voriconazole

General

Genetic Implications:

Pronunciation:
vor-i-kon-a-zole

Trade Name(s)

• Vfend

Ther. Class.

antifungals

Pharm. Class.

azoles

Indications

• Invasive aspergillosis.
• Candidemia (in patients without neutropenia) and serious Candida infections in skin, bladder, abdomen, kidney, and wounds.
• Esophageal candidiasis.
• Scedosporiosis and fusariosis in patients intolerant of or refractory to other therapies.

Action

Inhibits fungal ergosterol synthesis leading to production of abnormal fungal plasma membrane.

Therapeutic Effect(s):

Antifungal activity.

Spectrum:

Spectrum is notable for activity against:

• Aspergillus spp.,
• Candida spp.,
• Scedosporium apiospermum,
• Fusarium spp.

Pharmacokinetics

Absorption: 96% absorbed following oral administration; IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues.

Metabolism and Excretion: Primarily metabolized by liver via the CYP2C19, CYP2C9, and CYP3A4 isoenzymes; <2% excreted unchanged in urine.  The CYP2C19 isoenzyme exhibits genetic polymorphism; 15–20% of Asian patients and 3–5% of White and Black patients may be poor metabolizers and may have significantly ↑ voriconazole concentrations and an ↑ risk of adverse effects.

Half-life: Dose-dependent (adults: 6–9 hr); ↑ in hepatic impairment.

TIME/ACTION PROFILE (plasma concentrations)

Contraindication/Precautions

Contraindicated in:

• Concurrent use of dihydroergotamine, carbamazepine, efavirenz (≥400 mg/day), ergotamine, finerenone, ivabradine, lurasidone, naloxegol, phenobarbital, pimozide, rifabutin, rifampin, ritonavir (400 mg every 12 hr), quinidine, sirolimus, St. John's wort, tolvaptan, and venetoclax;
• Tablets contain lactose and should be avoided in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption;
• Severe hepatic impairment;
• OB:   Pregnancy.

Use Cautiously in:

• Mild to moderate hepatic impairment (↓ IV and PO maintenance doses);
• Renal impairment (CCr <50 mL/min) (vehicle in IV formulation can accumulate resulting in toxicity; avoid use of IV unless potential benefit greatly outweighs potential risk, use oral form only);
• Congenital/acquired QT interval prolongation, HF, sinus bradycardia, hypokalemia, hypomagnesemia, or symptomatic arrhythmias;
• Hematologic malignancy (↑ risk of hepatotoxicity);
• Rep:  Women of reproductive potential;
• Lactation:  Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
• Pedi:  Children <2 yr (safety and effectiveness not established); suspension contains benzyl alcohol, which may cause potentially fatal gasping syndrome in neonates; ↑ risk of photosensitivity reactions in children.

Adverse Reactions/Side Effects

CV: changes in BP, edema, QT interval prolongation, tachycardia

Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), MELANOMA, photosensitivity, rash, SQUAMOUS CELL CARCINOMA, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS

EENT: visual disturbances, eye hemorrhage

Endo: ADRENAL INSUFFICIENCY, hyperglycemia

F and E: hypokalemia, hypomagnesemia

GI: abdominal pain, diarrhea, HEPATOTOXICITY, nausea, pancreatitis, vomiting

MS: fluorosis, periostitis

Neuro: dizziness, hallucinations, headache

Misc: chills, fever, infusion reactions

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Carbamazepine,  phenobarbital, and  rifampin  may significantly ↓ levels and effectiveness; concurrent use contraindicated.
• May significantly ↑ levels of  ivabradine,  pimozide, and  quinidine, which can ↑ the risk of QT interval prolongation and torsades de pointes; concurrent use contraindicated.
• May significantly ↑ levels and risk of toxicity of  dihydroergotamine,  ergotamine,  lurasidone,  sirolimus, and  tolvaptan ; concurrent use contraindicated.
• May ↑ levels of  naloxegol, which could precipitate symptoms of opioid withdrawal; concurrent use contraindicated.
• Concurrent use with  efavirenz  at dose of ≥400 mg every 24 hr is contraindicated, as it may significantly ↑ efavirenz levels and significantly ↓ voriconazole levels; if used together, ↑ oral maintenance dose of voriconazole to 400 mg every 12 hr and ↓ dose of efavirenz to 300 mg daily.
• Concurrent use with  ritonavir  at dose of 400 mg every 12 hr is contraindicated, as ritonavir may significantly ↓ voriconazole levels; use with ritonavir at dose of 100 mg every 12 hr; should be avoided if possible.
• Concurrent use with  rifabutin  may significantly ↑ rifabutin levels and significantly ↓ voriconazole levels; concurrent use contraindicated; if used together, ↑ oral maintenance dose of voriconazole to 400 mg every 12 hr and ↓ dose of efavirenz to 300 mg daily.
• Concurrent use with  venetoclax  at initiation and during ramp-up phase in patients with chronic lymphocytic leukemia or small lymphocytic leukemia is contraindicated because may ↑ risk of tumor lysis syndrome.
• May significantly ↑ levels of  finerenone, which could ↑ risk of hyperkalemia; concurrent use contraindicated.
•  Fluconazole  may ↑ levels and risk of toxicity; avoid concurrent use.
• May ↑ levels and risk of toxicity of  cyclosporine ; ↓ cyclosporine dose by 50%.
• May ↑ levels and risk of toxicity of  tacrolimus ; ↓ tacrolimus dose to ⅓ of the starting dose.
• May ↑ levels and risk of toxicity of  glasdegib ; avoid concurrent use.
• May ↑ levels and risk of toxicity of tyrosine kinase inhibitors, including  axitinib,  bosutinib,  cabozantinib,  ceritinib,  cobimetinib,  dabrafenib,  dasatinib,  ibrutinib,  nilotinib,  ribociclib, and  sunitinib ; if concurrent use cannot be avoided, ↓ tyrosine kinase inhibitor dose.
• May ↑ levels and risk of toxicity of  eszopiclone ; ↓ eszopiclone dose.
• May ↑ levels and risk of toxicity of  tretinoin ; closely monitor patient for signs/symptoms of pseudotumor cerebri or hypercalcemia.
• May ↑ levels and risk of toxicity of  HMG-CoA reductase inhibitors, some  benzodiazepines  (alprazolam,  midazolam,  triazolam ),  fentanyl,  oxycodone,  NSAIDs  (ibuprofen,  diclofenac ), some  calcium channel blockers,  sulfonylureas  (glipizide,  glyburide ),  phenytoin,  warfarin, and  vinca alkaloids  (vincristine,  vinblastine ); dose ↓ may be needed and careful monitoring required during concurrent use.
• May ↑  methadone  levels and risk of QT interval prolongation.
• May ↑ levels of  corticosteroids  and risk of adrenal suppression.
• May ↑ levels and risk of toxicity of  ivacaftor ; ↓ ivacaftor dose.
• Concurrent use with  hormonal contraceptives  containing  ethinyl estradiol  and  norethindrone  may ↑ voriconazole, ethinyl estradiol, and norethindrone levels.
• May ↑ levels and risk of toxicity of  everolimus ; concurrent use not recommended.
• May ↑ levels and risk of toxicity of  omeprazole ; if patient receiving ≥40 mg/day of omeprazole, ↓ omeprazole dose by 50%. Similar effects may occur with other  proton pump inhibitors.
• May ↑ levels and risk of toxicity of  protease inhibitors  and  non-nucleoside reverse transcriptase inhibitors ; frequent monitoring recommended.
•  Non-nucleoside reverse transcriptase inhibitors  may induce or inhibit the metabolism of voriconazole; frequent monitoring recommended.
•  Letermovir  may ↓ levels and effectiveness; avoid concurrent use.
• Use with  methotrexate  may ↑ risk of photosensitivity reactions.

Drug-Natural Products:

 St. John's wort  may significantly ↓ levels and effectiveness; concurrent use contraindicated.

Route/Dosage

Invasive Aspergillosis, Scedosporiosis, or Fusariosis

IV PO (Adults  ≥40 kg): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 4 mg/kg IV every 12 hr (use 5 mg/kg IV every 12 hr if concurrently using with phenytoin). Continue IV therapy for ≥7 days; then switch to oral maintenance dose once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  200 mg PO every 12 hr (use 400 mg PO every 12 hr if concurrently using with phenytoin or efavirenz); if response inadequate, may ↑ to 300 mg every 12 hr. Total duration of therapy: ≥6–12 wk.

IV PO (Adults  <40 kg): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 4 mg/kg IV every 12 hr (use 5 mg/kg IV every 12 hr if concurrently using with phenytoin). Continue IV therapy for ≥7 days; then switch to oral maintenance dose once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  100 mg PO every 12 hr (use 200 mg PO every 12 hr if concurrently using with phenytoin; use 400 mg PO every 12 hr if concurrently using with efavirenz); if response inadequate, may ↑ to 150 mg every 12 hr. Total duration of therapy: ≥6–12 wk.

IV PO (Children  ≥15 yr): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 4 mg/kg IV every 12 hr. Continue IV therapy for ≥7 days; then switch to oral maintenance dose once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  200 mg every 12 hr; if response inadequate, may ↑ to 300 mg every 12 hr. Total duration of therapy: ≥6–12 wk.

IV PO (Children  12–14 yr and ≥50 kg): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 4 mg/kg IV every 12 hr. Continue IV therapy for ≥7 days; then switch to oral maintenance dose once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  200 mg every 12 hr; if response inadequate, may ↑ to 300 mg every 12 hr. Total duration of therapy: ≥6–12 wk.

IV PO (Children  12–14 yr and <50 kg): Loading dose (IV):  9 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 8 mg/kg IV every 12 hr; if response inadequate, may ↑ maintenance dose by 1 mg/kg. Continue IV therapy for ≥7 days; then switch to oral maintenance dose once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  9 mg/kg every 12 hr (not to exceed 350 mg every 12 hr); if response inadequate, may ↑ by 1 mg/kg or 50 mg (not to exceed 350 mg every 12 hr). Total duration of therapy: ≥6–12 wk.

IV PO (Children  2–11 yr): Loading dose (IV):  9 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 8 mg/kg IV every 12 hr; if response inadequate, may ↑ maintenance dose by 1 mg/kg. Continue IV therapy for ≥7 days; then switch to oral maintenance dose once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  9 mg/kg every 12 hr (not to exceed 350 mg every 12 hr); if response inadequate, may ↑ by 1 mg/kg or 50 mg (not to exceed 350 mg every 12 hr). Total duration of therapy: ≥6–12 wk.

Hepatic Impairment 
IV PO (Adults): Mild or moderate hepatic impairment:  Use standard IV loading dose; ↓ maintenance doses (IV or PO) by 50%;  Severe hepatic impairment:  Not recommended.

Candidemia in Non-Neutropenic Patients or Other Deep Tissue Candida Infections

IV PO (Adults  ≥40 kg): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 3–4 mg/kg IV every 12 hr (use 5 mg/kg IV every 12 hr if concurrently using with phenytoin). Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  200 mg PO every 12 hr (use 400 mg PO every 12 hr if concurrently using with phenytoin or efavirenz); if response inadequate, may ↑ to 300 mg every 12 hr. Total duration of therapy: ≥14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV PO (Adults  <40 kg): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 3–4 mg/kg IV every 12 hr (use 5 mg/kg IV every 12 hr if concurrently using with phenytoin). Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  100 mg PO every 12 hr (use 200 mg PO every 12 hr if concurrently using with phenytoin; use 400 mg PO every 12 hr if using concurrently with efavirenz); if response inadequate, may ↑ to 150 mg every 12 hr. Total duration of therapy: ≥14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV PO (Children  ≥15 yr): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 3–4 mg/kg IV every 12 hr. Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  200 mg every 12 hr; if response inadequate, may ↑ to 300 mg every 12 hr. Total duration of therapy: ≥14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV PO (Children  12–14 yr and ≥50 kg): Loading dose (IV):  6 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 3–4 mg/kg IV every 12 hr. Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  200 mg every 12 hr; if response inadequate, may ↑ to 300 mg every 12 hr. Total duration of therapy: ≥14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV PO (Children  12–14 yr and <50 kg): Loading dose (IV):  9 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 8 mg/kg IV every 12 hr; if response inadequate, may ↑ maintenance dose by 1 mg/kg. Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  9 mg/kg every 12 hr (not to exceed 350 mg every 12 hr); if response inadequate, may ↑ by 1 mg/kg or 50 mg (not to exceed 350 mg every 12 hr). Total duration of therapy: ≥14 days following resolution of symptoms or following last positive culture, whichever is longer.

IV PO (Children  2–11 yr): Loading dose (IV):  9 mg/kg IV every 12 hr for 2 doses, followed by  maintenance dose (IV)  of 8 mg/kg IV every 12 hr; if response inadequate, may ↑ maintenance dose by 1 mg/kg. Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  9 mg/kg every 12 hr (not to exceed 350 mg every 12 hr); if response inadequate, may ↑ by 1 mg/kg or 50 mg (not to exceed 350 mg every 12 hr). Total duration of therapy: ≥14 days following resolution of symptoms or following last positive culture, whichever is longer.

Hepatic Impairment 
IV PO (Adults): Mild or moderate hepatic impairment:  Use standard IV loading dose; ↓ maintenance doses (IV or PO) by 50%;  Severe hepatic impairment:  Not recommended.

Esophageal Candidiasis

PO (Adults  ≥40 kg): 200 mg every 12 hr (use 400 mg every 12 hr if concurrently using with phenytoin or efavirenz); if response inadequate, may ↑ to 300 mg every 12 hr. Duration of therapy: ≥14 days and for ≥7 days following resolution of symptoms.

PO (Adults  <40 kg): 100 mg every 12 hr (use 200 mg every 12 hr if concurrently using with phenytoin; use 400 mg every 12 hr if using concurrently with efavirenz); if response inadequate, may ↑ to 150 mg every 12 hr. Duration of therapy: ≥14 days and for ≥7 days following resolution of symptoms.

PO (Children  ≥15 yr): 200 mg every 12 hr; if response inadequate, may ↑ to 300 mg every 12 hr. Duration of therapy: ≥14 days and for ≥7 days following resolution of symptoms.

PO (Children  12–14 yr and ≥50 kg): 200 mg every 12 hr; if response inadequate, may ↑ to 300 mg every 12 hr. Duration of therapy: ≥14 days and for ≥7 days following resolution of symptoms.

IV PO (Children  12–14 yr and <50 kg): Initiate therapy with  maintenance dose (IV)  of 4 mg/kg IV every 12 hr; if response inadequate, may ↑ maintenance dose by 1 mg/kg. Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  9 mg/kg every 12 hr (not to exceed 350 mg every 12 hr); if response inadequate, may ↑ by 1 mg/kg or 50 mg (not to exceed 350 mg every 12 hr). Total duration of therapy: ≥14 days and for ≥7 days following resolution of symptoms.

IV PO (Children  2–11 yr): Initiate therapy with  maintenance dose (IV)  of 4 mg/kg IV every 12 hr; if response inadequate, may ↑ maintenance dose by 1 mg/kg. Switch to oral dosing once patient has clinically improved and can tolerate oral medications.  Maintenance dose (PO):  9 mg/kg every 12 hr (not to exceed 350 mg every 12 hr); if response inadequate, may ↑ by 1 mg/kg or 50 mg (not to exceed 350 mg every 12 hr). Total duration of therapy: ≥14 days and for ≥7 days following resolution of symptoms.

Hepatic Impairment 
IV PO (Adults): Mild or moderate hepatic impairment:  Use standard IV loading dose; ↓ maintenance doses (IV or PO) by 50%;  Severe hepatic impairment:  Not recommended.

Availability (generic available)

Tablets: 50 mg, 200 mg

Oral suspension (orange flavor): 40 mg/mL

Powder for injection: 200 mg/vial

Assessment

• Monitor for signs/symptoms of fungal infections before and during therapy.
• Monitor ECG and QT interval before and periodically during therapy.
• Monitor visual function, including visual acuity, visual field, and color perception, in patients receiving >28 days of therapy. Vision usually returns to normal within 14 days after discontinuation of therapy.
• Monitor for allergic reactions (flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, rash) during infusions. Symptoms occur immediately upon start of infusion. May require discontinuation of voriconazole.
• Monitor patients with risk factors for acute pancreatitis (recent chemotherapy, hematopoietic stem cell transplantation) for signs/symptoms of pancreatitis (abdominal pain, ↑ serum amylase and lipase).
• Assess for rash periodically during therapy. May cause SJS.  If severe skin reaction occurs or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, or eosinophilia, discontinue voriconazole.

Lab Test Considerations:

Obtain specimens for culture and histopathology before therapy to isolate and identify organism. Therapy may be started before results are received.

• Monitor liver function tests (AST, ALT, and bilirubin) before starting, weekly during 1st mo, and monthly during therapy. If abnormal liver function tests occur, monitor for development of severe hepatic injury.  If liver enzymes markedly ↑ or clinical signs and symptoms of liver disease develops,  discontinue voriconazole.
• Monitor renal function during therapy.

Implementation

• Do not confuse Vfend with Venofer, or Vimpat.
• Once patient can tolerate oral medication, PO voriconazole may be used.
• Correct electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia) before starting and during therapy.
• PO Administer >1 hr before or after a meal.
  • Shake suspension well (approximately 10 sec) before measuring suspension. Use oral dispenser provided to ensure accurate dose. Do not mix suspension with other medicine, flavored liquid, or syrup. Store suspension at room temperature up to 14 days; then discard.

Patient/Family Teaching

• Explain purpose and side effects of medication to patient. Advise patient to read  Patient Information  before starting therapy. Advise patient to take as directed, on an empty stomach.
• Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications.
• May cause blurred vision, photophobia, and dizziness. Caution patient to avoid driving and other activities requiring alertness until response to medication is known. Also advise patient to avoid driving at night.
• Advise patient to avoid direct sunlight, sunlamps, and tanning beds. Use sunscreen and protective clothing to prevent severe sunburn. Advise patient to have dermatologic evaluation on a regular basis to allow early detection and management of premalignant lesions; squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy.
• Advise patient to notify health care provider if rash or signs and symptoms of allergic reaction occur.
• Rep:   May cause fetal harm. Advise women of reproductive potential to use effective contraception and notify health care provider if pregnancy is planned or suspected or if breastfeeding. Monitor for adverse reactions if voriconazole is administered concurrently with oral contraceptives.

Evaluation/Desired Outcomes

Resolution of fungal infections.