Fungal infection, severe; treatment: Limited data available (case series and reports); dosing regimens variable: IV: Usual reported dose: 12 to 20 mg/kg/day divided every 8 to 12 hours; doses up to 24 mg/kg/day have been used; dosing based on experience in 23 neonates of which the majority were premature (minimum GA: 24 weeks) (Celik 2013; Doby 2012; Turan 2011); earlier data describes lower daily doses of 4 to 8 mg/kg/day divided every 12 hours (Celik 2013; Frankenbusch 2006; Kohli 2008; Santos 2007). In the rare instance in which conversion to oral therapy described, oral therapy was initiated at same IV dose. Note: Pharmacokinetic neonatal data is sparse; consider monitoring serum concentrations (trough); the frequency dependent upon several factors and some suggest more frequent monitoring in neonates (Chen 2012).
Note: 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 (Friberg 2012).
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) (Bartelink 2013).
Children 2 to <12 years: Note: Monitor serum concentrations to maintain trough concentrations of 2 to 6 mcg/mL (Red Book [AAP 2018]).
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 (Friberg 2012).
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 (IDSA [Patterson 2016]): 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 (IDSA [Patterson 2016]).
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 (Friberg 2012; IDSA [Patterson 2016]).
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 (Friberg 2012).
<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 (eg, AML, recurrent ALL, allogeneic HSCT): Limited data available:
Children 2 to <12 years (Dvorak 2012; ESCMID [Hope 2012]; Friberg 2012):
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 (Friberg 2012).
<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 (Dvorak 2012; ESCMID [Hope 2012]; Friberg 2012).
Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (ESCMID [Hope 2012]; Friberg 2012).
≥50 kg:
IV: 4 mg/kg/dose every 12 hours (Tomblyn 2009).
Oral: 200 mg every 12 hours (Tomblyn 2009; Wingard 2010).
Adolescents ≥15 years:
IV: 4 mg/kg/dose every 12 hours (Tomblyn 2009).
Oral: 200 mg every 12 hours (Tomblyn 2009; Wingard 2010).
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 (IDSA [Pappas 2016]).
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 (Friberg 2012).
<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 (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 (IDSA [Pappas 2016]).
Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Friberg 2012).
<50 kg: Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Friberg 2012; IDSA [Pappas 2016]).
≥50 kg: Oral: 200 to 300 mg (3 to 4 mg/kg/dose) twice daily (Friberg 2012; IDSA [Pappas 2016]).
Adolescents ≥15 years: Oral: 200 to 300 mg (3 to 4 mg/kg/dose) twice daily (IDSA [Pappas 2016]).
Candidiasis, esophageal, treatment: Note: Voriconazole is not considered a first-line therapy for esophageal candidiasis (IDSA [Pappas 2016]).
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 (Friberg 2012).
<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 (IDSA [Pappas 2016]).
Fluconazole-refractory infection: Limited data available: Treatment should continue for 14 to 21 days (IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (IDSA [Pappas 2016]).
Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Friberg 2012).
<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 (Friberg 2012; IDSA [Pappas 2016]).
Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Friberg 2012; IDSA [Pappas 2016]).
≥50 kg: IV, Oral: 200 mg (3 mg/kg/dose) twice daily (IDSA [Pappas 2016]).
Adolescents ≥15 years: IV, Oral: 200 mg (3 mg/kg/dose) twice daily (IDSA [Pappas 2016]).
Candidiasis, oropharyngeal, fluconazole-refractory; treatment: Limited data available: Treatment should continue for up to 28 days (IDSA [Pappas 2016]).
Children 2 to <12 years: Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (IDSA [Pappas 2016]).
Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Friberg 2012).
<50 kg: Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Friberg 2012; IDSA [Pappas 2016]).
≥50 kg: Oral: 200 mg twice daily (Friberg 2012; IDSA [Pappas 2016]).
Adolescents ≥15 years: Oral: 200 mg twice daily (IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (IDSA [Pappas 2016]).
Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmacokinetics (Friberg 2012).
<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 (Friberg 2012; IDSA [Pappas 2016]).
Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Friberg 2012; IDSA [Pappas 2016]).
≥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 (Friberg 2012; IDSA [Pappas 2016]).
Oral: 300 mg (4 mg/kg/dose) twice daily (Friberg 2012; IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
Oral: 300 mg (4 mg/kg/dose) twice daily (IDSA [Pappas 2016]).
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:
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 (Friberg 2012).
<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.
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) (Heintz 2009): 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.
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.
(For additional information see "Voriconazole: Drug information")
Note: Therapeutic drug monitoring: Adjust dose based on serum trough concentration to ensure efficacy and avoid toxicity. Timing and frequency of concentration monitoring is individualized (HHS [OI adult 2020]; IDSA [Chapman 2008]; IDSA [Patterson 2016]; IDSA [Wheat 2007]).
Aspergillosis:
Allergic bronchopulmonary (alternative agent): Oral: 200 mg twice daily for ≥16 weeks in combination with systemic corticosteroids (IDSA [Patterson 2016]); 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 (Akuthota 2022).
Chronic cavitary pulmonary:
IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (IDSA [Patterson 2016]). Note: Some experts reserve IV therapy for severely ill patients (Denning 2020).
Oral: 200 mg twice daily; may increase to 300 mg twice daily based on therapeutic drug monitoring (Denning 2020; IDSA [Patterson 2016]).
Duration: ≥6 months; some patients require prolonged, potentially lifelong therapy (Denning 2020; IDSA [Patterson 2016]).
Invasive (including disseminated and extrapulmonary):
Note: For severe or progressive infection, some experts use as part of a combination antifungal regimen (Patterson 2022).
IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (IDSA [Patterson 2016]). Note: Once a patient is able to tolerate oral administration, consider transition to oral formulation (IDSA [Patterson 2016]).
Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (IDSA [Patterson 2016]).
Duration: Minimum of 6 to 12 weeks, depending on degree/duration of immunosuppression, disease site, and response to therapy (IDSA [Patterson 2016]); immunosuppressed patients may require more prolonged treatment (AST-IDCOP [Husain 2019]; Patterson 2022).
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 (IDSA [Patterson 2016]).
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 (Durand 2020; Hariprasad 2008; Hoenigl 2013; IDSA [Patterson 2016]; Kramer 2006; Riddell 2011).
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 (Durand 2020; IDSA [Patterson 2016]). Note: May also consider intravitreal injection even if vitritis is not apparent, as occult vitreal involvement is possible (Durand 2020).
Systemic:
IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (IDSA [Patterson 2016]). Note: Once a patient is able to tolerate oral administration, consider transition to oral formulation (IDSA [Patterson 2016]).
Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (IDSA [Patterson 2016]). 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 (Durand 2020).
Duration: Usually ≥1 month to several months, depending on cause and extent of infection and response to therapy; some patients require prolonged therapy (Durand 2020).
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 (IDSA [Patterson 2016]; Prajna 2010; Prajna 2013).
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) (IDSA [Pappas 2016]; Kauffman 2021b).
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 (IDSA [Pappas 2016]).
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) (IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
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) (IDSA [Pappas 2016]).
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 (IDSA [Pappas 2016]).
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 (Durand 2022a; Durand 2022b).
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 (IDSA [Pappas 2016]). Intravitreal dose may be repeated in several days if no improvement (Durand 2022a; Durand 2022b).
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 (Durand 2022b).
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 (Durand 2022b). 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 (IDSA [Pappas 2016]; Durand 2022b).
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 (AST-IDCOP [Aslam 2019]; HHS [OI adult 2020]; IDSA [Pappas 2016]; Kauffman 2021a).
Oropharyngeal, fluconazole-refractory (alternative agent) (off-label use): Oral: 200 mg twice daily for up to 28 days (IDSA [Pappas 2016]).
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 (HHS [OI adult 2020]).
Duration: Varies based on site and severity of infection, as well as host immune status; in some cases, lifelong therapy is needed (HHS [OI adult 2020]; IDSA [Galgiani 2016]).
Meningitis: Oral: 400 mg twice daily for 2 doses, followed by 200 to 400 mg twice daily (HHS [OI adult 2020]). Duration is lifelong because of the high relapse rate (HHS [OI adult 2020]; IDSA [Galgiani 2016]).
Fusariosis (alternative agent):
Invasive:
IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Perfect 2003; Stanzani 2007; manufacturer's labeling). Note: Some experts suggest initial combination antifungal therapy for patients with severe immunosuppression, severe disease, or persistently positive blood cultures with monotherapy (Nucci 2021).
Oral, following improvement with initial IV therapy: 200 mg twice daily (Nucci 2021; Perfect 2003; Stanzani 2007; manufacturer's labeling).
Duration: Often prolonged and depends on site of infection, severity, immune status, and response to therapy (Nucci 2021).
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 (Klont 2005; Lee 2009; Nucci 2021; Prajna 2017). Duration depends on response to therapy; several months are often warranted (Nucci 2021).
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 (IDSA [Freifeld 2011]; IDSA [Patterson 2016]; Walsh 2002b; Wingard 2020).
Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (IDSA [Freifeld 2011]; IDSA [Patterson 2016]; Walsh 2002b).
Prophylaxis against invasive fungal infections (alternative agent) (off-label use):
Hematologic malignancy or post-hematopoietic cell transplant:
IV: 4 mg/kg twice daily (ASBMT [Tomblyn 2009]).
Oral: 200 mg twice daily (ASBMT [Tomblyn 2009]; IDSA [Patterson 2016]; Maertens 2018; Wingard 2010).
Duration: Varies based on degree and duration of immunosuppression (ASBMT [Tomblyn 2009]; ASCO/IDSA [Taplitz 2018]; IDSA [Patterson 2016]; Marks 2011; Wingard 2010).
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 (AST-IDCOP [Husain 2019]; Husain 2006; Palmer 2020).
Oral: 200 mg twice daily (Balogh 2016; IDSA [Patterson 2016]); may give a loading dose of 400 mg twice daily for the first 2 doses (AST-IDCOP [Husain 2019]; Husain 2006; Palmer 2020).
Duration: Varies based on patient risk factors and transplant center protocol (AST-IDCOP [Husain 2019]; Balogh 2016; Fishman 2020; Husain 2006; IDSA [Patterson 2016]; Palmer 2020).
Scedosporiosis:
IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Costa 2021; Perfect 2003; Troke 2008).
Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily (Costa 2021; Perfect 2003; Troke 2008).
Duration: Often prolonged and varies based on clinical response and patient immune status (Costa 2021).
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 (Perfect 2003; Supparatpinyo 2021).
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 (Supparatpinyo 2021).
Following IV induction therapy: Oral: 200 mg twice daily for a total of 12 weeks (Supparatpinyo 2007; Supparatpinyo 2021). 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 (HHS [OI adult 2020]). 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) (HHS [OI adult 2020]; Supparatpinyo 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 (Abel 2008; manufacturer's labeling).
CrCl <50 mL/minute:
Oral, Ophthalmic: No dosage adjustment necessary (manufacturer's labeling; expert opinion).
IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Abel 2008); 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 (Kim 2016; Lilly 2013; Neofytos 2012; Oude Lashof 2012). If IV therapy is used, monitor serum creatinine frequently and change to oral voriconazole when possible (expert opinion).
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 (Bilbao-Meseguer 2018; Udy 2010).
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 (Calandra 2016; expert opinion).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (voriconazole component) (manufacturer's labeling):
Oral, Ophthalmic: No dosage adjustment or supplemental doses necessary.
IV: No dosage adjustment necessary for voriconazole component of the IV formulation (expert opinion); 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 (Hafner 2010; von Mach 2006). If IV therapy is used, use with caution and change to oral voriconazole when possible (expert opinion).
Peritoneal dialysis:
Oral, Ophthalmic: No dosage adjustment necessary (Peng 2005; expert opinion).
IV: No dosage adjustment necessary for voriconazole component of the IV formulation (expert opinion); 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 (expert opinion).
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 (expert opinion).
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 (Kiser 2015; expert opinion).
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 (expert opinion).
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 (Burkhardt 2010).
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
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
Yes
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
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 (IDSA [Pappas 2016]).
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 (Williams 2012).
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 (IDSA [Pappas 2016]; IDSA [Patterson 2016]).
Ophthalmic (off-label): Administer an extemporaneously prepared voriconazole 10 mg/mL (1%) ophthalmic solution to the affected eye.
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).
Powder for injection: Store vials between 15°C to 30°C (59°F to 86°F). Reconstituted solutions are stable for up to 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F).
Powder for oral suspension: Store at 2°C to 8°C (36°F to 46°F). Reconstituted oral suspension is stable for up to 14 days if stored at 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze.
Tablets: Store at 15°C to 30°C (59°F to 86°F).
Treatment of invasive aspergillosis; treatment of candidemia in non-neutropenic patients and esophageal candidiasis; treatment of disseminated Candida infections of the skin and abdomen, kidney, bladder wall, and wounds; treatment of serious fungal infections caused by Scedosporium apiospermum or Fusarium spp (including Fusarium solanae) in patients intolerant of, or refractory to, other therapy (All indications: FDA approved in ages ≥2 years and adults)
Vfend may be confused with Venofer, Vimpat.
Voriconazole may be confused with fluconazole, itraconazole, posaconazole.
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)
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)
Skin photosensitivity has been reported, including erythematous rashes in sun-exposed areas (Ref), bullous phototoxicity (Ref), and pseudoporphyria (Ref). Photosensitivity may persist for several months after discontinuation of voriconazole (Ref). Rare cases of skin malignancy (malignant melanoma, squamous cell carcinoma [SCC]) have also been reported (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)
• 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)
Azole antifungals, including voriconazole, may cause hepatotoxicity (ranging from mild, asymptomatic liver abnormalities to hepatic failure) (Ref). Overall, hepatotoxicity is rare in pediatric patients; however, one report suggested event rates comparable to adults (Ref). Acute hepatic failure and death have been reported in a child (Ref). Upon discontinuation of therapy, recovery usually takes ~6 to 10 weeks (Ref).
Mechanism: Unknown; likely dose and concentration-dependent. Theories range from ability of voriconazole to alter human sterol synthesis to significant drug-drug interactions leading to increased voriconazole plasma levels (Ref). Note: Mitochondrial dysfunction may contribute to hepatotoxicity associated with ketoconazole and posaconazole, but not voriconazole (Ref).
Onset: Varied; most cases occur during 10 to 28 days of therapy (Ref).
Risk Factors:
• Preexisting liver disease (Ref)
• Patients with lung transplantation: Age <40 years, cystic fibrosis, early initiation (within 30 days) (Ref)
• Concurrent hepatotoxic agents and drug interactions (Ref)
• Voriconazole dose and concentration (eg, >4 mg/L) (Ref)
• Voriconazole has a higher risk of liver injury compared to fluconazole and echinocandins (Ref). Voriconazole also appears to have higher risk of hepatotoxicity compared to isavuconazole (Ref).
• Cross-reactivity among oral azole antifungals has not been consistently reported in patients with histories of hepatotoxicity (Ref)
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)
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)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. The following adverse drug reactions occurred in adults only unless otherwise specified.
>10%:
Cardiovascular: Hypertension (children, adolescents: 11%; adults: <2%)
Dermatologic: Skin rash (children, adolescents: 13%; adults: 2% to 4%) (table 1)
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%)
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)
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: Increased serum creatinine (children, adolescents: <5%; adults: ≤21%)
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 block (<2%), atrioventricular nodal arrhythmia (<2%), bigeminy (<2%), bradycardia (children, adolescents, adults: <5%), bundle branch block (<2%), cardiac failure (<2%), cardiomegaly (<2%), cardiomyopathy (<2%), cerebral ischemia (<2%), cerebrovascular accident (<2%), chest pain (<2%), deep vein thrombophlebitis (<2%), edema (<2%), endocarditis (<2%), extrasystoles (<2%), facial edema (<2%), flushing (children, adolescents: <5%), 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%) (Poluzzi 2010), vasodilation (<2%), ventricular fibrillation (<2%), ventricular tachycardia (<2%)
Dermatologic: Allergic dermatitis (children, adolescents: <5%), alopecia (children, adolescents, adults: <5%) (Malani 2014), 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%), furunculosis (<2%), maculopapular rash (<2%), pruritus (children, adolescents, adults: <5%), psoriasis (<2%), skin discoloration (<2%), skin photosensitivity (<2%) (Frick 2010), 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%), glycosuria (<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 gamma-glutamyl transferase (children, adolescents, adults: <5%), increased lactate dehydrogenase (<2%), pseudoporphyria (<2%) (Rodriguez-Nava 2019)
Gastrointestinal: Abdominal distention (children, adolescents, adults: ≤5%), ageusia (<2%), anorexia (<2%), cholestasis (children and adolescents: <5%), cholecystitis (<2%), cholelithiasis (<2%), 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%) (Ref), parotid gland enlargement (<2%), perforated duodenal ulcer (<2%), periodontitis (<2%), peritonitis (<2%), proctitis (<2%), stomatitis (<2%), xerostomia (<2%)
Genitourinary: Anuria (<2%), blighted ovum (<2%), dysmenorrhea (<2%), dysuria (<2%), epididymitis (<2%), hematuria (<2%), hemorrhagic cystitis (<2%), impotence (<2%), nephrosis (<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%), granuloma (<2%), hemolytic anemia (<2%), leukopenia (children, adolescents, adults: <5%), lymphadenopathy (<2%), lymphangitis (<2%), macrocytic anemia (<2%), malignant melanoma (<2%) (Levine 2016 27581783), megaloblastic anemia (<2%), microcytic anemia (<2%), pancytopenia (children, adolescents, adults: <5%), petechia (<2%), prolonged bleeding time (<2%), purpuric disease (<2%), rectal hemorrhage (<2%), splenomegaly (<2%), squamous cell carcinoma (<2%) (Levine 2016), thrombocytopenia (children, adolescents: 10%; adults: <2%), thrombotic thrombocytopenic purpura (<2%)
Hepatic: Ascites (<2%), cholestatic jaundice (adults: 2%), hepatic coma (<2%), hepatic failure (<2%) (Sherpbier 2003), hepatitis (<2%), hepatomegaly (<2%), hyperbilirubinemia (children, adolescents: <5%; adults: ≤1%), jaundice (children, adolescents, adults: <5%)
Hypersensitivity: Angioedema (<2%) (Ref), fixed drug eruption (<2%), hypersensitivity reaction (children, adolescents, adults: <5%), nonimmune anaphylaxis (<2%) (Ref), tongue edema (<2%)
Immunologic: Graft versus host disease (<2%)
Infection: Bacterial infection (<2%), herpes simplex infection (<2%), infection (<2%), 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%), ataxia (children, adolescents, adults: <5%), brain edema (<2%), cerebral hemorrhage (<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 and adolescents: <5%), encephalitis (<2%), encephalopathy (<2%) (Foolad 2018), euphoria (<2%), extrapyramidal reaction (<2%), flank pain (<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 4) , 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%), vertigo (children, adolescents, adults: <5%), voice disorder (<2%)
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%), asthenia (children, adolescents, adults: <5%), back pain (<2%), discoid lupus erythematosus (<2%), increased creatine phosphokinase blood specimen (<2%), lower limb cramp (<2%), myalgia (children, adolescents, adults: <5%), myopathy (<2%), ostealgia (<2%), osteomalacia (<2%), osteonecrosis (<2%), osteoporosis (<2%), tremor (<2%)
Ophthalmic: Accommodation disturbance (<2%), blepharitis (<2%), chromatopsia (adults: ≤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%) (Bayhan 2016), papilledema (<2%), photophobia (children, adolescents, adults: ≤6%), retinal hemorrhage (<2%), retinitis (<2%), scleritis (<2%) (Bayhan 2016), 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%), hydronephrosis (<2%), increased blood urea nitrogen (<2%), nephritis (<2%), renal insufficiency (children, adolescents: 5%; adults: ≤1%), 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: Multiorgan failure (<2%)
<1%: Renal: Acute kidney injury (Wang 2010; Yasu 2018) (table 5)
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 |
Postmarketing:
Dermatologic: Changes in nails (Malani 2014), cutaneous lupus erythematosus (Ezra 2016), phototoxicity (Barbosa 2014; Kim 2018)
Hepatic: Hepatotoxicity (Ferrajulo 2010; Lo Re 2016)
Immunologic: Drug reaction with eosinophilia and systemic symptoms (Kaneko 2018)
Nervous system: Peripheral neuropathy (Baxter 2011)
Neuromuscular & skeletal: Periosteal disease (Cormican 2018; Hussain 2018), skeletal fluorosis (Cormican 2018; Hussain 2018)
Ophthalmic: Episcleritis (Bayhan 2016), vision color changes (Bayhan 2016)
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).
Canadian labeling: Additional contraindications (not in the US labeling): Coadministration with astemizole (not available in Canada), cisapride (not available in Canada), eszopiclone (when used in patients ≥65 years of age), lovastatin, midazolam (oral), simvastatin, terfenadine (not available in Canada), and triazolam.
Documentation of allergenic cross-reactivity for imidazole antifungals is limited; however, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
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.
The frequency of hepatotoxic reactions is higher in pediatric patients; the overall incidence of transaminases >3 x ULN is 27.2% in pediatric patients compared to 17.7% in adults. A correlation between liver function test abnormalities and higher plasma drug concentrations and/or doses has not been clearly observed in pediatric patients (Driscoll 2011; Neely 2010; Soler-Palacín 2012) as it has in adults. Monitor liver function and bilirubin at baseline and periodically during therapy; if abnormal LFTs occur during therapy, additional close monitoring for more severe hepatic injury recommended; if more severe hepatic injury develops, discontinuation of therapy should be considered. Frequency of phototoxic reactions is higher in pediatric patients. Reports of a 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 (Bernhard 2012; Soler-Palacín 2012) and others have reported phototoxicities without any relation to dose and/or concentration (Frick 2010; Hansford 2012). In pediatric patients, an increased risk and earlier onset of photosensitivity reactions have been observed with concurrent methotrexate therapy (van Hasselt 2013). Squamous cell carcinoma has been reported in patients who experience phototoxic reactions; sun avoidance and dermatologic follow up is recommended in patients who experience phototoxic reactions, even after discontinuation.
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.
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)
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
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
Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. 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, 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: The recommended dose of atogepant is 10 mg once daily when coadministered with strong CYP3A4 inhibitors. 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
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
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
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
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. 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: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. 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: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Management: Consider alternatives to any strong CYP3A4 inhibitor for patients being treated with dabrafenib. If such a combination cannot be avoided, monitor closely for evidence of dabrafenib-related adverse effects. 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
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
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
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. 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: When combined with strong CYP3A4 inhibitors, administer two elexacaftor/tezacaftor/ivacaftor tablets (100 mg/50 mg/75 mg) in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor (150 mg) alone should be administered. 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: 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
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: Voriconazole may increase the serum concentration of Fedratinib. Risk X: Avoid combination
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
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 decrease the serum concentration of 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. Risk X: Avoid combination
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: For use with voriconazole 200 mg twice daily - reduce ibrutinib to 140 mg daily (for B-cell malignancies) and reduce ibrutinib to 280 mg daily (for GVHD). Avoid concomitant use of ibrutinib with higher voriconazole doses. 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, reduce lapatinib dose to 500 mg daily. 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: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Lemborexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lemborexant. 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. Risk X: Avoid combination
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. Risk X: Avoid combination
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
Mefloquine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mefloquine. Risk C: Monitor therapy
Meloxicam: Voriconazole may increase the serum concentration of Meloxicam. 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
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
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
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
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
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
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: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib dose to 400 mg. Further dose reductions may also be required if adverse reactions occur. Risk D: Consider therapy modification
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: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg per day to 200 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
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. Risk X: Avoid combination
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
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 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). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Risk X: Avoid combination
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
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 the serum concentration of Ripretinib. Risk C: Monitor therapy
Ritonavir: May increase the serum concentration of Voriconazole. Ritonavir may decrease 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: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Roflumilast. 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, Oral) 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
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
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
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: CYP3A4 Inhibitors (Strong) 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
Telithromycin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Telithromycin. Risk C: Monitor therapy
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: When used together with a strong CYP3A4 inhibitor, the recommended dose of upadacitinib is 15 mg/day. Coadministration of the upadacitinib 30 mg/day dose together with a strong CYP3A4 inhibitor is not recommended. 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
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.
Women of childbearing potential should use effective contraception during treatment.
Adverse events were observed in animal reproduction studies. Voriconazole can cause fetal harm when administered to a pregnant woman.
Hepatic function (transaminases and bilirubin) at initiation, weekly during the first month and monthly during course of treatment; serum electrolytes (particularly calcium, magnesium, and potassium) prior to initiation and during therapy; periodic renal function tests (particularly serum creatinine); adrenal function (as clinically appropriate, during and after treatment) and signs/symptoms of adrenal insufficiency; visual acuity, visual field, and color perception if treatment course continues >28 days; ECG (as clinically appropriate); pancreatic function in patients at risk for acute pancreatitis; voriconazole trough concentrations; phototoxic reactions (higher incidence in pediatric patients); total body skin examination yearly or more frequently if lesions occur; signs/symptoms of fluorosis or periostitis (eg, skeletal pain, radiologic findings).
Trough: 1 to 6 mcg/mL; some have suggested a higher minimum trough (2 mcg/mL) for disseminated infections or those in isolated sites (Chen 2012)
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.
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)
Renal function impairment: 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).
1% ophthalmic solution:
A 1% ophthalmic solution may be made using voriconazole powder for solution for intravenous infusion. Aseptically reconstitute 200 mg voriconazole powder with 19 mL of sterile water for injection or with sterile water for injection containing 0.01% benzalkonium chloride solution to obtain 20 mL of a 10 mg/mL (1%) solution. Follow with sterile filtration through a 0.22 micron filter. Package in a sterile container for use as an eye drop solution.
Stability of the 1% solution prepared with sterile water for injection was demonstrated for up to 30 days. Protection from light and refrigeration did not have an effect on stability (Dupuis 2009). Stability of the 1% solution prepared with sterile water for injection containing 0.01% benzalkonium chloride solution and stored under refrigeration (2°C to 8°C [36°F to 46°F]) and in an amber high-density polyethylene (HDPE) eye drop bottle was demonstrated for up to 14 weeks (Al-Badriyeh 2009).
Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).
Solution (reconstituted) (Vfend IV Intravenous)
200 mg (per each): $72.36
Solution (reconstituted) (Voriconazole Intravenous)
200 mg (per each): $50.00 - $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
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