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Voriconazole

Pronunciation

Pronunciation

(vor i KOE na zole)

Index Terms

  • UK109496

Dosage Forms

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

Solution Reconstituted, Intravenous:

Generic: 200 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

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

Vfend IV: 200 mg (1 ea)

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

Brand Names: U.S.

  • Vfend
  • Vfend IV

Pharmacologic Category

  • Antifungal Agent, Oral
  • Antifungal Agent, Parenteral

Pharmacology

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.

Absorption

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

Distribution

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

Vd:

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

Adults: 4.6 L/kg

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: 0.73-8.03 hours) (Driscoll 2011)

Adults: 1 to 2 hours

Half-Life Elimination

Variable, dose-dependent. Note: Steady-state trough concentrations are achieved within 1 day when an IV loading dose is administered and 5 days if no loading dose is used.

Protein Binding

58%

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).

Special Populations: Children

Overall, 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).

Use: Labeled Indications

Treatment of fungal infections: 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 in children >12 years of age, adolescents and adults

Use: Unlabeled

Prophylaxis of fungal infections: Prophylaxis in intermediate or high risk neutropenic cancer patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), neutropenic allogeneic hematopoietic stem cell recipients, and patients with significant graft-versus-host disease

Empiric antifungal treatment: Empiric antifungal therapy (second-line) for persistent neutropenic fever; for fungal meningitis or osteoarticular infections; or for catheter-related bloodstream infections due to Malassezia furfur

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.

Dosing: Adult

Note: Actual body weight should be used for all weight-based dosing calculations.

Aspergillosis, invasive, including disseminated and extrapulmonary infection: Duration of therapy should be a minimum of 6-12 weeks or throughout period of immunosuppression (Walsh 2008); duration of therapy in HIV-positive patients should be until resolution of infection and CD4 count >200 cells/mm3 (HHS [OI adult 2015]):

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

IDSA recommendations (Walsh 2008): May consider oral therapy in place of IV with dosing of 4 mg/kg (rounded up to convenient tablet dosage form) every 12 hours; however, IV administration is preferred in serious infections since comparative efficacy with the oral formulation has not been established.

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 (Pappas 2009):

Initial: 400 mg every 12 hours for 2 doses

Maintenance: 200 mg every 12 hours

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

Esophageal candidiasis:

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

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.

Endophthalmitis, fungal (off-label use; Pappas 2009): IV: 6 mg/kg every 12 hours for 2 doses, then 3 to 4 mg/kg 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.

Meningitis (secondary to contaminated [eg, Exserohilum rostratum] steroid products) (off-label use) (CDC [parameningeal] 2012; Kauffman 2013): Note: Consult an infectious disease specialist and current CDC guidelines for specific treatment recommendations. Therapy duration is ≥3 months; trough serum concentrations must be maintained between 2 to 5 mcg/mL.

IV: 6 mg/kg every 12 hours. If patient does not improve or has severe disease, consider adding amphotericin B (liposomal).

Oral (only in mild disease in adherent patients whose trough concentrations/response to therapy can be closely monitored): 6 mg/kg every 12 hours (CDC [parameningeal] 2012).

Osteoarticular infection involving the spine, discitis, epidural abscess or vertebral osteomyelitis (secondary to contaminated [eg, Exserohilum rostratum] steroid products) (off-label use) (CDC [osteoarticular] 2012; Kauffman 2013): IV: 6 mg/kg every 12 hours for ≥3 months. Note: Consult an infectious disease specialist and current CDC guidelines for specific treatment recommendations. Trough serum concentrations must be maintained between 2 to 5 mcg/mL. If patient has severe disease, consider adding amphotericin B (liposomal). Patients may be switched to oral therapy if condition has improved or stabilized.

Osteoarticular infection not involving the spine (secondary to contaminated [eg, Exserohilum rostratum] steroid products) (off-label use) (CDC [osteoarticular] 2012; Kauffman 2013): Note: Consult an infectious disease specialist and current CDC guidelines for specific treatment recommendations. Therapy duration is ≥3 months. Trough serum concentrations must be maintained between 2 to 5 mcg/mL.

IV: 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours. If patient has severe disease, consider adding amphotericin B (liposomal)

Oral (only in mild disease in adherent patients whose trough concentrations/response to therapy can be closely monitored): 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours

Penicillium 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: Actual body weight should be used for all weight-based dosing calculations.

Aspergillosis, invasive including disseminated and extrapulmonary infection treatment (off-label use):

Children >2 to <12 years (< 40 kg): Duration of therapy should be a minimum of 6 to 12 weeks or throughout period of immunosuppression (Walsh 2008):

IV: Note: Data suggest higher doses (mg/kg) are required; consider using a loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose: 8 to 9 mg/kg/dose every 12 hours; maximum dose: 350 mg. Monitoring of concentrations may be warranted (Driscoll 2011; Red Book [AAP 2012]).

Non-HIV-exposed/-positive (Walsh 2008): 5 to 7 mg/kg/dose every 12 hours; see Note regarding higher dose recommendations

HIV-exposed/-positive (CDC 2009): See Note regarding higher dose recommendations.

Initial: 6 to 8 mg/kg/dose (maximum: 400 mg/dose) every 12 hours for 2 doses on day 1

Maintenance: 7 mg/kg/dose (maximum: 200 mg/dose) every 12 hours; change to oral administration when able; duration of therapy (IV and oral combined): ≥12 weeks but should be individualized

Oral suspension: May consider oral therapy once the patient is stable

Non-HIV-exposed/-positive (Red Book [AAP 2012]): 9 mg/kg/dose every 12 hours

HIV-exposed/-positive (CDC 2009): Note: Data suggest higher doses (mg/kg) are required (9 mg/kg every 12 hours) (Red Book [AAP 2012])

Initial: 8 mg/kg/dose (maximum: 400 mg/dose) every 12 hours for 2 doses on day 1

Maintenance: 7 mg/kg/dose (maximum: 200 mg/dose) every 12 hours

Children ≥12 years and Adolescents: Refer to adult dosing.

Candidiasis or other serious fungal infection, treatment (off-label use; Driscoll 2011; Red Book [AAP 2012]):

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: 8 to 9 mg/kg/dose every 12 hours; maximum dose: 350 mg

Children ≥12 years and Adolescents: Refer to adult dosing.

Catheter-related bloodstream infections due to Malassezia furfur (off-label use; Mermel 2009):

Children >2 to <12 years: IV: Note: Recent data suggest higher doses (mg/kg) than described in the guideline may be required (Driscoll 2011):

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

Maintenance: 4 mg/kg every 12 hours.

Children ≥12 years and Adolescents: Refer to adult dosing.

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

Esophageal candidiasis:

US labeling: Children ≥12 years and Adolescents: Refer to adult dosing.

Alternative dosing: HIV-infected patients (alternative to preferred therapy): Adolescents: Refer to adult dosing.

Infection prophylaxis in graft-versus-host disease (GVHD) (off-label use; Tombyln 2009; Wingard 2010):

Children >2 to <12 years: Note: The optimal duration of prophylaxis in GVHD has not been determined.

IV: 4 mg/kg every 12 hours (maximum dose not to exceed weight-based oral dose)

Oral:

Weight <20 kg: 50 mg every 12 hours

Weight ≥20 kg: 100 mg every 12 hours

Children ≥12 years and Adolescents: Refer to adult dosing.

Infection prophylaxis in standard- or high-risk patients with allogeneic hematopoietic stem cell transplant (HSCT) or certain autologous HSCT (off-label use): Adolescents (> 40 kg): Refer to adult dosing.

Penicillium marneffei infection in HIV-infected patients (off-label use; HHS [OI adult 2015]): Refer to adult dosing.

Dosing: Renal Impairment

IV:

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

CrCl <50 mL/minute: There are no specific dosage adjustments provided in the manufacturer’s labeling. Due to accumulation of the intravenous vehicle (cyclodextrin), the manufacturer recommends the use of oral voriconazole in these patients unless an assessment of the benefit:risk justifies the use of IV voriconazole; if IV therapy is used, closely monitor serum creatinine and change to oral voriconazole when possible. IV therapy has been used in select patients with CrCl <50 mL/minute using varying doses (median duration of treatment 7 to 10 days) (Neofytos 2012; Oude Lashof 2012).

Oral:

Mild to severe impairment: No dosage adjustment necessary.

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

Continuous renal replacement therapy (CRRT) (Heintz 2009): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH, CVVHD, and CVVHDF: Loading dose of 400 mg every 12 hours for 2 doses, followed by 200 mg every 12 hours.

Dosing: Hepatic Impairment

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

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

Reconstitution

Powder for injection: Reconstitute 200 mg vial with 19 mL of sterile water for injection (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.

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 2 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.

Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Compatibility

Stable in NS, LR, D5WLR, D5W1/2NS, D5W, D5W with KCl 20 mEq, 1/2NS, or D5WNS. Do not infuse concomitantly into same line or cannula with other drug infusions. Do not infuse concomitantly 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.

Y-site administration: Incompatible with tigecycline.

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

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). Monitor therapy

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

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: Voriconazole 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

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. Avoid combination

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: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

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

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

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

Bosentan: CYP2C9 Inhibitors (Moderate) 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 to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. 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). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor or temporarily stopping budesonide therapy during CYP3A4 inhibitor use. Monitor patients closely for signs/symptoms of corticosteroid excess. Consider therapy modification

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

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

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

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. 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

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Chloramphenicol: 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 may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Cisapride: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cisapride. Isavuconazonium considerations are addressed in separate monographs. Avoid combination

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

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

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

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

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

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. Consider therapy modification

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

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

Contraceptives (Estrogens): Voriconazole may decrease the metabolism of Contraceptives (Estrogens). Contraceptives (Estrogens) may increase the serum concentration of Voriconazole. Monitor therapy

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

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

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

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

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

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

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Buprenorphine; Gefitinib; Hydrocodone. 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: Voriconazole may enhance the QTc-prolonging effect of Dasatinib. Voriconazole may increase the serum concentration of Dasatinib. Management: This combination should be avoided; consider reducing dasatinib dose if voriconazole must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Monitor ECG closely. Consider therapy modification

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: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of DOCEtaxel. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

Dofetilide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Dofetilide. Avoid combination

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

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: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

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

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

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

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

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

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

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

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. 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. 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

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

Estazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. 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

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

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

Fluconazole: May increase the serum concentration of Voriconazole. Avoid combination

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

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

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

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

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

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

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

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 prescribing information for specific age- and weight-based recommendations. 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

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

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

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

Luliconazole: May increase the serum concentration of CYP2C19 Substrates. Monitor therapy

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

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

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

Methadone: Voriconazole may increase the serum concentration of Methadone. Management: Methadone dose reduction may be necessary when used with voriconazole. With any concurrent use, monitor patients 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

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 300 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. 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

Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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

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

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 such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

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

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

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

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

Pimozide: Antifungal Agents (Azole Derivatives, Systemic) may enhance the arrhythmogenic effect of Pimozide. Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Pimozide. This increase in serum concentrations may lead to QTc interval prolongation and ventricular arrhythmias. Applicable Isavuconazonium considerations are addressed in separate monographs. Avoid combination

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

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

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

Propafenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. 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. Management: In patients receiving omeprazole 40 mg/day or greater, reduce omeprazole dose by half when initiating voriconazole. Monitor therapy

QUEtiapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce the quetiapine dose to one sixth of the regular dose following strong CYP3A4 inhibitor initiation. In patients receiving strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and up-titrate as needed. Consider therapy modification

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

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

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

Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

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

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

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

Telaprevir: Voriconazole may increase the serum concentration of Telaprevir. Telaprevir may decrease the serum concentration of Voriconazole. Telaprevir may increase the serum concentration of Voriconazole. Management: Concurrent use of telaprevir and voriconazole should be avoided due to the uncertain impact on drug concentrations and effects unless the benefit/risk ratio justifies its use. Consider therapy modification

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

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

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

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: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. 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: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

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

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

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

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. 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

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day 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

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

Zolpidem: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Zolpidem. Applicable Isavuconazonium considerations are addressed in separate monographs. 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%:

Central nervous system: Hallucination (2% to 12%; auditory and/or visual and likely serum concentration-dependent)

Ophthalmic: Visual disturbance (19%)

Renal: Increased serum creatinine (1% to 21%)

2% to 10%:

Cardiovascular: Tachycardia (≤2%)

Central nervous system: Chills (≤4%), headache (≤3%)

Dermatologic: Skin rash (≤7%)

Endocrine & metabolic: Hypokalemia (≤2%)

Gastrointestinal: Nausea (1% to 5%), vomiting (1% to 4%)

Hepatic: Increased serum alkaline phosphatase (4% to 5%), increased serum AST (2% to 4%), increased serum ALT (2% to 3%), cholestatic jaundice (1% to 2%)

Ophthalmic: Photophobia (2%)

Miscellaneous: Fever (≤6%)

<2%, postmarketing, and/or case reports (limited to important or life-threatening): Acute renal failure, adrenocortical insufficiency, agranulocytosis, alopecia, anaphylactoid reaction, anemia (aplastic, hemolytic, macrocytic, megaloblastic, or microcytic), angioedema, anorexia, anuria, arthritis, ascites, ataxia, atrial arrhythmia, atrial fibrillation, atrioventricular block, bacterial infection, bigeminy, blighted ovum, bone marrow depression, bradycardia, brain disease, bundle branch block, cardiac arrest, cardiac failure, cardiomegaly, cardiomyopathy, cellulitis, cerebral edema, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, chest pain, cholecystitis, cholelithiasis, cholestasis, chromatopsia, color blindness, coma, confusion, convulsions, corneal opacity, cyanosis, deafness, deep vein thrombophlebitis, deep vein thrombosis, delirium, dementia, dental fluorosis, depersonalization, depression, diabetes insipidus, diarrhea, discoid lupus erythematosus, disseminated intravascular coagulation, drowsiness, duodenal ulcer (active), duodenitis, dyspnea, eczema, edema, encephalitis, endocarditis, eosinophilia, erythema multiforme, esophageal ulcer, exfoliative dermatitis, extrapyramidal reaction, extrasystoles, fixed drug eruption, fungal infection, gastric ulcer, gastrointestinal hemorrhage, glucose tolerance decreased, graft versus host disease, Guillain-Barre syndrome, hematemesis, hemorrhagic cystitis, hepatic coma, hepatic failure, hepatitis, hepatomegaly, herpes simplex infection, hydronephrosis, hyperbilirubinemia, hypercholesterolemia, hyper-/hypocalcemia, hyper-/hypoglycemia, hyper-/hypomagnesemia, hyper-/hyponatremia, hyper-/hypotension, hyper-/hypothyroidism, hyperkalemia, hypersensitivity reaction, hyperuricemia, hypophosphatemia, hypoxia, impotence, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased susceptibility to infection, intestinal perforation, intracranial hypertension, jaundice, leukopenia, lymphadenopathy, lymphangitis, maculopapular rash, malignant melanoma, melanosis, multi-organ failure, myasthenia, myocardial infarction, myopathy, nephritis, nephrosis, neuropathy, nocturnal amblyopia, nodal arrhythmia, nodule, nystagmus, oculogyric crisis, optic atrophy, optic neuritis, orthostatic hypotension, osteomalacia, osteonecrosis, osteoporosis, otitis externa, palpitations, pancreatitis, pancytopenia, papilledema, paresthesia, perforated duodenal ulcer, periosteal disease, peripheral edema, peritonitis, petechia, pleural effusion, pneumonia, prolonged bleeding time, prolonged QT interval on ECG, pruritus, pseudomembranous colitis, pseudoporphyria, psoriasis, psychosis, pulmonary edema, pulmonary embolism, purpura, rectal hemorrhage, renal insufficiency, renal tubular necrosis, respiratory distress syndrome, respiratory tract infection, retinal hemorrhage, retinitis, seizure, sepsis, skin discoloration, skin photosensitivity, splenomegaly, squamous cell carcinoma, Stevens-Johnson syndrome, subconjunctival hemorrhage, substernal pain, suicidal ideation, supraventricular extrasystole, supraventricular tachycardia, syncope, thrombocytopenia, thrombophlebitis, thrombotic thrombocytopenic purpura, tongue edema, tonic-clonic seizures, torsades de pointes, toxic epidermal necrolysis, uremia, urinary incontinence, urinary retention, urinary tract infection, urticaria, uterine hemorrhage, uveitis, vaginal hemorrhage, vasodilation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, visual field defect

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. 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 in severely ill patients; 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 CDC recommendations for Exserohilum rostratum in Reference Range section) (CDC 2012).

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.

• Pancreatitis: Monitor pancreatic function in patients (children and adults) at risk for acute pancreatitis (eg, recent chemotherapy or hematopoietic stem cell transplantation). Pancreatitis has occurred in pediatric patients.

• 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.

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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

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); monitor trough serum concentrations on day 5 of therapy and weekly thereafter for 4 to 6 weeks or when dosing adjustments are made; for infections other than meningitis or osteoarticular infections, may consider obtaining voriconazole trough level to assure therapeutics serum concentrations, in patients failing therapy or in those exhibiting signs of toxicity; pancreatic function (in patients at risk for acute pancreatitis); total body skin examination yearly (more frequently if lesions noted)

Trough recommendations in adult patients:

Meningitis or osteoarticular infections for Exserohilum rostratum (CDC 2012): 2 to 5 mcg/mL

Other infections (Dolton 2012; Hamada 2012; Mitsani 2012; Park 2012):

Efficacy: >1.0 mcg/mL

Toxicity: <4.0 mcg/mL

Therapeutic range in adult patients (CDC 2012; Dolton 2012; Hamada 2012; Mitsani 2012; Park 2012; Tomblyn 2009): 1 to 5 mcg/mL

Refer to Additional Information/Pharmacotherapy Pearls for detailed discussion of these data and data in pediatric patients.

Pregnancy Risk Factor

D

Pregnancy Considerations

Voriconazole can cause fetal harm when administered to a pregnant woman. Voriconazole was teratogenic and embryotoxic in animal studies, and lowered plasma estradiol in animal models. Women of childbearing potential should use effective contraception during treatment. Should be used in pregnant woman only if benefit to mother justifies potential risk to the fetus.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or nausea. Have patient report immediately to prescriber signs of hepatic impairment, signs of pancreatitis, signs of renal impairment, angina, tachycardia, syncope, sensitivity to light, blurred vision, chills, osteodynia, severe dizziness, arrhythmia, hallucinations, hyperhidrosis, vision changes, mole changes, skin growths, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis, injection site pain or irritation, or signs of infusion-related reactions (rare) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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