungal infections from the inpatient setting, reliant on intravenous infusions, to the outpatient setting with a convenient oral medication.

1.3 Position in Modern Antifungal Therapy and Global Health

More than three decades after its introduction, fluconazole remains a cornerstone of the global antifungal armamentarium.[6] Its enduring relevance stems from a combination of factors: proven efficacy against common fungal pathogens, a predictable pharmacokinetic profile, and the flexibility of administration via both oral and intravenous routes.[1] It is frequently used as the standard-of-care comparator in clinical trials for new antifungal drugs, a testament to its established role as a therapeutic benchmark.[7]

The global importance of fluconazole is formally recognized by its inclusion on the World Health Organization's List of Essential Medicines, a compilation of medications considered crucial for meeting the most important needs in a health system.[2] Its widespread clinical use is further evidenced by prescription statistics; in 2022, fluconazole was the 160th most commonly prescribed medication in the United States, with over 3 million prescriptions filled.[2] This sustained, high-volume use underscores its continued utility in treating a spectrum of infections ranging from common mucosal candidiasis to life-threatening cryptococcal meningitis.

2.0 Physicochemical Properties

The identity, purity, and formulation of a pharmaceutical agent are fundamentally defined by its chemical and physical properties. This section details the physicochemical characteristics of fluconazole.

2.1 Chemical Identification and Nomenclature

Fluconazole is identified by a standardized set of names and codes to ensure unambiguous recognition in clinical, regulatory, and research settings.

• International Union of Pure and Applied Chemistry (IUPAC) Name: The systematic chemical name for fluconazole is 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol.[1]
• CAS Registry Number: The unique identifier assigned by the Chemical Abstracts Service is 86386-73-4.[1] A deprecated CAS number, 123631-92-5, has also been recorded.[1]
• DrugBank Accession Number: The drug is cataloged in the DrugBank database under the accession ID DB00196.[1]
• Other Identifiers: Additional identifiers used across various databases and regulatory systems include:
• UNII (Unique Ingredient Identifier): 8VZV102JFY [1]
• ChEBI (Chemical Entities of Biological Interest) ID: CHEBI:46081 [1]
• ChEMBL ID: CHEMBL106 [1]
• Manufacturers' Codes: UK-49858 [11]
• Synonyms and Trade Names: The drug is known by several synonyms, including Fluconazol and the Latin Fluconazolum.[8] It is marketed globally under numerous trade names, the most widely recognized of which are Diflucan and Triflucan (Pfizer), as well as Biozolene and Elazor.[1]

2.2 Molecular Structure and Formula

Fluconazole's chemical structure dictates its mechanism of action and pharmacokinetic properties.

• Chemical Structure: Structurally, fluconazole is a tertiary alcohol. The core is a propan-2-ol molecule that is symmetrically substituted at the first and third positions with 1H-1,2,4-triazol-1-yl groups. The second position of the propane backbone is asymmetrically substituted with a 2,4-difluorophenyl group.[1] This arrangement classifies it as a difluorobenzene and a conazole antifungal drug.[1]
• Molecular Formula: The empirical formula for fluconazole is C13​H12​F2​N6​O.[2]
• Molecular Weight: The calculated molar mass is consistently reported in the range of 306.27 g/mol to 306.3 g/mol.[1]

2.3 Physical Characteristics

• Appearance: In its pure form, fluconazole is a white to off-white crystalline solid or powder.[1]
• Melting Point: The melting point of the crystalline solid is in the range of 138–140 °C.[1]
• Solubility: Fluconazole is described as slightly soluble in water.[1] Quantitative analysis shows its solubility in phosphate-buffered saline (PBS) at a physiological pH of 7.2 is approximately 0.2 mg/mL.[14] It demonstrates much greater solubility in various organic solvents, a property crucial for the preparation of laboratory stock solutions and intravenous formulations. Its solubility is approximately 33 mg/mL in dimethyl sulfoxide (DMSO), 20 mg/mL in ethanol, and 16 mg/mL in dimethylformamide (DMF).[14]

The fundamental physicochemical properties are summarized in Table 1 for ease of reference.

Table 1: Key Chemical and Physical Identifiers of Fluconazole

Property	Value	Source(s)
IUPAC Name	2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol	1
CAS Number	86386-73-4	1
DrugBank ID	DB00196	1
Molecular Formula	C13​H12​F2​N6​O	2
Molecular Weight	306.27–306.3 g/mol	2
Appearance	White to off-white crystalline solid/powder	1
Melting Point	138–140 °C	1
Solubility in Water	Slightly soluble	1
Solubility in PBS (pH 7.2)	~0.2 mg/mL	14
Solubility in DMSO	~33 mg/mL	14
Solubility in Ethanol	~20 mg/mL	14
Common Trade Names	Diflucan, Triflucan	1

3.0 Clinical Pharmacology

The therapeutic effect of any drug is a direct consequence of its interaction with biological targets. This section details the mechanism of action, pharmacodynamic effects, and spectrum of activity of fluconazole.

3.1 Mechanism of Action: Selective Inhibition of Fungal Cytochrome P450 14-α-Demethylase

The primary pharmacological target of fluconazole is the fungal cytochrome P450 (CYP) enzyme, lanosterol 14-α-demethylase.[3] This enzyme plays an indispensable role in the fungal sterol biosynthesis pathway. Specifically, it catalyzes the oxidative removal of a methyl group from lanosterol, a critical step in its conversion to ergosterol.[6] Fluconazole, through the nitrogen atoms in its triazole rings, binds to the heme iron atom in the active site of the fungal enzyme, potently and selectively inhibiting its function.[3]

The clinical success and favorable safety profile of fluconazole are fundamentally dependent on its high degree of selectivity for the fungal P450 enzyme over analogous mammalian P450 enzymes. While both fungal and human cells utilize P450 systems for sterol synthesis, fluconazole's molecular configuration allows it to bind with substantially greater affinity to the fungal target than to the human enzymes responsible for cholesterol and steroid hormone synthesis.[3] This selectivity creates a wide therapeutic window, permitting the administration of doses sufficient to disrupt fungal cell processes while largely sparing host cell functions. This was a major improvement over older, less selective azoles like ketoconazole, which had a greater propensity for inhibiting human steroidogenesis, leading to dose-limiting endocrine adverse effects.[3]

3.2 Pharmacodynamic Effects: Disruption of Ergosterol Synthesis and Fungal Membrane Integrity

Ergosterol is the principal sterol in the fungal cell membrane, where it serves a function analogous to that of cholesterol in mammalian cell membranes: maintaining structural integrity, fluidity, and the proper function of membrane-bound enzymes.[5] By inhibiting lanosterol 14-α-demethylase, fluconazole effectively blocks the production of ergosterol.[5]

This blockade has two major downstream consequences for the fungal cell. First, the depletion of ergosterol compromises the physical integrity of the cell membrane. Second, the enzymatic block leads to the intracellular accumulation of lanosterol and other 14-alpha-methylated sterol precursors.[5] These precursor sterols are toxic to the cell; their abnormal incorporation into the membrane further disrupts its structure and function, leading to increased permeability and the leakage of essential intracellular components.[4]

Collectively, these effects arrest the growth and replication of the fungus. For Candida species, this action is primarily considered fungistatic, meaning it inhibits growth rather than actively killing the fungal cells.[5] This distinction has important clinical implications. The ultimate clearance of the infection relies on a competent host immune system to eliminate the inhibited, non-replicating pathogens. In immunocompromised patients, such as those with advanced HIV or undergoing chemotherapy, the host immune response is impaired. Consequently, fungistatic activity alone may be insufficient for complete eradication, which explains the necessity for longer treatment courses and, in many cases, long-term suppressive (maintenance) therapy to prevent the relapse of infections like cryptococcal meningitis or recurrent candidiasis.[2]

Additional, secondary mechanisms may contribute to fluconazole's antifungal effect, including the inhibition of endogenous respiration and the inhibition of the yeast-to-hyphae morphological transition, a key step in the invasion of host tissues by some fungi.[4]

3.3 Spectrum of Activity

Fluconazole is a broad-spectrum antifungal agent, though its activity is most pronounced against yeasts and certain endemic fungi.[3] Its clinical spectrum includes:

• Highly Susceptible Organisms: Fluconazole demonstrates excellent activity against most Candida species, particularly Candida albicans, Candida parapsilosis, and Candida tropicalis. It is also highly active against Cryptococcus neoformans. Furthermore, it is effective against many of the dimorphic fungi that cause endemic mycoses, including Blastomyces dermatitidis, Coccidioides immitis (the causative agent of Valley Fever), and Histoplasma capsulatum.[2]
• Organisms with Variable or Intrinsic Resistance: The spectrum of fluconazole is not all-encompassing. It has notably less activity against Candida glabrata, which often exhibits dose-dependent susceptibility or acquired resistance.[2] It possesses no clinically useful activity against Candida krusei, which is considered intrinsically resistant to fluconazole.[2] Similarly, its activity against filamentous molds, such as Aspergillus species, is limited, and it is not used for the treatment of aspergillosis.[3]

4.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The movement of fluconazole through the human body—its absorption, distribution, metabolism, and excretion (ADME)—is a defining feature of the drug and central to its clinical success and utility. Its pharmacokinetic profile is characterized by predictability, convenience, and excellent tissue penetration.

4.1 Absorption and Bioavailability

Following oral administration, fluconazole is absorbed rapidly and almost completely from the gastrointestinal tract.[29] Its absolute oral bioavailability is exceptionally high, consistently reported to be greater than 90% when compared to intravenous administration.[29] This near-perfect bioavailability means that the drug largely escapes first-pass metabolism in the gut wall and liver, ensuring that oral doses achieve systemic exposure nearly identical to that of intravenous doses.[29] This property has a direct and significant clinical benefit: it allows for equivalent daily doses for both oral and IV routes, facilitating a seamless transition (or "step-down") from parenteral to oral therapy without the need for dose adjustment, which simplifies treatment regimens and enables earlier hospital discharge.[29]

Peak plasma concentrations (Cmax​) are typically reached within 1 to 2 hours after an oral dose.[29] Furthermore, the absorption of fluconazole is not significantly affected by the presence of food or by changes in gastric pH (e.g., from antacids), which provides valuable flexibility in dosing administration relative to meals.[29]

4.2 Distribution

Fluconazole distributes extensively throughout the body, a property facilitated by its low degree of binding to plasma proteins, which is only 11-12%.[3] This low binding means a large fraction of the drug in circulation is unbound and free to diffuse from the bloodstream into tissues. The apparent volume of distribution (

Vd​) is approximately 0.7 L/kg, which is close to the volume of total body water, indicating that the drug does not merely remain in the vascular compartment but penetrates widely into body tissues and fluids.[29]

The drug's ability to penetrate specialized compartments is particularly noteworthy. It achieves therapeutic concentrations in saliva, sputum, skin, nails, and vaginal fluids.[5] Most critically, fluconazole readily crosses the blood-brain barrier and penetrates the central nervous system (CNS). In patients with fungal meningitis, concentrations in the cerebrospinal fluid (CSF) reach 50% to 90% of simultaneous plasma concentrations.[3] This combination of high oral bioavailability and excellent CNS penetration represents a unique "pharmacokinetic trifecta" that revolutionized the management of CNS fungal infections. Before fluconazole, treating conditions like cryptococcal meningitis necessitated prolonged and toxic intravenous therapy with agents like amphotericin B.[3] Fluconazole enabled, for the first time, effective and long-term suppressive therapy with a well-tolerated oral agent, transforming the standard of care and dramatically improving patient quality of life.

4.3 Metabolism

In contrast to many other azole antifungals, fluconazole is metabolically stable and undergoes minimal biotransformation in the liver.[5] This lack of significant metabolism contributes to its predictable pharmacokinetics, as its clearance is less dependent on the highly variable function of hepatic enzymes.

4.4 Elimination and Half-Life

The primary route of elimination for fluconazole is via the kidneys.[3] Approximately 80% of an administered dose is excreted as unchanged, active drug in the urine.[3] This predominantly renal clearance of the parent drug is a double-edged sword. On one hand, it minimizes the impact of liver disease on the drug's pharmacokinetics and leads to high concentrations of active drug in the urinary tract, making it effective for treating susceptible

Candida urinary tract infections.[5] On the other hand, it makes the drug's clearance almost entirely dependent on renal function, meaning that any degree of kidney impairment can lead to drug accumulation and an increased risk of dose-related toxicity.[26]

Fluconazole possesses a long terminal plasma elimination half-life (t1/2​), which averages around 30 hours, with a reported range of 22 to 32 hours.[3] This long half-life is the pharmacokinetic basis for the convenient once-daily dosing regimen used for most indications, which enhances patient adherence.[6]

4.5 Pharmacokinetics in Special Populations

• Renal Impairment: As expected from its primary route of elimination, the pharmacokinetics of fluconazole are significantly altered in patients with renal dysfunction. A reduction in renal function leads to decreased drug clearance and a prolonged half-life, necessitating dose adjustments to prevent accumulation.[5] Fluconazole is effectively removed by hemodialysis; a standard 3-hour session reduces plasma concentrations by approximately 50%.[32]
• Critically Ill Patients: The pharmacokinetics of fluconazole can be highly variable in critically ill patient populations. Studies have demonstrated significant inter- and intra-subject variability in drug exposure, with a notable proportion of patients failing to achieve target therapeutic trough concentrations.[35] Pathophysiological changes in this population, such as augmented renal clearance (ARC) or the need for continuous renal replacement therapy (CRRT), are major covariates that influence drug exposure and may necessitate therapeutic drug monitoring to ensure efficacy.[35]

Table 2 provides a summary of key pharmacokinetic parameters and their clinical relevance.

Table 2: Summary of Key Pharmacokinetic Parameters for Fluconazole

Parameter	Value	Clinical Implication	Source(s)
Oral Bioavailability	>90%	Allows for oral and IV doses to be considered equivalent, facilitating easy IV-to-PO step-down therapy.	29
Time to Peak Plasma Conc. (Tmax​)	1–2 hours	Indicates rapid absorption after oral administration.	29
Plasma Protein Binding	11–12%	Low binding contributes to extensive distribution of free, active drug into tissues and body fluids.	3
Volume of Distribution (Vd​)	~0.7 L/kg	Wide distribution throughout total body water, including excellent penetration into the CNS, saliva, and skin.	29
CSF:Plasma Ratio	0.5–0.9 (50–90%)	Achieves high, therapeutic concentrations in the CNS, making it a cornerstone for treating fungal meningitis.	3
Metabolism	Minimal	Predictable pharmacokinetics, less affected by liver function compared to other azoles.	5
Primary Route of Elimination	Renal (~80% unchanged)	Dose adjustment is critical in patients with renal impairment. Effective for urinary tract infections.	3
Elimination Half-Life (t1/2​)	~30 hours (range 22-32)	Long half-life supports convenient once-daily dosing for most indications, improving adherence.	3

5.0 Clinical Indications and Therapeutic Use

The clinical applications of fluconazole are broad, encompassing the treatment and prevention of fungal infections across a wide spectrum of severity and patient populations. Its indications can be conceptually organized into three main categories: treatment of superficial/mucosal infections, treatment of deep-seated/systemic infections, and prophylaxis in high-risk individuals.

5.1 FDA-Approved Indications

Fluconazole is approved by the U.S. Food and Drug Administration for the following conditions [1]:

5.1.1 Mucocutaneous Candidiasis

This category includes infections of the mucous membranes caused by susceptible Candida species.[1]

• Oropharyngeal Candidiasis (Oral Thrush): Fluconazole is a first-line therapy for fungal infections of the mouth and pharynx, particularly in immunocompromised patients.[1]
• Esophageal Candidiasis: It is indicated for the treatment of Candida infections extending into the esophagus, which typically represents a more severe form of mucosal disease.[1]
• Vulvovaginal Candidiasis (Vaginal Yeast Infections): Fluconazole is highly effective and widely used for this common condition. A single 150 mg oral dose is the standard treatment for uncomplicated infections, offering significant convenience over multi-day topical regimens.[1] For patients with recurrent or severe vulvovaginal candidiasis, more prolonged or maintenance regimens are employed.[26]

5.1.2 Systemic Candida Infections

Fluconazole is indicated for the treatment of invasive candidiasis, where the fungus has entered the bloodstream or deep tissues.[1] These serious infections include:

• Candidemia (presence of Candida in the blood)
• Disseminated candidiasis (spread to multiple organs)
• Candida pneumonia
• Candida peritonitis (inflammation of the abdominal lining)
• Candida urinary tract infections.[1]

5.1.3 Cryptococcal Meningitis

Fluconazole plays a pivotal role in the management of meningitis caused by Cryptococcus neoformans.[1] It is used for:

• Initial (Consolidation) Therapy: Often following an induction phase with a more potent agent like amphotericin B, fluconazole is used to complete the initial course of treatment.[3]
• Maintenance (Suppressive) Therapy: In immunocompromised patients, particularly those with Acquired Immunodeficiency Syndrome (AIDS), long-term, low-dose fluconazole is the standard of care to prevent the relapse of cryptococcal meningitis.[3]

5.1.4 Prophylaxis in Immunocompromised Hosts

Fluconazole is approved for the prevention of candidiasis in select high-risk patient populations who are susceptible to opportunistic fungal infections.[1] This includes:

• Patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.[1]
• Patients with advanced HIV infection to prevent opportunistic infections.[2]
• Premature infants at high risk for invasive candidiasis.[2]

5.2 Off-Label and Other Investigated Uses

Beyond its formally approved indications, the favorable properties of fluconazole have led to its widespread off-label use for other mycoses, particularly the endemic fungal infections.[5] These include:

• Coccidioidomycosis (Valley Fever): Fluconazole is a mainstay of therapy, especially for chronic pulmonary or disseminated disease, and is considered a first-line agent for coccidioidal meningitis due to its excellent CNS penetration.[1]
• Blastomycosis: Used for step-down therapy after initial treatment with amphotericin B, or as primary therapy for mild-to-moderate non-meningeal disease.[2]
• Histoplasmosis: Employed for mild-to-moderate disseminated disease or as long-term suppressive therapy in immunocompromised patients.[2]
• Dermatophytoses: Used for fungal infections of the skin and nails (onychomycosis) that are extensive or refractory to topical therapy.[2]
• Tinea Versicolor: An oral option for widespread or recurrent infections.[2]

5.3 Clinical Trials Context

The established efficacy and safety profile of fluconazole have positioned it as a standard-of-care comparator arm in numerous clinical trials evaluating new antifungal agents.[7] Its use as a benchmark against which investigational drugs like rezafungin and ibrexafungerp are measured underscores its foundational role in antifungal therapy for conditions like invasive candidiasis and vaginal yeast infections.[7]

6.0 Dosage and Administration Guidelines

The safe and effective use of fluconazole is critically dependent on appropriate dosing, which varies significantly based on the indication, patient age and weight, and renal function. A loading dose, typically twice the daily maintenance dose, is recommended on the first day of therapy for most multiple-dose regimens to achieve plasma concentrations near steady-state by the second day.[26]

6.1 Available Formulations

Fluconazole is available in several formulations to accommodate different clinical scenarios:

• Oral Tablets: Supplied in strengths of 50 mg, 100 mg, 150 mg, and 200 mg.[37]
• Powder for Oral Suspension: Provided as a dry powder that is reconstituted with water to yield a liquid suspension, typically at concentrations of 10 mg/mL or 40 mg/mL. This formulation is essential for pediatric patients and adults who have difficulty swallowing tablets.[26]
• Intravenous (IV) Solution: A sterile solution for infusion, generally used for initial treatment of severe infections or in patients who cannot take medication orally.[2]

6.2 Dose Adjustments for Renal Impairment and Hemodialysis

Given that fluconazole is primarily eliminated unchanged by the kidneys, dose adjustment is mandatory in patients with renal impairment to prevent drug accumulation and toxicity.[5]

• Single-Dose Therapy: No dose adjustment is necessary for single-dose indications, such as uncomplicated vaginal candidiasis.[26]
• Multiple-Dose Therapy:
• Moderate Renal Impairment (Creatinine Clearance [CrCl] ≤ 50 mL/min, not on dialysis): After a standard loading dose on day 1, the daily maintenance dose should be reduced by 50%.[5]
• Patients on Regular Hemodialysis: Patients should receive a standard loading dose, followed by 100% of the recommended daily dose after each hemodialysis session. On non-dialysis days, a reduced dose according to CrCl should be administered.[26]

6.3 Dosing Regimens by Indication and Population

The following table provides a comprehensive summary of recommended dosing regimens for major indications in adult and pediatric populations, based on FDA labeling and major clinical guidelines. Doses for children are weight-based and should not exceed the maximum recommended adult dose (typically 600 mg/day).[6]

Table 3: Recommended Dosing Regimens for Major Indications (Adult & Pediatric)

Indication	Patient Population	Loading Dose	Maintenance Dose	Typical Duration of Therapy	Key Considerations	Source(s)
Vulvovaginal Candidiasis (Uncomplicated)	Adults	None	150 mg as a single oral dose	Single Dose	---	6
Vulvovaginal Candidiasis (Recurrent/Complicated)	Adults	150 mg	150 mg every 72 hours for 3 doses, then 150 mg once weekly	6 months for maintenance phase	For patients with frequent recurrences.	26
Oropharyngeal Candidiasis (Oral Thrush)	Adults	200 mg on Day 1	100 mg once daily	At least 2 weeks	To reduce risk of relapse.	26
	Children (≥6 mo)	6 mg/kg on Day 1	3 mg/kg once daily	At least 2 weeks	Max dose 600 mg/day.	39
Esophageal Candidiasis	Adults	200 mg on Day 1	100 mg once daily (up to 400 mg/day)	Min. 3 weeks, and for 2 weeks after symptom resolution.	Dose may be increased based on response.	38
	Children (≥6 mo)	6 mg/kg on Day 1	3 mg/kg once daily (up to 12 mg/kg/day)	Min. 3 weeks, and for 2 weeks after symptom resolution.	Dose may be increased for severe infections.	38
Systemic Candidiasis (e.g., Candidemia)	Adults	800 mg on Day 1	400 mg once daily (up to 800 mg/day)	Highly variable; guided by clinical/microbiological clearance.	Duration depends on source control and immune status.	26
	Children (≥3 mo)	25 mg/kg on Day 1	12 mg/kg once daily	At least 3 weeks and for 2 weeks after negative cultures.	Dose adjustments needed for neonates.	26
Cryptococcal Meningitis (Acute Treatment)	Adults	400 mg on Day 1	200 mg once daily (up to 400-800 mg/day)	10-12 weeks after CSF becomes culture-negative.	Often follows induction with Amphotericin B.	26
	Children	12 mg/kg on Day 1	6-12 mg/kg once daily	10-12 weeks after CSF becomes culture-negative.	---	26
Cryptococcal Meningitis (Suppressive Therapy)	Adults (esp. AIDS)	None	200 mg once daily	Long-term, potentially lifelong.	To prevent relapse.	26
	Children (esp. AIDS)	None	6 mg/kg once daily	Long-term, potentially lifelong.	To prevent relapse.	26
Prophylaxis (Bone Marrow Transplant)	Adults	400 mg once daily	400 mg once daily	Until neutrophil recovery.	Start before anticipated neutropenia.	38
Neonatal Dosing (Systemic Candida)	GA < 30 wks	25 mg/kg on Day 1	9 mg/kg once daily	As per systemic candidiasis guidelines.	Dosing interval may be extended (q48-72h) in first weeks of life.	4
	GA ≥ 30 wks	25 mg/kg on Day 1	12 mg/kg once daily	As per systemic candidiasis guidelines.	Dosing interval may be extended (q48-72h) in first weeks of life.	4

Note: This table is a summary and is not a substitute for clinical judgment or the full prescribing information. Doses may need adjustment based on clinical response, pathogen susceptibility, and patient-specific factors. GA = Gestational Age.

7.0 Safety Profile and Tolerability

While generally well-tolerated, fluconazole is associated with a range of adverse drug reactions (ADRs), from common and mild to rare and life-threatening. A thorough understanding of this safety profile is essential for patient monitoring and risk mitigation.

7.1 Overview of Common Adverse Drug Reactions

The most frequently encountered ADRs associated with fluconazole therapy are typically mild to moderate in severity and often involve the gastrointestinal and nervous systems.[2]

• Gastrointestinal Effects: Nausea, vomiting, diarrhea, and abdominal pain are commonly reported.[2] Dyspepsia (indigestion) and flatulence also occur.[5]
• Nervous System Effects: The most common ADR across many studies is headache, with an incidence of up to 13%.[2] Dizziness is also frequently reported.[2]
• Other Common Effects: Skin rash is a common finding.[2] Changes in taste perception (taste perversion) are also noted.[5]

7.2 Analysis of Serious Adverse Events

Beyond the common side effects, fluconazole carries a risk of several serious, albeit less frequent, toxicities that require vigilant monitoring and immediate action if they occur.

7.2.1 Hepatotoxicity and Liver Failure

This is one of the most significant safety concerns with fluconazole. The drug has been associated with rare but serious cases of hepatic toxicity, which can manifest as hepatitis, cholestasis, or hepatocellular necrosis.[2] In the most severe instances, this can progress to fulminant hepatic failure, which may be fatal.[28] This risk appears to be higher in patients with serious underlying medical conditions.[43] While hepatotoxicity is often reversible upon discontinuation of the drug, routine monitoring of liver function tests (transaminases, bilirubin) is prudent, especially during prolonged therapy or in patients with pre-existing liver disease.[5]

7.2.2 Cardiac Effects: QT Interval Prolongation and Torsades de Pointes

Fluconazole can affect cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium channel current (Ikr​).[43] This inhibition can lead to a prolongation of the QT interval on the electrocardiogram (ECG).[2] A prolonged QT interval increases the risk of life-threatening polymorphic ventricular tachycardia, specifically Torsades de Pointes.[4] The risk is elevated in patients with underlying proarrhythmic conditions, such as structural heart disease, advanced cardiac failure, or electrolyte abnormalities (particularly hypokalemia and hypomagnesemia). The risk is also significantly amplified when fluconazole is co-administered with other medications known to prolong the QT interval.[2]

7.2.3 Severe Dermatologic Reactions

Rarely, fluconazole has been implicated in severe, life-threatening exfoliative skin disorders.[28] These include Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which are medical emergencies characterized by widespread blistering and sloughing of the skin and mucous membranes.[2] Fatal outcomes have been reported, especially in patients with severe underlying diseases like AIDS.[43] Any patient who develops a progressive rash while on fluconazole should be monitored closely, and the drug must be discontinued immediately if lesions advance.[28]

7.2.4 Other Serious Reactions

• Anaphylaxis: Rare cases of severe, immediate hypersensitivity reactions have been reported.[2]
• Hematologic Effects: Rare reports of blood dyscrasias include leukopenia (including neutropenia and agranulocytosis) and thrombocytopenia, which can increase the risk of infection and bleeding, respectively.[2]
• Neurologic Effects: Seizures have been reported, although a definitive causal relationship can be difficult to establish as many patients receiving fluconazole have underlying conditions that predispose them to seizures (e.g., cryptococcal meningitis).[2]
• Adrenal Insufficiency: Reversible cases of adrenal gland dysfunction have been reported in patients receiving azole antifungals, including fluconazole.[43]

Table 4 organizes the adverse drug reactions associated with fluconazole by System Organ Class.

Table 4: Common and Serious Adverse Drug Reactions by System Organ Class

System Organ Class	Adverse Reaction	Frequency/Notes	Source(s)
Gastrointestinal Disorders	Nausea, Abdominal Pain, Vomiting, Diarrhea	Very Common (≥10% for some) or Common (1-10%)	2
	Dyspepsia, Flatulence, Dry Mouth	Uncommon (0.1-1%)	5
Nervous System Disorders	Headache	Very Common (up to 13%)	42
	Dizziness, Taste Perversion	Common (1-10%)	24
	Seizures, Paresthesia, Somnolence, Tremor	Uncommon (0.1-1%) or Rare (<0.1%)	6
Hepatobiliary Disorders	Elevated Liver Enzymes (ALT, AST, ALP)	Common (1-10%)	2
	Hepatic Failure, Hepatitis, Hepatocellular Necrosis, Cholestasis	Rare (<0.1%); A major safety concern, can be fatal.	6
Skin and Subcutaneous Tissue Disorders	Rash	Common (1-10%)	2
	Alopecia (Hair Loss), Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)	Rare (<0.1%); SJS/TEN are life-threatening.	2
Cardiac Disorders	QT Prolongation, Torsades de Pointes	Rare (<0.1%); Life-threatening ventricular arrhythmia.	2
Blood and Lymphatic System Disorders	Leukopenia (Neutropenia, Agranulocytosis), Thrombocytopenia	Rare (<0.1%)	2
Immune System Disorders	Anaphylaxis	Rare (<0.1%)	4
Metabolism and Nutrition Disorders	Hypokalemia, Hypercholesterolemia, Hypertriglyceridemia	Uncommon (0.1-1%) or Rare (<0.1%)	2
Endocrine Disorders	Adrenal Insufficiency	Rare (<0.1%); Reversible cases reported.	43

8.0 Contraindications, Warnings, and Precautions

The safe prescribing of fluconazole requires strict adherence to its contraindications and a vigilant awareness of its warnings and precautions, particularly in at-risk patient populations.

8.1 Absolute Contraindications

The use of fluconazole is absolutely contraindicated in the following situations:

• Hypersensitivity: Patients with a known history of hypersensitivity (e.g., anaphylaxis) to fluconazole or any of the excipients in the formulation.[4] While there is no definitive information on cross-hypersensitivity with other azole antifungals, caution is advised when prescribing fluconazole to patients with a history of allergy to other azoles.[24]
• Coadministration with Specific QT-Prolonging Drugs: The concurrent use of fluconazole with certain drugs that are known to prolong the QT interval and are also metabolized by the CYP3A4 enzyme is contraindicated due to the high risk of life-threatening cardiac arrhythmias. This includes, but is not limited to, erythromycin, pimozide, and quinidine.[4]
• Coadministration with Other Specific Agents: Prescribing information also lists contraindications for co-administration with triazolam (a benzodiazepine), flibanserin, lomitapide, and lonafarnib due to the potential for severe adverse events from markedly increased plasma concentrations of these drugs.[49]

8.2 Major Warnings

Fluconazole carries several major warnings regarding potentially life-threatening toxicities. While not all formulations carry a formal "black box warning" in the United States, these concerns are of equivalent clinical gravity.

• Hepatotoxicity: The FDA-approved labeling for fluconazole includes a prominent warning regarding the risk of hepatic injury.[28] It has been associated with rare but serious cases of hepatotoxicity, including fatalities. This risk is primarily observed in patients with serious underlying medical conditions.[43] The hepatotoxicity is usually, but not always, reversible upon discontinuation of therapy.[28] This warning underscores the need for cautious use in patients with liver dysfunction and consideration of liver function monitoring.
• Potential for Fetal Harm (Teratogenicity): Fluconazole use during pregnancy is a significant concern. Multiple case reports have described a rare but distinct pattern of congenital anomalies in infants exposed in utero to chronic, high-dose maternal fluconazole (400–800 mg/day) during most or all of the first trimester.[6] The observed anomalies—including brachycephaly, abnormal facies, cleft palate, and bone and heart defects—are consistent with findings from animal teratogenicity studies.[43] Furthermore, some epidemiological studies have suggested an increased risk of spontaneous abortion even with a single 150 mg dose, although these findings have limitations and are not definitively confirmed.[27] Due to these risks, fluconazole should be avoided during pregnancy, especially the first trimester, unless the potential benefit for a life-threatening maternal infection clearly outweighs the substantial risk to the fetus.[5] Women of childbearing potential should be advised to use effective contraception during and for one week after completing therapy.[24]

8.3 Precautions for Use in At-Risk Populations

The safety profile of fluconazole necessitates a holistic patient assessment, as the risk of adverse events is not uniform across all populations. A patient at risk for one serious toxicity is often at risk for others. For example, a critically ill patient with sepsis may have underlying renal dysfunction (increasing drug levels), electrolyte abnormalities (increasing QT risk), and be on multiple other medications (increasing interaction risk), while their underlying illness itself increases the risk of hepatotoxicity.

• Pre-existing Medical Conditions: Extreme caution is warranted in patients with:
• Liver Dysfunction: Due to the risk of hepatotoxicity.[45]
• Renal Impairment: Dose adjustment is mandatory to prevent drug accumulation.[5]
• Proarrhythmic Conditions: Including structural heart disease, heart failure, and a personal or family history of long QT syndrome.[5]
• Electrolyte Imbalances: Particularly hypokalemia, hypomagnesemia, or hypocalcemia, as these can exacerbate the QT-prolonging effect of fluconazole.[24]
• Hereditary Conditions: The powder for oral suspension formulation contains sucrose and should not be used in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.[24] Similarly, the tablets contain lactose and should be used with caution in patients with galactose intolerance.[27]

8.4 Use in Pregnancy and Lactation

• Pregnancy: As detailed in the warnings section, fluconazole is potentially teratogenic, especially at high doses in the first trimester.[6] Its use should be avoided unless absolutely necessary for a severe or life-threatening maternal fungal infection.[5]
• Lactation: Fluconazole is secreted into human milk at concentrations that are similar to those found in the mother's plasma.[2] While some sources have deemed it "compatible with nursing" and serious adverse effects in infants have not been widely reported, extensive safety data, particularly with repeated or high-dose use, are lacking.[5] The decision to use fluconazole in a breastfeeding mother should involve a careful weighing of the potential benefits to the mother against the potential risks to the infant.[38]

9.0 Significant Drug Interactions

Fluconazole has an extensive and clinically significant drug interaction profile, with over 500 potential interactions documented.[33] The majority of these arise from its potent effects on the cytochrome P450 (CYP) enzyme system, while others are pharmacodynamic in nature. Vigilant medication review is a critical component of safe fluconazole prescribing.

9.1 Pharmacokinetic Interactions: Role as a Potent CYP450 Inhibitor

The primary mechanism for fluconazole's pharmacokinetic interactions is its inhibition of key drug-metabolizing enzymes.[50] It is classified as a

strong inhibitor of CYP2C19, a strong inhibitor of CYP2C9, and a moderate inhibitor of CYP3A4.[11]

By inhibiting these enzymes, fluconazole blocks the metabolic clearance of numerous co-administered drugs that are substrates for these pathways. This leads to increased plasma concentrations and prolonged half-lives of the affected drugs, thereby amplifying their pharmacologic effects and significantly increasing the risk of dose-related toxicities.[45] Due to fluconazole's long elimination half-life, this inhibitory effect can persist for 4 to 5 days after the drug is discontinued, a crucial consideration when starting or stopping therapy.[48]

9.2 Pharmacodynamic Interactions

Pharmacodynamic interactions occur when two drugs have additive or synergistic effects on the body. The most critical pharmacodynamic interaction involving fluconazole is:

• Additive QT Prolongation: Fluconazole intrinsically prolongs the QT interval. When it is co-administered with other drugs that share this property, the risk of inducing a life-threatening arrhythmia like Torsades de Pointes is significantly increased.[2] This includes a wide range of medications such as certain antiarrhythmics (amiodarone), antipsychotics (quetiapine, pimozide), antidepressants (citalopram), and antibiotics (erythromycin, clarithromycin).[45] Many of these combinations are contraindicated or require extreme caution with ECG monitoring.

9.3 Drug-Food Interactions

There are no clinically significant interactions between fluconazole and food. It can be administered without regard to meals.[29] For patients who experience gastrointestinal side effects like nausea, taking the medication with food may improve tolerability.[53] Patients are generally advised to avoid alcohol while taking fluconazole, as the combination may increase the risk of liver damage.[49]

9.4 Clinically Critical Interactions

The vast number of potential interactions necessitates a focus on those with the highest clinical significance. Table 5 provides a practical guide to some of the most critical drug interactions, detailing their mechanism, consequences, and recommended management strategies.

Table 5: Clinically Significant Drug Interactions with Fluconazole: Mechanism and Management Recommendations

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Severity	Recommended Management	Source(s)
Warfarin	Inhibition of CYP2C9	Increased warfarin levels, elevated INR, significant risk of major bleeding.	Major	Monitor INR very closely upon initiation, cessation, or dose change of fluconazole. Proactive warfarin dose reduction is often necessary.	4
Phenytoin	Inhibition of CYP2C9	Increased phenytoin levels, risk of toxicity (nystagmus, ataxia, CNS depression).	Major	Monitor phenytoin serum concentrations and for signs of toxicity. Dose reduction may be required.	4
Certain Statins (Atorvastatin, Simvastatin, Lovastatin)	Inhibition of CYP3A4	Increased statin levels, heightened risk of myopathy and rhabdomyolysis.	Major	Avoid combination if possible. Consider switching to a statin not metabolized by CYP3A4 (e.g., pravastatin, rosuvastatin) or temporarily hold the statin.	49
Immunosuppressants (Cyclosporine, Tacrolimus, Sirolimus)	Inhibition of CYP3A4	Increased immunosuppressant levels, risk of nephrotoxicity and other toxicities.	Major	Careful monitoring of immunosuppressant trough levels and renal function is mandatory. Significant dose reductions are often required.	4
Certain Benzodiazepines (Midazolam, Triazolam)	Inhibition of CYP3A4	Markedly increased benzodiazepine levels, risk of profound and prolonged sedation and respiratory depression.	Major	Co-administration with triazolam is contraindicated. Use with midazolam requires extreme caution, dose reduction, and close monitoring.	4
Sulfonylureas (Glipizide, Glyburide)	Inhibition of CYP2C9	Increased sulfonylurea levels, risk of severe and prolonged hypoglycemia.	Major	Monitor blood glucose frequently. Dose reduction of the sulfonylurea may be necessary.	4
Clopidogrel	Inhibition of CYP2C19	Prevents metabolic activation of the prodrug clopidogrel, leading to reduced antiplatelet effect and increased risk of thrombotic events.	Major	Avoid combination. Select an alternative antifungal agent if possible.	52
QT-Prolonging Drugs (Amiodarone, Quinidine, Erythromycin, Pimozide, certain Antipsychotics/Antidepressants)	Additive Pharmacodynamic Effect	Synergistic QT interval prolongation, high risk of Torsades de Pointes.	Major	Combination with many of these agents (e.g., quinidine, erythromycin, pimozide) is contraindicated. Others require extreme caution, baseline and follow-up ECG, and electrolyte monitoring.	45

10.0 Antifungal Resistance

The emergence of antifungal resistance is a growing global health threat, and fluconazole, due to its widespread use, has been a significant driver of this phenomenon. Understanding the mechanisms and clinical implications of resistance is crucial for effective stewardship and patient management.

10.1 Known Mechanisms of Resistance

Fungal pathogens, particularly Candida species, have evolved several sophisticated mechanisms to evade the effects of fluconazole.[48] The principal mechanisms include:

• Target Site Modification: The most direct form of resistance involves alterations to the drug's target, the lanosterol 14-α-demethylase enzyme. Point mutations in the gene that codes for this enzyme, ERG11, can change the enzyme's conformation, reducing the binding affinity of fluconazole and rendering it less effective.[48]
• Target Overexpression: Fungi can overcome the inhibitory effect of fluconazole by simply producing more of the target enzyme. Upregulation of the ERG11 gene leads to an increased quantity of lanosterol 14-α-demethylase, which can titrate out the available drug, allowing ergosterol synthesis to proceed.[48]
• Efflux Pump Upregulation: A primary and highly effective mechanism of resistance involves the active removal of fluconazole from the fungal cell. This is accomplished by membrane-bound transporter proteins known as efflux pumps. Overexpression of the genes encoding these pumps, particularly those from the ATP-binding cassette (ABC) superfamily (e.g., CDR1, CDR2) and the major facilitator superfamily (e.g., MDR1), leads to a high capacity to pump fluconazole out of the cell, preventing it from reaching the necessary intracellular concentration to inhibit its target.[48] This mechanism often confers cross-resistance to other azole antifungals.

10.2 Clinically Relevant Resistant Species

While most isolates of Candida albicans remain susceptible to fluconazole, the landscape of candidiasis has shifted, with an increasing prevalence of non-albicans Candida species that have reduced susceptibility.

• Candida krusei: This species is considered to possess intrinsic (natural) resistance to fluconazole and is not a therapeutic target for the drug.[2] Treatment of C. krusei infections requires alternative antifungal agents.
• Candida glabrata: This species is a major concern regarding fluconazole resistance. While some isolates are susceptible, many exhibit dose-dependent susceptibility or acquired resistance, often through the upregulation of efflux pumps.[2] Infections caused by C. glabrata may require higher doses of fluconazole or, more commonly, a switch to an alternative class of antifungal, such as an echinocandin.[2]

The widespread and often prolonged use of fluconazole, particularly for prophylaxis in high-risk populations, has exerted significant selective pressure on fungal populations. This pressure suppresses the growth of susceptible species like C. albicans but creates an ecological niche for the emergence and proliferation of intrinsically resistant or less-susceptible species like C. krusei and C. glabrata.[2] This epidemiological shift is a direct consequence of the drug's success and widespread application. It has fundamentally altered clinical practice, such that for serious infections like candidemia, initial empiric therapy can no longer automatically assume fluconazole susceptibility. Current guidelines often recommend initial treatment with broader-spectrum agents, like echinocandins, pending formal species identification and antifungal susceptibility testing.[2]

10.3 Strategies to Mitigate Resistance

Combating the rise of resistance requires a multi-pronged, stewardship-focused approach:

• Diagnostics: Rapid identification of the infecting fungal species and, where available, in vitro susceptibility testing are crucial to guide appropriate therapy.
• Judicious Use: Prescribing fluconazole only when indicated, avoiding its use for non-fungal conditions or for pathogens known to be resistant.
• Optimal Dosing: Using appropriate doses and ensuring an adequate duration of therapy to maximize the chances of fungal eradication and minimize the selection of resistant subpopulations.
• Alternative Therapies: Employing alternative antifungal classes, such as echinocandins or polyenes, as first-line therapy for severe infections where resistance is common or suspected, such as candidemia in a hospitalized patient.[2]

11.0 Synthesis and Concluding Remarks

Fluconazole stands as a landmark achievement in antimicrobial therapy. Its development and introduction fundamentally reshaped the management of fungal infections, offering for the first time a highly effective, orally bioavailable, and relatively safe systemic agent. Its legacy is defined by its revolutionary pharmacokinetic profile—the combination of near-complete oral absorption, minimal metabolism, and outstanding penetration into difficult-to-treat sites like the central nervous system. This profile transformed the prognosis for patients with life-threatening conditions such as cryptococcal meningitis, shifting the paradigm from prolonged, toxic intravenous treatments to manageable, long-term oral therapy.

However, the profound clinical importance of fluconazole is balanced by a profile of significant liabilities that demand careful and knowledgeable clinical practice. The optimal use of this drug involves a critical trade-off, weighing its proven efficacy and convenience against three major areas of concern. The first is the potential for rare but severe, and sometimes fatal, hepatotoxicity, a risk that mandates caution in patients with liver disease. The second is its cardiotoxic potential, specifically the risk of QT interval prolongation and Torsades de Pointes, which requires a careful assessment of patient risk factors and co-administered medications. The third, and perhaps most frequently encountered in daily practice, is its extensive and complex drug-drug interaction profile, driven by its potent inhibition of multiple cytochrome P450 enzymes. Safe prescribing of fluconazole is impossible without a vigilant approach to identifying and managing these interactions.

Furthermore, the very success of fluconazole has contributed to the modern challenge of antifungal resistance. Decades of widespread use have applied selective pressure that has fostered the emergence of less-susceptible non-albicans Candida species, altering the epidemiology of candidiasis and necessitating an evolution in treatment guidelines.

In conclusion, despite the advent of newer antifungal agents and the growing challenge of resistance, fluconazole's unique combination of efficacy, affordability, and ease of use ensures its enduring and essential role in the global fight against fungal disease. Its place on the WHO's List of Essential Medicines is well-earned. The future of its effective use, however, depends not on its past successes but on the continued diligence of clinicians—a deep understanding of its pharmacology, a profound respect for its safety profile, and a perpetually vigilant approach to navigating its many interactions in an increasingly complex medical landscape.

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