voriconazole

Therapeutic Classification: antifungals

Pharmacologic Classification: azoles

REMS

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.

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

Therapeutic effects:

Antifungal activity.

Spectrum:

Spectrum is notable for activity against:
- Aspergillus spp.
- Candida spp.
- Scedosporium apiospermum
- Fusarium spp.

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

Distribution: Widely distributed to tissues.

Metabolism/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 Caucasian 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.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	rapid	1–2 hr	12 hr
IV	rapid	end of infusion	12 hr

Contraindicated in:

Concurrent use of dihydroergotamine, carbamazepine, efavirenz (≥400 mg/day), ergotamine, 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.

CV: changes in BP, peripheral 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

F and E: hyperglycemia, hypokalemia, hypomagnesemia

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

MS: fluorosis, periostitis

Neuro: dizziness, hallucinations, headache

Misc: chills, fever, infusion reactions

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 doses of ≥400 mg every 24 hr is contraindicated, since 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, since ritonavir may significantly ↓ voriconazole levels; use with ritonavir at dose of 100 mg every 12 hr; should also be avoided, if possible.
Concurrent use with rifabutin may significantly ↑ rifabutin 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 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.
Fluconazole may ↑ levels and the risk of toxicity; avoid concurrent use.
May ↑ levels and the risk of toxicity of cyclosporine; ↓ cyclosporine dose by 50%.
May ↑ levels and the risk of toxicity of tacrolimus; ↓ tacrolimus dose to ⅓ of the starting dose.
May ↑ levels and the risk of toxicity of glasdegib; avoid concurrent use.
May ↑ levels and the 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, ↓ dose of tyrosine kinase inhibitor.
May ↑ levels and the risk of toxicity of eszopiclone; ↓ dose of eszopiclone.
May ↑ levels and the risk of toxicity of tretinoin; closely monitor patient for signs/symptoms of pseudotumor cerebri or hypercalcemia.
May ↑ levels and the 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 the 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 the risk of toxicity of everolimus; concurrent use not recommended.
May ↑ levels and the 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 the 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.

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.

(Generic available)

Tablets: 50 mg; 200 mg
Oral suspensionorange flavor: 40 mg/mL
Powder for injection: 200 mg/vial

Monitor for signs and symptoms of fungal infections prior to and during therapy.
Obtain specimens for culture and histopathology prior to therapy to isolate and identify organism. Therapy may be started before results are received.
Monitor visual function including visual acuity, visual field, and color perception in patients receiving more than 28 days of therapy. Vision usually returns to normal within 14 days after discontinuation of therapy.
Monitor for allergic reactions during infusion of voriconazole (flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, rash). Symptoms occur immediately upon start of infusion. May require discontinuation.
Monitor patients with risk factors for acute pancreatitis (recent chemotherapy, hematopoietic stem cell transplantation) for the signs of pancreatitis (abdominal pain, ↑ serum amylase and lipase).
Assess for rash periodically during therapy. May cause SJS. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Lab Test Considerations:

Monitor liver function tests (AST, ALT, and bilirubin) prior to, weekly during first mo and monthly during therapy. If abnormal liver function tests occur, monitor for development of severe hepatic injury. Discontinue therapy if markedly ↑ or clinical signs and symptoms of liver disease develop.
- Monitor renal function (serum creatinine) during therapy.

Once patient can tolerate oral medication, PO voriconazole may be used.
Correct electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia) prior to initiation and during therapy.
PO: Administer at least 1 hr before or 1 hr 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.

IV Administration:

Do not administer voriconazole with blood products or concentrated electrolytes, even in separate lines. Non-concentrated electrolytes can be infused at same time, but separate lines must be used. TPN can be administered simultaneously but must be via separate line or via a different port in a multi-lumen catheter.
Intermittent Infusion: Reconstitution: Reconstitute each 200-mg vial with 19 mL of sterile water for injection to achieve concentration of 10 mg/mL. Calculate volume of 10 mg/mL solution required for patient dose. Diluent: Withdraw and discard equal volume of diluent from infusion bag or bottle to be used. Withdraw required volume of voriconazole solution from vial(s) and add to appropriate volume of 0.9% NaCl, LR, D5/LR, D5/0.45% NaCl, D5W, 0.45% NaCl, or D5/0.9% NaCl. Reconstituted solution stable for 24 hr if refrigerated. Discard partially used vials.Concentration: Final concentration of infusion should be 0.5–5 mg/mL.
Rate: Infuse over 1–3 hr at a rate not to exceed 3 mg/kg/hr.

Advise patient to take voriconazole as directed, on an empty stomach. Advise patient to read Patient Information before starting voriconazole and with each Rx refill in case of changes.
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 during voriconazole therapy.
Advise patient to avoid direct sunlight, sunlamps and tanning beds during voriconazole therapy. 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.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Advise patient to notify health care professional if rash or signs and symptoms of allergic reaction occur.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception and notify health care professional if pregnancy is planned or suspected, or if breastfeeding. Monitor for adverse reactions if voriconazole is administered concurrently with oral contraceptives. If pregnancy is detected, discontinue medication as soon as possible.

Resolution of fungal infections.

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US Brand Names ⬆