Voriconazole: A Comprehensive Monograph on its Pharmacology, Clinical Use, and Risk Management

Executive Summary & Drug Profile

Overview

Voriconazole is a second-generation, broad-spectrum triazole antifungal agent, representing a cornerstone in the management of severe, life-threatening invasive fungal infections.[1] As a synthetic derivative of fluconazole, it was engineered for an expanded spectrum of activity, particularly against molds.[4] It is established as the first-line therapy for invasive aspergillosis and is a critical agent for treating infections caused by fluconazole-resistant

Candida species and rare, often refractory, molds such as Scedosporium and Fusarium.[1]

The clinical utility of voriconazole is defined by a central paradox: its potent, life-saving efficacy is counterbalanced by a highly complex pharmacological profile. This profile is characterized by highly variable, non-linear pharmacokinetics, a narrow therapeutic window, and a significant potential for drug-drug interactions and notable toxicities.[3] Consequently, the successful clinical application of voriconazole demands a sophisticated understanding of its properties and a commitment to individualized patient management, including therapeutic drug monitoring, to navigate the fine line between efficacy and toxicity.

Chemical and Physical Identity

A comprehensive chemical and physical profile is essential for the identification, formulation, and research of voriconazole.

Nomenclature and Identifiers

Voriconazole is identified by a range of names and codes that reflect its development and regulatory history.

• DrugBank ID: DB00582 [1]
• Type: Small Molecule [1]
• CAS Number: 137234-62-9 [1]
• IUPAC Name: (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.[2] An alternative systematic name is (αR,βS)-α-(2,4-difluorophenyl)-5-fluoro-β-methyl-α(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol.[1]
• Synonyms & Development Codes: Vfend, Voriconazol, Voriconazolum, VCZ, UK-109496, UK-51,060, DRG 0301, VRC.[1]

Structural and Molecular Data

The chemical structure of voriconazole consists of a core butanol backbone substituted with a difluorophenyl group, a fluoropyrimidine ring, and a 1H-1,2,4-triazole ring, classifying it structurally as a pyrimidine and triazole derivative.[2]

• Chemical Formula: C16​H14​F3​N5​O [7]
• Molecular Weight: Approximately 349.31 g/mol [2]

Physicochemical Properties

• Appearance: A white to almost white or light-colored crystalline powder.[8]
• Solubility: It is practically insoluble in water, with a predicted solubility of 0.0978 mg/mL.[13] This low aqueous solubility necessitates the inclusion of a solubilizing agent, sulfobutyl ether beta-cyclodextrin sodium, in the intravenous formulation.[8] The drug is soluble in organic solvents such as methanol and dimethyl sulfoxide (DMSO).[13]
• Melting Point: The melting point ranges from 130.0 to 134.0 °C.[13]
• Stability and Storage: Voriconazole is stable for at least four years when stored appropriately.[4] It is recommended to be stored at room temperature in a cool, dark place, with some sources specifying a temperature below 15°C.[4]

Table 1: Chemical and Physical Properties of Voriconazole

Property	Value	Source(s)
CAS Number	137234-62-9	1
Molecular Formula	C16​H14​F3​N5​O	8
Molecular Weight	349.31 g/mol	7
IUPAC Name	(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol	7
Appearance	White to light-colored powder or crystal	8
Solubility in Water	Insoluble (predicted 0.0978 mg/mL)	13
Solubility (Organic)	Soluble in Methanol, DMSO	13
Melting Point	130.0 - 134.0 °C	13

Comprehensive Pharmacological Profile

Mechanism of Action

Voriconazole belongs to the triazole class of antifungal medications and exerts its therapeutic effect through a highly specific molecular mechanism.[1] The primary mode of action is the potent and selective inhibition of a fungal cytochrome P450 (CYP) enzyme known as lanosterol 14-alpha-demethylase, or CYP51.[1] This enzyme is a pivotal component in the biosynthesis of ergosterol, a sterol unique to fungi that is analogous to cholesterol in mammalian cells.[6]

By binding to and inhibiting CYP51, voriconazole effectively blocks the demethylation of lanosterol, a crucial step in the ergosterol synthesis pathway.[1] This inhibition leads to two critical downstream effects within the fungal cell: the depletion of ergosterol and the simultaneous accumulation of toxic 14-alpha-methylated sterol precursors.[1] The absence of sufficient ergosterol disrupts the structural integrity and fluidity of the fungal cell membrane. The accumulation of abnormal sterols further perturbs the membrane by interfering with the proper packing of phospholipids and hindering the function of essential membrane-bound enzymes, such as chitin synthase. This cascade of events increases membrane permeability, leading to leakage of cellular contents and ultimately resulting in the inhibition of fungal growth (fungistatic effect) or, in some cases, fungal cell death (fungicidal effect).[1]

The chemical structure of voriconazole, specifically the replacement of one of fluconazole's triazole rings with a fluorinated pyrimidine and the addition of an α-methyl group, confers a broader spectrum of activity and a higher affinity for fungal CYP51. This enhanced affinity makes it effective against certain fungal strains that have developed resistance to fluconazole.[1]

Pharmacodynamics

The pharmacodynamics of voriconazole describe the relationship between drug concentration and its antifungal effect. This relationship is complex and varies depending on the target pathogen. Voriconazole generally exhibits a fungistatic (growth-inhibiting) effect against yeast species such as Candida, but it can be fungicidal (lethal) against certain filamentous molds, most notably Aspergillus species.[1]

In vitro time-kill studies have revealed that voriconazole's activity is non-concentration-dependent.[24] This means that once a certain threshold concentration is reached, further increases in the drug level do not significantly enhance the rate or extent of its antifungal effect. A near-maximal effect is typically observed at concentrations approximately three times the minimum inhibitory concentration (MIC) of the target organism.[24]

The key pharmacodynamic index that best predicts clinical efficacy is the ratio of the area under the concentration-time curve over a 24-hour period to the MIC (AUC/MIC).[25] For example, in an in vitro model of infection with the mold

Scedosporium apiospermum, a near-maximal antifungal effect was achieved with an AUC/MIC ratio of approximately 100.[25]

The relationship between voriconazole plasma concentration and clinical response in patients is notably non-linear. An analysis of data from nine clinical trials, encompassing 825 patients, demonstrated that the probability of a successful clinical outcome was diminished at both extremes of drug exposure. The response rate was suboptimal for patients with an average plasma concentration (Cavg​) below 0.5 µg/mL (57% response) and was also lowest for patients with a Cavg​ of 5.0 µg/mL or higher (56% response). The maximal response rate (74%) was observed in patients with a Cavg​ between 3.0 and 4.0 µg/mL, establishing a therapeutic window that is crucial for guiding therapy.[27]

Pharmacokinetics

The clinical use of voriconazole is profoundly influenced by its complex pharmacokinetic profile, which is characterized by non-linear kinetics and substantial inter-individual variability.

Absorption and Bioavailability

Voriconazole demonstrates excellent oral bioavailability, estimated to be 96% in healthy adults under fasting conditions, which is a significant clinical advantage.[1] This high bioavailability facilitates a convenient transition from initial intravenous (IV) therapy to subsequent oral administration. Absorption is rapid, with peak plasma concentrations (

Cmax​) typically reached within 1 to 2 hours after an oral dose.[15]

However, this favorable profile is complicated by a significant drug-food interaction. Administration of voriconazole tablets with a high-fat meal has been shown to reduce the mean Cmax​ and area under the curve (AUC) by 34% and 24%, respectively.[28] To ensure consistent and maximal absorption, it is imperative that oral formulations are administered on an empty stomach, at least one hour before or one to two hours after a meal.[29] Bioavailability can also be reduced in specific populations, such as pediatric patients and transplant recipients, which may be attributable to differences in first-pass metabolism or gastrointestinal disturbances post-surgery.[1]

Distribution

Voriconazole is widely distributed throughout the body, reflected by its large apparent volume of distribution (Vd​) of approximately 4.6 L/kg.[1] It is moderately bound to plasma proteins, with a binding fraction of 58%.[1] A critical feature of its distribution is its ability to penetrate various tissues and achieve therapeutic concentrations in key sites of infection, including the lungs, liver, spleen, kidneys, and heart.[1] Importantly, voriconazole crosses the blood-brain barrier, achieving concentrations in the cerebrospinal fluid (CSF) that are approximately 50% of those in plasma, making it a viable treatment for fungal infections of the central nervous system (CNS).[5]

Metabolism

Voriconazole undergoes extensive hepatic metabolism, with less than 2% of an administered dose being excreted unchanged in the urine.[3] This metabolism is primarily mediated by the cytochrome P450 (CYP) family of isoenzymes, specifically

CYP2C19 (the major pathway), CYP3A4, and CYP2C9.[1]

The principal metabolic pathway is N-oxidation, mediated mainly by CYP2C19, which produces the major circulating metabolite, voriconazole N-oxide. This metabolite accounts for approximately 72% of radiolabeled metabolites in plasma but possesses minimal antifungal activity and therefore does not contribute to the drug's overall efficacy.[1] Other, less prominent metabolic routes include hydroxylation of the methyl group and the fluoropyrimidine ring, to which CYP3A4 and CYP2C19 also contribute.[3]

Elimination

A defining characteristic of voriconazole is its non-linear (or dose-dependent) elimination kinetics.[1] This phenomenon arises from the saturation of its primary metabolic enzyme, CYP2C19, at therapeutic concentrations. As the dose increases, the metabolic pathway becomes saturated, meaning the body's capacity to clear the drug reaches a ceiling. This results in a disproportionately larger increase in plasma concentration for a given dose increase and a terminal half-life that is dose-dependent rather than constant.[1]

Pharmacokinetic Variability

The most significant challenge in the clinical use of voriconazole is its profound inter- and intra-individual pharmacokinetic variability, which makes predicting a patient's drug exposure based on standard dosing highly unreliable.[5] This variability is the primary reason for the drug's narrow therapeutic window and is driven by several interconnected factors.

The central mechanism underpinning this variability is the saturable, non-linear metabolism mediated by CYP2C19. Because this enzyme system can be overwhelmed, even small changes in a patient's metabolic capacity can lead to dramatic shifts in drug concentration, pushing them from subtherapeutic to potentially toxic levels, or vice versa.[5] This inherent non-linearity amplifies the effects of other sources of variability.

The most critical of these sources is the genetic polymorphism of the CYP2C19 gene.[10] Individuals can be categorized based on their genotype as poor metabolizers (PMs), who lack functional enzyme activity; intermediate metabolizers (IMs); extensive (normal) metabolizers (EMs); or ultrarapid metabolizers (UMs), who have increased enzyme activity. PMs exhibit significantly reduced voriconazole clearance, and studies have shown that their drug exposure (AUC) can be up to four times higher than that of EMs given the same dose.[6]

The clinical consequence of this genetic variability is that a standard dosing regimen is often inappropriate for a large proportion of the patient population. Pharmacokinetic modeling studies predict that a standard oral dose of 200 mg twice daily may result in subtherapeutic trough concentrations in over 60% of normal metabolizers, risking treatment failure.[11] Conversely, the same dose can lead to supratherapeutic, potentially toxic concentrations in a high percentage of patients with reduced CYP2C19 activity (PMs and IMs).[11] This direct link between genetics, non-linear kinetics, and clinical outcomes (treatment failure at low levels, toxicity at high levels) establishes therapeutic drug monitoring (TDM) not as an ancillary measure, but as a fundamental and indispensable component of safe and effective voriconazole therapy.

Other factors contributing to pharmacokinetic variability include:

• Drug-Drug Interactions: Co-administration of drugs that induce or inhibit CYP2C19 and/or CYP3A4 can drastically alter voriconazole clearance.[5]
• Age: Children demonstrate higher, more linear clearance compared to adults and thus require higher weight-based doses to achieve equivalent therapeutic exposures.[33]
• Hepatic Function: As the liver is the primary site of metabolism, impaired function leads to reduced clearance.[9]
• Inflammation: In critically ill patients, the level of systemic inflammation, as measured by C-reactive protein (CRP), has been shown to correlate with voriconazole concentrations, adding another layer of complexity to dosing in this population.[35]

Table 2: Summary of Voriconazole Pharmacokinetic Parameters

Parameter	Value / Description	Key Influencing Factors	Source(s)
Oral Bioavailability	~96% (fasting)	Food (high-fat meal reduces absorption), patient population (lower in pediatrics, transplant)	1
Time to Peak (Tmax​)	1–2 hours	Food	15
Volume of Distribution (Vd​)	~4.6 L/kg	-	1
Plasma Protein Binding	~58%	-	1
Primary Metabolic Enzymes	CYP2C19 (major), CYP3A4, CYP2C9	Genetic polymorphism (CYP2C19), drug-drug interactions	1
Major Metabolite	Voriconazole N-oxide (inactive)	-	1
Elimination Kinetics	Non-linear (Michaelis-Menten)	Saturable metabolism at therapeutic doses	5
Terminal Half-life	Dose-dependent	Dose, CYP2C19 genotype, liver function	1

Clinical Efficacy and Therapeutic Applications

Antifungal Spectrum of Activity

Voriconazole possesses a broad spectrum of in vitro antifungal activity, which underpins its use against a wide range of clinically important pathogens.[5]

• Yeasts: It is highly active against numerous Candida species, including C. albicans, C. tropicalis, and C. parapsilosis. Critically, its spectrum includes species that are often inherently resistant or have acquired resistance to fluconazole, such as Candida krusei and many strains of Candida glabrata.[4] It also demonstrates activity against other pathogenic yeasts like Cryptococcus neoformans and Trichosporon beigelii.[4]
• Molds: Voriconazole is a potent agent against filamentous molds, particularly Aspergillus species. Its activity covers A. fumigatus, A. flavus, A. niger, and A. terreus, the last of which is notably often resistant to amphotericin B.[4]
• Other Pathogens: A key strength of voriconazole is its activity against rare and emerging fungal pathogens that are notoriously difficult to treat. This includes members of the genera Scedosporium (e.g., S. apiospermum, the asexual form of Pseudallescheria boydii) and Fusarium.[6] Furthermore, it is active against several endemic dimorphic fungi responsible for systemic mycoses, including Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum.[5]

Approved Indications and Clinical Trial Evidence

Voriconazole is approved by major regulatory bodies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), for use in adults and pediatric patients aged two years and older for several serious fungal infections.[42]

• Invasive Aspergillosis (IA): Voriconazole is indicated as a primary, first-line treatment for IA.[8] This indication is supported by foundational Phase III trials (e.g., NCT00001757, NCT00001810) that established its efficacy and safety profile in this life-threatening condition.[46] Its standing as a primary therapy has been further defined by comparative studies against other antifungals like posaconazole (NCT01782131).[46]
• Candidemia and other Deep Tissue Candida Infections: It is approved for the treatment of candidemia (fungal bloodstream infection) in non-neutropenic patients, as well as other deep tissue Candida infections, including disseminated infections involving the skin, abdomen, kidney, and wounds.[8] A pivotal comparative trial (NCT00163111) evaluated voriconazole against a standard regimen of amphotericin B followed by fluconazole for candidemia, providing key evidence for this indication.[47]
• Esophageal Candidiasis: Voriconazole is an approved oral therapy for esophageal candidiasis, a common mucosal infection in immunocompromised individuals.[8]
• Serious Infections caused by Scedosporium and Fusarium species: It is indicated as a salvage therapy for serious infections caused by Scedosporium apiospermum and Fusarium species in patients who are intolerant of, or have infections refractory to, other antifungal therapies. This establishes its role as a critical agent for these rare but often fatal mycoses.[6]

An analysis of early post-marketing data from 2001 to 2003 revealed that voriconazole was rapidly adopted by clinicians and used predominantly for unapproved (off-label) indications immediately following its launch.[48] At that time, only 12.5% of its use corresponded to its narrow initial FDA-approved indications. This pattern suggests a significant unmet clinical need for a broad-spectrum, mold-active azole, which drove its widespread use in real-world practice for life-threatening infections, often ahead of formal label expansions. This highlights the dynamic interplay between regulatory approval and the pressing demands of clinical medicine.

Table 3: Summary of Key Clinical Trials for Primary Indications

NCT Identifier	Trial Title / Purpose	Indication	Phase	Comparator(s)	Key Relevance
NCT00001757 / NCT00001810	Open-label trial of voriconazole for primary or secondary treatment of invasive fungal infections.	Invasive Fungal Infections (primarily IA)	III	N/A (Non-comparative)	Foundational studies establishing the efficacy and safety of voriconazole for invasive aspergillosis, leading to its approval as first-line therapy.46
NCT01782131	Study of the safety and efficacy of posaconazole versus voriconazole for the treatment of invasive aspergillosis.	Invasive Aspergillosis	III	Posaconazole	Head-to-head comparison that helps define the relative roles of two primary mold-active azoles in the treatment of IA.46
NCT00163111	Study comparing voriconazole to amphotericin B followed by fluconazole in patients with candidemia.	Candidemia (non-neutropenic)	III	Amphotericin B followed by Fluconazole	Key comparative trial demonstrating the efficacy of voriconazole as a primary treatment for candidemia, supporting its FDA indication.47
NCT00015665	Emergency use of voriconazole in patients with life-threatening invasive fungal infections.	Life-threatening Fungal Infections	N/A	N/A	Provided early access and data on voriconazole's utility in critically ill patients with refractory or rare infections.46

Dosing, Administration, and Therapeutic Drug Monitoring (TDM)

Formulations

Voriconazole is available in multiple formulations to accommodate different clinical scenarios:

• Intravenous (IV): Supplied as a lyophilized powder (200 mg per vial) that must be reconstituted and then diluted for infusion. The IV formulation contains sulfobutyl ether beta-cyclodextrin sodium (SBECD) as a solubilizing vehicle to overcome the drug's poor water solubility.[8]
• Oral Tablets: Available as film-coated tablets in 50 mg and 200 mg strengths.[8]
• Oral Suspension: Provided as a powder for reconstitution, which forms an orange-flavored suspension with a concentration of 40 mg/mL.[8]

Dosing and Administration

Due to its pharmacokinetic properties, therapy for serious invasive fungal infections must be initiated with an intravenous loading dose. This strategy is essential to rapidly achieve plasma concentrations that are near steady-state, allowing for an immediate therapeutic effect.[5]

• Adult Dosing (for IA, Scedosporiosis, Fusariosis):
• Loading Dose: 6 mg/kg administered intravenously every 12 hours for the first 24 hours (two doses).[29]
• Maintenance Dose: Following the loading dose, the maintenance regimen is 4 mg/kg IV every 12 hours. When clinically appropriate, patients can be switched to an oral maintenance dose of 200 mg every 12 hours (for patients weighing 40 kg or more).[29]
• Pediatric Dosing (ages 2 to <12 years, and 12-14 years <50 kg):
• Loading Dose: 9 mg/kg administered intravenously every 12 hours for the first 24 hours.[29]
• Maintenance Dose: 8 mg/kg IV every 12 hours, or an oral maintenance dose of 9 mg/kg every 12 hours (up to a maximum of 350 mg per dose).[29]
• Administration Guidelines:
• The IV infusion must be administered over a period of 1 to 3 hours at a maximum rate of 3 mg/kg/hour. It must not be given as an IV bolus injection.[30]
• Oral tablets and suspension should be taken on an empty stomach, at least one hour before or one hour after a meal, to ensure optimal absorption.[29]

Dose Adjustments

Dosing may need to be modified based on patient characteristics, clinical response, or organ function.

• Body Weight: Adult patients weighing less than 40 kg should receive a lower oral maintenance dose of 100 mg every 12 hours.[29]
• Response and Tolerability: For patients with an inadequate clinical response, the oral maintenance dose may be increased (e.g., from 200 mg to 300 mg twice daily in adults >40 kg). Conversely, if a patient is unable to tolerate the dose, it can be reduced in 50 mg increments.[30]
• Hepatic Impairment: In patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B), the standard loading dose should be administered, but the maintenance dose must be halved. Voriconazole has not been studied in severe chronic cirrhosis (Child-Pugh C) and should only be used if the potential benefit outweighs the significant risk.[9]
• Renal Impairment: No dose adjustment is necessary for the oral formulations of voriconazole. However, the intravenous formulation should be avoided in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min). This is not due to the drug itself but because of the potential for accumulation of the intravenous solubilizing vehicle, SBECD. In these patients, oral therapy is the preferred route of administration.[29]

Therapeutic Drug Monitoring (TDM)

The practical application of voriconazole's complex pharmacokinetic data culminates in the strong recommendation for TDM in all patients. TDM is essential to navigate the drug's high pharmacokinetic variability, non-linear kinetics, and narrow therapeutic window, thereby optimizing efficacy while minimizing the risk of toxicity.[11]

• Target Trough Concentration (Cmin​): The generally accepted therapeutic range for voriconazole trough plasma concentrations is 1.0 to 5.5 mg/L (or µg/mL).[35]
• Concentrations below 1.0 mg/L are associated with an increased risk of treatment failure and the development of resistance.[27]
• Concentrations exceeding 5.5 to 6.0 mg/L are correlated with a significantly higher incidence of adverse events, particularly neurotoxicity (e.g., hallucinations, encephalopathy) and hepatotoxicity.[10]
• Timing of Monitoring: Trough levels should be measured after the patient has reached steady-state, which is typically 2 to 5 days after initiating therapy or after any change in dose or interacting medications.[38]
• The clinical necessity of TDM is underscored by findings from a meta-analysis indicating that only about 56% of patients receiving standard voriconazole doses achieve plasma concentrations within the target therapeutic range, leaving a large proportion of patients either underdosed or at risk for toxicity.[33]

Table 4: Recommended Dosing Regimens for Voriconazole in Adults and Pediatrics

Patient Population	Indication	Route	Loading Dose	Maintenance Dose
Adult (≥40 kg)	Invasive Aspergillosis, Scedosporiosis, Fusariosis	IV	6 mg/kg q12h x 24h	4 mg/kg q12h
		Oral	N/A	200 mg q12h
Adult (<40 kg)	Invasive Aspergillosis, Scedosporiosis, Fusariosis	Oral	N/A	100 mg q12h
Pediatric (2 to <12 yrs & 12-14 yrs <50 kg)	Invasive Aspergillosis, Scedosporiosis, Fusariosis	IV	9 mg/kg q12h x 24h	8 mg/kg q12h
		Oral	N/A	9 mg/kg q12h (max 350 mg q12h)

Sources: [29]

Safety Profile, Adverse Events, and Risk Management

Common and Serious Adverse Reactions

The use of voriconazole is associated with a distinct profile of adverse reactions, some of which are common and manageable, while others are serious and require immediate attention. The most frequently reported adverse events in clinical trials include visual disturbances, pyrexia (fever), rash, nausea, vomiting, diarrhea, headache, and elevations in liver function tests.[55]

• Visual Disturbances: This is a very common and characteristic side effect, affecting up to 30-40% of patients. Symptoms include altered or enhanced light perception, blurred vision, changes in color vision (chromatopsia), and photophobia.[54] These effects are typically transient, mild to moderate, and reversible upon discontinuation of the drug. However, for treatment courses extending beyond 28 days, monitoring of visual function is recommended due to postmarketing reports of prolonged visual adverse events, including optic neuritis and papilledema.[54]
• Hepatotoxicity: Voriconazole is associated with a risk of liver injury. Serious hepatic reactions, including clinical hepatitis, cholestasis, and rare but fatal cases of fulminant hepatic failure, have been reported.[1] These events occur primarily in patients with serious underlying conditions, such as hematological malignancies. It is mandatory to measure serum transaminase levels and bilirubin at the start of therapy and to monitor them regularly (at least weekly for the first month) throughout the treatment course. If liver function tests become markedly elevated, discontinuation of voriconazole should be considered.[57]
• QT Prolongation and Arrhythmias: Like some other azole antifungals, voriconazole has been associated with prolongation of the QT interval on the electrocardiogram. There have been rare reports of serious ventricular arrhythmias, such as torsade de pointes, and cardiac arrest, particularly in critically ill patients with multiple confounding risk factors (e.g., history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia).[55] Any pre-existing electrolyte imbalances (potassium, magnesium, calcium) must be corrected before and during therapy.[41]
• Infusion-Related Reactions: The intravenous administration of voriconazole can trigger anaphylactoid-type reactions, with symptoms including flushing, fever, sweating, tachycardia, chest tightness, and dyspnea. These reactions typically occur immediately upon starting the infusion and may necessitate stopping the administration.[29]
• Severe Cutaneous Adverse Reactions (SCARs): Life-threatening skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with voriconazole use. If a patient develops a severe, exfoliative cutaneous reaction, the drug must be discontinued immediately.[29]

Long-Term Toxicity

The expanding use of voriconazole for prolonged treatment and prophylaxis has brought to light a unique spectrum of chronic toxicities that were not fully apparent from the initial, shorter-term clinical trials.

• Photosensitivity and Cutaneous Malignancy: Voriconazole induces photosensitivity, a condition where the skin becomes abnormally sensitive to sunlight.[29] This effect is more than a simple nuisance; it is a direct precursor to a more sinister long-term risk. The pathogenesis begins with the observation that patients on voriconazole are highly susceptible to sunburn. This photosensitivity, with prolonged and duration-dependent use of the drug, is mechanistically linked to a significantly increased risk of developing skin cancers, most notably squamous cell carcinoma (SCC).[53] The SCCs that arise in this context tend to be more aggressive and multifocal than those in the general population.[53] This causal chain transforms photosensitivity from a manageable side effect into a major risk factor for malignancy. This necessitates a proactive and non-negotiable risk management strategy for all patients on long-term voriconazole, involving strict counseling on sun avoidance, consistent use of broad-spectrum sunscreen, protective clothing, and regular dermatological surveillance, particularly for high-risk individuals like transplant recipients.
• Periostitis and Fluorosis: Prolonged therapy can lead to debilitating bone pain. Postmarketing surveillance has confirmed cases of skeletal fluorosis (the accumulation of excess fluoride in bone) and periostitis (inflammation of the periosteum, the membrane covering bones).[53] This toxicity is attributed to the three fluorine atoms present on the voriconazole molecule.
• Other Long-Term Effects: Chronic administration has also been associated with the development of peripheral neuropathy, alopecia (hair loss), and changes to the nails.[53]

Contraindications, Warnings, and Precautions

• Contraindications: Co-administration of voriconazole with potent CYP3A4 inducers (e.g., rifampin, carbamazepine, phenobarbital, St. John's Wort) is contraindicated. These drugs can dramatically increase voriconazole's metabolism, leading to subtherapeutic plasma levels and a high risk of clinical failure.[37] It is also contraindicated with certain drugs that are sensitive CYP3A4 substrates and are known to prolong the QT interval, such as quinidine and cisapride, due to the risk of life-threatening arrhythmias.[58]
• Warnings: The product label carries specific warnings regarding the risks of hepatic toxicity, QT prolongation, visual disturbances, SCARs, and photosensitivity, as detailed above.[29]
• Precautions: Caution is advised when using voriconazole in patients with pre-existing liver disease, proarrhythmic conditions, or renal impairment (specifically for the IV formulation). The oral formulations contain lactose (tablets) and sucrose (suspension), which requires consideration in patients with rare hereditary intolerances to these sugars.[8]

Drug-Drug and Drug-Food Interactions

Cytochrome P450-Mediated Interactions

Voriconazole's extensive metabolism through the cytochrome P450 system makes it a focal point for numerous and complex drug-drug interactions. It is both a substrate for and an inhibitor of several key CYP enzymes, creating a "two-way street" of interactions that can significantly complicate therapy, especially in the poly-medicated patients who typically require it.

Voriconazole as a Victim (Drugs Affecting Voriconazole Levels)

Voriconazole plasma concentrations are highly susceptible to alteration by co-administered drugs that affect its metabolic enzymes.

• Inducers: Drugs that are potent inducers of CYP3A4 and/or CYP2C19 can significantly accelerate the metabolism of voriconazole, leading to dangerously low, subtherapeutic plasma concentrations and a high risk of treatment failure. Key inducers include rifampin, carbamazepine, phenytoin, long-acting barbiturates, and the herbal supplement St. John's Wort. Co-administration with these agents is generally contraindicated or requires substantial increases in the voriconazole maintenance dose and careful TDM (e.g., with phenytoin or efavirenz).[30]

Voriconazole as a Perpetrator (Voriconazole Affecting Other Drugs)

Voriconazole itself is a potent inhibitor of CYP2C19, a moderate inhibitor of CYP2C9, and a clinically significant inhibitor of CYP3A4.[1] By inhibiting these enzymes, it can dramatically increase the plasma concentrations and potential for toxicity of numerous other drugs metabolized by these pathways.

• Immunosuppressants: Voriconazole significantly increases levels of calcineurin inhibitors like cyclosporine and tacrolimus, as well as mTOR inhibitors like sirolimus. Co-administration requires substantial dose reductions of the immunosuppressant (often by 50-70%) and vigilant TDM of both drugs.
• Anticoagulants: It increases the exposure and anticoagulant effect of warfarin (a CYP2C9 substrate). Close and frequent monitoring of prothrombin time or INR is mandatory, with appropriate warfarin dose adjustments.[39]
• Other Significant Interactions: Voriconazole can also increase concentrations of statins (risk of myopathy/rhabdomyolysis), benzodiazepines (risk of prolonged sedation), vinca alkaloids (risk of neurotoxicity), sulfonylureas (risk of hypoglycemia), opioids (e.g., methadone, oxycodone), and certain calcium channel blockers.[37] Co-administration with amiodarone should generally be avoided due to the compounded risk of QT prolongation and life-threatening arrhythmias.[58]

Drug-Food Interactions

The absorption of oral voriconazole is significantly impacted by the presence of food. Administration with meals, particularly high-fat meals, can reduce its bioavailability.[28] To ensure maximal and predictable absorption, it is essential that both the tablet and oral suspension formulations of voriconazole be administered on an empty stomach, defined as at least

one hour before or one to two hours after a meal.[29]

Table 5: Clinically Significant Drug Interactions with Voriconazole

Interacting Drug/Class	Mechanism of Interaction	Effect on Voriconazole or Other Drug	Clinical Management Recommendation
Drugs Affecting Voriconazole
Rifampin, Carbamazepine, St. John's Wort	Potent induction of CYP3A4/2C19	↓↓↓ Voriconazole levels (risk of failure)	Contraindicated. Avoid co-administration.
Phenytoin, Efavirenz	Induction of CYP3A4/2C19	↓↓ Voriconazole levels	Avoid if possible. If necessary, increase voriconazole maintenance dose and monitor levels.
Drugs Affected by Voriconazole
Cyclosporine, Tacrolimus, Sirolimus	Inhibition of CYP3A4	↑↑↑ Immunosuppressant levels (risk of nephrotoxicity, neurotoxicity)	Reduce immunosuppressant dose significantly (e.g., by 50-70%) and perform TDM for both drugs.
Warfarin	Inhibition of CYP2C9	↑↑ Warfarin levels (risk of bleeding)	Monitor INR closely and frequently; adjust warfarin dose as needed.
Statins (e.g., Atorvastatin)	Inhibition of CYP3A4	↑↑ Statin levels (risk of myopathy)	Consider dose reduction or switching to a statin not metabolized by CYP3A4.
Amiodarone, Quinidine	Inhibition of CYP3A4; Additive QT prolongation	↑↑ Amiodarone/Quinidine levels; ↑↑↑ Risk of Torsade de Pointes	Contraindicated or Generally Avoid. Monitor ECG if use is unavoidable.

Sources: [30]

Special Populations and Emerging Applications

Use in Special Populations

• Pediatrics (≥2 years): The pharmacokinetics of voriconazole in children differ markedly from adults. Children exhibit higher, more linear (less saturable) clearance, necessitating higher weight-based dosing to achieve comparable therapeutic exposures. The recommended IV loading dose is 9 mg/kg, with a maintenance dose of 8 mg/kg IV or 9 mg/kg orally.[29] The safety and efficacy in children younger than two years have not been established, and its use is not recommended in this age group.[39]
• Renal Impairment: The oral formulation of voriconazole can be used without dose adjustment in patients with any degree of renal impairment. However, the intravenous formulation should be avoided in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) unless the potential benefit justifies the risk. This precaution is due to the potential for the IV vehicle, SBECD, to accumulate in these patients, not the active drug itself. Oral therapy is the preferred route in this population.[29]
• Hepatic Impairment: For patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), the standard loading dose should be given, but the maintenance dose should be halved. Given the drug's potential for hepatotoxicity, patients with pre-existing liver disease require careful monitoring.[9]

Prophylaxis in Immunocompromised Patients

Voriconazole is an important option for primary antifungal prophylaxis in high-risk immunocompromised patients where coverage against molds is desired. This includes patients undergoing induction chemotherapy for acute leukemia or those who have received an allogeneic hematopoietic stem cell transplant (HSCT).[52]

A key randomized, double-blind trial compared voriconazole with fluconazole for prophylaxis in allogeneic HSCT recipients.[63] While the overall rates of fungal-free survival were similar between the two groups, the voriconazole arm experienced significantly fewer

Aspergillus infections (9 vs. 17 cases), demonstrating its specific advantage in preventing invasive mold disease.[63]

Despite its prophylactic use, breakthrough invasive fungal infections (bIFIs) remain a clinical challenge. A comprehensive systematic review of bIFIs in patients on mold-active azole prophylaxis found that infections occurring during voriconazole therapy were often caused by pathogens outside its primary spectrum of activity (e.g., Mucorales) or occurred in the context of documented subtherapeutic drug concentrations.[65] These findings underscore the limitations of voriconazole's antifungal spectrum and reinforce the critical importance of employing TDM even when the drug is used for prophylaxis.

Emerging Formulations: Inhaled Voriconazole

The development of a Voriconazole Inhalation Powder (VIP) represents a significant and logical evolution in antifungal therapy, aimed directly at overcoming the primary limitations of systemic administration. The core problem with systemic voriconazole is its narrow therapeutic window, where efficacy is threatened by subtherapeutic levels and safety is compromised by toxic supratherapeutic levels that cause hepatotoxicity, neurotoxicity, and visual disturbances.[10] Since the primary site of infection for invasive aspergillosis is the lung, the therapeutic strategy behind VIP is to deliver the drug directly to the site of infection.[67] This approach is hypothesized to achieve high, fungicidal concentrations within the pulmonary tissue while maintaining low systemic plasma concentrations, thereby maximizing local efficacy and dramatically reducing the risk of systemic toxicity.[67]

Phase 1 and 1b clinical trials (e.g., NCT04576325, NCT04229303) have been conducted to evaluate the safety, tolerability, and pharmacokinetics of VIP in both healthy volunteers and patients with stable asthma.[68] Early results from these studies are promising, suggesting that inhaled voriconazole is well-tolerated with no significant adverse effects on pulmonary function. Crucially, these studies did not observe the clinically significant hepatic or visual toxicities associated with oral or IV voriconazole, and systemic drug exposure was found to be much lower than with systemic administration.[68]

Reflecting its potential, an expanded access program (NCT05897294) has been established to provide VIP to patients with pulmonary aspergillosis who have limited or no other treatment options, signaling a potential future role for this formulation in the treatment and prevention of pulmonary fungal diseases.[71]

Regulatory History and Market Status

Approval Timeline

• U.S. Food and Drug Administration (FDA): The innovator product, Vfend®, developed by Pfizer, first received FDA approval on May 24, 2002, for its intravenous and oral tablet formulations.[6] The oral suspension formulation was subsequently approved on December 19, 2003.[72] The pediatric indication was later expanded on January 29, 2019, to include children two years of age and older.[43]
• European Medicines Agency (EMA): Vfend® was granted a marketing authorization valid throughout the European Union on March 19, 2002.[44] Generic versions, such as Voriconazole Accord, were later approved based on bioequivalence to the reference product, with the first generic approvals occurring around 2013.[45]

Market Landscape

• Innovator Product: The original brand name for voriconazole is Vfend®, manufactured by Pfizer.[1]
• Generic Availability: Following patent expirations and litigation settlements, the first generic versions of voriconazole entered the U.S. market around 2011 for tablets and 2012 for the injectable form.[7] Today, numerous pharmaceutical companies manufacture and market generic voriconazole in all three formulations (IV, tablet, and oral suspension).[72]
• Brand Names: In addition to Vfend®, voriconazole is marketed globally under a wide variety of brand names, including Voriconazol, Voritek, Voriz, Pinup, and Vodask, among others.[1]

Expert Synthesis and Recommendations

Integrated Clinical Perspective

Voriconazole stands as an indispensable, often life-saving, therapeutic agent in the modern armamentarium against invasive fungal diseases. Its role as a first-line therapy for invasive aspergillosis is undisputed, and its broad spectrum and excellent oral bioavailability represent major clinical assets.

However, the drug's profound clinical utility is inextricably linked to, and constrained by, its challenging pharmacological profile. The central feature of this profile is its unpredictable, non-linear pharmacokinetics, a direct consequence of its metabolism via the saturable and genetically polymorphic CYP2C19 enzyme. This single characteristic is the nexus from which its greatest clinical challenges arise: a narrow therapeutic window, a high intrinsic risk of both underdosing (leading to therapeutic failure) and overdosing (leading to toxicity), and an extensive, complex web of drug-drug interactions that demand constant vigilance from the clinician.

Recommendations for Optimized Clinical Use

To harness the efficacy of voriconazole while mitigating its inherent risks, a proactive and informed management strategy is essential.

• Embrace Therapeutic Drug Monitoring (TDM): TDM should not be considered an optional adjunct but rather the standard of care for all patients receiving voriconazole. Initial dosing regimens should be viewed merely as a starting point, with prompt TDM-guided adjustments made to achieve and maintain a steady-state trough concentration within the target range of 1.0–5.5 mg/L.
• Proactive Interaction Management: A meticulous medication reconciliation is mandatory before initiating therapy. Clinicians must anticipate, screen for, and actively manage potential drug-drug interactions, paying special attention to co-administered immunosuppressants (cyclosporine, tacrolimus), anticoagulants (warfarin), and any potent inducers or inhibitors of CYP enzymes.
• Vigilant Safety Monitoring: Regular monitoring of liver function tests is non-negotiable. Patients receiving long-term therapy must be thoroughly educated on the risks of photosensitivity and counseled on strict sun protection measures. Regular dermatological surveillance is warranted to screen for premalignant and malignant skin lesions. Any new or worsening neurologic, visual, or skeletal symptoms should be promptly investigated as potential signs of drug toxicity.

Future Research Directions

Despite its established role, several areas of research are needed to further optimize the use of voriconazole.

• Refining TDM: Further studies are needed to define optimal TDM targets for specific, less common pathogens (e.g., Scedosporium, Fusarium) and in challenging patient populations, such as the critically ill or those on extracorporeal membrane oxygenation (ECMO).
• Inhaled Formulations: The clinical role, efficacy, and long-term safety of inhaled voriconazole require further investigation through Phase II/III trials to determine its place in the treatment and prophylaxis of pulmonary fungal infections.
• Pharmacogenetic Dosing: The development and validation of pharmacogenetic-guided initial dosing algorithms, incorporating CYP2C19 genotype, could significantly reduce the time required to achieve therapeutic concentrations, potentially improving early clinical outcomes.
• Mitigating Long-Term Toxicity: Research into strategies to mitigate the mechanisms of long-term toxicities, particularly cutaneous squamous cell carcinoma and skeletal fluorosis, is crucial for improving the safety of prolonged therapy.
• Combination Therapies: Continued investigation into the efficacy of voriconazole in combination regimens, such as with echinocandins for refractory aspergillosis or with immunomodulators like interferon-gamma, may offer new hope for patients with the most difficult-to-treat infections.[59]

Works cited

1. Voriconazole: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 22, 2025, https://go.drugbank.com/drugs/DB00582
2. Voriconazole | C16H14F3N5O | CID 71616 - PubChem, accessed July 22, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Voriconazole
3. PharmGKB Summary: Voriconazole Pathway, Pharmacokinetics - PMC - PubMed Central, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5405706/
4. Voriconazole (DRG 0301, UK 109496, VRC, CAS Number: 137234 ..., accessed July 22, 2025, https://www.caymanchem.com/product/15633/voriconazole
5. Voriconazole: A New Triazole Antifungal Agent | Clinical Infectious Diseases | Oxford Academic, accessed July 22, 2025, https://academic.oup.com/cid/article/36/5/630/454409
6. Voriconazole: the newest triazole antifungal agent - PMC - PubMed Central, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1201014/
7. Voriconazole - Wikipedia, accessed July 22, 2025, https://en.wikipedia.org/wiki/Voriconazole
8. Vfend (voriconazole) i.v., tablets and suspension label, accessed July 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021266s032lbl.pdf
9. Voriconazole tablets I.P. and voriconazole powder for solution for infusion I.P. VFEND - Pfizer, accessed July 22, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=15028
10. Voriconazole Pathway, Pharmacokinetics - PharmGKB, accessed July 22, 2025, https://www.pharmgkb.org/pathway/PA166160640
11. Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing - Oxford Academic, accessed July 22, 2025, https://academic.oup.com/jac/article/69/6/1633/834658
12. [Voriconazole (100 mg)] - CAS [137234-62-9] - USP Store, accessed July 22, 2025, https://store.usp.org/product/1718008
13. Voriconazole 137234-62-9 | TCI AMERICA - Tokyo Chemical Industry, accessed July 22, 2025, https://www.tcichemicals.com/US/en/p/V0116
14. 21-266 VFEND Chemistry Review Part 1 - accessdata.fda.gov, accessed July 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-266_VFEND_chemr_P1.pdf
15. Formulation Diary, accessed July 22, 2025, https://www.formulationdiary.com/Home/Details/VORICONAZOLE
16. Definition of voriconazole - NCI Drug Dictionary, accessed July 22, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/voriconazole
17. Voriconazole | C16H14F3N5O - ChemSpider, accessed July 22, 2025, https://www.chemspider.com/Chemical-Structure.64684.html
18. voriconazole - PharmGKB, accessed July 22, 2025, https://www.pharmgkb.org/chemical/PA10233
19. Voriconazole | Antifungal | Antifection - TargetMol, accessed July 22, 2025, https://www.targetmol.com/compound/voriconazole
20. Voriconazole = 98 HPLC 137234-62-9 - Sigma-Aldrich, accessed July 22, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/pz0005
21. Voriconazole (UK-109, 496), anti-fungal agent (CAS 188416-29-7) (ab141067) | Abcam, accessed July 22, 2025, https://www.abcam.com/en-us/products/biochemicals/voriconazole-uk-109-496-fungal-agent-ab141067
22. What is the mechanism of Voriconazole? - Patsnap Synapse, accessed July 22, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-voriconazole
23. Product Information for Vfend (voriconazole) - Therapeutic Goods Administration (TGA), accessed July 22, 2025, https://www.tga.gov.au/sites/default/files/auspar-voriconazole-130521-pi.pdf
24. Evaluation of Voriconazole Pharmacodynamics Using Time-Kill Methodology | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed July 22, 2025, https://journals.asm.org/doi/10.1128/aac.44.7.1917-1920.2000
25. Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed July 22, 2025, https://journals.asm.org/doi/10.1128/aac.02516-17
26. Variability of Voriconazole Plasma Levels Measured by New High-Performance Liquid Chromatography and Bioassay Methods | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed July 22, 2025, https://journals.asm.org/doi/10.1128/aac.00957-06
27. Observational Study of the Clinical Efficacy of Voriconazole and Its Relationship to Plasma Concentrations in Patients - PubMed Central, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3186950/
28. 21-266 VFEND Clinical Pharmacology Biopharmaceutics Review - accessdata.fda.gov, accessed July 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-266_VFEND_biopharmr.pdf
29. Voriconazole: Package Insert / Prescribing Information - Drugs.com, accessed July 22, 2025, https://www.drugs.com/pro/voriconazole.html
30. Voriconazole - GlobalRPH, accessed July 22, 2025, https://globalrph.com/renal/voriconazole/
31. Voriconazole and Alcohol/Food Interactions - Drugs.com, accessed July 22, 2025, https://www.drugs.com/food-interactions/voriconazole.html
32. www.drugs.com, accessed July 22, 2025, https://www.drugs.com/food-interactions/voriconazole.html#:~:text=You%20may%20experience%20reduced%20absorption,body%20to%20absorb%20the%20medication.
33. Associated factors with voriconazole plasma concentration: a systematic review and meta-analysis - Frontiers, accessed July 22, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1368274/full
34. Population Pharmacokinetics of Voriconazole in Adults - PMC - PubMed Central, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3256045/
35. Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study - MDPI, accessed July 22, 2025, https://www.mdpi.com/2079-6382/12/7/1100
36. Population pharmacokinetics of voriconazole and initial dosage optimization in patients with talaromycosis - Frontiers, accessed July 22, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.982981/full
37. drug interactions with voriconazole.- | Download Table, accessed July 22, 2025, https://www.researchgate.net/figure/drug-interactions-with-voriconazole_tbl2_51045394
38. Clinical Practice Guidelines : Antifungal prophylaxis for children with cancer or undergoing haematopoietic stem cell transplant - The Royal Children's Hospital, accessed July 22, 2025, https://www.rch.org.au/clinicalguide/guideline_index/Antifungal_prophylaxis_for_children_with_cancer_or_undergoing_haematopoietic_stem_cell_transplant/
39. Data Sheet Template - Medsafe, accessed July 22, 2025, https://www.medsafe.govt.nz/profs/datasheet/v/vfendtabinj.pdf
40. Inhibition of Voriconazole Metabolism by Meropenem: A Role for Inflammation? | Clinical Infectious Diseases | Oxford Academic, accessed July 22, 2025, https://academic.oup.com/cid/article/66/10/1643/4827565
41. Voriconazole (oral route) - Side effects & dosage - Mayo Clinic, accessed July 22, 2025, https://www.mayoclinic.org/drugs-supplements/voriconazole-oral-route/description/drg-20095248
42. Voriconazole: MedlinePlus Drug Information, accessed July 22, 2025, https://medlineplus.gov/druginfo/meds/a605022.html
43. Voriconazole (Vfend) Pediatric Review - FDA, accessed July 22, 2025, https://www.fda.gov/media/161021/download
44. Vfend | European Medicines Agency (EMA), accessed July 22, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/vfend
45. Voriconazole Accord | European Medicines Agency (EMA), accessed July 22, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/voriconazole-accord
46. Fungal Infection Completed Phase 3 Trials for Voriconazole (DB00582) | DrugBank Online, accessed July 22, 2025, https://go.drugbank.com/indications/DBCOND0031276/clinical_trials/DB00582?phase=3&status=completed
47. A Clinical Study Intended To Compare Treatment With Voriconazole To Treatment With Amphotericin Followed By Fluconazole In Patients With Candidemia, A Serious Fungus Infection Of The Blood. | ClinicalTrials.gov, accessed July 22, 2025, https://clinicaltrials.gov/study/NCT00163111
48. Utilization and Comparative Effectiveness of Caspofungin and Voriconazole Early after Market Approval in the U.S - Our journal portfolio - PLOS, accessed July 22, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083658
49. Voriconazole Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed July 22, 2025, https://www.drugs.com/dosage/voriconazole.html
50. VFEND® (voriconazole) Dosage and Administration | Pfizer Medical - US, accessed July 22, 2025, https://www.pfizermedical.com/vfend/dosage-admin
51. A Study To Evaluate The Safety Of Voriconazole As Treatment Of Invasive Aspergillosis (Fungal Infection) And Other Rare Molds In Children | ClinicalTrials.gov, accessed July 22, 2025, https://clinicaltrials.gov/study/NCT00836875
52. 1604-Antifungal prophylaxis in immunocompromised adults - eviQ, accessed July 22, 2025, https://www.eviq.org.au/clinical-resources/side-effect-and-toxicity-management/prophylaxis-and-treatment/1604-antifungal-prophylaxis-in-immunocompromised-a
53. Adverse effects of voriconazole: Over a decade of use - PubMed, accessed July 22, 2025, https://pubmed.ncbi.nlm.nih.gov/27581783/
54. voriconazole interactions with CYP450 enzymes | Download Table - ResearchGate, accessed July 22, 2025, https://www.researchgate.net/figure/oriconazole-interactions-with-CYP450-enzymes_tbl2_51240072
55. Voriconazole Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 22, 2025, https://www.drugs.com/sfx/voriconazole-side-effects.html
56. Voriconazole (Vfend): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed July 22, 2025, https://www.webmd.com/drugs/2/drug-63366-5326/voriconazole-oral/voriconazole-oral/details
57. VFEND® (voriconazole) Warnings and Precautions | Pfizer Medical - US, accessed July 22, 2025, https://www.pfizermedical.com/vfend/warnings
58. Amiodarone and voriconazole Interactions - Drugs.com, accessed July 22, 2025, https://www.drugs.com/drug-interactions/amiodarone-with-voriconazole-167-0-2309-0.html?professional=1
59. Voriconazole With or Without Interferon Gamma in Treating Patients With Aspergillosis or Other Fungal Infections | ClinicalTrials.gov, accessed July 22, 2025, https://clinicaltrials.gov/study/NCT00059878
60. Showing BioInteractions for Voriconazole (DB00582) | DrugBank Online, accessed July 22, 2025, https://go.drugbank.com/drugs/DB00582/biointeractions
61. Efficacy and safety of voriconazole in immunocompromised patients: systematic review and meta-analysis - PubMed, accessed July 22, 2025, https://pubmed.ncbi.nlm.nih.gov/29262742/
62. Voriconazole for secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients: results of the VOSIFI study | Haematologica, accessed July 22, 2025, https://haematologica.org/article/view/5762
63. Antifungal Prophylaxis in Immunocompromised Patients - PMC, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5016014/
64. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation - PubMed, accessed July 22, 2025, https://pubmed.ncbi.nlm.nih.gov/20826719/
65. Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review - PubMed, accessed July 22, 2025, https://pubmed.ncbi.nlm.nih.gov/38752732/
66. Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review | Clinical Infectious Diseases | Oxford Academic, accessed July 22, 2025, https://academic.oup.com/cid/article/79/1/151/7673806
67. A Novel Inhalable Dry Powder to Trigger Delivery of Voriconazole for Effective Management of Pulmonary Aspergillosis - PubMed Central, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11280232/
68. TFF Pharmaceuticals Announces Topline Results of Voriconazole Inhalation Powder Phase 1 Clinical Trial | Nasdaq, accessed July 22, 2025, https://www.nasdaq.com/press-release/tff-pharmaceuticals-announces-topline-results-of-voriconazole-inhalation-powder-phase
69. Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Inhaled Voriconazole in Healthy Volunteers and Subjects With Stable Asthma - PubMed, accessed July 22, 2025, https://pubmed.ncbi.nlm.nih.gov/39918069/
70. Pharmacokinetic Profile of Voriconazole Inhalation Powder in Adult Subjects With Asthma, accessed July 22, 2025, https://clinicaltrials.gov/study/NCT04576325
71. Study Details | Voriconazole Inhalation Powder for the Treatment of Pulmonary Aspergillosis, accessed July 22, 2025, https://clinicaltrials.gov/study/NCT05897294
72. Generic Vfend Availability - Drugs.com, accessed July 22, 2025, https://www.drugs.com/availability/generic-vfend.html
73. Drug Approval Package: Vfend (Voriconazole) NDA #21266 & 21267 - accessdata.fda.gov, accessed July 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-266_21-267_vfend.cfm
74. Public Assessment Report Scientific discussion Voriconazol Pharmathen 200 mg powder for solution for infusion (Voriconazole) NL/H/3159/001/DC Date: 10 March 2016 - Cbg-meb.nl, accessed July 22, 2025, https://db.cbg-meb.nl/pars/h115096.pdf
75. Human medicines European public assessment report (EPAR): Voriconazole Accord, voriconazole, Date of authorisation: 16/05/2013, Revision: 19, Status, accessed July 22, 2025, https://efim.org/node/141028
76. en.wikipedia.org, accessed July 22, 2025, https://en.wikipedia.org/wiki/Voriconazole#:~:text=Voriconazole%2C%20sold%20under%20the%20brand,a%20number%20of%20fungal%20infections.
77. Voriconazole and Caspofungin Acetate in Treating Invasive Fungal Infections in Patients With Weakened Immune Systems | ClinicalTrials.gov, accessed July 22, 2025, https://clinicaltrials.gov/study/NCT00238355