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Voriconazole: Drug information

Voriconazole: Drug information
(For additional information see "Voriconazole: Patient drug information" and see "Voriconazole: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Vfend;
  • Vfend IV
Brand Names: Canada
  • APO-Voriconazole [DSC];
  • JAMP-Voriconazole;
  • SANDOZ Voriconazole;
  • TEVA-Voriconazole;
  • Vfend
Pharmacologic Category
  • Antifungal Agent, Azole Derivative;
  • Antifungal Agent, Oral;
  • Antifungal Agent, Parenteral
Dosing: Adult

Dosage guidance:

Dosing: Therapeutic drug monitoring is recommended; adjust dose based on serum trough concentration to ensure efficacy and avoid toxicity. Timing and frequency of concentration monitoring is individualized (Ref).

Aspergillosis

Aspergillosis:

Allergic bronchopulmonary (alternative agent): Oral: 200 mg twice daily for ≥16 weeks in combination with systemic corticosteroids (Ref); may give a loading dose of 400 mg twice daily for the first 2 doses. Note: Some experts reserve for patients who are unable to taper corticosteroids or have an exacerbation of allergic bronchopulmonary aspergillosis (Ref).

Chronic cavitary pulmonary:

IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Some experts reserve IV therapy for severely ill patients (Ref).

Oral: 200 mg twice daily; may increase to 300 mg twice daily based on therapeutic drug monitoring (Ref).

Duration: ≥6 months; some patients require prolonged, potentially lifelong therapy (Ref).

Invasive (including disseminated and extrapulmonary):

Note: For severe or progressive infection, some experts use as part of a combination antifungal regimen (Ref).

IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Once a patient is able to tolerate oral administration, consider transition to oral formulation (Ref).

Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).

Duration: Minimum of 6 to 12 weeks, depending on degree/duration of immunosuppression, disease site, and response to therapy (Ref); immunosuppressed patients may require more prolonged treatment (Ref).

Ocular (off-label use):

Endophthalmitis:

Note: Administer a combination of both intraocular (intravitreal and/or intracameral depending on sites of involvement) and systemic (IV or oral) antifungal therapy (Ref).

Intraocular: Note: For intraocular injections, extemporaneously prepare dose in 0.1 mL of sterile water or NS.

Intravitreal injection: For involvement of the vitreous: 100 mcg per 0.1 mL (sterile water or NS) administered intravitreally once. Intravitreal dose may be repeated in several days if no improvement (Ref).

Intracameral injection: For involvement of the anterior segment: 50 mcg per 0.1 mL to 100 mcg per 0.1 mL (sterile water or NS) administered intracamerally (into the aqueous) once (Ref). Note: May also consider intravitreal injection even if vitritis is not apparent, as occult vitreal involvement is possible (Ref).

Systemic:

IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Once a patient is able to tolerate oral administration, consider transition to oral formulation (Ref).

Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref). If the oral formulation is used as initial therapy for mild cases, give a loading dose of 400 mg twice daily for the first 2 doses (Ref).

Duration: Usually ≥1 month to several months, depending on cause and extent of infection and response to therapy; some patients require prolonged therapy (Ref).

Keratitis: Note: Optimal dose not defined.

Ophthalmic: Instill 1 drop of an extemporaneously prepared 1% ophthalmic solution topically to the cornea of the affected eye(s) every 1 hour while awake for 1 week, then every 2 hours while awake for 2 weeks, with further continuation at physician discretion (Ref).

Blastomycosis

Blastomycosis (off-label use):

Note: For initial treatment of mild to moderate disease (alternative agent) or step-down therapy after amphotericin B for more severe infection, especially CNS disease (Ref).

IV: 6 mg/kg IV twice daily for 2 doses, then 3 mg/kg IV twice daily (Ref).

Oral: 200 to 400 mg twice daily (Ref).

Duration: 6 to 12 months; ≥12 months is recommended for patients with moderately severe to severe disseminated infection, osteoarticular or CNS infection, and for all patients who are immunocompromised (Ref).

Candidiasis, treatment

Candidiasis, treatment:

Candidemia (neutropenic and non-neutropenic patients), including disseminated candidiasis (alternative agent):

Initial therapy: IV: 400 mg twice daily for 2 doses, then 200 to 300 mg IV or orally twice daily or weight-based dosing (6 mg/kg IV twice daily for 2 doses, then 3 to 4 mg/kg IV or orally twice daily) (Ref).

Step-down therapy (for clinically stable patients who have responded to initial therapy with negative repeat cultures): Note: For susceptible Candida krusei isolates, voriconazole is the preferred step-down agent (Ref).

Oral: 200 mg twice daily; for susceptible isolates of Candida glabrata, use 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).

Duration: Treat for ≥14 days after first negative blood culture and resolution of signs/symptoms; continue until resolution of neutropenia, if present; metastatic complications warrant a longer duration (Ref).

Cardiac infection, native or prosthetic valve endocarditis or device infection (eg, implantable cardiac defibrillator, pacemaker) (alternative agent) (off-label use): Note: Reserve for patients with fluconazole-resistant/voriconazole-susceptible isolates (Ref).

Step-down therapy (for clinically stable, blood culture–negative patients following initial therapy with non-azole parenteral therapy): Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).

Duration: For device infection without endocarditis, 4 weeks after device removal for generator pocket infections and ≥6 weeks after device removal for wire infections. For endocarditis, ≥6 weeks after valve replacement surgery, with longer duration for perivalvular abscesses or other complications; long-term suppressive therapy is recommended for prosthetic valve endocarditis or if valve cannot be replaced (Ref).

Endophthalmitis (with or without vitritis) (off-label use):

Note: Administer a combination of both intraocular (intravitreal and/or intracameral depending on sites of involvement) and systemic (IV or oral) antifungal therapy. For patients with endogenous endophthalmitis without vitritis or macular involvement, intraocular antifungals may not be necessary (Ref).

Intraocular: Note: For intraocular injections, extemporaneously prepare dose in 0.1 mL of sterile water or NS.

Intravitreal injection: 100 mcg per 0.1 mL (sterile water or NS) administered intravitreally once (Ref). Intravitreal dose may be repeated in several days if no improvement (Ref).

Intracameral injection: For exogenous cases involving primarily the aqueous: 50 mcg per 0.1 mL (sterile water or NS) administered intracamerally (into the aqueous) once. Note: May also consider intravitreal injection even if vitritis is not apparent, as occult vitreal involvement is possible (Ref).

Ophthalmic: For exogenous cases with concurrent keratitis: Instill 1 drop of an extemporaneously prepared 1% ophthalmic solution topically to the cornea of the affected eye(s) every 1 hour (Ref). Duration depends on response to therapy.

Systemic: IV, Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily or weight-based dosing (6 mg/kg twice daily for 2 doses, then 3 to 4 mg/kg twice daily) for ≥4 to 6 weeks until resolution (Ref).

Esophageal: IV, Oral: 200 mg twice daily or weight-based dosing (3 mg/kg twice daily) for 14 to 28 days. Note: Reserve for fluconazole-refractory disease or as an alternative initial agent for patients with HIV (Ref).

Oropharyngeal, fluconazole-refractory (alternative agent) (off-label use): Oral: 200 mg twice daily for up to 28 days (Ref).

Coccidioidomycosis, refractory to conventional therapy

Coccidioidomycosis, refractory to conventional therapy (alternative agent) (off-label use): Note: Initial parenteral antifungal therapy may be warranted.

Nonmeningeal infection (eg, bone and/or joint infection, pulmonary infection in select patients): Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily (Ref).

Duration: Varies based on site and severity of infection, as well as host immune status; in some cases, lifelong therapy is needed (Ref).

Meningitis: Oral: 400 mg twice daily for 2 doses, followed by 200 to 400 mg twice daily (Ref). Duration is lifelong because of the high relapse rate (Ref).

Fusariosis

Fusariosis (alternative agent):

Invasive:

IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Some experts suggest combination antifungal therapy for patients with severe immunosuppression, severe disease, or increasing skin lesions or persistently positive blood cultures with monotherapy (Ref); in addition, the CDC recommends initial combination therapy for CNS infection (Ref).

Oral, following improvement with initial IV therapy: 200 mg twice daily (Ref). Note: For patients with CNS infection, the CDC recommends higher doses of 6 mg/kg (400 mg) twice daily with therapeutic drug monitoring (Ref).

Duration: Often prolonged and depends on site of infection, severity, immune status, and response to therapy (Ref).

Keratitis: Ophthalmic: Instill 1 drop of an extemporaneously prepared 1% ophthalmic solution topically to the affected eye(s) every 1 hour; may extend dosing interval based on response. May be used alone or in combination with systemic therapy depending on the severity of illness (Ref). Duration depends on response to therapy; several months are often warranted (Ref).

Neutropenic fever

Neutropenic fever (empiric antifungal therapy) (alternative agent) (off-label use):

IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref).

Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).

Prophylaxis against invasive fungal infections

Prophylaxis against invasive fungal infections (alternative agent) (off-label use):

Hematologic malignancy or post-hematopoietic cell transplant:

IV: 4 mg/kg twice daily (Ref).

Oral: 200 mg twice daily (Ref).

Duration: Varies based on degree and duration of immunosuppression (Ref).

Solid organ transplant:

IV: 4 mg/kg twice daily; may give a loading dose of 6 mg/kg twice daily for the first 2 doses (Ref).

Oral: 200 mg twice daily (Ref); may give a loading dose of 400 mg twice daily for the first 2 doses (Ref).

Duration: Varies based on patient risk factors and transplant center protocol (Ref).

Scedosporiosis

Scedosporiosis:

IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref).

Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily (Ref).

Duration: Often prolonged and varies based on clinical response and patient immune status (Ref).

Talaromycosis

Talaromycosis (formerly Penicilliosis) (alternative agent) (off-label use):

Treatment, mild disease (skin lesions without bloodstream infection): Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily for 12 weeks, then continue with long-term suppression therapy (Ref).

Treatment, moderate to severe disease:

Induction therapy: IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily for at least 3 days (Ref).

Following IV induction therapy: Oral: 200 mg twice daily for a total of 12 weeks (Ref). If oral therapy is used for induction therapy (eg, when IV formulation is unavailable), give 600 mg twice daily for 2 doses, then 400 mg twice daily for 2 weeks, then 200 mg twice daily for 10 weeks (Ref). Continue with long-term suppression therapy after either regimen.

Long-term suppression therapy (secondary prophylaxis): Oral: 200 mg twice daily until cellular immunity is restored (for patients with HIV, when CD4 count >100 cells/mm3 and virologic suppression with antiretroviral therapy is sustained for ≥6 months) (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function:

CrCl ≥50 mL/minute: Oral, Ophthalmic, IV: No dosage adjustment necessary (Ref).

CrCl <50 mL/minute:

Oral, Ophthalmic: No dosage adjustment necessary (Ref).

IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Ref); however, use of oral voriconazole or alternative antifungals is preferred if clinically appropriate. IV formulations contain the vehicle sulfobutylether-beta-cyclodextrin (SBECD), which may accumulate. Cyclodextrins have been associated with kidney injury in animal models; however, small studies suggest similar rates of nephrotoxicity to noncyclodextrin-containing antifungals in patients receiving short durations (eg, <10 days) of therapy (Ref). If IV therapy is used, monitor serum creatinine frequently and change to oral voriconazole when possible (Ref).

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):

Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).

Oral, IV: Initiate therapy with the maximum recommended indication-specific dose; subsequent dosage adjustments should be made based on therapeutic drug monitoring to ensure pharmacokinetic/pharmacodynamic targets are met (Ref).

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (voriconazole component) (Ref):

Oral, Ophthalmic: No dosage adjustment or supplemental doses necessary.

IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Ref); however, use of oral voriconazole or alternative antifungals is preferred if clinically appropriate. Exposure to SBECD, the carrier excipient in the IV formulation, is increased compared to patients with normal kidney function despite removal by hemodialysis (Ref). If IV therapy is used, use with caution and change to oral voriconazole when possible (Ref).

Peritoneal dialysis:

Oral, Ophthalmic: No dosage adjustment necessary (Ref).

IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Ref); however, use of oral voriconazole or alternative antifungals is preferred if clinically appropriate. Exposure to SBECD, the carrier excipient in the IV formulation, is expected to be increased compared to patients with normal renal function. If IV therapy is used, use with caution and change to oral voriconazole when possible (Ref).

CRRT:

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.

Oral, Ophthalmic: No dosage adjustment necessary (Ref).

IV: Use of oral voriconazole therapy or alternative antifungals is preferred when clinically appropriate; however, due to removal of SBECD, the carrier excipient in the IV formulation, via CRRT, limited data suggest that usual indication-specific doses of IV voriconazole can be considered (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.

Oral, Ophthalmic: No dosage adjustment necessary (Ref).

IV: Use of oral voriconazole therapy or alternative antifungals is preferred when clinically appropriate. If necessary, usual indication-specific doses of IV voriconazole can be considered; however, use with caution with frequent monitoring of kidney function and conversion to oral voriconazole when possible; a small study in patients receiving extended daily dialysis showed significant accumulation of SBECD, the carrier excipient in the IV formulation (Ref).

Dosing: Hepatic Impairment: Adult

Mild to moderate impairment (Child-Pugh class A or B): Following standard loading dose, reduce maintenance dosage by 50%

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Should only be used if benefit outweighs risk; monitor closely for toxicity

Dosing: Obesity: Adult

The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):

Weight-based dosing: IV, Oral: Initial: Use adjusted body weight for weight-based dose calculations; adjust dose based on serum trough concentration to ensure efficacy and avoid toxicity. Refer to adult dosing for indication-specific doses (Ref).

Fixed (non-weight based) dosing: Oral, IV: Initial: No dosage adjustment necessary; use standard doses based on indication (expert opinion). Adjust dose based on serum trough drug concentration to ensure efficacy and avoid toxicity (Ref). Refer to adult dosing for indication-specific doses.

Rationale for recommendations:

Voriconazole exhibits nonlinear clearance and does not distribute widely into adipose tissue. Use of either weight-based or fixed (non-weight based) dosing is acceptable; in patients with obesity, there are no data directly comparing weight-based vs fixed (non-weight based) dosing (Ref).

Weight-based dosing: Pharmacokinetic studies in patients with obesity have demonstrated that supratherapeutic trough drug concentration may result when actual body weight is used to calculate weight-based doses. To avoid supratherapeutic trough concentrations and associated toxicity, use adjusted body weight to calculate the weight-based dose (Ref).

Fixed (non-weight based) dosing: Fixed dosing has been evaluated in a small number of patients with obesity and is considered an acceptable dosing approach; however, more data evaluating clinical outcomes with this method are needed (Ref).

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Voriconazole: Pediatric drug information")

Dosage guidance:

Dosage form information: In pediatric patients <12 years, bioequivalence between the oral tablet and suspension has not been determined; due to possible shortened gastric transit time in infants and children, absorption of tablets may be different than adults; dosing recommendations for infants and children are based on studies with the oral suspension. Data suggests higher doses (mg/kg) than adults are required in patients <15 years and weighing <50 kg.

General dosing, susceptible infection: Note: Dosage adjustment may be required if patient does not have adequate response, cannot tolerate dose, or adequate trough concentrations are not achieved; monitor trough concentrations closely (Ref).

Infants and Children <2 years: Limited data available: IV, Oral (Oral suspension): Initial: 9 mg/kg/dose every 12 hours followed by monitoring of serum trough concentrations typically initiated after 3 to 5 days; adjust dose to achieve target trough; median final dosage: 31.5 mg/kg/day (range: 12 to 71 mg/kg/day) divided every 12 hours; Note: Doses >40 mg/kg/day were administered in 3 divided doses; dosing based on a retrospective pharmacokinetic analysis of patients receiving voriconazole after hematopoietic stem cell transplants (n=11; age range: 0.3 to 2 years) (Ref).

Children 2 to <12 years: Note: Monitor serum concentrations to maintain trough concentrations of 2 to 6 mcg/mL (Ref).

Loading dose: IV: 9 mg/kg/dose every 12 hours for 2 doses on day 1.

Maintenance:

IV: 8 mg/kg/dose every 12 hours.

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose; Note: In most patients, oral therapy is not recommended as initial therapy for treatment; it is recommended to convert from parenteral to oral therapy only after significant clinical improvement has been observed.

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

IV:

<50 kg: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 4 to 8 mg/kg/dose every 12 hours.

≥50 kg: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 3 to 4 mg/kg/dose every 12 hours.

Oral:

<50 kg: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

≥50 kg: 200 mg every 12 hours.

Adolescents ≥15 years:

IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by a maintenance dose of 3 to 4 mg/kg/dose every 12 hours.

Oral:

<40 kg: 100 mg every 12 hours.

≥40 kg: 200 mg every 12 hours.

Aspergillosis, invasive, including disseminated and extrapulmonary infection; treatment

Aspergillosis, invasive, including disseminated and extrapulmonary infection; treatment (Ref): Note: Duration of therapy should be a minimum of 6 to 12 weeks, although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement (Ref).

Dosage adjustment may be required if patient does not have adequate response, cannot tolerate dose, or adequate trough concentrations are not achieved; monitor trough concentrations closely; therapeutic drug monitoring is critical to ensure efficacy and minimize toxicity; may consider switching to oral therapy once patient is stable and able to tolerate (Ref).

Children 2 to <12 years:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

≥50 kg:

IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg/dose every 12 hours.

Oral: 200 to 300 mg every 12 hours.

Adolescents ≥15 years:

IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg/dose every 12 hours.

Oral: 200 to 300 mg every 12 hours.

Candidiasis, prophylaxis for patients at high risk of invasive candidiasis

Candidiasis, prophylaxis for patients at high risk of invasive candidiasis (eg, AML, recurrent ALL, allogeneic HSCT): Limited data available:

Children 2 to <12 years (Ref):

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

≥50 kg:

IV: 4 mg/kg/dose every 12 hours (Ref).

Oral: 200 mg every 12 hours (Ref).

Adolescents ≥15 years:

IV: 4 mg/kg/dose every 12 hours (Ref).

Oral: 200 mg every 12 hours (Ref).

Candidiasis, invasive; treatment

Candidiasis, invasive; treatment: Note: Voriconazole is considered an alternative therapy and offers little advantage over fluconazole as first-line therapy of candidemia. Step-down therapy to oral voriconazole is recommended only in select clinically stable patients with certain voriconazole-susceptible isolates (eg, Candida krusei) and negative repeat cultures (Ref).

Children 2 to <12 years:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

≥50 kg:

IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 3 to 4 mg/kg/dose every 12 hours.

Oral: 200 to 300 mg every 12 hours.

Adolescents ≥15 years:

IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 3 to 4 mg/kg/dose every 12 hours.

Oral: 200 to 300 mg every 12 hours.

Candidiasis, endocarditis/implantable cardiac devices; treatment

Candidiasis, endocarditis/implantable cardiac devices (eg, pacemaker, ICD, VAD); treatment: Limited data available: Note: Voriconazole should only be used as step-down therapy in clinically stable, culture-negative patients following initial therapy.

Children 2 to <12 years: Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg: Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

≥50 kg: Oral: 200 to 300 mg (3 to 4 mg/kg/dose) twice daily (Ref).

Adolescents ≥15 years: Oral: 200 to 300 mg (3 to 4 mg/kg/dose) twice daily (Ref).

Candidiasis, esophageal, treatment

Candidiasis, esophageal, treatment: Note: Voriconazole is not considered a first-line therapy for esophageal candidiasis (Ref).

Children 2 to <12 years:

IV: 4 mg/kg/dose every 12 hours.

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: 4 mg/kg/dose every 12 hours.

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

≥50 kg: Oral: 200 mg twice daily.

Adolescents ≥15 years: Oral: 200 mg twice daily (Ref).

Fluconazole-refractory infection: Limited data available: Treatment should continue for 14 to 21 days (Ref).

Children 2 to <12 years:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

≥50 kg: IV, Oral: 200 mg (3 mg/kg/dose) twice daily (Ref).

Adolescents ≥15 years: IV, Oral: 200 mg (3 mg/kg/dose) twice daily (Ref).

Candidiasis, oropharyngeal, fluconazole-refractory; treatment

Candidiasis, oropharyngeal, fluconazole-refractory; treatment: Limited data available: Treatment should continue for up to 28 days (Ref).

Children 2 to <12 years: Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg: Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

≥50 kg: Oral: 200 mg twice daily (Ref).

Adolescents ≥15 years: Oral: 200 mg twice daily (Ref).

Candidiasis, endophthalmitis, voriconazole-susceptible isolates

Candidiasis, endophthalmitis (with or without vitritis), voriconazole-susceptible isolates: Limited data available:

Systemic therapy: Note: For patients with vitritis or with macular involvement (with or without vitritis), an intravitreal injection of voriconazole or amphotericin B deoxycholate is also recommended (Ref).

Children 2 to <12 years:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).

≥50 kg:

IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 300 mg (4 mg/kg/dose) twice daily (Ref).

Oral: 300 mg (4 mg/kg/dose) twice daily (Ref).

Adolescents ≥15 years:

IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 300 mg (4 mg/kg/dose) twice daily (Ref).

Oral: 300 mg (4 mg/kg/dose) twice daily (Ref).

Intravitreal therapy: Patients with vitritis or with macular involvement (with or without vitritis): Children ≥2 years and Adolescents: Intravitreal: 100 mcg of an extemporaneously prepared solution in 0.1 mL sterile water or NS; concomitant systemic antifungal therapy is also recommended.

Scedosporiosis, fusariosis, treatment

Scedosporiosis, fusariosis, treatment:

Children 2 to <12 years:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

Children ≥12 years and Adolescents ≤15 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Ref).

<50 kg:

IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses, followed by maintenance dose of 8 mg/kg/dose every 12 hours.

Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.

≥50 kg:

IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses, followed by 4 mg/kg/dose every 12 hours.

Oral: 200 mg every 12 hours.

Adolescents ≥15 years:

IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses, followed by 4 mg/kg/dose every 12 hours.

Oral: 200 mg every 12 hours.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for inadequate response:

Children ≥2 years and Adolescents <15 years weighing <50 kg:

IV: Increase by 1 mg/kg/dose increments.

Oral: Increase by 1 mg/kg/dose or 50 mg increments; maximum dose: 350 mg/dose.

Children ≥12 years and Adolescents <15 years weighing ≥50 kg and Adolescents ≥15 years (regardless of weight):

IV: Increase by 1 mg/kg/dose increments.

Oral:

<40 kg: Titrate in 50 mg/dose increments; minimum recommended dose: 100 mg every 12 hours; maximum recommended dose in manufacturer's labeling: 300 mg/dose.

≥40 kg: Increase to 300 mg every 12 hours.

Dosage adjustment for patients unable to tolerate treatment:

Children ≥2 years and Adolescents <15 years weighing <50 kg:

IV: Reduce dose by 1 mg/kg/dose increments.

Oral: Reduce dose by 1 mg/kg/dose increments or 50 mg increments.

Children ≥12 years and Adolescents <15 years weighing ≥50 kg and Adolescents ≥15 years:

IV: Reduce dose by 1 mg/kg/dose increments.

Oral: Reduce dose by 50 mg increments. Minimum dose in patients <40 kg: 100 mg/dose; Minimum dose in patients ≥40 kg: 200 mg/dose.

Dosing: Kidney Impairment: Pediatric

Oral: Children ≥2 years and Adolescents:

Mild to severe impairment: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; has not been studied. Based on experience in adult patients, it is unlikely that dosage adjustment is necessary.

Dialysis: Poorly dialyzed; no supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis (IHD) with thrice weekly sessions or peritoneal dialysis.

Continuous renal replacement therapy (CRRT) (Ref): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate).

Parenteral: IV: Children ≥2 years and Adolescents:

CrCl ≥50 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.

CrCl <50 mL/minute: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; has not been studied. Due to accumulation of the intravenous vehicle (cyclodextrin), in adult patients, the manufacturer recommends the use of oral voriconazole in these patients unless an assessment of risk:benefit justifies the use of IV voriconazole; if IV therapy is used, closely monitor serum creatinine and change to oral voriconazole when possible.

Dosing: Hepatic Impairment: Pediatric

Baseline hepatic impairment:

Children ≥2 years and Adolescents:

Mild to moderate impairment: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling (has not been studied); based on adult data, dosage reduction may be necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Should only be used if benefit outweighs risk; monitor closely for toxicity.

Adverse Reactions (Significant): Considerations
Acute kidney injury

There have been isolated case reports of worsening kidney function with IV voriconazole, leading to acute kidney injury (Ref). Historically, it has been recommended to avoid IV voriconazole in patients with CrCl <50 mL/minute because of the potential for the carrier excipient, sulfobutylether-beta-cyclodextrin (SBECD), to accumulate and potentially lead to kidney injury. Data from small retrospective studies suggest that select patients with baseline kidney impairment may safely receive short durations (eg, <10 days) of IV voriconazole (Ref).

Mechanism: The excipient SBECD manufactured with IV voriconazole is a second-generation cyclodextrin, and it is the polysubstitution of the hydroxyl hydrogens in the naturally occurring beta-cyclodextrin that might confer less nephrotoxicity (Ref). It has been postulated that the SBECD formulation has properties that do not reabsorb at the renal tubules and do not concentrate in the intracellular tissues (Ref).

Onset: Varied (Ref).

Risk factors:

• Cumulative IV voriconazole dose (≥400 mg/kg) (Ref)

• First-generation cyclodextrin excipient (Ref)

• Baseline kidney impairment (Ref)

• Concurrent use of potentially nephrotoxic medications (eg, foscarnet) (Ref)

Cardiovascular effects

Azole antifungals, including voriconazole, have been associated with prolonged QT interval on ECG, which may lead to torsades de pointes (TdP) or polymorphic ventricular arrhythmias, in both adult and pediatric patients. Numerous cases have been reported with voriconazole (Ref), some of which have occurred independently of drug concentrations (Ref). Drug-drug interactions commonly play a significant role in risk related to cardiovascular effects with voriconazole either by an additive pharmacodynamic effect, reducing the clearance of voriconazole, or by lowering potassium and/or magnesium concentrations (Ref).

Mechanism: One proposed mechanism is that azole antifungals may block the IKr channel (Ref). Another possible mechanism is depression of rapidly activating delayed rectifier potassium channels (Ref).

Onset: Varied; QT prolongation occurred within the first 24 hours up to 23 days after initiation (Ref).

Risk factors:

Drug-induced QTc prolongation/TdP (in general):

• Females (Ref)

• Age >65 years (Ref)

• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)

• Genetic defects of cardiac ion channels (Ref)

• History of drug-induced TdP (Ref)

• Congenital long QT syndrome (Ref)

• Longer baseline QTc interval (eg, >450 msec) or lengthening of the QTc by ≥60 msec (Ref)

• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)

• Bradycardia (Ref)

• Hepatic impairment (Ref)

• Kidney impairment (Ref)

• Diuretic use (Ref)

• Sepsis (Ref)

• Concurrent administration of multiple medications (≥2) that prolong the QT interval or medications with drug interactions that increase serum concentrations of QT-prolonging medications (Ref)

• Some data suggest HIV may be a risk factor, even in antiretroviral therapy-naive patients, especially in patients with CD4 count <200 cells/mm3 (Ref)

Dermatologic reactions

Skin photosensitivity has been reported, including erythematous rashes in sun-exposed areas (Ref), bullous phototoxicity (Ref), and pseudoporphyria (Ref) in all ages; a higher frequency of phototoxic reactions has been reported in pediatric patients. Photosensitivity may persist for several months after discontinuation of voriconazole (Ref). Rare cases of skin malignancy (malignant melanoma, squamous cell carcinoma [SCC]), cutaneous SCC in situ have also been reported in adult and pediatric patients (Ref). Severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (Ref) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported (Ref). Alopecia has also been reported (Ref).

Mechanism:

• Phototoxicity/skin malignancies: Dose and/or time-related. Unknown; inhibition of CYP3A4 and CYP2C9 by voriconazole may lead to increased levels of the phototoxic compound tretinoin (Ref). Another hypothesis suggests that voriconazole and/or its N-oxide primary metabolite are chromophores, generating phototoxic reactions (Ref).

• SCARs: Non–dose-related; immunologic (ie, T-cell-mediated) (Ref).

Onset:

• Photosensitivity: Varied; 1 week to 3 years (Ref).

• Non-melanoma skin cancer: Delayed; mean treatment delay of 36 months. In some patients, voriconazole had been discontinued for 6 months before diagnosis (Ref).

• SCARs: Varied; usually occurs 1 to 8 weeks after initiation (Ref); reexposure may lead to more rapid onset (usually within 1 to 4 days) (Ref).

Risk factors:

Phototoxicity:

• Higher dose (Ref)); causal relationship of phototoxic reactions to dose and/or serum concentration have been mixed in pediatric patients with a dose- and/or concentration-dependent relationship reported in some cases and phototoxicities without any relation to dose and/or concentration reported in other cases (Ref)

• Pediatric patients (Ref)

• Concurrent methotrexate (Ref)

Skin malignancy:

• Prior history of severe phototoxic reaction (Ref)

• Higher dose (SCC) (Ref)

• Longer duration of therapy (SCC, especially in patients with lung transplantation) (Ref).

• Immunosuppression (SCC, especially in patients with lung or hematopoietic cell transplantation) (Ref)

• Ultra-rapid metabolizers (SCC) (Ref)

General:

• Cross-sensitivity: Cross-reactivity among oral azole antifungals has not been consistently reported in patients with histories of immunologic reactions. No cross-reactivity was noted between fluconazole and voriconazole (Ref), or posaconazole and voriconazole (Ref). Following a graded oral challenge, isavuconazole has been tolerated in a patient with a history of angioedema following voriconazole (Ref)

Hepatotoxicity

Azole antifungals, including voriconazole, may cause hepatotoxicity (ranging from mild, asymptomatic increased serum transaminases to hepatic failure) in adult and pediatric patients (Ref). Hepatotoxic reactions occurred more frequently in pediatric patients versus adults in pooled clinical trials. Acute hepatic failure and death have been reported in a child (Ref). If intervention is required, liver injury is generally reversible within ~2 weeks after dose reduction or discontinuation but may recur upon rechallenge (Ref).

Mechanism: Not clearly established; possible mechanisms include alteration of human sterol synthesis and significant drug-drug interactions due to CYP450 metabolism (Ref). Possibly dose- and concentration-related in adult patients (Ref)

Onset: Varied; most cases occur within the first month of therapy (but may occur at any time) (Ref).

Risk Factors:

• Possibly dose and concentration-related (eg, >4 mg/L) in adult patients (Ref); however, a correlation has not been clearly established in pediatric patients (Ref)

• Preexisting liver disease (Ref)

• Concurrent hepatotoxic agents and drug interactions (Ref)

• In patients with lung transplantation, additional risk factors include age <40 years, cystic fibrosis, early initiation (within 30 days) (Ref)

• Cross-reactivity among oral azole antifungals has not been consistently reported in patients with histories of hepatotoxicity (Ref)

Ocular and neurological effects

Voriconazole may cause visual disturbance, including blurred vision, optic neuritis, vision color changes, episcleritis, and scleritis (Ref). Visual disturbances may resolve within 24 hours to 2 weeks after discontinuation (Ref). Voriconazole may also cause audio or visual hallucination which may last up to 5 days and are reversible with discontinuation (Ref). Peripheral neuropathy (PN) has also been reported with numbness or tingling in the extremities, which may be rapidly debilitating and irreversible (Ref). Encephalopathy has also been reported (Ref).

Mechanism:

• Visual disturbances: May be due to effects on rod and cone pathways, hypothesized to be a disinhibition that puts the retina in a more light-adapted state (with increased light sensitivity) (Ref).

• Hallucinations: May be caused by active CNS penetration, attributed to higher trough concentrations, which commonly occurs with IV administration.

• PN: Unknown; may be caused by a sensory-predominant axonal neuropathy. Mitochondrial diseases may be the root cause of axonal neuropathies (Ref).

Onset:

• Visual disturbances: Rapid; within a couple of days of initiation (Ref)

• Hallucinations: Rapid; within 24 hours of initiation (Ref)

• PN: Delayed; >1 month after initiation (Ref)

Risk factors:

• Visual disturbances: High trough concentrations (>5 mg/L) (Ref)

• Hallucinations: High trough concentrations (>5 mg/L) (Ref)

• PN: Long-term use and accumulation of voriconazole (Ref)

Skeletal effects

Periosteal disease may occur with voriconazole and is manifested as increased serum alkaline phosphatase, skeletal fluorosis, and conventional radiographs and nuclear scans showing periostitis (Ref). Periostitis is painful and reversible with discontinuation (Ref). Pain usually improves 2 weeks to 4 months after discontinuation, with lab values (alkaline phosphatase) and radiographic findings following this time course (Ref).

Mechanism: Dose and duration-dependent; voriconazole is a trifluorinated compound, with 65 mg of fluoride in a 400 mg dose, much greater than the 3 to 4 mg of fluoride required for daily intake (Ref). Fluoride can integrate into the extracellular matrix as fluorapatite, making bone density increase and become more resistant to resorption. This increase in bone density can cause osteosclerosis (bone brittleness), decrease the structural integrity, and make patients more prone to fractures. Fluorapatite can stimulate osteoblastic activity which can lead to periostitis and exostosis (Ref).

Onset: Delayed; ~6 months to 3 years after chronic use; however, shorter exposures such as 6 weeks have also been documented (Ref).

Risk factors:

• Dose (400 mg daily) and duration of use (Ref)

• Elevated fluoride levels (Ref)

• Post-transplantation (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults unless otherwise specified.

>10%:

Cardiovascular: Hypertension (children, adolescents: 11%; adults: <2%)

Dermatologic: Skin rash (children, adolescents: 13%; adults: 2% to 4%) (table 1)

Voriconazole: Adverse Reaction: Skin Rash

Drug (Voriconazole)

Comparator

Population

Number of Patients (Voriconazole)

Number of Patients (Comparator)

Comments

13%

N/A

Children and adolescents

105

N/A

N/A

4%

4%

Adults

468

185

Comparator: amphotericin B

4%

0.8%

Adults

468

131

Comparator: amphotericin B followed by fluconazole

2%

0.5%

Adults

200

191

Comparator: fluconazole

Endocrine & metabolic: Hyperkalemia (≤17%), hypokalemia (children, adolescents: 11%; adults: <1%)

Gastrointestinal: Abdominal pain (children, adolescents: 12%; adults: <2%), diarrhea (children, adolescents: 11%; adults: <2%), nausea (children, adolescents: 13%; adults: 1% to 4%), vomiting (children, adolescents: 20%; adults: 1% to 3%)

Hepatic: Increased serum alanine aminotransferase (children, adolescents, adults: 2% to 23%), increased serum alkaline phosphatase (children, adolescents, adults: 4% to 23% (table 2)), increased serum aspartate aminotransferase (children, adolescents, adults: 2% to 20%)

Voriconazole: Adverse Reaction: Increased Serum Alkaline Phosphatase

Drug (Voriconazole)

Comparator

Population

Indication

Number of Patients (Voriconazole)

Number of Patients (Comparator)

Comments

8%

N/A

Children and adolescents

N/A

97

N/A

N/A

23%

23%

Adults

Candidemia

261

115

Comparator: amphotericin B followed by fluconazole

10%

8%

Adults

Esophageal candidiasis

187

186

Comparator: fluconazole

16%

22%

Adults

Invasive aspergillosis

181

173

Comparator: amphotericin B

5%

2%

Adults

N/A

200

191

Comparator: fluconazole

4%

2%

Adults

N/A

468

185

Comparator: amphotericin B

4%

2%

Adults

N/A

468

131

Comparator: amphotericin B followed by fluconazole

Ophthalmic: Visual disturbance (children, adolescents: 26%, adults: 14% to 16%; likely serum concentration dependent [Imhof 2006; Pascual 2008; Tan 2006]) (table 3)

Voriconazole: Adverse Reaction: Visual Disturbance

Drug (Voriconazole)

Comparator

Population

Number of Patients (Voriconazole)

Number of Patients (Comparator)

Comments

26%

N/A

Children and adolescents

105

N/A

N/A

16%

4%

Adults

200

191

Comparator: fluconazole

14%

0.5%

Adults

468

185

Comparator: amphotericin B

14%

0%

Adults

468

131

Comparator: amphotericin B followed by fluconazole

Renal: Renal insufficiency (children, adolescents: 5%; adults: ≤1%; increased serum creatinine: children, adolescents: <5%; adults: ≤21%; acute kidney injury: <1%) (table 4)

Voriconazole: Adverse Reaction: Acute Kidney Injury

Drug (Voriconazole)

Comparator

Population

Number of Patients (Voriconazole)

Number of Patients (Comparator)

Comments

0.4%

6%

Adults

468

185

Comparator: Amphotericin B

0.4%

5%

Adults

468

131

Comparator: Amphotericin B followed by fluconazole

0%

0%

Adults

200

191

Comparator: Fluconazole

Respiratory: Epistaxis (children, adolescents: 16%; adults: <2%)

Miscellaneous: Fever (children, adolescents: 25%; adults: 2%)

1% to 10%:

Cardiovascular: Acute myocardial infarction (<2%), atrial fibrillation (<2%), atrioventricular nodal arrhythmia (<2%), bigeminy (<2%), bradycardia (children, adolescents, adults: <5%), bundle branch block (<2%), cardiomegaly (<2%), cardiomyopathy (<2%), chest pain (<2%), complete atrioventricular block (<2%), deep vein thrombophlebitis (<2%), edema (<2%), endocarditis (<2%), extrasystoles (<2%), flushing (children, adolescents: <5%), heart failure (<2%), hypotension (children, adolescents: 9%; adults: <2%), orthostatic hypotension (<2%), peripheral edema (children, adolescents: 9%; adults: <2%), phlebitis (children, adolescents, adults: <5%), prolonged QT interval on ECG (<2%), pulmonary embolism (<2%), substernal pain (<2%), supraventricular extrasystole (<2%), supraventricular tachycardia (children, adolescents, adults: <5%), syncope (children, adolescents, adults: <5%), tachycardia (children, adolescents: 7%; adults: 1%), thrombophlebitis (<2%), torsades de pointes (<2%), vasodilation (<2%), ventricular fibrillation (<2%), ventricular tachycardia (<2%)

Dermatologic: Allergic dermatitis (children, adolescents: <5%), alopecia (children, adolescents, adults: <5%), cellulitis (<2%), cheilitis (<2%), contact dermatitis (children, adolescents, adults: <5%), diaphoresis (<2%), ecchymoses (<2%), eczema (<2%), erythema multiforme (<2%), exfoliative dermatitis (children, adolescents, adults: <5%), fixed drug eruption (<2%), furunculosis (<2%), maculopapular rash (<2%), malignant melanoma (<2%), pruritus (children, adolescents, adults: <5%), psoriasis (<2%), skin discoloration (<2%), skin photosensitivity (<2%), Stevens-Johnson syndrome (<2%), toxic epidermal necrolysis (<2%) (Gomulka 2014), urticaria (children, adolescents, adults: <5%), xeroderma (<2%)

Endocrine & metabolic: Adrenocortical insufficiency (<2%), albuminuria (<2%), decreased glucose tolerance (<2%), decreased libido (<2%), diabetes insipidus (<2%), hypercalcemia (children, adolescents, adults: <5%), hypercholesterolemia (<2%), hyperglycemia (children, adolescents: 7%; adults: <2%), hypermagnesemia (children, adolescents, adults: <5%), hypernatremia (<2%), hyperphosphatemia (children, adolescents: <5%), hyperthyroidism (<2%), hyperuricemia (<2%), hypervolemia (<2%), hypoalbuminemia (children, adolescents: 5%), hypocalcemia (children, adolescents: 6%; adults: <2%), hypoglycemia (children, adolescents, adults: <5%), hypomagnesemia (children, adolescents, adults: ≤5%), hyponatremia (<2%), hypophosphatemia (children, adolescents: 6%; adults: <2%), hypothyroidism (<2%), increased lactate dehydrogenase (<2%), pseudoporphyria (<2%)

Gastrointestinal: Abdominal distention (children, adolescents, adults: ≤5%), ageusia (<2%), anorexia (<2%), cholecystitis (<2%), cholelithiasis (<2%), cholestasis (children and adolescents: <5%), Clostridioides difficile colitis (<2%), constipation (children, adolescents, adults: ≤5%), duodenitis (<2%), dysgeusia (<2%), dyspepsia (children, adolescents, adults: <5%), dysphagia (<2%), esophageal ulcer (<2%), esophagitis (<2%), flatulence (<2%), gastric ulcer (<2%), gastroenteritis (<2%), gastrointestinal hemorrhage (<2%), gingival hemorrhage (<2%), gingival hyperplasia (<2%), gingivitis (<2%), glossitis (<2%), hematemesis (<2%), intestinal perforation (<2%), melanosis (<2%), melena ( <2%), oral inflammation (children, adolescents: 6%), oral mucosa ulcer (<2%), pancreatitis (<2%), parotid gland enlargement (<2%), perforated duodenal ulcer (<2%), periodontitis (<2%), peritonitis (<2%), proctitis (<2%), rectal hemorrhage (<2%), stomatitis (<2%), xerostomia (<2%)

Genitourinary: Anuria (<2%), blighted ovum (<2%), dysmenorrhea (<2%), dysuria (<2%), epididymitis (<2%), glycosuria (<2%), hematuria (<2%), hemorrhagic cystitis (<2%), impotence (<2%), oliguria (<2%), pelvic pain (<2%), scrotal edema (<2%), uremia (<2%), urinary incontinence (<2%), urinary retention (<2%), urinary tract infection (<2%), uterine hemorrhage (<2%), vaginal hemorrhage (<2%)

Hematologic & oncologic: Agranulocytosis (<2%), anemia (children, adolescents, adults: <5%), aplastic anemia (<2%), disseminated intravascular coagulation (<2%), eosinophilia (<2%), hemolytic anemia (<2%), leukopenia (children, adolescents, adults: <5%), lymphadenopathy (<2%), lymphangitis (<2%), macrocytic anemia (<2%), megaloblastic anemia (<2%), microcytic anemia (<2%), pancytopenia (children, adolescents, adults: <5%), petechia (<2%), prolonged bleeding time (<2%), purpuric disease (<2%), splenomegaly (<2%), squamous cell carcinoma (<2%; including cutaneous squamous cell carcinoma in situ), thrombocytopenia (children, adolescents: 10%; adults: <2%), thrombotic thrombocytopenic purpura (<2%)

Hepatic: Ascites (<2%), cholestatic jaundice (2%), hepatic coma (<2%), hepatic failure (<2%), hepatitis (<2%), hepatomegaly (<2%), hyperbilirubinemia (children, adolescents: <5%; adults: ≤1%), increased gamma-glutamyl transferase (children, adolescents, adults: <5%), jaundice (children, adolescents, adults: <5%)

Hypersensitivity: Angioedema (<2%), facial edema (<2%), hypersensitivity reaction (children, adolescents, adults: <5%), nonimmune anaphylaxis (<2%), tongue edema (<2%)

Immunologic: Graft-versus-host disease (<2%)

Infection: Herpes simplex infection (<2%), infection (<2%; including bacterial infection, fungal infection), sepsis (<2%)

Local: Inflammation at injection site (<2%), injection-site infection (<2%), pain at injection site (<2%)

Nervous system: Abnormal dreams (<2%), agitation (children, adolescents, adults: <5%), akathisia (<2%), amnesia (<2%), anxiety (children, adolescents, adults: <5%), asthenia (children, adolescents, adults: <5%), ataxia (children, adolescents, adults: <5%), brain edema (<2%), cerebral hemorrhage (<2%), cerebral ischemia (<2%), cerebrovascular accident (<2%), chills (children, adolescents, adults: <5%), coma (<2%), confusion (<2%), delirium (<2%), dementia (<2%), depersonalization (<2%), depression (children, adolescents, adults: <5%), dizziness (children, adolescents, adults: ≤5%), drowsiness (<2%), emotional lability (children, adolescents: <5%), encephalitis (<2%), encephalopathy (<2%), euphoria (<2%), extrapyramidal reaction (<2%), Guillain-Barre syndrome (<2%), hallucination (children, adolescents, adults: ≤5%; literature suggests up to ~17% incidence; likely serum concentration dependent [Bayhan 2016; Imhof 2006; Pascual 2008; Tan 2006]) (table 5), headache (children, adolescents: 10%; adults: 2%), hypertonia (<2%), hypoesthesia (<2%), hypothermia (children, adolescents: <5%), insomnia (children, adolescents, adults: <5%), intracranial hypertension (<2%), lethargy (children, adolescents: <5%), myasthenia (<2%), neuralgia (<2%), neuropathy (<2%), pain (<2%), paresthesia (children, adolescents, adults: <5%), psychosis (<2%), seizure (children, adolescents, adults: <5%; including tonic clonic), suicidal ideation (<2%), tremor (<2%), vertigo (children, adolescents, adults: <5%), voice disorder (<2%)

Voriconazole: Adverse Reaction: Hallucination

Drug (Voriconazole)

Comparator

Population

Number of Patients (Voriconazole)

Number of Patients (Comparator)

Comments

5%

N/A

Children and adolescents

105

N/A

N/A

3%

0.5%

Adults

468

185

Comparator: amphotericin B

3%

0%

Adults

468

131

Comparator: amphotericin B followed by fluconazole

0%

0%

Adults

200

191

Comparator: fluconazole

Neuromuscular & skeletal: Arthralgia (children, adolescents, adults: <5%), arthritis (<2%), back pain (<2%), discoid lupus erythematosus (<2%), increased creatine phosphokinase in blood specimen (<2%), lower limb cramp (<2%), myalgia (children, adolescents, adults: <5%), myopathy (<2%), ostealgia (<2%), osteomalacia (<2%), osteonecrosis (<2%), osteoporosis (<2%)

Ophthalmic: Accommodation disturbance (<2%), blepharitis (<2%), chromatopsia (≤1%), color blindness (<2%), conjunctivitis (children, adolescents, adults: <5%), corneal opacity (<2%), diplopia (<2%), dry eye syndrome (children, adolescents, adults: <5%), eye pain (<2%), keratitis (children, adolescents, adults: <5%), keratoconjunctivitis (<2%), mydriasis (<2%), night blindness (<2%), nystagmus disorder (children, adolescents, adults: <5%), oculogyric crisis (<2%), optic atrophy (<2%), optic neuritis (<2%), papilledema (<2%), photophobia (children, adolescents, adults: ≤6%), retinal hemorrhage (<2%), retinitis (<2%), scleritis (<2%), subconjunctival hemorrhage (<2%), uveitis (<2%), visual field defect (<2%)

Otic: Deafness (<2%), hypoacusis (<2%), otalgia (<2%), otitis externa (<2%), tinnitus (children, adolescents, adults: <5%)

Renal: Decreased creatinine clearance (<2%), flank pain (<2%), hydronephrosis (<2%), increased blood urea nitrogen (<2%), nephritis (<2%), nephrosis (<2%), renal pain (<2%), renal tubular necrosis (<2%)

Respiratory: Acute respiratory distress syndrome (<2%), bronchospasm (children, adolescents: <5%), cough (children, adolescents: 10%; adults: <2%), cyanosis (<2%), dyspnea (children, adolescents: 6%; adults: <2%), flu-like symptoms (<2%), hemoptysis (children, adolescents, adults: ≤5%), hypoxia (<2%), nasal congestion (children, adolescents: <5%), pharyngitis (<2%), pleural effusion (<2%), pneumonia (<2%), pulmonary edema (<2%), respiratory failure (children, adolescents: <5%), respiratory tract infection (<2%), rhinitis (<2%), sinusitis (<2%), tachypnea (children and adolescents: <5%), upper respiratory tract infection (children and adolescents: 5%)

Miscellaneous: Granuloma (<2%), multiorgan failure (<2%)

Postmarketing:

Dermatologic: Changes in nails (Malani 2014), cutaneous lupus erythematosus (Ezra 2016), phototoxicity (Barbosa 2014; Kim 2018)

Hepatic: Hepatotoxicity (Ferrajulo 2010; Lo Re 2016; Mohammed 2022)

Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (Kaneko 2018)

Nervous system: Peripheral neuropathy (Baxter 2011)

Neuromuscular & skeletal: Myositis (Happaerts 2022), periosteal disease (Cormican 2018; Hussain 2018, Murray 2022), skeletal fluorosis (Cormican 2018; Hussain 2018)

Ophthalmic: Episcleritis (Bayhan 2016), ocular epitheliopathy (ocular surface dysplasia) (Agarwal 2022), vision color changes (Bayhan 2016)

Contraindications

Hypersensitivity to voriconazole or any component of the formulation; coadministration with barbiturates (long acting), carbamazepine, efavirenz (≥400 mg daily), ergot derivatives (ergotamine and dihydroergotamine), ivabradine, lurasidone, naloxegol, pimozide, quinidine, rifampin, rifabutin, ritonavir (≥800 mg daily; also avoid low-dose [eg, 200 mg daily] dosing if possible), sirolimus, St. John's wort, tolvaptan, venetoclax (during initiation and ramp-up phase in chronic lymphocytic leukemia or small lymphocytic lymphoma patients).

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Canadian labeling: Additional contraindications (not in the US labeling): Coadministration with eszopiclone (when used in patients ≥65 years of age), lovastatin, midazolam (oral), simvastatin, and triazolam.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Reversible adrenal insufficiency in patients receiving an azole with or without concurrent corticosteroid use has been reported. Cushing syndrome in patients taking voriconazole concurrently with corticosteroids has also been reported. Monitor adrenal function as clinically necessary during and after treatment, particularly in patients receiving corticosteroids concomitantly. Educate patients to get medical care if signs and symptoms of adrenal insufficiency or Cushing syndrome occur.

• Dermatologic reactions: Patients, including children, should avoid exposure to direct sunlight and should use protective clothing and high SPF sunscreen.

• Toxicity symptoms: Voriconazole demonstrates nonlinear pharmacokinetics. Dose modifications may result in unpredictable changes in serum concentrations and contribute to toxicity. It is important to note that cutoff trough threshold values ranged widely among studies; however, an upper limit of <5.0 mg/L would be reasonable for most disease states (see Reference Range section).

Disease-related concerns:

• Electrolyte abnormalities: Correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating and during therapy.

• Hepatic impairment: Use with caution; adjustments to maintenance dosing is required in mild to moderate hepatic cirrhosis (Child-Pugh class A and B). In patients with severe hepatic insufficiency use only if the benefit outweighs the potential risk.

• Renal impairment: The manufacturer recommends avoiding the use of IV voriconazole in patients with renal impairment due to potential accumulation of the excipient sulfobutylether-beta-cyclodextrin, which may lead to kidney injury. However, limited data suggest that patients with baseline kidney impairment may safely receive short durations of IV voriconazole (Kim 2016; Lilly 2013; Neofytos 2012; Oude Lashof 2012).

Dosage form specific issues:

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

• Oral:

- Lactose: Tablets contain lactose; avoid administration in hereditary galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption.

- Sucrose: Suspension contains sucrose; use caution with fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption.

Warnings: Additional Pediatric Considerations

The bioequivalence of the oral suspension and tablets has not been evaluated in pediatric patients. Studies have shown children <12 years of age have a lower bioavailability than adults (Friberg 2012; Karlsson 2009); it is recommended to initiate therapy in children with intravenous regimen and only switch to oral therapy once significant clinical improvement has been observed. The oral dosing recommended for children is based on studies that utilized the oral suspension formulation. Oral bioavailability may be limited in children 2 to 12 years with malabsorption and very low weight for age; in these cases, intravenous voriconazole is recommended.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Generic: 200 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Vfend IV: 200 mg (1 ea) [latex free]

Vfend IV: 200 mg (1 ea)

Generic: 200 mg (1 ea)

Suspension Reconstituted, Oral:

Vfend: 40 mg/mL (75 mL) [contains sodium benzoate; orange flavor]

Generic: 40 mg/mL (75 mL)

Tablet, Oral:

Vfend: 50 mg, 200 mg

Generic: 50 mg, 200 mg

Generic Equivalent Available: US

Yes

Pricing: US

Solution (reconstituted) (Vfend IV Intravenous)

200 mg (per each): $72.36

Solution (reconstituted) (Voriconazole Intravenous)

200 mg (per each): $27.49 - $152.58

Suspension (reconstituted) (Vfend Oral)

40 mg/mL (per mL): $8.20

Suspension (reconstituted) (Voriconazole Oral)

40 mg/mL (per mL): $14.07 - $22.51

Tablets (Vfend Oral)

50 mg (per each): $1.79

200 mg (per each): $4.47

Tablets (Voriconazole Oral)

50 mg (per each): $9.72 - $19.88

200 mg (per each): $23.70 - $79.52

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Vfend: 200 mg (1 ea)

Generic: 200 mg (1 ea)

Suspension Reconstituted, Oral:

Vfend: 40 mg/mL (70 mL) [contains sodium benzoate]

Tablet, Oral:

Vfend: 50 mg, 200 mg

Generic: 50 mg, 200 mg

Administration: Adult

Oral: Administer 1 hour before or 1 hour after a meal. Shake oral suspension for approximately 10 seconds before each use. Enteral tube feedings may decrease oral absorption; may hold tube feedings for 1 hour before and 1 hour after a voriconazole dose (Ref).

IV: Infuse over 1 to 3 hours (rate not to exceed 3 mg/kg/hour). Do not administer as an IV bolus injection. Do not infuse concomitantly into same line or cannula with other drug infusions. Do not infuse concomitantly even in separate lines or cannulas with concentrated electrolyte solutions or blood products. May be infused simultaneously with nonconcentrated electrolytes or TPN through a separate IV line. If TPN is infused through a multiple lumen catheter, use a different port than used for voriconazole.

Intravitreal (off-label): Administer an extemporaneously prepared solution of 100 mcg/0.1 mL of voriconazole in sterile water or NS intravitreally (Ref).

Ophthalmic (off-label): Administer an extemporaneously prepared voriconazole 10 mg/mL (1%) ophthalmic solution to the affected eye.

Administration: Pediatric

Oral: Administer at least one hour before or one hour after a meal; maintain adequate hydration unless instructed to restrict fluid intake.

Oral suspension: Shake suspension for approximately 10 seconds before use; do not mix suspension with other medications, flavoring agents, or other fluids.

Parenteral: IV infusion: Do not administer IV push; voriconazole must be administered by IV infusion over 1 to 3 hours at a rate not to exceed 3 mg/kg/hour. Do not infuse concomitantly into same line or cannula with other drug infusions, including TPN.

Intravitreal: Administer an extemporaneously prepared solution of 100 mcg/0.1 mL of voriconazole in sterile water or NS intravitreally (Ref).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration. For IV preparation, double gloves, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) are recommended. Double gloving, a gown, and (if dosage form allows) CSTDs are required during IV administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use: Labeled Indications

Treatment of fungal infections in patients ≥2 years of age: Treatment of invasive aspergillosis; treatment of esophageal candidiasis; treatment of candidemia (in non-neutropenic patients); treatment of disseminated Candida infections of the skin and abdomen, kidney, bladder wall, and wounds; treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. (including Fusarium solani) in patients intolerant of, or refractory to, other therapy

Use: Off-Label: Adult

Blastomycosis; Candidiasis, cardiac infection (native or prosthetic valve endocarditis or device infection); Candidiasis, endophthalmitis; Candidiasis, oropharyngeal (fluconazole-refractory); Coccidioidomycosis, refractory to conventional therapy; Neutropenic fever, empiric antifungal therapy; Prophylaxis against invasive fungal infections, hematologic malignancy patients or hematopoietic cell transplant recipients; Prophylaxis against invasive fungal infections, solid organ transplant recipients; Talaromycosis (formerly Penicilliosis)

Medication Safety Issues
Sound-alike/look-alike issues:

Vfend may be confused with Venofer, Vimpat.

Voriconazole may be confused with fluconazole, itraconazole, posaconazole.

Metabolism/Transport Effects

Substrate of CYP2C19 (major), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (moderate), CYP2C9 (weak), CYP3A4 (strong)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily. Risk D: Consider therapy modification

Abrocitinib: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Abrocitinib. Risk C: Monitor therapy

Acalabrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Acalabrutinib. Risk X: Avoid combination

Adagrasib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Adagrasib may increase the serum concentration of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Adagrasib. Management: Consider alternatives to this combination. Avoid use of adagrasib and strong CYP3A4 inhibitors until adagrasib concentrations have reached stead state (ie, after 8 days of therapy). If combined monitor closely for QTc interval prolongation and arrhythmias Risk D: Consider therapy modification

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Management: Avoid concomitant use of ado-trastuzumab emtansine and strong CYP3A4 inhibitors when possible. Consider alternatives that do not inhibit CYP3A4 or consider administering after CYP3A4 inhibitor discontinuation. Monitor for toxicities if combined. Risk D: Consider therapy modification

ALfentanil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALfentanil. Management: If use of alfentanil and strong CYP3A4 inhibitors is necessary, consider dosage reduction of alfentanil until stable drug effects are achieved. Frequently monitor patients for respiratory depression and sedation when these agents are combined. Risk D: Consider therapy modification

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Risk X: Avoid combination

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan dose to 6.25 mg and maximum dose to 12.5 mg in any 24-period when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Risk D: Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Risk C: Monitor therapy

ALPRAZolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam. Risk X: Avoid combination

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy

Amiodarone: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Amiodarone. Risk X: Avoid combination

Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy

AmLODIPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine. Risk C: Monitor therapy

Antihepaciviral Combination Products: May decrease the serum concentration of Voriconazole. Management: Concurrent use of voriconazole with antihepaciviral combination products should be avoided unless the patient-specific benefit/risk ratio justifies the use of voriconazole. Decreased efficacy of voriconazole is possible. Risk D: Consider therapy modification

Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Risk C: Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Risk X: Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, CYP2D6 genotype, and use of CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP3A4 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg). Max dose is 441 mg in CYP2D6 PMs or if also taking strong CYP2D6 inhibitors. Risk D: Consider therapy modification

Artemether and Lumefantrine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Artemether and Lumefantrine. Risk C: Monitor therapy

Asciminib: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Asciminib. Risk C: Monitor therapy

Astemizole: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Astemizole. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Astemizole. Risk X: Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Risk X: Avoid combination

Atazanavir: May decrease the serum concentration of Voriconazole. Atazanavir may increase the serum concentration of Voriconazole. Voriconazole may decrease the serum concentration of Atazanavir. Management: Voriconazole should not be used in a patient who is being treated with ritonavir-boosted atazanavir unless the benefits of the combination outweigh the potential risks. Extra monitoring for both loss of effectiveness and toxicity is warranted. Risk D: Consider therapy modification

Atogepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended atogepant dose is 10 mg once daily with a concurrent strong CYP3A4 inhibitor. If used for treatment of chronic migraine, concurrent use of atogepant with strong CYP3A4 inhibitors should be avoided. Risk D: Consider therapy modification

Atorvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avacopan. Management: Decrease the avacopan dose to 30 mg once daily during coadministration with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Risk X: Avoid combination

Avapritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avapritinib. Risk X: Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Risk D: Consider therapy modification

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Risk X: Avoid combination

Beclomethasone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Beclomethasone (Systemic). Risk C: Monitor therapy

Bedaquiline: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Bedaquiline. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Bedaquiline. Management: Consider alternatives to this drug combination and avoid use for more than 14 days. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Belzutifan: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Belzutifan. Risk C: Monitor therapy

Benidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benidipine. Risk C: Monitor therapy

Benperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol. Risk C: Monitor therapy

Benzhydrocodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Risk C: Monitor therapy

Betamethasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Nasal). Risk C: Monitor therapy

Betamethasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic). Risk C: Monitor therapy

Betamethasone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Systemic). Risk C: Monitor therapy

Betamethasone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Topical). Risk C: Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Risk X: Avoid combination

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Risk C: Monitor therapy

Bosentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosentan. Risk C: Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Risk X: Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a strong CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. Risk D: Consider therapy modification

Brigatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modification

Brivaracetam: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Brivaracetam. Risk C: Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Management: Consider alternatives to the use of bromocriptine with strong CYP3A4 inhibitors. If combined, monitor closely for increased bromocriptine toxicities and consider bromocriptine dose reductions. Risk D: Consider therapy modification

Bromperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromperidol. Risk C: Monitor therapy

Brotizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brotizolam. Risk C: Monitor therapy

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Risk C: Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Management: Consider alternatives to this combination when possible. If combined, monitor for increased corticosteroid adverse effects during coadministration of inhaled budesonide and strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and a strong CYP3A4 inhibitor, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider therapy modification

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Risk X: Avoid combination

Buprenorphine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Buprenorphine. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of BusPIRone. Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities if combined with strong CYP3A4 inhibitors. Dose adjustments of buspirone or a strong CYP3A4 inhibitor should be based on clinical assessment. Risk D: Consider therapy modification

Butorphanol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Butorphanol. Risk C: Monitor therapy

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Risk D: Consider therapy modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, decrease cabozantinib capsules (Cometriq) by 40 mg from previous dose or decrease cabozantinib tablets (Cabometyx) by 20 mg from previous dose. Risk D: Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Risk C: Monitor therapy

Calcitriol (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcitriol (Systemic). Risk C: Monitor therapy

Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol. Risk C: Monitor therapy

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Risk C: Monitor therapy

Capmatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Capmatinib. Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Cariprazine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Decrease cariprazine dose 50% (4.5 mg to 1.5 mg or 3 mg; 1.5 mg to 1.5 mg every other day) if starting a strong CYP3A4 inhibitor. If on a strong CYP3A4 inhibitor, start cariprazine at 1.5 mg day 1, 0 mg day 2, then 1.5 mg daily. May increase to 3 mg daily Risk D: Consider therapy modification

Carisoprodol: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Carisoprodol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Carisoprodol. Risk C: Monitor therapy

Ceritinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ceritinib. Management: Avoid use of ceritinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease ceritinib dose by one-third (to the nearest 150 mg) and monitor patients for ceritinib toxicities including QTc prolongation. Risk D: Consider therapy modification

ChlordiazePOXIDE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ChlordiazePOXIDE. Risk C: Monitor therapy

Ciclesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ciclesonide (Oral Inhalation). Risk C: Monitor therapy

Cilnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilnidipine. Risk C: Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Cinacalcet: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet. Risk C: Monitor therapy

Cisapride: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Cisapride. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Cisapride. Risk X: Avoid combination

Cisapride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cisapride. Risk X: Avoid combination

Citalopram: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with voriconazole, which is a moderate CYP2C19 inhibitor. Monitor for citalopram toxicity (eg, serotonin syndrome), QTc prolongation, and arrhythmias (including torsades de pointes). Risk D: Consider therapy modification

Clarithromycin: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Clarithromycin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Clindamycin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

CloBAZam: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

ClonazePAM: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ClonazePAM. Risk C: Monitor therapy

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk C: Monitor therapy

Cobicistat: Voriconazole may increase the serum concentration of Cobicistat. Cobicistat may increase the serum concentration of Voriconazole. Management: Careful consideration of the risk/benefit ratio for voriconazole use is recommended prior to its use in patients who are being treated with cobicistat-containing products. If coadministered, monitor for voriconazole and cobicistat toxicity. Risk D: Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Risk X: Avoid combination

Codeine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of P-gp inhibitors, and hepatic/renal function. See interaction monograph for details Risk D: Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Risk X: Avoid combination

Copanlisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities. Risk D: Consider therapy modification

Cortisone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cortisone. Risk C: Monitor therapy

Crizotinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, crizotinib dose adjustments are required, which vary according to indication. See full interaction monograph for details. Risk D: Consider therapy modification

CycloSPORINE (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE (Systemic). Fluconazole and isavuconazonium considerations are addressed in separate monographs. Management: Consider reducing cyclosporine doses by 50% to 80% during coadministration with ketoconazole, 50% with voriconazole or itraconazole, and 25% with posaconazole. Cyclosporine dose reductions may be required with other azoles. Risk D: Consider therapy modification

CYP2C19 Inducers (Moderate): May decrease the serum concentration of Voriconazole. Risk C: Monitor therapy

CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Voriconazole. Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Voriconazole. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Voriconazole. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Voriconazole. Management: Consider alternatives to this combination when possible. If combined, monitor for decreased voriconazole concentrations and effects. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Voriconazole. Risk C: Monitor therapy

Cyproterone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cyproterone. Risk C: Monitor therapy

Dabrafenib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dabrafenib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dabrafenib. Management: Consider alternatives to these QT-prolonging strong CYP3A4 inhibitors for patients being treated with dabrafenib. If such a combination cannot be avoided, monitor closely for dabrafenib-related adverse effects, including QTc interval prolongation. Risk D: Consider therapy modification

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Risk X: Avoid combination

Daridorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daridorexant. Risk X: Avoid combination

Darifenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Darifenacin. Management: Limit the darifenacin dose to no more than 7.5 mg daily if combined with strong CYP3A4 inhibitors. Monitor patients for increased darifenacin toxicities (eg, dry mouth, constipation, headache, CNS effects) when these agents are combined. Risk D: Consider therapy modification

Darunavir: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Darunavir. Management: This combination should be avoided unless the risks of potentially altered drug concentrations are outweighed by potential benefits of therapy. Risk D: Consider therapy modification

Dasatinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dasatinib. Management: Avoid this combination if possible. If combined, decrease dasatinib dose from 140 mg to 40 mg, 100 mg to 20 mg, or 70 mg to 20 mg. If taking 60 mg or 40 mg daily, stop dasatinib until the CYP3A4 inhibitor is discontinued. Monitor for prolonged QT interval Risk D: Consider therapy modification

Deflazacort: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

Delamanid: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Delamanid. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Delamanid. Management: If coadministration of delamanid with any strong CYP3A4 inhibitor is considered necessary, very frequent monitoring of ECGs is recommended throughout the full delamanid treatment period. Risk D: Consider therapy modification

DexAMETHasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DexAMETHasone (Ophthalmic). Risk C: Monitor therapy

DexAMETHasone (Systemic): May decrease the serum concentration of Voriconazole. Risk C: Monitor therapy

DiazePAM: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of DiazePAM. Risk C: Monitor therapy

Dichlorphenamide: Antifungal Agents (Azole Derivatives, Systemic) may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy

Diclofenac (Systemic): Voriconazole may increase the serum concentration of Diclofenac (Systemic). Risk C: Monitor therapy

Diclofenac (Topical): Voriconazole may increase the serum concentration of Diclofenac (Topical). Risk C: Monitor therapy

Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Risk C: Monitor therapy

DilTIAZem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DilTIAZem. Risk C: Monitor therapy

DOCEtaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities. Risk D: Consider therapy modification

Domperidone: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone. Risk X: Avoid combination

Doxazosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Doxazosin. Risk C: Monitor therapy

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

DOXOrubicin (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy

DroNABinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DroNABinol. Risk C: Monitor therapy

Dronedarone: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone. Risk X: Avoid combination

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Risk C: Monitor therapy

Duvelisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor. Monitor closely for evidence of altered response to treatment. Risk D: Consider therapy modification

Dydrogesterone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dydrogesterone. Risk C: Monitor therapy

Ebastine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ebastine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ebastine. Risk C: Monitor therapy

Efavirenz: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Efavirenz. Management: Use of standard doses of these drugs is contraindicated. The voriconazole oral maintenance dose should be increased to 400 mg every 12 hours, and the efavirenz dose should be reduced to 300 mg daily. Risk D: Consider therapy modification

Efonidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Efonidipine. Risk C: Monitor therapy

Elacestrant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elacestrant. Risk X: Avoid combination

Elagolix: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix. Management: Use of the elagolix 200 mg twice daily dose with a strong CYP3A4 inhibitor for longer than 1 month is not recommended. Limit combined use of the elagolix 150 mg once daily dose with a strong CYP3A4 inhibitor to a maximum of 6 months. Risk D: Consider therapy modification

Elagolix, Estradiol, and Norethindrone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Elagolix, Estradiol, and Norethindrone may decrease the serum concentration of CYP3A4 Inhibitors (Strong). Specifically, concentrations of strong CYP3A4 inhibitors that are also CYP3A4 substrates may be decreased. Risk X: Avoid combination

Elbasvir and Grazoprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elbasvir and Grazoprevir. Management: Consider alternatives to this combination when possible. If combined, monitor for increased elbasvir/grazoprevir toxicities, including ALT elevations. Risk D: Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Management: Administer elexacaftor/tezacaftor/ivacaftor in the morning, twice a week, 3 to 4 days apart, with no evening doses of ivacaftor alone. Specific dosing varies by age and weight. See full monograph for details. Risk D: Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with strong CYP3A4 inhibitors. Use of strong CYP3A4 inhibitors is contraindicated in CYP2D6 IMs, PMs, or in CYP2D6 EMs who are also taking strong or moderate CYP2D6 inhibitors. Risk D: Consider therapy modification

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and strong CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 150 mg; or from 300 mg, 225 mg, or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combination

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Risk X: Avoid combination

Erdafitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly. Risk D: Consider therapy modification

Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates). Risk X: Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of erlotinib-associated adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Risk D: Consider therapy modification

Erythromycin (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Erythromycin (Systemic). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Escitalopram: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Escitalopram. Risk C: Monitor therapy

Estrogen Derivatives: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Eszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Risk D: Consider therapy modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Risk C: Monitor therapy

Etravirine: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Etravirine. Risk C: Monitor therapy

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Management: Consider avoiding use of strong CYP3A4 inhibitors with everolimus. If combined, closely monitor for increased everolimus serum concentrations and toxicities. Everolimus dose reductions will likely be required. Risk D: Consider therapy modification

Evogliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin. Risk C: Monitor therapy

Fedratinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated. Risk D: Consider therapy modification

Felodipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Felodipine. Management: Consider using lower felodipine doses when combined with strong CYP3A4 inhibitors. Monitor patients for increased felodipine effects and toxicities (eg, hypotension, edema) when combined. Risk D: Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a strong CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Limit fesoterodine doses to 4 mg daily in patients who are also receiving strong CYP3A4 inhibitors. This combination is not recommended in pediatric patients weighing 25 kg up to 35 kg. Risk D: Consider therapy modification

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Finerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Finerenone. Risk X: Avoid combination

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Management: Use of flibanserin with strong CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid combination

Flucloxacillin: May decrease the serum concentration of Voriconazole. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced voriconazole serum concentrations and efficacy. Increased voriconazole doses may be needed. Risk D: Consider therapy modification

Fluconazole: May enhance the QTc-prolonging effect of Voriconazole. Fluconazole may increase the serum concentration of Voriconazole. Risk X: Avoid combination

Flunitrazepam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flunitrazepam. Risk C: Monitor therapy

Fluorouracil Products: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Risk X: Avoid combination

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Consider alternatives to this combination if possible. Coadministration of fluticasone propionate and strong CYP3A4 inhibitors is not recommended. If combined, monitor patients for systemic corticosteroid adverse effects (eg, adrenal suppression). Risk D: Consider therapy modification

Fluticasone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Topical). Risk C: Monitor therapy

Fosamprenavir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosamprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosaprepitant. Risk X: Avoid combination

Fosphenytoin-Phenytoin: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Increase maintenance dose of voriconazole from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours in patients who weigh 40 kg or more or from 100 mg to 200 mg orally every 12 hours for patients who weigh less than 40 kg. Risk D: Consider therapy modification

Fostamatinib: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fostamatinib. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Galantamine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Galantamine. Risk C: Monitor therapy

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Risk C: Monitor therapy

Gilteritinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Gilteritinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of gilteritinib with strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. Risk D: Consider therapy modification

Glasdegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib. Risk D: Consider therapy modification

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the extended-release guanfacine dose 50% when combined with a strong CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider therapy modification

Halofantrine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Haloperidol: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Hormonal Contraceptives: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone. Risk C: Monitor therapy

Hydrocortisone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

Ibrexafungerp: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrexafungerp. Management: Decrease the ibrexafungerp dose to 150 mg every 12 hours for 2 doses in patients receiving strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Ibrutinib: Voriconazole may increase the serum concentration of Ibrutinib. Management: Ibrutinib dose reductions are required when combined with voriconazole. Dose recommendations depend on the indication for ibrutinib, age of the patient, and the voriconazole dose. See full Lexi Interact monograph for details. Risk D: Consider therapy modification

Ibuprofen: Voriconazole may increase the serum concentration of Ibuprofen. Specifically, concentrations of the S-(+)-ibuprofen enantiomer may be increased. Risk C: Monitor therapy

Idelalisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib. Management: Use alternative therapies that are not strong CYP3A4 inhibitors whenever possible. If unable to use alternative drugs, monitor patients more frequently for idelalisib toxicities. Risk D: Consider therapy modification

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Risk C: Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Risk C: Monitor therapy

Indinavir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Indinavir. Risk C: Monitor therapy

Infigratinib: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Infigratinib. Risk X: Avoid combination

Inhibitors of the Proton Pump (PPIs and PCABs): Voriconazole may increase the serum concentration of Inhibitors of the Proton Pump (PPIs and PCABs). Inhibitors of the Proton Pump (PPIs and PCABs) may increase the serum concentration of Voriconazole. Risk C: Monitor therapy

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. Management: Avoid administration of strong CYP3A4 inhibitors during and within 1 week prior to irinotecan administration, unless no therapeutic alternatives to these agents exist. If combined, monitor closely for increased irinotecan toxicities. Risk D: Consider therapy modification

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Risk X: Avoid combination

Isradipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Isradipine. Risk C: Monitor therapy

Istradefylline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Istradefylline. Management: Limit the maximum istradefylline dose to 20 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased istradefylline effects/toxicities. Risk D: Consider therapy modification

Itraconazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Itraconazole. Risk C: Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Risk X: Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full drug interaction monograph content for age- and weight-specific recommendations. Risk D: Consider therapy modification

Ivosidenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Avoid using strong CYP3A4 inhibitors together with ivosidenib if possible. If the combination must be used, reduce the ivosidenib dose to 250 mg once daily and monitor for increased ivosidenib toxicities, including QTc interval prolongation. Risk D: Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Management: Avoid use of ixabepilone and strong CYP3A4 inhibitors when possible. If combined, reduce the ixabepilone dose to 20 mg/m2. The previous ixabepilone dose can be resumed 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Ketamine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ketamine. Risk C: Monitor therapy

Ketoconazole (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ketoconazole (Systemic). Risk C: Monitor therapy

Lacidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacidipine. Risk C: Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: Avoid use of lapatinib and strong CYP3A4 inhibitors when possible. If combined, a reduced lapatinib dose of 500 mg daily should be considered. The previous lapatinib dose can be resumed 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Larotrectinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor's half-life. Risk D: Consider therapy modification

Lefamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4. Risk X: Avoid combination

Lemborexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lemborexant. Risk X: Avoid combination

Leniolisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Leniolisib. Risk X: Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Risk X: Avoid combination

Letermovir: May decrease the serum concentration of Voriconazole. Management: If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced voriconazole serum concentrations and efficacy. Risk D: Consider therapy modification

Leuprolide and Norethindrone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Leuprolide and Norethindrone. Specifically, concentrations of norethindrone may increase. Risk C: Monitor therapy

Levamlodipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levamlodipine. Risk C: Monitor therapy

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Risk C: Monitor therapy

Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination

Levomethadone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomethadone. Risk C: Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: The dose of levomilnacipran should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Lidocaine (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Risk X: Avoid combination

Lonafarnib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lonafarnib. Risk X: Avoid combination

Lopinavir: May decrease the serum concentration of Voriconazole. Management: This combination should be avoided unless the risks of potentially subtherapeutic voriconazole concentrations are outweighed by potential benefits of therapy. Risk D: Consider therapy modification

Lorlatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily. Risk D: Consider therapy modification

Lovastatin: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Lovastatin. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Risk X: Avoid combination

Lumacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumacaftor and Ivacaftor. Management: When initiating or resuming lumacaftor/ivacaftor after a therapy interruption of 7 days or more, reduce the lumacaftor/ivacaftor dose to 1 tablet daily or 1 packet of oral granules every other day for the first week, and then resume the standard dose. Risk D: Consider therapy modification

Lumateperone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumateperone. Management: Limit the lumateperone dose to 10.5 mg once daily when used with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Risk X: Avoid combination

Lurbinectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurbinectedin. Management: Avoid concomitant use of lurbinectedin and strong CYP3A4 inhibitors. If coadministration with a strong CYP3A4 inhibitor cannot be avoided, reduce the lurbinectedin dose by 50%. Risk D: Consider therapy modification

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Risk X: Avoid combination

Manidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce maraviroc to 150mg twice/day in adult and pediatrics weighing 40kg or more. See full interaction monograph for dose adjustments in pediatrics weighing 10 to less than 40kg. Do not use if CrCl less than 30mL/min or in those weighing less than 10 kg. Risk D: Consider therapy modification

Mavacamten: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mavacamten. Risk X: Avoid combination

Mavacamten: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Mavacamten. Risk X: Avoid combination

Mefloquine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mefloquine. Risk C: Monitor therapy

Meperidine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine. Risk C: Monitor therapy

Methadone: Voriconazole may enhance the QTc-prolonging effect of Methadone. Voriconazole may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with voriconazole. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Risk D: Consider therapy modification

Methotrexate: May enhance the photosensitizing effect of Voriconazole. Risk C: Monitor therapy

Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapy

Midazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Midazolam. Management: Avoid use of nasal midazolam and strong CYP3A4 inhibitors whenever possible, and consider alternatives to use with other routes of midazolam (oral, IV, IM). If combined, consider lower midazolam doses and monitor for increased midazolam toxicities. Risk D: Consider therapy modification

Midostaurin: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Midostaurin. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Midostaurin. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: For treatment of hyperglycemia in Cushing's syndrome, start mifepristone at 300 mg/day, may titrate to a maximum of 900 mg/day. If starting a strong CYP3A4 inhibitor and taking > 300 mg/day mifepristone, decrease the mifepristone dose by 300 mg/day. Risk D: Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Risk D: Consider therapy modification

Mirtazapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirtazapine. Risk C: Monitor therapy

Mirvetuximab Soravtansine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirvetuximab Soravtansine. Risk C: Monitor therapy

Mitapivat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mitapivat. Risk X: Avoid combination

Mizolastine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Mizolastine. Risk X: Avoid combination

Mobocertinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Mobocertinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase serum concentrations of the active metabolite(s) of Mobocertinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Mobocertinib. Risk X: Avoid combination

Moclobemide: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Moclobemide. Risk C: Monitor therapy

Mometasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mometasone (Nasal). Risk C: Monitor therapy

Mometasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mometasone (Oral Inhalation). Risk C: Monitor therapy

Mometasone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mometasone (Topical). Risk C: Monitor therapy

Naldemedine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine. Risk C: Monitor therapy

Nalfurafine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine. Risk C: Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Risk X: Avoid combination

Nelfinavir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nelfinavir. Risk C: Monitor therapy

Neratinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib. Risk X: Avoid combination

Nevirapine: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Nevirapine. Risk C: Monitor therapy

NiCARdipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiCARdipine. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NIFEdipine. Management: Consider alternatives to this combination when possible. If combined, initiate nifedipine at the lowest dose available and monitor patients closely for increased nifedipine effects and toxicities (eg, hypotension, edema). Risk D: Consider therapy modification

Nilotinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Nilotinib. Management: Avoid concomitant use of nilotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, nilotinib dose reductions are required. Monitor patients for nilotinib toxicities including QTc prolongation and arrhythmias. Risk D: Consider therapy modification

Nilvadipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilvadipine. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Risk X: Avoid combination

Nirmatrelvir and Ritonavir: May decrease the serum concentration of Voriconazole. Nirmatrelvir and Ritonavir may increase the serum concentration of Voriconazole. Management: Consider avoiding this combination if possible. NIH COVID-19 treatment guidelines state voriconazole may be continued in patients treated with nirmatrelvir and ritonavir, but patients should be monitored for adverse effects. Risk D: Consider therapy modification

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination

Nitrendipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nitrendipine. Risk C: Monitor therapy

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 100 mg twice daily and the dose of olaparib capsules should be reduced to 150 mg twice daily. Risk D: Consider therapy modification

Oliceridine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy

Omaveloxolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Omaveloxolone. Management: Avoid this combination if possible. If coadministration is required, decrease the omaveloxolone dose to 50 mg daily and monitor closely for adverse reactions. Discontinue coadministration if adverse reactions occur. Risk D: Consider therapy modification

Omeprazole: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Omeprazole. Risk C: Monitor therapy

Ondansetron: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Orelabrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Orelabrutinib. Risk X: Avoid combination

Osilodrostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Osilodrostat. Management: Reduce osilodrostat dose by 50% during coadministration with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Osimertinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Risk C: Monitor therapy

OxyBUTYnin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyBUTYnin. Risk C: Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Risk C: Monitor therapy

PACLitaxel (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Pacritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pacritinib. Risk X: Avoid combination

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Management: Avoid concurrent use of strong CYP3A4 inhibitors with palbociclib when possible. If the use of a strong CYP3A4 inhibitor cannot be avoided, decrease the palbociclib dose to 75 mg/day. Risk D: Consider therapy modification

Palovarotene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palovarotene. Risk X: Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Monitor patient response to therapy closely for evidence of more severe adverse effects related to panobinostat therapy. Risk D: Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Specifically, serum concentrations of the active moiety valdecoxib may be increased. Risk C: Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Risk C: Monitor therapy

PAZOPanib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of PAZOPanib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of PAZOPanib. Risk X: Avoid combination

Pemigatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pemigatinib. Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the strong inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider therapy modification

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Pexidartinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pexidartinib. Management: If combined use cannot be avoided, pexidartinib dose should be reduced. For the 125 mg capsules: reduce pexidartinib doses of 500 mg or 375 mg daily to 125 mg twice daily. Reduce pexidartinib 250 mg daily to 125 mg once daily. Risk D: Consider therapy modification

PHENobarbital: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Pimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination

Piperaquine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Piperaquine. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Pirtobrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pirtobrutinib. Management: Avoid concomitant use when possible. If combined, reduce the pirtobrutinib dose by 50 mg. If current dose is 50 mg, interrupt pirtobrutinib treatment during strong CYP3A4 inhibitor use. Risk D: Consider therapy modification

Polatuzumab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased. Risk C: Monitor therapy

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Avoid concomitant use if possible. If combined, reduce ponatinib dose as follows: If taking 45 mg, reduce to 30 mg; if taking 30 mg, reduce to 15 mg; if taking 15 mg, reduce to 10 mg. If taking 10 mg, avoid concomitant use with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination

Pralsetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider therapy modification

Prazepam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Prazepam. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Risk C: Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Risk C: Monitor therapy

Primidone: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Proguanil: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Proguanil. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Proguanil. Risk C: Monitor therapy

Propofol: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Propofol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Antidepressants (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Risk C: Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): Voriconazole may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Voriconazole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Risk X: Avoid combination

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QUEtiapine: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QUEtiapine. Management: Reduce the quetiapine dose to one-sixth of the regular dose when initiating these strong CYP3A4 inhibitors. In patients already receiving these strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and titrate cautiously as needed. Risk D: Consider therapy modification

QuiNIDine: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of QuiNIDine. Risk X: Avoid combination

Quinidine (Non-Therapeutic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Quinidine (Non-Therapeutic). Risk C: Monitor therapy

Quizartinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Quizartinib. Management: If combination is necessary, reduce quizartinib dose as follows: from 53 mg daily to 26.5 mg daily; from 35.4 mg daily to 17.7 mg daily; from 26.5 mg daily to 17.7 mg daily. If taking 17.7 mg daily avoid quizartinib while on the strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Radotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib. Risk X: Avoid combination

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Risk X: Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Risk C: Monitor therapy

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Risk X: Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Risk X: Avoid combination

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Risk C: Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: The use of retapamulin with strong CYP3A4 inhibitors is not recommended in patients less than 2 years old. No action is required in other populations. Risk C: Monitor therapy

Ribociclib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ribociclib. Management: Avoid concomitant use of ribociclib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease the ribociclib dose to 400 mg daily. Monitor for ribociclib toxicities including QTc prolongation and arrhythmias. Risk D: Consider therapy modification

Rifabutin: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Rifabutin. Risk X: Avoid combination

RifAMPin: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Rifamycin: May decrease the serum concentration of Voriconazole. Risk C: Monitor therapy

Rilpivirine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rilpivirine. Risk C: Monitor therapy

Rimegepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rimegepant. Risk X: Avoid combination

Riociguat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Riociguat. Risk C: Monitor therapy

Ripretinib: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ripretinib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ripretinib. Risk C: Monitor therapy

Ritonavir: May decrease the serum concentration of Voriconazole. Ritonavir may increase the serum concentration of Voriconazole. Management: Concurrent voriconazole and high-dose ritonavir (adult doses of 400 mg every 12 hrs or greater) is contraindicated. Voriconazole with lower-dose ritonavir should be avoided unless benefits outweigh risk of inadequate voriconazole concentrations. Risk D: Consider therapy modification

Rivaroxaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. For clarithromycin, refer to more specific clarithromycin-rivaroxaban monograph recommendations. Risk C: Monitor therapy

Roflumilast-Containing Products: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Roflumilast-Containing Products. Risk C: Monitor therapy

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy

Rupatadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine. Risk X: Avoid combination

Ruxolitinib (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib (Systemic). Management: This combination should be avoided under some circumstances; dose adjustments may be required in some circumstances and depend on the indication for ruxolitinib. See monograph for details. Risk D: Consider therapy modification

Ruxolitinib (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib (Topical). Risk X: Avoid combination

Saccharomyces boulardii: Antifungal Agents (Systemic and Oral [Non-Absorbable]) may diminish the therapeutic effect of Saccharomyces boulardii. Risk X: Avoid combination

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Risk X: Avoid combination

Saquinavir: May enhance the QTc-prolonging effect of Voriconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Selpercatinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Selpercatinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Selpercatinib. Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120mg twice/day to 40mg twice/day, or from 160mg twice/day to 80mg twice/day. Monitor QT interval more closely for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification

Selumetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Selumetinib. Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modification

Sertindole: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Sertindole. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Sertindole. Risk X: Avoid combination

Sibutramine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Sibutramine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sibutramine. Risk C: Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary arterial hypertension (PAH) should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, consider using a lower starting dose of 25 mg and monitor patients for sildenafil toxicities. Risk D: Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Risk X: Avoid combination

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Risk X: Avoid combination

Simvastatin: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Risk X: Avoid combination

Sirolimus (Conventional): Voriconazole may increase the serum concentration of Sirolimus (Conventional). Risk X: Avoid combination

Sirolimus (Protein Bound): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

Sirolimus (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus (Topical). Risk C: Monitor therapy

Solifenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin. Management: Limit adult solifenacin doses to 5 mg daily and limit doses in pediatric patients to the recommended weight-based starting dose (and do not increase the dose) when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Risk X: Avoid combination

Sparsentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sparsentan. Risk X: Avoid combination

St John's Wort: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination

SUFentanil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil. Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression). Risk D: Consider therapy modification

Sulfonylureas: Voriconazole may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy

SUNItinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of SUNItinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of SUNItinib. Management: Avoid when possible. If combined, decrease sunitinib dose to a minimum of 37.5 mg daily when treating GIST or RCC. Decrease sunitinib dose to a minimum of 25 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Risk X: Avoid combination

Tacrolimus (Systemic): Voriconazole may increase the serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to approximately one-third of the original dose when starting concurrent voriconazole. Tacrolimus whole blood trough concentrations should be monitored closely beginning within 1 to 3 days of concomitant use. Risk D: Consider therapy modification

Tacrolimus (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tacrolimus (Topical). Risk C: Monitor therapy

Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Avoid this combination in patients taking tadalafil for pulmonary arterial hypertension. In patients taking tadalafil for ED or BPH, max tadalafil dose is 2.5 mg if taking daily or 10 mg no more frequently than every 72 hours if used as needed. Risk D: Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Risk X: Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Risk C: Monitor therapy

Tazemetostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tazemetostat. Risk X: Avoid combination

Temsirolimus: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be increased. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors. If coadministration is unavoidable, decrease temsirolimus dose to 12.5 mg per week. Resume previous temsirolimus dose 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Terfenadine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Terfenadine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Terfenadine. Risk X: Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor and Ivacaftor. Management: If combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph for details. Risk D: Consider therapy modification

Thiotepa: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Thiotepa. Management: Avoid coadministration of thiotepa and strong CYP3A4 inhibitors. If concomitant use cannot be avoided, monitor for thiotepa adverse effects and decreased efficacy. Risk D: Consider therapy modification

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Risk X: Avoid combination

Tisotumab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tisotumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full Lexi Interact monograph for details. Risk D: Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended dose of tolterodine is 2 mg per day (1 mg twice daily for immediate-release tablets or 2 mg daily for extended-release capsules) when used together with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination

Toremifene: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Toremifene. Management: Avoid concomitant use of toremifene and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, monitor patients for toremifene toxicities including QTc prolongation and TdP. Risk D: Consider therapy modification

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Risk X: Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

TraZODone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Tretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tretinoin (Systemic). Risk C: Monitor therapy

Triamcinolone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Nasal). Risk C: Monitor therapy

Triamcinolone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Ophthalmic). Risk C: Monitor therapy

Triamcinolone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Systemic). Management: Consider alternatives to this combination when possible. If combined, monitor for increased corticosteroid adverse effects during coadministration of triamcinolone and strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Triamcinolone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Topical). Risk C: Monitor therapy

Triazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triazolam. Risk X: Avoid combination

Ubrogepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ubrogepant. Risk X: Avoid combination

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Risk X: Avoid combination

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Risk C: Monitor therapy

Upadacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib. Management: Upadacitinib dose adjustments are needed when combined with strong CYP3A4 inhibitors. Specific adjustments vary based on upadacitinib indication. See full interact monograph for details. Risk D: Consider therapy modification

Valbenazine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Vardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Limit Levitra (vardenafil) dose to a single 2.5 mg dose within a 24-hour period if combined with strong CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and strong CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider therapy modification

Vemurafenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Vemurafenib. Management: Avoid concomitant use of vemurafenib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined monitor patients for vemurafenib toxicities including QTc prolongation and TdP, and consider a vemurafenib dose reduction. Risk D: Consider therapy modification

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: Coadministration is contraindicated during venetoclax initiation and ramp-up in CLL/SLL patients. Reduced venetoclax doses are required during ramp-up for patients with AML, and all maintenance therapy. See full Lexi Interact monograph for details. Risk D: Consider therapy modification

Venlafaxine: Voriconazole may enhance the adverse/toxic effect of Venlafaxine. Voriconazole may increase the serum concentration of Venlafaxine. Risk C: Monitor therapy

Verapamil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Verapamil. Risk C: Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy

Vilanterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilanterol. Risk C: Monitor therapy

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit the maximum vilazodone dose to 20 mg daily in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modification

VinBLAStine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinBLAStine. Risk C: Monitor therapy

VinCRIStine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine. Management: Seek alternatives to this combination when possible. If combined, monitor closely for vincristine toxicities (eg, neurotoxicity, gastrointestinal toxicity, myelosuppression). Risk D: Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Risk C: Monitor therapy

Vinflunine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Vinflunine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Risk X: Avoid combination

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): CYP2C9 Inhibitors (Weak) may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Voclosporin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Voclosporin. Risk X: Avoid combination

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Risk X: Avoid combination

Zanubrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg once daily during coadministration with a strong CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider therapy modification

Zolpidem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem. Risk C: Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: If coadministered with strong CYP3A4 inhibitors, initiate zopiclone at 3.75 mg in adults, with a maximum dose of 5 mg. Monitor for zopiclone toxicity (eg, drowsiness, confusion, lethargy, ataxia, respiratory depression). Risk D: Consider therapy modification

Zuranolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuranolone. Management: Reduce the zuranolone dose to 30 mg once daily when used concomitantly with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Food Interactions

Food may decrease voriconazole absorption. Management: Oral voriconazole should be taken 1 hour before or 1 hour after a meal. Maintain adequate hydration unless instructed to restrict fluid intake.

Reproductive Considerations

Women of childbearing potential should use effective contraception during treatment.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Voriconazole can cause fetal harm when administered to a pregnant woman.

Breastfeeding Considerations

It is not known if voriconazole is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring Parameters

Hepatic function at initiation, weekly during the first month and then monthly during course of treatment if no abnormalities noted; renal function (particularly serum creatinine, at baseline and periodically during therapy; especially with IV formulation in patients with CrCl <50 mL/min); serum electrolytes (particularly calcium, magnesium and potassium) prior to initiation and during therapy; visual function (visual acuity, visual field and color perception) if treatment course continues >28 days; phototoxic reactions (especially in pediatric patients); pancreatic function (in patients at risk for acute pancreatitis); total body skin examination yearly (more frequently if lesions noted); signs/symptoms of fluorosis or periostitis (eg, skeletal pain, radiologic findings).

Monitoring of serum trough concentrations is recommended for the majority of patients, but especially in the following infections: Invasive aspergillosis treatment (and prolonged prophylaxis), endophthalmitis, and CNS fusariosis (CDC 2023; IDSA [Patterson 2016]; MSG-ERC [Johnson 2020]; Riddell 2011).

For invasive aspergillosis, the Infectious Diseases Society of America recommends monitoring trough serum concentrations after steady state has been reached (4 to 7 days after therapy initiation); the need for continued or repeat monitoring is a patient specific decision influenced by many factors (eg, infection severity, cost, assay availability) (IDSA [Patterson 2016]). For CNS fusariosis, the CDC recommends monitoring trough serum concentrations on day 5 and then weekly for the first 4 to 6 weeks of treatment and when dosage adjustments are made (CDC 2023).

Reference Range

Trough recommendations in adult patients:

Aspergillosis, invasive (non-CNS infection):

Efficacy: >1 to 1.5 mcg/mL (IDSA [Patterson 2016])

Minimize toxicity: <5 to 6 mcg/mL (IDSA [Patterson 2016])

Aspergillosis, CNS infection (meningitis, ventriculitis):

Goal: Trough levels between 2 and 5 mcg/mL (IDSA [Tunkel 2017])

Endophthalmitis:

Goal: Trough levels between 2 and 5 mcg/mL (Riddell 2011)

Fusariosis, CNS infection:

Goal: Trough levels between 4 and 5 mcg/mL (CDC 2023)

Other infections:

Goal: Trough levels between 1 and 5 mcg/mL (ASBMT [Tomblyn 2009]; Dolton 2012; Hamada 2012; Luong 2016; Mitsani 2012; Park 2012; Telles 2023)

Mechanism of Action

Interferes with fungal cytochrome P450 activity (selectively inhibits 14-alpha-lanosterol demethylation), decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting fungal cell membrane formation.

Pharmacokinetics (Adult Data Unless Noted)

Note: Overall, in pediatric patients, voriconazole pharmacokinetics are complex. In pediatric patients 12 to 14 years and weighing >50 kg and adolescents ≥15 years (regardless of weight) data suggests that the pharmacokinetics are similar to adults (Friberg 2012). In pediatric patients <12 years of age, voriconazole pharmacokinetics are poorly understood, exhibiting both inter- and intrapatient variability; individualized dosing is recommended (Friberg 2012; Karlsson 2009; Stockman 2014; Walsh 2010).

Distribution: Extensive tissue distribution; CSF concentration ~50% of plasma concentration (Walsh 2008)

Vd:

Children 2 to <12 years: Biphasic, Vd (central): 0.81 L/kg; Vd (peripheral): 2.2 L/kg (Karlsson 2009)

Adults: 4.6 L/kg

Protein binding: 58%

Metabolism: Hepatic, via CYP2C19 (major pathway) and CYP2C9 and CYP3A4 (less significant); saturable (may demonstrate nonlinearity); the N-oxide major metabolite has minimal antifungal activity; CYP2C19 exhibits genetic polymorphism (15% to 20% Asians may be poor metabolizers of voriconazole; 3% to 5% Caucasians and African Americans may be poor metabolizers). In children 2 to 12 years, metabolic clearance is faster than in adults (Walsh 2010). In children 2 to 12 years, the majority of data has shown that the pharmacokinetic parameters of voriconazole are affected by a patient's CYP2C19 genotype (Hicks 2014; Narita 2013; Wang 2014) although, an initial report suggested CYP2C19 genotype had no apparent effect on exposure in children (Driscoll 2011).

Bioavailability: Oral:

Children 2 to <12 years: Reported range highly variable: ~45% to 64% (Friberg 2012; Karlsson 2009) and values as high as 80% have been reported (Neely 2010)

Adults: 96%

Half-life elimination: Variable, dose-dependent. Steady-state is achieved by day 3 when an IV loading dose is administered and between days 5 and 8 if no loading dose is used (Purkins 2003).

Time to peak: Oral:

Children 2 to <12 years: Median: 1.1 hours (range: 0.73 to 8.03 hours) (Driscoll 2011)

Adults: 1 to 2 hours

Excretion: Urine (<2% as unchanged drug)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Accumulation of the IV vehicle sulfobutyl ether beta-cyclodextrin sodium (SBECD) occurs in patients with renal impairment (CrCl <50 mL/minute).

Hepatic function impairment: AUC is 3.2-fold higher in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Voricet | Voricona denk;
  • (AR) Argentina: Kefidim | Vfend | Voriconazol | Voriconazol richet | Voriconazol sandoz | Vorinova;
  • (AT) Austria: Vfend | Voriconazol Accord | Voriconazol actavis | Voriconazol aristo | Voriconazol pfizer | Voriconazol ratiopharm | Voriconazol sandoz | Voriconazol stada;
  • (AU) Australia: Apo-voriconazole | Vfend | Vorcon | Voriconazole apotex | Voriconazole myx | Voriconazole sandoz | Voriconazole Wockhardt | Vttack | Vzole | Zolfend;
  • (BD) Bangladesh: Voricon | Vorizol;
  • (BE) Belgium: Vfend | Voriconazole ab | Voriconazole accord | Voriconazole mylan | Voriconazole teva;
  • (BG) Bulgaria: Voriconazole accordpharma | Voriconazole actavis | Voriconazole sandoz | Vorifungal;
  • (BR) Brazil: Veac | Velenaxol | Vfend | Vori | Voriconazol | Vzom;
  • (CH) Switzerland: Vfend | Voriconazol Accord | Voriconazol mepha | Voriconazol pfizer | Voriconazol sandoz;
  • (CL) Chile: Vfend | Zivenad;
  • (CN) China: Di er da ning | Hui bang ling | Pi na pu | Vfend;
  • (CO) Colombia: Invotas | Neucler | Vfend | Viconazol | Voriconazol | Voricox | Voriole;
  • (CZ) Czech Republic: Verria | Vfend | Voriconazol polpharma | Voriconazole accord | Voriconazole fresenius kabi | Voriconazole olikla | Voriconazole stada | Voriconazole teva | Vorikonazol accord | Vorikonazol actavis | Vorikonazol mylan | Vorikonazol sandoz;
  • (DE) Germany: Vfend | Voriconazol 1 a pharma | Voriconazol Accord | Voriconazol aluid | Voriconazol amneal | Voriconazol aristo | Voriconazol beta | Voriconazol denk | Voriconazol eberth | Voriconazol elpen | Voriconazol fresenius kabi | Voriconazol heumann | Voriconazol hexal | Voriconazol mylan | Voriconazol puren | Voriconazol ratiopharm | Voriconazol rotexmedica | Voriconazol stada | Voriconazol zentiva;
  • (DK) Denmark: Vfend;
  • (DO) Dominican Republic: Vfend;
  • (EC) Ecuador: Candiox | Vfend;
  • (EE) Estonia: Verria | Vfend | Voriconazole accord | Voriconazole teva;
  • (EG) Egypt: Conazoglob | Ergoconazol | Fungilimit | Vfend | Voricofungal;
  • (ES) Spain: Vfend | Voriconazol Accord | Voriconazol aristo | Voriconazol aurovitas | Voriconazol dr. reddys | Voriconazol kern pharma | Voriconazol normon | Voriconazol sandoz | Voriconazol teva;
  • (ET) Ethiopia: Voriconazol denk | Voriconazole msn;
  • (FI) Finland: Vfend | Voriconazole accord | Voriconazole fresenius kabi | Voriconazole orion | Voriconazole sandoz;
  • (FR) France: Vfend | Voriconazole accord | Voriconazole arrow | Voriconazole biogaran | Voriconazole fresenius kabi | Voriconazole hikma | Voriconazole mylan | Voriconazole ohre pharma | Voriconazole panpharma | Voriconazole reddy pharma | Voriconazole sandoz | Voriconazole teva;
  • (GB) United Kingdom: Vfend | Voriconazole accord | Voriconazole actavis | Voriconazole ibisqus | Voriconazole milpharm | Voriconazole pfizer | Voriconazole teva | Voriconazole zentiva;
  • (GR) Greece: Vfend | Voriconazole accord | Voriconazole aenorasis | Voriconazole/bradex | Voriconazole/Demo | Voriconazole/teva | Vortimal;
  • (HK) Hong Kong: Vfend;
  • (HR) Croatia: Vfend | Vorikonazol Pliva | Vornal;
  • (HU) Hungary: Vfend | Voramol | Voriconazol eberth | Voriconazole accord | Voriconazole onkogen | Voriconazole teva | Vorikonazol actavis;
  • (ID) Indonesia: Vfend;
  • (IE) Ireland: Vfend | Voriconazole accord | Voriconazole actavis | Voriconazole rowex | Voriconazole teva;
  • (IL) Israel: Vfend;
  • (IN) India: Verz | Vfend | Vhope | Vocozo | Vonaz | Voraze | Vorib | Vorier | Vorifit | Vorifix | Vorik af | Vorilyn | Voritek | Voritrol | Voritrop | Voriz | Vorizol | Vorzu | Vosicaz | Voxpert | Zypower;
  • (IT) Italy: Vfend | Voriconazolo accord | Voriconazolo aurobindo | Voriconazolo doc | Voriconazolo doc generici | Voriconazolo dr reddy's | Voriconazolo eg | Voriconazolo fresenius kabi | Voriconazolo mylan | Voriconazolo mylan pharma | Voriconazolo sandoz | Voriconazolo teva | Voriconazolo teva italia;
  • (JO) Jordan: Vecanzol | Vfend;
  • (JP) Japan: Vfend | Voriconazole amel | Voriconazole jg | Voriconazole nichiiko | Voriconazole teva | Voriconazole towa;
  • (KE) Kenya: Candivor;
  • (KR) Korea, Republic of: Vfend | Vorico;
  • (LB) Lebanon: Vfend | Voriconazole ohre pharma;
  • (LT) Lithuania: Verria | Vfend | Voriconazol sandoz | Voriconazole accord | Voriconazole teva;
  • (LU) Luxembourg: Vfend | Voriconazole accord;
  • (LV) Latvia: Vfend | Voriconazole accord | Voriconazole elpen | Voriconazole teva;
  • (MA) Morocco: Vfend;
  • (MX) Mexico: Avefhad | Baraloxil | Ekomikane | Enoira | Eukomikane | Joss | Sinchampol | Taralmo | Vfend | Voriconazol;
  • (MY) Malaysia: Vfend;
  • (NL) Netherlands: Vfend | Voriconazol | Voriconazol aristo | Voriconazol aurobindo | Voriconazol cf | Voriconazol mylan | Voriconazol sandoz | Voriconazol stada | Voriconazol teva | Voriconazole accord;
  • (NO) Norway: Vfend | Voriconazole accord | Voriconazole fresenius kabi | Voriconazole sandoz;
  • (NZ) New Zealand: Vfend | Vttack;
  • (PE) Peru: Veac | Vfend | Vizol | Voriole | Vorzole;
  • (PH) Philippines: Vorzole;
  • (PK) Pakistan: Baxid | Hevezole | Hongos | Noric | Rifcon | Varitex | Vecot | Vorcon | Voric | Vorica | Voricon | Voriconazole normon | Vorimax | Vorinaz | Vorizole;
  • (PL) Poland: Vfend | Voriconazol adamed | Voriconazol polpharma | Voriconazole accord | Voriconazole actavis | Voriconazole fresenius kabi | Voriconazole genoptim | Voriconazole Genoptim Voriconazole Pharmathen | Voriconazole mylan | Voriconazole sandoz | Voriconazole stada | Voriconazole teva | Voriconazole zentiva | Voricostad;
  • (PR) Puerto Rico: Vfend;
  • (PT) Portugal: Vfend | Voriconazol aurovitas | Voriconazol hikma | Voriconazol mylan | Voriconazol normon | Voriconazol teva;
  • (PY) Paraguay: Vfend | Voriconazol imedic | Voriconazol prosalud | Voriole;
  • (RO) Romania: Verria | Vfend | Voramol | Voriconazol dr. reddy's | Voriconazol sandoz | Voriconazol zentiva | Voriconazole accord;
  • (RU) Russian Federation: Biflurin | Vfend | Vifend | Vikand | Voriconazole akri | Voriconazole canon | Voriconazole sandoz | Voriconazole teva | Voricoz;
  • (SA) Saudi Arabia: Apo-voriconazole | Vfend | Vfonaz | Volcon | Vultera;
  • (SE) Sweden: Vfend | Voriconazole accord | Voriconazole actavis | Voriconazole fresenius kabi | Voriconazole orion | Voriconazole sandoz | Voriconazole teva | Vorikonazol ebb;
  • (SG) Singapore: Vfend;
  • (SI) Slovenia: Vfend | Voriconazol Accord | Vorikonazol accord | Vorikonazol sandoz;
  • (SK) Slovakia: Verria | Vfend | Voriconazole actavis | Voriconazole fresenius kabi | Vorikonazol mylan | Vorikonazol sandoz;
  • (TH) Thailand: Vfend | Voriconazole sandoz | Vzon 200;
  • (TN) Tunisia: V zolex | Vfend | Vorico;
  • (TR) Turkey: Fungavor | Trozasin | Vfend | Voranex | Vorazyr | Vorent | Vorifull | Vorigen | Voriject | Vorikandin | Vorix | Vorzol;
  • (TW) Taiwan: Alvoazole | Vaway | Vfend;
  • (UA) Ukraine: Vfend | Vizealot | Voriconazol Alvogen | Voritab;
  • (UY) Uruguay: Vfend | Voriconazol normon | Voriole;
  • (ZA) South Africa: Vfend
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