Voriconazole

Dosage Forms

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

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

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Absorption

Well absorbed after oral administration; multiple doses administered with high-fat meals demonstrate decreased C_max and AUC

Distribution

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

V_d:

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

Adults: 4.6 L/kg

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).

Excretion

Urine (<2% as unchanged drug)

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

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).

Protein Binding

58%

Use in Specific Populations

Special Populations: Renal Function Impairment

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

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

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

Use: Off Label

Acute myelogenous leukemia (prophylaxis of fungal infections)b

Data from a prospective, randomized, double-blind, placebo-controlled phase III study supports the use of voriconazole as prophylaxis for fungal infections in AML patients undergoing induction chemotherapy Vehreschild 2007. Additional trials may be necessary to further define the role of voriconazole in this condition.

Allogeneic hematopoietic stem cell transplant (prophylaxis of fungal infections)byes

Data from a prospective, open-label, multicenter study supports the use of voriconazole as secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients Cordonnier 2010. Additional trials may be necessary to further define the role of voriconazole in this condition.

Based on the European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients, voriconazole is effective and recommended for use in neutropenic allogeneic stem cell transplant patients as antifungal prophylaxis Maertens 2011.

Allogeneic hematopoietic stem cell transplant patients with graft-versus-host disease (prophylaxis of fungal infections)byes

Data from a multicenter, randomized, double-blind trial supports the use of voriconazole in the prevention of invasive fungal infection after allogeneic hematopoietic cell transplant, including patients with graft-versus-host disease (GVHD) Wingard 2010. Additional trials may be necessary to further define the role of voriconazole in patients with this condition.

Based on the Center for International Blood and Marrow Transplant Research, the National Marrow Donor Program, the European Blood and Marrow Transplant Group, and multiple other organizations Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplant Recipients, voriconazole is an effective and recommended option for antifungal prophylaxis in hematopoietic cell transplant patients with GVHD. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients also support the use of voriconazole for antifungal prophylaxis in allogeneic hematopoietic stem cell transplant patients with graft-versus-host disease (high risk patients) Maertens 2011.

Aspergillosis, invasive (prophylaxis during prolonged neutropenia)yes

Based on the Infectious Diseases Society of America (IDSA) Practice Guidelines for the Diagnosis and Management of Aspergillosis, oral voriconazole is an effective and recommended therapeutic option for the prophylaxis of invasive aspergillosis (IA) when prolonged neutropenia is present in patients at high risk for IA (eg, patients with hematologic disorders with inadequate functioning neutrophils, acute leukemia with repeated and/or prolonged neutropenia, history of IA before transplant).

Aspergillosis, ocularyes

Based on the Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Management of Aspergillosis, voriconazole (ophthalmic administration) is effective and recommended for the treatment of Aspergillus endophthalmitis and keratitis. For the treatment of endophthalmitis, concomitant systemic voriconazole is recommended.

Candidiasis, endophthalmitisyes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, voriconazole is an effective and recommended agent for patients with endophthalmitis due to Candida spp. Systemic voriconazole therapy is recommended in patients with or without vitritis. Intravitreal voriconazole (in addition to systemic antifungal therapy) is recommended only in patients with vitritis or with macular involvement (with or without vitritis).

Candidiasis, esophagealyes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis and the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, intravenous voriconazole is an effective and recommended treatment option for oropharyngeal candidiasis in fluconazole-refractory patients or in HIV-positive patients (alternative therapy).

Candidiasis, intravascular infectionsyes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, oral voriconazole is an effective and recommended treatment for patients with candida intravascular infections, including patients with endocarditis (native or prosthetic valve) or infections of implantable cardiac devices (pacemaker, implantable cardiac defibrillator) due to Candida spp. that are fluconazole-resistant/voriconazole-susceptible.

Candidiasis, oropharyngeal (fluconazole-refractory)yes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, oral voriconazole is an effective and recommended treatment option for fluconazole-refractory oropharyngeal candidiasis.

Coccidioidal meningitis (salvage therapy) (non-HIV infected patients)cyes

Limited data from case reports have demonstrated efficacy of voriconazole in patients with coccidioidal meningitis who did not respond to initial conventional therapy (eg, fluconazole) Cortez 2003, Proia 2004.

Based on the Infectious Diseases Society of America (IDSA) guidelines for the treatment of coccidioidomycosis, voriconazole may be considered for salvage therapy for coccidioidal meningitis.

Coccidioidomycosis (treatment/chronic suppressive therapy) in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, oral voriconazole is an effective and recommended alternative agent in the treatment of coccidioidomycosis (mild infections [eg, focal pneumonia]) and in chronic suppressive therapy of coccidioidomycosis in HIV-infected patients.

Empiric antifungal therapy (neutropenic fever)yes

Based on the Infectious Diseases Society of America (IDSA) Practice Guidelines for the Diagnosis and Management of Aspergillosis, voriconazole is effective and recommended for empiric antifungal therapy in high-risk neutropenic patients who remain febrile despite broad-spectrum antibiotic therapy. According to the guidelines, empiric therapy is not recommended for patients with an anticipated duration of neutropenia <10 days, unless other findings indicate a suspected invasive fungal infection.

Myelodysplastic syndrome (prophylaxis of fungal infections)c

Data from an open-label, randomized study suggest that voriconazole may be beneficial as antifungal prophylaxis in patients with myelodysplastic syndrome undergoing induction chemotherapy or first salvage Mattiuzzi 2011.

Talaromyces marneffei infection in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, voriconazole is an effective and recommended alternative agent for the treatment of Talaromyces marneffei infection in HIV-infected patients.

Contraindications

Hypersensitivity to voriconazole or any component of the formulation; coadministration with astemizole, barbiturates (long acting), carbamazepine, cisapride, efavirenz (≥400 mg daily), ergot derivatives (ergotamine and dihydroergotamine), pimozide, quinidine, rifampin, rifabutin, ritonavir (≥800 mg daily; also avoid low dose [eg, 200 mg daily] dosing if possible), sirolimus, St John’s wort, terfenadine

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.

Dosage and Administration

Dosing: Adult

Aspergillosis, invasive, including disseminated and extrapulmonary infection; treatment:

IV:

Initial: 6 mg/kg every 12 hours for 2 doses

Maintenance dose: 4 mg/kg every 12 hours

Oral: Maintenance dose:

Manufacturer's labeling: Note: If patient has inadequate clinical response, titrate in 50 mg/dose increments for weight <40 kg and 100 mg/dose increments for weight ≥40 kg.

Weight <40 kg: 100 mg every 12 hours

Weight ≥40 kg: 200 mg every 12 hours

Alternate recommendations: Oral: 200 to 300 mg every 12 hours or weight-based dosing (3 to 4 mg/kg) every 12 hours. Note: In patients able to tolerate oral administration, may consider oral in place of IV; however, IV administration is recommended in seriously ill patients (IDSA [Patterson 2016]).

Duration of therapy: 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]).

Aspergillosis, invasive (prophylaxis during prolonged neutropenia) (alternative therapy) (off-label use): Oral: 200 mg twice daily (IDSA [Patterson 2016])

Aspergillosis, ocular (off-label use):

Endophthalmitis: Intravitreal: 100 mcg/0.1 mL of an extemporaneously prepared solution administered intravitreally (need for a repeat dose is at physician discretion); concomitant systemic (IV or oral) voriconazole therapy is also recommended (Hariprasad 2008; Hoenigl 2013; Kramer 2006; IDSA [Patterson 2016]; Riddell 2011).

Keratitis: Ophthalmic: Dosing may vary; the following dosing regimen has been used in trials: 1 drop of an extemporaneously prepared 1% ophthalmic solution applied topically to the cornea of the affected eye every 1 hour while awake for 1 week, then every 2 hours while awake for 2 weeks; further continuation was at physician discretion (IDSA [Patterson 2016]; Prajna 2010; Prajna 2013)

Candidemia in non-neutropenic patients and disseminated Candida infections in skin, and infections in abdomen, kidney, bladder wall and wounds: Treatment should continue for a minimum of 14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV:

Initial: 6 mg/kg every 12 hours for 2 doses

Maintenance: 3 to 4 mg/kg every 12 hours

Oral:

Manufacturer's labeling: Maintenance dose: Note: If patient has inadequate clinical response, titrate in 50 mg/dose increments for weight <40 kg and 100 mg/dose increments for weight ≥40 kg

Weight <40 kg: 100 mg every 12 hours

Weight ≥40 kg: 200 mg every 12 hours

Alternate recommendations (IDSA [Pappas 2016]): Candidemia in non-neutropenic patients:

Initial therapy: 400 mg (6 mg/kg) IV every 12 hours for 2 doses, followed by 200 mg (3 mg/kg) IV or orally every 12 hours. Note: Voriconazole is considered alternative therapy and offers little advantage over fluconazole as first-line therapy of candidemia.

Step-down therapy (after patient has responded to initial therapy): Oral:

Isolates of C. glabrata (voriconazole-susceptible isolates): 200 to 300 mg (3 to 4 mg/kg) twice daily

Isolates of C. krusei (selected cases): 200 mg every 12 hours

Duration: Continue for 14 days after first negative blood culture and resolution of signs/symptoms; step-down therapy to voriconazole (eg, after 5 to 7 days in nonneutropenic patients) is recommended only in select clinically stable patients with certain voriconazole-susceptible isolates and negative repeat cultures.

Candidiasis, endophthalmitis (with or without vitritis) (off-label use) (IDSA [Pappas 2016]): Voriconazole-susceptible isolates:

Systemic therapy: Loading dose: 400 mg (6 mg/kg) IV twice daily for 2 doses, then 300 mg (4 mg/kg) IV or orally twice daily for at least 4 to 6 weeks until examination indicates resolution; for patients with vitritis or with macular involvement (with or without vitritis), an intravitreal injection of voriconazole or amphotericin B deoxycholate is also recommended.

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

Candidiasis, esophageal:

US labeling: Oral: Treatment should continue for a minimum of 14 days, and for at least 7 days following resolution of symptoms. Note: If patient has inadequate clinical response, titrate in 50 mg/dose increments for weight <40 kg and 100 mg/dose increments for weight ≥40 kg

Weight <40 kg: 100 mg every 12 hours; maximum: 300 mg daily

Weight ≥40 kg: 200 mg every 12 hours; maximum: 600 mg daily

Alternative dosing:

Fluconazole-refractory: Oral, IV (off-label route): 200 mg (3 mg/kg) twice daily for 14 to 21 days (IDSA [Pappas 2016])

HIV-positive patients (alternative to preferred therapy): Oral, IV (off-label route): 200 mg twice daily for 14 to 21 days (HHS [OI adult 2015])

Candidiasis, intravascular infections (off-label use) (IDSA [Pappas 2016]): Fluconazole-resistant/voriconazole-susceptible isolates:

Endocarditis, native or prosthetic valve: Oral: 200 to 300 mg twice daily; voriconazole should only be used as step-down therapy in clinically stable, culture-negative patients following initial therapy with an amphotericin B lipid formulation (with or without flucytosine) or an echinocandin; antifungal therapy should continue for at least 6 weeks after valve replacement surgery (longer durations recommended in patients with perivalvular abscesses or other complications).

Implantable cardiac devices (eg, pacemaker. ICD, VAD): Oral: 200 to 300 mg twice daily; voriconazole should only be used as step-down therapy in clinically stable, culture-negative patients following initial therapy with an amphotericin B lipid formulation (with or without flucytosine) or an echinocandin; antifungal therapy should continue for 4 to 6 weeks after device removal (4 weeks for infections limited to generator pockets and at least 6 weeks for infections involving the wires).

Candidiasis, oropharyngeal (fluconazole-refractory) (off-label use): Oral: 200 mg twice daily for up to 28 days (IDSA [Pappas 2016])

Coccidioidomycosis in HIV-infected patients (alternative to preferred therapy) (off-label use) (HHS [OI adult 2015]): Oral:

Mild infections (eg, focal pneumonia): 200 mg twice daily; patients who complete initial therapy should be considered for lifelong suppressive therapy.

Chronic suppressive therapy: 200 mg twice daily

Coccidioidal meningitis (salvage therapy) (non-HIV infected patients) (off-label use):

IV: 6 mg/kg every 12 hours for two doses, then 4 mg/kg every 12 hours (Cortez 2003)

Oral: 200 mg twice daily (IDSA [Galgiani 2016]); limited data (case reports) also report using higher doses (range: 250 mg to 400 mg twice daily) during the treatment course based on clinical response to therapy (Cortez 2003; Proia 2004).

Empiric antifungal therapy (neutropenic fever) (off-label use): IV: Initial: 6 mg/kg every 12 hours for 2 doses; maintenance dose: 4 mg/kg every 12 hours. Note: May consider oral therapy in place of IV therapy, with dosing of 200 to 300 mg orally every 12 hours or weight-based dosing (3 to 4 mg/kg) every 12 hours (IDSA [Patterson 2016])

Scedosporiosis, fusariosis:

IV:

Initial: 6 mg/kg every 12 hours for 2 doses

Maintenance dose: 4 mg/kg every 12 hours for >7 days

Oral: Maintenance dose: Note: If patient has inadequate clinical response, titrate in 50 mg/dose increments for weight <40 kg and 100 mg/dose increments for weight ≥40 kg.

Weight <40 kg: 100 mg every 12 hours.

Weight ≥40 kg: 200 mg every 12 hours.

Infection prophylaxis in graft-versus-host disease (GVHD) (high-risk patients) (off-label use) (Maertens 2011; Tomblyn 2009; Wingard 2010): Note: The optimal duration of prophylaxis in GVHD has not been determined.

Oral: Weight >40 kg: 200 mg every 12 hours

IV: Weight >40 kg: 4 mg/kg every 12 hours

Infection prophylaxis in standard- or high-risk patients with allogeneic hematopoietic stem cell transplant (HSCT) or certain autologous HSCT (off-label use) (Castagna 2012; Maertens 2011; Tomblyn 2009; Wingard 2010): Note: Begin prophylaxis at the start of chemotherapy or the day of transplantation. The ASBMT recommends continuing prophylaxis until engraftment (ie, 30 days) or for 7 days after the ANC reaches >1000 cells/mm³ (Tomblyn 2009). The IDSA recommends anti-mold prophylaxis in allograft HSCT patients "through the neutropenic period and beyond," based on a demonstrated survival advantage in patients receiving prophylaxis for 75 days post-HSCT, or until cessation of immunosuppressive therapy (Freifeld 2011).

Oral: Weight >40 kg: 200 mg every 12 hours

IV: Weight >40 kg: 4 mg/kg every 12 hours.

Talaromyces marneffei infection in HIV-infected patients (off-label use) (HHS [OI adult 2015]):

Acute infection in severely ill patients: 6 mg/kg IV every 12 hours for 2 doses, then 4 mg/kg IV every 12 hours for at least 3 days, followed by 200 mg orally twice daily for a maximum of 12 weeks; follow with itraconazole chronic maintenance therapy

Mild disease: Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily for a maximum of 12 weeks; follow with itraconazole chronic maintenance therapy

Dosage adjustment in patients with inadequate response:

IV: Maintenance dose may be increased from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours, depending upon condition.

Oral: Maintenance dose may be increased from 200 mg every 12 hours to 300 mg every 12 hours in patients weighing ≥40 kg (or to 150 mg every 12 hours in patients <40 kg), depending upon condition.

Dosage adjustment in patients unable to tolerate treatment:

IV: Maintenance dose may be reduced from 4 mg/kg every 12 hours to 3 mg/kg every 12 hours, depending upon condition.

Oral: Maintenance dose may be reduced in 50 mg decrements to a minimum dosage of 200 mg every 12 hours in patients weighing ≥40 kg (or to 100 mg every 12 hours in patients <40 kg), depending upon condition.

Dosage adjustment in patients receiving concomitant CYP450 enzyme inducers or substrates:

Efavirenz: Oral: Increase maintenance dose of voriconazole to 400 mg every 12 hours and reduce efavirenz dose to 300 mg once daily; upon discontinuation of voriconazole, return to the initial dose of efavirenz.

Phenytoin:

IV: Increase voriconazole maintenance dose to 5 mg/kg every 12 hours.

Oral: Increase voriconazole maintenance dose to 400 mg every 12 hours in patients ≥40 kg (200 mg every 12 hours in patients <40 kg).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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 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.

Dosage adjustment in patients receiving concomitant CYP450 enzyme inducers or substrates: There are no pediatric-specific recommendations provided. Monitor for efficacy and adverse reactions; adjust dose accordingly; based on experience in adult patients, consider increased voriconazole maintenance doses with concomitant efavirenz and phenytoin; adjustment of efavirenz dose is also required.

Dosing: Obesity

Use ideal body weight (IBW) for most obese patients in weight-based dosing calculations; consider using an adjusted body weight (adjusted body weight=0.4 [total body weight – IBW] + IBW) in obese patients with life-threatening invasive fungal infections. Confirm selection of an appropriate dose with therapeutic drug monitoring (Eljaaly 2016).

Reconstitution

Powder for injection: Reconstitute 200 mg vial with 19 mL of SWFI (use of automated syringe is not recommended). Resultant solution (20 mL) has a concentration of 10 mg/mL. Prior to infusion, must dilute to ≤5 mg/mL with NS, LR, D₅WLR, D₅W¹/₂NS, D₅W, D₅W with KCl 20 mEq, ¹/₂NS, or D₅WNS. Do not dilute with 4.2% sodium bicarbonate infusion.

Powder for oral suspension: Add 46 mL of water to the bottle to make 40 mg/mL suspension. Shake vigorously for ~1 minute. Do not refrigerate or freeze.

Extemporaneously Prepared

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]).

Administration

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.

Storage

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).

Drug Interactions

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. Consider therapy modification

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

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. 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. Consider therapy modification

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

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

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

ALPRAZolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam. Management: Consider using an alternative agent that is less likely to interact. If combined, monitor for increased therapeutic/toxic effects of alprazolam if combined with a strong CYP3A4 inhibitor. Consider therapy modification

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

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

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

Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. 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. Consider therapy modification

Antineoplastic Agents (Vinca Alkaloids): Voriconazole may enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Voriconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Consider therapy modification

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

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

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

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. Avoid combination

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

AtorvaSTATin: Voriconazole may increase the serum concentration of AtorvaSTATin. Management: Monitor for toxic effects of atorvastatin (e.g., myalgia, rhabdomyolysis, liver function test abnormalities) during concomitant treatment, and reduce atorvastatin dose when possible. Consider use of fluva-, rosuva-, pitava-, or pravastatin when possible. Consider therapy modification

Avanafil: Voriconazole may increase the serum concentration of Avanafil. Avoid combination

Avapritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avapritinib. 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. Consider therapy modification

Barbiturates: May decrease the serum concentration of Voriconazole. Exceptions: Methohexital; PENTobarbital; Secobarbital; Thiopental. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. 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. Consider therapy modification

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

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

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

Bictegravir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bictegravir. Monitor therapy

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

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

Bosentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. 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. 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 moderate CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. 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). Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

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

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

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

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Buprenorphine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Buprenorphine. 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. Consider therapy modification

Busulfan: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Busulfan. Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. 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, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

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

Calcium Channel Blockers: Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Exceptions: Clevidipine. Consider therapy modification

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

Cannabidiol: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. Monitor therapy

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

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

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

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 concomitant use of ceritinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease ceritinib dose by one-third and monitor patients for ceritinib toxicities including QTc prolongation and arrhythmias. Consider therapy modification

Chloramphenicol (Systemic): May increase the serum concentration of Voriconazole. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cilostazol: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cilostazol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Reduce the cilostazol dose to 50 mg twice daily in patients who are also receiving moderate inhibitors of CYP2C19. Monitor clinical response to cilostazol closely. Consider therapy modification

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

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

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. Consider therapy modification

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

Codeine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine. 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 full monograph for details. Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. 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. Consider therapy modification

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. 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, decrease crizotinib dose to 250 mg daily. Monitor patients for crizotinib toxicities including QTc prolongation and arrhythmias. 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. Consider therapy modification

CycloSPORINE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

CYP2C19 Inducers (Moderate): May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Monitor therapy

CYP2C19 Substrates (High risk with Inhibitors): CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Monitor therapy

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Substrates (High risk with Inhibitors): CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); AmLODIPine; Benzhydrocodone; Buprenorphine; Gefitinib; HYDROcodone; Mirtazapine; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

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. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

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

Darunavir: May decrease the serum concentration of Voriconazole. Avoid combination

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 concomitant use of dasatinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, dasatinib dose reductions are required. Monitor patients for dasatinib toxicities including QTc prolongation and arrhythmias. 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. 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. Consider therapy modification

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

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

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

Diclofenac (Systemic): Voriconazole may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used with voriconazole. Arthrotec (diclofenac and misoprostol) labeling recommends limiting the total daily dose to a maximum of 50 mg twice daily. Consider therapy modification

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

Didanosine: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Consider therapy modification

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

Dihydroergotamine: Voriconazole may increase the serum concentration of Dihydroergotamine. Avoid combination

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. 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. Avoid combination

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

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. 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. Avoid combination

Drospirenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Management: Drospirenone use is contraindicated specifically when the strong CYP3A4 inhibitors atazanavir and cobicistat are administered concurrently. Caution should be used when drospirenone is coadministered with other strong CYP3A4 inhibitors. Consider therapy modification

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. 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. Consider therapy modification

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/day. Consider therapy modification

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. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. 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. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Elvitegravir: Voriconazole may increase the serum concentration of Elvitegravir. Management: Careful consideration of the risk/benefit ratio for voriconazole use is recommended prior to its use in patients treated with elvitegravir-containing products. 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 using strong CYP3A4 inhibitors together with encorafenib if possible. If the combination must be used, reduce the encorafenib dose and monitor QT interval. See monograph for details. Consider therapy modification

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

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. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: Voriconazole may increase the serum concentration of Eplerenone. 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. Consider therapy modification

Ergoloid Mesylates: Voriconazole may increase the serum concentration of Ergoloid Mesylates. Avoid combination

Ergonovine: Voriconazole may increase the serum concentration of Ergonovine. Avoid combination

Ergotamine: Voriconazole may increase the serum concentration of Ergotamine. 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 severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Erythromycin (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. Monitor therapy

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

Estrogen Derivatives (Contraceptive): Voriconazole may decrease the metabolism of Estrogen Derivatives (Contraceptive). Estrogen Derivatives (Contraceptive) may increase the serum concentration of Voriconazole. 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). Consider therapy modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Etravirine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Etravirine. Applicable Isavuconazonium considerations are addressed in separate monographs. Etravirine may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with itraconazole or ketoconazole. Etravirine may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with voriconazole. Management: Monitor for increased effects/toxicity of etravirine. Antifungal dose adjustment may be needed for ketoconazole, itraconazole, or posaconazole but specific dosing guidelines are lacking. Consider therapy modification

Everolimus: Voriconazole may increase the serum concentration of Everolimus. Avoid combination

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

Fedratinib: Voriconazole may increase the serum concentration of Fedratinib. Avoid combination

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

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

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

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fosamprenavir: Voriconazole may increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be increased. Fosamprenavir may increase the serum concentration of Voriconazole. Monitor therapy

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

Fosphenytoin: May decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosphenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

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

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

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. 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 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. Consider therapy modification

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. 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. Avoid combination

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

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

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

Idelalisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib. Monitor therapy

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. 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. Consider therapy modification

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

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. 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. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

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. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

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. Consider therapy modification

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

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

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

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 half-life. Consider therapy modification

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

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

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

Letermovir: May decrease the serum concentration of Voriconazole. Monitor therapy

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

Levomethadone: Voriconazole may increase the serum concentration of Levomethadone. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

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

Lopinavir: May decrease the serum concentration of Voriconazole. Avoid combination

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. Consider therapy modification

Losartan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Losartan. Applicable Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination

Lumacaftor and Ivacaftor: May decrease the serum concentration of Voriconazole. Management: Concurrent use of lumacaftor/ivacaftor and voriconazole is not recommended. Consider an alternative antifungal such as fluconazole if appropriate. If this combination cannot be avoided, monitor patients for decreased voriconazole efficacy. Consider therapy modification

Lumateperone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumateperone. Avoid combination

Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Monitor therapy

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

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. 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. Consider therapy modification

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

MedroxyPROGESTERone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone. Monitor therapy

Meloxicam: Voriconazole may increase the serum concentration of Meloxicam. Monitor therapy

Meperidine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine. 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. Consider therapy modification

Methylergonovine: Voriconazole may increase the serum concentration of Methylergonovine. Avoid combination

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. 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. Consider therapy modification

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 900 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. 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. Consider therapy modification

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

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

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

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

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

Nelfinavir: Voriconazole may increase the serum concentration of Nelfinavir. Monitor therapy

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

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. Consider therapy modification

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

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

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

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

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. Consider therapy modification

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

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: Voriconazole may enhance the adverse/toxic effect of OxyCODONE. Voriconazole may increase the serum concentration of OxyCODONE. Management: A reduced oxycodone dose may be necessary with concurrent voriconazole. Increased frequency and duration of monitoring for oxycodone-related adverse effects is recommended. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. 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 adult dose to 400 mg. Further dose reductions may also be required. 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. 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, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day. Consider therapy modification

Phenytoin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Phenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Concomitant therapy with itraconazole, voriconazole, or ketoconazole and phenytoin should probably be avoided, as antifungal failure is likely. Consider selecting alternative antifungal therapy. Consider therapy modification

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. Consider therapy modification

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

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

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

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

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

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

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

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

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

Progestins (Contraceptive): Voriconazole may increase the serum concentration of Progestins (Contraceptive). Progestins (Contraceptive) may increase the serum concentration of Voriconazole. Monitor therapy

Proton Pump Inhibitors: Voriconazole may increase the serum concentration of Proton Pump Inhibitors. Proton Pump Inhibitors may increase the serum concentration of Voriconazole. Exceptions: Omeprazole. 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). Exceptions: Citalopram. 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. Exceptions: Pimozide; QUEtiapine. 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. Exceptions: QuiNIDine. 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. 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. Exceptions: Dronedarone. 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. Exceptions: Ivosidenib. 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). Exceptions: Astemizole; Bedaquiline; Cisapride; Delamanid; Terfenadine. 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). Exceptions: Domperidone; Halofantrine; Midostaurin; Piperaquine; Toremifene. 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. 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 combined with strong CYP3A4 inhibitors. Monitor patients for quetiapine toxicities, including QTc prolongation and torsades de pointes. Consider therapy modification

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

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

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

Ranolazine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ranolazine. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Avoid combination

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

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

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. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Management: Consider avoiding when possible. Use efavirenz with voriconazole only if voriconazole is dosed at 400 mg every 12 hours and efavirenz is dosed at 300 mg daily (adult doses) throughout therapy. Avoid Atripla (efavirenz/emtricitabine/tenofovir). Exceptions: Delavirdine; Etravirine; Rilpivirine. Consider therapy modification

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. Consider therapy modification

Rifamycin Derivatives: Voriconazole may increase the serum concentration of Rifamycin Derivatives. Rifamycin Derivatives may decrease the serum concentration of Voriconazole. Avoid combination

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

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. Avoid combination

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

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

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. 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. 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. 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. Monitor therapy

Sildenafil: Voriconazole may increase the serum concentration of Sildenafil. Management: Concurrent voriconazole is not recommended when sildenafil is used for treatment of pulmonary arterial hypertension. If sildenafil is used to treat erectile dysfunction, an initial dose of 25 mg is recommended with concurrent voriconazole. Consider therapy modification

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

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

Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination

Sirolimus: Voriconazole may increase the serum concentration of Sirolimus. Avoid combination

Solifenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin. Management: Limit solifenacin doses to 5 mg daily when combined with strong CYP3A4 inhibitors. Consider therapy modification

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

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

St John's Wort: May decrease the serum concentration of Voriconazole. 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). Consider therapy modification

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

SUNItinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose decreases are recommended, and vary by indication. See full monograph for details. Consider therapy modification

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

Tacrolimus (Systemic): Voriconazole may increase the serum concentration of Tacrolimus (Systemic). Management: When starting voriconazole in patients already receiving tacrolimus, reduce tacrolimus dose to one-third of the original dose. Monitor tacrolimus blood levels closely. Consider therapy modification

Tacrolimus (Topical): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus (Topical). Applicable Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Tadalafil: Voriconazole may increase the serum concentration of Tadalafil. Consider therapy modification

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

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

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

Telithromycin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Telithromycin. Monitor therapy

Temsirolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors whenever possible. If combined, decrease temsirolimus dose to 12.5 mg per week and monitor patients for increased temsirolimus effects and toxicities. 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. Avoid combination

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

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

Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor and Ivacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor alone should be administered. 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: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inhibitors. If concomitant use is unavoidable, monitor for adverse effects and decreased efficacy. 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. Avoid combination

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 monograph for details. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. 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. Consider therapy modification

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

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. 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. Consider therapy modification

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

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

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

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Upadacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib. Monitor therapy

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. Consider therapy modification

Vardenafil: Voriconazole may increase the serum concentration of Vardenafil. Management: Limit vardenafil dosing to a maximum of 2.5 mg per 24 hours in patients receiving concurrent therapy with strong CYP3A4 inhibitors, such as voriconazole. 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. Consider therapy modification

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy. Consider therapy modification

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

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

Vilanterol: May increase the serum concentration of CYP3A4 Inhibitors (Strong). Monitor therapy

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult 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. Consider therapy modification

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

Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination

Vitamin K Antagonists (eg, warfarin): Voriconazole may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

Voxelotor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inhibitors. If concomitant use is unavoidable, reduce the voxelotor dose to 1,000 mg once daily. Consider therapy modification

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. Consider therapy modification

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

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification

Adverse Reactions

>10%:

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

Dermatologic: Skin rash (children and adolescents: 13%; adults: 2% to 4%)

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

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

Hepatic: Increased serum alkaline phosphatase (adults: 4% to 23%; children and adolescents: 8%), increased serum alanine aminotransferase (2% to 23%), increased liver enzymes (2% to 22%), increased serum aspartate aminotransferase (2% to 20%), hyperbilirubinemia (≤19%)

Ophthalmic: Visual disturbance (14% to 26%; likely serum concentration dependent [Imhof 2006; Pascual 2008; Tan 2006])

Renal: Increased serum creatinine (adults: ≤21%; children and adolescents: <5%)

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

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

1% to 10%:

Cardiovascular: Hypotension (children and adolescents: 9%; adults: <2%), peripheral edema (≤9%), tachycardia (children and adolescents: 7%; adults: 1%), bradycardia (<5%), flushing (children and adolescents: <5%), palpitations (<5%), phlebitis (<5%), supraventricular tachycardia (<5%), syncope (<5%), acute myocardial infarction (adults: <2%), atrial arrhythmia (adults: <2%), atrial fibrillation (adults: <2%), atrioventricular block (adults: <2%), bigeminy (adults: <2%), bundle branch block (adults: <2%), cardiac failure (adults: <2%), cardiomegaly (adults: <2%), cardiomyopathy (adults: <2%), cerebral ischemia (adults: <2%), cerebrovascular accident (adults: <2%), chest pain (adults: <2%), deep vein thrombophlebitis (adults: <2%), edema (adults: <2%), endocarditis (adults: <2%), extrasystoles (adults: <2%), facial edema (adults: <2%), nodal arrhythmia (adults: <2%), orthostatic hypotension (adults: <2%), prolonged bleeding time (adults: <2%), prolonged QT interval on ECG (adults: <2%), pulmonary embolism (adults: <2%), substernal pain (adults: <2%), supraventricular extrasystole (adults: <2%), thrombophlebitis (adults: <2%), torsades de pointes (adults: <2%), vasodilation (adults: <2%), ventricular arrhythmia (adults: <2%), ventricular fibrillation (adults: <2%), ventricular tachycardia (adults: <2%)

Central nervous system: Headache (children and adolescents: 10%; adults: 2%), hallucination (3% to 5%; likely serum concentration dependent [Imhof 2006; Pascual 2008; Tan 2006]), dizziness (≤5%), agitation (<5%), anxiety (<5%), ataxia (<5%), chills (children and adolescents: <5%; adults: <1%), depression (<5%), emotional lability (children and adolescents: <5%), hypothermia (children and adolescents: <5%), insomnia (<5%), lethargy (children and adolescents: <5%), paresthesia (<5%), seizure (<5%), vertigo (<5%), abnormal dreams (adults: <2%), akathisia (adults: <2%), amnesia (adults: <2%), cerebral edema (adults: <2%), cerebral hemorrhage (adults: <2%), coma (adults: <2%), confusion (adults: <2%), delirium (adults: <2%), dementia (adults: <2%), depersonalization (adults: <2%), drowsiness (adults: <2%), encephalitis (adults: <2%), encephalopathy (adults: <2%), euphoria (adults: <2%), extrapyramidal reaction (adults: <2%), flank pain (adults: <2%), Guillain-Barre syndrome (adults: <2%), hypertonia (adults: <2%), hypoesthesia (adults: <2%), intracranial hypertension (adults: <2%), myasthenia (adults: <2%), neuralgia (adults: <2%), neuropathy (adults: <2%), pain (adults: <2%), psychosis (adults: <2%), suicidal ideation (adults: <2%), tonic clonic epilepsy (adults: <2%), voice disorder (adults: <2%)

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

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

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

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

Hematologic & oncologic: Thrombocytopenia (children and adolescents: 10%; adults: <2%), anemia (<5%), leukopenia (<5%), pancytopenia (<5%), agranulocytosis (adults: <2%), aplastic anemia (adults: <2%), bone marrow depression (adults: <2%), disseminated intravascular coagulation (adults: <2%), eosinophilia (adults: <2%), granuloma (adults: <2%), hemolytic anemia (adults: <2%), lymphadenopathy (adults: <2%), lymphangitis (adults: <2%), macrocytic anemia (adults: <2%), malignant melanoma (adults: <2%), megaloblastic anemia (adults: <2%), microcytic anemia (adults: <2%), petechia (adults: <2%), purpuric disease (adults: <2%), rectal hemorrhage (adults: <2%), splenomegaly (adults: <2%), squamous cell carcinoma (adults: <2%), thrombotic thrombocytopenic purpura (adults: <2%)

Hepatic: Abnormal hepatic function tests (3% to 6%), jaundice (<5%), cholestatic jaundice (adults: 2%), ascites (adults: <2%), hepatic coma (adults: <2%), hepatic failure (adults: <2%), hepatitis (adults: <2%), hepatomegaly (adults: <2%)

Hypersensitivity: Hypersensitivity reaction (<5%), angioedema (adults: <2%), fixed drug eruption (adults: <2%), nonimmune anaphylaxis (adults: <2%), tongue edema (adults: <2%)

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

Infection: Bacterial infection (adults: <2%), fungal infection (adults: <2%), herpes simplex infection (adults: <2%), infection (adults: <2%), sepsis (adults: <2%)

Local: Catheter pain (children and adolescents: <5%), injection site infection (adults: <2%), inflammation at injection site (adults: <2%), pain at injection site (adults: <2%)

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

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

Otic: Tinnitus (<5%), deafness (adults: <2%), otalgia (adults: <2%), otitis externa (adults: <2%), hypoacusis (adults: <2%)

Renal: Renal insufficiency (children and adolescents: 5%; adults: ≤1%), decreased serum creatinine (adults: <2%), hydronephrosis (adults: <2%), increased blood urea nitrogen (adults: <2%), nephritis (adults: <2%), renal pain (adults: <2%), renal tubular necrosis (adults: <2%)

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

Miscellaneous: Multiorgan failure (adults: <2%)

Frequency not defined:

Dermatologic: Cutaneous lupus erythematosus

Hepatic: Fulminant hepatitis

Ophthalmic: Vision color changes

<1%, postmarketing, and/or case reports: Acute renal failure, changes in nails (Malani 2014), periosteal disease (Cormican 2018; Hussain 2018), phototoxicity (Kim 2018), skeletal fluorosis (Cormican 2018; Hussain 2018)

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias/QT prolongation: QT interval prolongation has been associated with voriconazole use; rare cases of arrhythmia (including torsade de pointes), cardiac arrest, and sudden death have been reported, usually in seriously ill patients with comorbidities and/or risk factors (eg, prior cardiotoxic chemotherapy, cardiomyopathy [especially with concomitant heart failure], electrolyte imbalance, or concomitant QTc-prolonging drugs). Also use with caution in patients with potentially proarrhythmic conditions (eg, congenital or acquired QT syndrome, sinus bradycardia, or preexisting symptomatic arrhythmias); correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating and during therapy.
• Dermatologic reactions: Rare cases of malignancy (melanoma, squamous cell carcinoma [SCC]) have been reported in patients with prior onset of severe photosensitivity reactions or exposure to standard dose long-term voriconazole therapy (in lung transplant recipients, SCC increased by ~6% per 60 days with a 28% absolute risk increase at 5 years [Singer 2012]). Other serious exfoliative cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have also been reported. Patients, including children, should avoid exposure to direct sunlight and should use protective clothing and high SPF sunscreen; may cause photosensitivity, especially with long-term use. Discontinue use in patients who develop an exfoliative cutaneous reaction or a skin lesion consistent with squamous cell carcinoma or melanoma. Periodic total body skin examinations should be performed, particularly with prolonged use. If phototoxic reactions occur, referral to a dermatologist and voriconazole discontinuation should be considered. If therapy is continued, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Pediatric patients are at particular risk for phototoxicity (see Special Populations).
• Hepatic toxicity: Serious (and rarely fatal) hepatic reactions (eg, hepatitis, cholestasis, fulminant failure) have been observed with voriconazole. In lung transplant recipients, median time to hepatic toxicity was 14 days with the majority occurring within 30 days of therapy initiation (Luong 2012). Use with caution in patients with serious underlying medical conditions (eg, hematologic malignancy); hepatic reactions have occurred in patients with no identifiable underlying risk factors. Pediatric patients are at higher risk of liver enzyme elevations. Liver dysfunction is usually reversible upon therapy discontinuation. Monitor serum transaminase and bilirubin at baseline and at least weekly for the first month of treatment. Monitoring frequency can then be reduced to monthly during continued use if no abnormalities are noted. If marked elevations occur compared to baseline, discontinue unless benefit/risk of treatment justifies continued use.
• Infusion-related reactions: Anaphylactoid-type reactions including tachycardia, dyspnea, chest tightness, faintness, nausea, rash, pruritus, fever, sweating and flushing have been observed; symptoms have appeared immediately upon initiating the infusion. Stop infusion for severe reactions or as clinical presentation indicates.
• Ocular effects: Visual changes, including blurred vision, changes in visual acuity, color perception, and photophobia, are commonly associated with treatment; postmarketing cases of optic neuritis and papilledema (lasting >1 month) have also been reported. Patients should be warned to avoid tasks which depend on vision, including operating machinery or driving. Changes are reversible on discontinuation following brief exposure/treatment regimens (≤28 days); reversibility following long-term administration has not been evaluated. If treatment continues >28 days, visual function (eg, acuity, visual field, color perception) should be monitored.
• Renal toxicity: Acute renal failure has been observed; use with caution in patients receiving concomitant nephrotoxic medications. Evaluate renal function (particularly serum creatinine) at baseline and periodically during therapy.
• Skeletal effects: Fluorosis and/or periostitis may occur during long-term therapy. If patient develops skeletal pain and radiologic findings of fluorosis or periostitis, discontinue therapy.
• Toxicity symptoms: Voriconazole demonstrates nonlinear pharmacokinetics. Dose modifications may result in unpredictable changes in serum concentrations and contribute to toxicity. For toxicity, the strongest correlations have been made between voriconazole trough concentrations and neurological and dermatological adverse events (Dolton 2012; Hamada 2012; Mitsani 2012; Park 2012; Soler-Palacin 2012). In these studies, increased toxicity was noted when trough concentrations exceeded threshold values. There are much less data supporting the existence between a cutoff threshold and hepatotoxicity. 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; elevated liver function tests and clinical signs of liver damage, such as jaundice, have been associated with voriconazole. 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. Evaluate hepatic function (particularly liver function tests and bilirubin) at baseline and periodically during therapy.
• Lactose intolerance: Tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
• Pancreatitis: Monitor pancreatic function in patients (children and adults) at risk for acute pancreatitis (eg, recent chemotherapy or hematopoietic stem cell transplantation). Pancreatitis has been observed during therapy.
• Renal impairment: Avoid the use of IV voriconazole in patients with renal impairment. See "Dosage forms specific issues: Injection: formulation." Evaluate renal function (particularly serum creatinine) at baseline and periodically during therapy.

Concurrent drug therapy issues:

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

Special populations:

• Pediatric pharmacokinetics: In pediatric patients, voriconazole pharmacokinetics are complex. In patients >14 years of age or 12 to 14 years and weighing >50 kg, data suggest that pharmacokinetics are similar to adults (Friberg 2012). In patients <12 years of age, the full pharmacokinetic profile for voriconazole is not completely defined and for patients <2 years, the data are sparse. In children 2 to <12 years, current data suggest voriconazole undergoes a high degree of variability in exposure with linear elimination at lower doses and nonlinear elimination at higher doses; therefore, to achieve similar AUC as adults, increased dosage is necessary in children (Friberg 2012; Karlsson 2009; Walsh 2004).
• Pediatric dermatologic reactions: Frequency of phototoxic reactions is higher in pediatric patients. Stringent photoprotective measures are necessary in children due to the risk of squamous cell carcinoma. In children experiencing photoaging injuries (eg, lentigines or ephelides), avoidance of sun and dermatologic follow-up are warranted even after treatment is discontinued.
• Pediatric hepatic reactions: Frequency of hepatotoxic reactions is higher in pediatric patients. Close monitoring of liver function tests is recommended; if tests become markedly elevated from baseline, consider discontinuation.

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.
• Injection: Avoid/limit use of IV formulation in patients with moderate to severe renal impairment (CrCl <50 mL/minute); injection contains excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin [SBECD]), which may accumulate, although the clinical significance of this finding is uncertain (Luke 2010); consider using oral voriconazole in these patients unless benefit of injection outweighs the risk. If injection is used in patients CrCl <50 mL/minute, monitor serum creatinine closely; if increases occur, consider changing therapy to oral voriconazole.
• Oral:

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

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

Other warnings/precautions:

• Monitoring: Evaluate renal function (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin) at baseline and periodically during therapy.

Monitoring Parameters

Hepatic function at initiation, weekly during the first month and monthly during course of treatment; renal function; serum electrolytes (particularly calcium, magnesium and potassium) prior to initiation and during therapy; visual function (visual acuity, visual field and color perception) if treatment course continues >28 days; phototoxic reactions (especially in pediatric patients); pancreatic function (in patients at risk for acute pancreatitis); total body skin examination yearly (more frequently if lesions noted).

Monitoring of serum trough concentrations is recommended in the following infections: invasive aspergillosis treatment (and prolonged prophylaxis) and endophthalmitis (IDSA [Patterson 2016]; Riddle 2011). For other infections, consider obtaining voriconazole trough level to assure therapeutics serum concentrations in patients failing therapy or in those exhibiting signs of toxicity.

For invasive aspergillosis, the Infectious Diseases Society of America recommends monitoring trough serum concentrations after steady state has been reached (4 to 7 days after therapy initiation); the need for continued or repeat monitoring is a patient specific decision influenced by many factors (eg, infection severity, cost, assay availability) (IDSA [Patterson 2016]).

Pregnancy

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Voriconazole can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should use effective contraception during treatment.

Patient Education

What is this drug used for?

• It is used to treat fungal infections.

Frequently reported side effects of this drug

• Abdominal pain
• Diarrhea
• Constipation
• Mouth irritation
• Common cold symptoms
• Cough
• Vomiting
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Lupus like rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Fast heartbeat
• Abnormal heartbeat
• Bone pain
• Severe headache
• Severe dizziness
• Passing out
• Chills
• Sensing things that seem real but are not
• Edema
• Bruising
• Bleeding
• Sweating a lot
• Vision changes
• Light sensitivity
• Mole changes
• Skin growths
• Sunburn
• Skin photosensitivity
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.