These Highlights Do Not Include All The Information Needed To Use Voriconazole Safely And Effectively. See Full Prescribing Information For Voriconazole.

Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum

See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous voriconazole on Day 1 followed by the recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously [see Clinical Pharmacology (12.3)].

LAB-0435-20.0

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Voriconazole tablets should be stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Voriconazole powder for Oral Suspension should be stored at 2° C to 8°C (36° F to 46° F) (in a refrigerator) before reconstitution. The shelf-life of the powder for oral suspension is 24 months.

The reconstituted suspension should be stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Keep the container tightly closed. The shelf-life of the reconstituted suspension is 14 days. Any remaining suspension should be discarded 14 days after reconstitution.

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.

Voriconazole, an azole antifungal agent is available as film-coated tablets for oral administration and as a powder for oral suspension. The structural formula is:

Voriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C₁₆H₁₄F₃N₅O and a molecular weight of 349.3.

Voriconazole drug substance is a white to light-colored powder.

Voriconazole Tablets contain 50 mg or 200 mg of voriconazole. The inactive ingredients include croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, and a coating containing hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

Voriconazole for Oral Suspension is a white to off-white powder providing a white to off-white orange-flavored suspension when reconstituted. Bottles containing 45 grams powder for oral suspension, which contain 3 g of voriconazole, are intended for reconstitution with water to produce a suspension containing 40 mg/mL voriconazole. The inactive ingredients include anhydrous citric acid, colloidal silicon dioxide, natural orange flavor, sodium benzoate, sodium citrate dihydrate, sucrose, titanium dioxide, and xanthan gum.

Pancreatitis has been observed in patients undergoing treatment with voriconazole [see Adverse Reactions (6.1, 6.2)] Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole treatment.

The safety and effectiveness of voriconazole have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data.

A total of 105 pediatric patients aged 2 to less than 12 [N=26] and aged 12 to less than 18 [N=79] from two, non-comparative Phase 3 pediatric studies and eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, voriconazole is not recommended for pediatric patients less than 2 years of age.

A higher frequency of liver enzyme elevations was observed in the pediatric patients [see Dosage and Administration (2.4), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation [see Warnings and Precautions (5.6)].

Voriconazole has not been studied in pediatric patients with hepatic or renal impairment [see Dosage and Administration (2.4, 2.5)]. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.5) and Warnings and Precautions (5.1, 5.10)].

In multiple dose therapeutic trials of voriconazole, 9.2% of patients were ≥65 years of age and 1.8% of patients were ≥75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (C_max) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3)].

Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.5)].

Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

• •
  Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or its excipients [see Warnings and Precautions (5.5) and Adverse Reactions (6.1, 6.2)]. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Refer to the prescribing information for other azole antifungal agents.
• •
  Concomittant use of voriconazole with the interacting drugs described and listed below in this section are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with voriconazole.
  • 1.
    Concomitant use of voriconazole is contraindicated with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life‑threatening reactions [see Drug Interactions (7)]:
    • •
      Eplerenone
    • •
      Ergot alkaloids (e.g., ergotamine, dihydroergotamine)
    • •
      Finerenone
    • •
      Ivabradine
    • •
      Lurasidone
    • •
      Naloxegol
    • •
      Pimozide
    • •
      Quinidine
    • •
      Rifabutin [see Clinical Pharmacology (12.3)]
    • •
      Sirolimus [see Clinical Pharmacology (12.3)]
    • •
      Tolvaptan
    • •
      Venetoclax: Coadministration at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7)].
    • •
      Voclosporin
  • 2.
    Concomitant use of voriconazole is contraindicated with drugs and herbal products that induce CYP2C19, CYP2C9, and/or CYP3A4 and for which significantly reduced voriconazole plasma concentrations may be associated with loss of efficacy [see Drug Interactions (7)]:
    • •
      Carbamazepine
    • •
      Efavirenz
      
      Concomitant use with efavirenz dosages of 400 mg every 24 hours or higher is contraindicated [see Clinical Pharmacology (12.3)].
    • •
      Long-acting barbiturates
    • •
      Rifabutin
    • •
      Rifampin
    • •
      Ritonavir
      
      Concomitant use with high-dose ritonavir (400 mg every 12 hours) is contraindicated. Concomitant use with low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Clinical Pharmacology (12.3)]
    • •
      St. John’s Wort [see Clinical Pharmacology (12.3)]

The following serious adverse reactions are described elsewhere in the labeling:

Hepatic Toxicity [see Warnings and Precautions (5.1)]

Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

Infusion Related Reactions [see Warnings and Precautions (5.3)]

Visual Disturbances [see Warnings and Precautions (5.4)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.

Table 9 and Table 10 provide listings of clinically significant drug interactions, including contraindicated drugs [see Contraindications (4)]. Drugs listed in Table 9 and Table 10 are a guide and not considered a comprehensive list of all possible drugs and herbal products that are contraindicated or may interact with voriconazole.

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Adverse Reactions (6.1)].

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1)]. Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

Voriconazole has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen’s disease) and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued. In addition, voriconazole has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during voriconazole therapy.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Read this Instructions for Use before you start taking voriconazole and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

Important information:

• •
  Follow your healthcare provider's instructions for the dose of voriconazole to take.
• •
  Ask your healthcare provider or pharmacist if you are not sure how to take voriconazole.
• •
  Voriconazole for oral suspension is a liquid form of voriconazole. Your pharmacist will mix (reconstitute) the medicine before it is dispensed to you. If voriconazole is still in powder form, do not use it. Return it to your pharmacist.
• •
  Always use the oral dispenser provided with voriconazole to make sure you measure the right amount of voriconazole.
• •
  Shake the closed bottle of mixed (reconstituted) oral suspension well for about 10 seconds before each use.

Each pack contains:

How to prepare the bottle and take voriconazole:

Rinse the oral dispenser after each use.

• •
  Pull the plunger out of the oral dispenser and wash both parts with warm soapy water.
• •
  Rinse both parts with water and allow to air dry after each use.
• •
  After air drying, push the plunger back into the oral dispenser.
• •
  Store the oral dispenser with voriconazole oral suspension in a clean safe place.

How should I store voriconazole oral suspension?

• •
  Store voriconazole oral suspension at room temperature between 59°F to 86°F (15°C to 30°C).
• •
  Do not refrigerate or freeze.
• •
  Keep the bottle cap tightly closed.
• •
  Use voriconazole oral suspension within 14 days after it has been mixed (reconstituted) by the pharmacist. The pharmacist will write the expiration date on the bottle label (the expiration date of the oral suspension is 14 days from the date it was mixed (reconstituted) by the pharmacist). Throw away (discard) any unused voriconazole after the expiration date.
• •
  Keep voriconazole and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

LAB-1397-7.0

Revised: 8/2024

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUC_τ); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 11).

When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

CYP2C19, significantly involved in the metabolism of voriconazole, exhibits genetic polymorphism. Approximately 15–20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3–5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUC_τ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts [see Clinical Pharmacology (12.3)].

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

A total of 22 patients aged 12 to 18 years with IA were included in the adult therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg every 12 hours.

Fifty-three pediatric patients aged 2 to less than 18 years old were treated with voriconazole in two prospective, open-label, non-comparative, multicenter clinical studies.

One study was designed to enroll pediatric patients with IA or infections with rare molds (such as Scedosporium or Fusarium). Patients aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous voriconazole loading dose of 9 mg/kg every 12 hours for the first 24-hours followed by an 8 mg/kg intravenous maintenance dose every 12 hours. After completing 7 days of intravenous therapy patients had an option to switch to oral voriconazole. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg). All other pediatric patients aged 12 to less than 18 years received the adult voriconazole dosage regimen. Patients received voriconazole for at least 6 weeks and up to a maximum of 12 weeks.

The study enrolled 31 patients with possible, proven, or probable IA. Fourteen of 31 patients, 5 of whom were 2 to less than 12 years old and 9 of whom were 12 to less than 18 years old, had proven or probable IA and were included in the modified intent-to-treat (MITT) efficacy analyses. No patients with rare mold were enrolled. A successful global response was defined as resolution or improvement in clinical signs and symptoms and at least 50% resolution of radiological lesions attributed to IA. The overall rate of successful global response at 6 weeks in the MITT population is presented in Table 17 below.

The second study enrolled 22 patients with invasive candidiasis including candidemia (ICC) and EC requiring either primary or salvage therapy. Patients with ICC aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous voriconazole loading dose of 9 mg/kg every 12 hours for the first 24 hours followed by an 8 mg/kg intravenous maintenance dose every 12-hours. After completing 5 days of intravenous therapy patients had an option to switch to oral voriconazole. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg). All other pediatric patients aged 12 to less than 18 years received the adult voriconazole dosage regimen. Voriconazole was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted.

Patients with primary or salvage EC aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous voriconazole dose of 4 mg/kg every 12 hours followed by an oral VORICONAZOLE dose of 9 mg/kg every 12 hours (maximum dose of 350 mg) when criteria for oral switch were met. All other pediatric patients aged 12 to less than 18 years received the adult voriconazole dosage regimen. Voriconazole was administered for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.

For EC, study treatment was initiated without a loading dose of intravenous voriconazole. Seventeen of these patients had confirmed Candida infection and were included in the MITT efficacy analyses. Of the 17 patients included in the MITT analyses, 9 were 2 to less than 12 years old (7 with ICC and 2 with EC) and 8 were 12 to less than 18 years old (all with EC). For ICC and EC, a successful global response was defined as clinical cure or improvement with microbiological eradication or presumed eradication. The overall rate of successful global response at EOT in the MITT population is presented in Table 18 below.

Voriconazole is an azole antifungal indicated for the treatment of adults and pediatric patients 2 years of age and older with:

• •
  Invasive aspergillosis (1.1)
• •
  Candidemia in non-neutropenics and other deep tissue Candida infections (1.2)
• •
  Esophageal candidiasis (1.3)
• •
  Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy (1.4)

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been postmarketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [see Adverse Reactions (6.2)].

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients receiving voriconazole and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after voriconazole treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.

Voriconazole is an antifungal drug [see Microbiology (12.4)].

Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia, and embryomortality [see Use in Specific Populations (8.1)].

If voriconazole is used during pregnancy, or if the patient becomes pregnant while taking voriconazole, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole [see Use in Specific Populations (8.3)].

Voriconazole is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1, 14.5) and Microbiology (12.4)].

Voriconazole is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)].

• •
  Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during voriconazole therapy (5.1)
• •
  Arrhythmias and QT Prolongation: Correct potassium, magnesium, and calcium prior to use; caution patients with proarrhythmic conditions (5.2)
• •
  Infusion Related Reactions (including anaphylaxis): Stop the infusion (5.3)
• •
  Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days (5.4)
• •
  Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions (5.5)
• •
  Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
• •
  Adrenal Dysfunction: Carefully monitor patients receiving voriconazole and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after voriconazole treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency (5.8)
• •
  Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole (5.9, 8.1, 8.3)
• •
  Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur (5.12)
• •
  Clinically Significant Drug Interactions: Review patient's concomitant medications (5.13, 7)
• •
  Patients with Hereditary Galactose Intolerance, Lapp Lactase Deficiency or Glucose-Galactose Malabsorption: voriconazole tablets should not be given to these patients because it contains lactose (5.14)

Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

• •
  Tablets: 50 mg, 200 mg (3)
• •
  For Oral Suspension: 40 mg/mL (200 mg/5 mL) when reconstituted (3)

• •
  Pediatrics: Safety and effectiveness in patients younger than 2 years has not been established (8.4)

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.2)].

Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of EC was demonstrated in Study 150–305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven EC. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent-to-Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against EC, as presented in Table 15.

Microbiologic success rates by Candida species are presented in Table 16.

Voriconazole is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Visual Disturbances

Patients should be instructed that visual disturbances such as blurring and sensitivity to light may occur with the use of voriconazole.

Photosensitivity

• •
  Advise patients of the risk of photosensitivity (with or without concomitant methotrexate), accelerated photoaging, and skin cancer.
• •
  Advise patients that voriconazole can cause serious photosensitivity and to immediately contact their healthcare provider for new or worsening skin rash.
• •
  Advise patients to avoid exposure to direct sun light and to use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Embryo-Fetal Toxicity

• •
  Advise female patients of the potential risks to a fetus.
• •
  Advise females of reproductive potential to use effective contraception during treatment with voriconazole.

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and postmarketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• •
  Congenital or acquired QT prolongation
• •
  Cardiomyopathy, in particular when heart failure is present
• •
  Sinus bradycardia
• •
  Existing symptomatic arrhythmias
• •
  Concomitant medicinal product that is known to prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)]

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3)].

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with voriconazole. If a patient develops a severe cutaneous adverse reaction, voriconazole should be discontinued [see Adverse Reactions (6.1, 6.2)].

NDC 59762-0935-3

75 mL (when reconstituted)

GREENSTONE^® BRAND

voriconazole

for oral suspension

ORANGE FLAVORED

40 mg/mL*

Rx only

8716724

LOT:

EXP:

See Table 9 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 10 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].

NDC 59762-0935-3

75 mL (when reconstituted)

GREENSTONE^® BRAND

voriconazole

for oral suspension

ORANGE FLAVORED

40 mg/mL*

Oral Dispenser Included

Important: Read assembly instructions

carefully before dispensing.

Contains Small Parts -

Keep out of reach of children.

Rx only

NDC 59762-0934-1

30 Tablets

GREENSTONE^® BRAND

voriconazole

tablets

50 mg

Rx only

The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg is shown in Table 2. For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of voriconazole [see Dosage and Administration (2.2)].

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement. Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The oral dose recommendation for children is based on studies in which voriconazole was administered as the powder for oral suspension formulation. Bioequivalence between the voriconazole powder for oral suspension and voriconazole tablets has not been investigated in a pediatric population.

Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.

NDC 59762-0936-1

30 Tablets

GREENSTONE^® BRAND

voriconazole

tablets

200 mg

Rx only

Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6 times the RMD on a body surface area basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4, or 1.4 times the RMD on a body surface area basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (Unscheduled DNA Synthesis assay).

Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD.

The following adverse reactions have been identified during post-approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatological Reactions

Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

Administer Voriconazole Tablets or Oral Suspension at least one hour before or after a meal.

The maintenance dose of voriconazole should be increased when coadministered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.2)].

Voriconazole is indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2, 14.5) and Microbiology (12.4)].

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open-label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150–608 are presented in Table 14.

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intra-abdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum

See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous voriconazole on Day 1 followed by the recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously [see Clinical Pharmacology (12.3)].

LAB-0435-20.0

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Voriconazole tablets should be stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Voriconazole powder for Oral Suspension should be stored at 2° C to 8°C (36° F to 46° F) (in a refrigerator) before reconstitution. The shelf-life of the powder for oral suspension is 24 months.

The reconstituted suspension should be stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Keep the container tightly closed. The shelf-life of the reconstituted suspension is 14 days. Any remaining suspension should be discarded 14 days after reconstitution.

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.

Voriconazole, an azole antifungal agent is available as film-coated tablets for oral administration and as a powder for oral suspension. The structural formula is:

Voriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C₁₆H₁₄F₃N₅O and a molecular weight of 349.3.

Voriconazole drug substance is a white to light-colored powder.

Voriconazole Tablets contain 50 mg or 200 mg of voriconazole. The inactive ingredients include croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, and a coating containing hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

Voriconazole for Oral Suspension is a white to off-white powder providing a white to off-white orange-flavored suspension when reconstituted. Bottles containing 45 grams powder for oral suspension, which contain 3 g of voriconazole, are intended for reconstitution with water to produce a suspension containing 40 mg/mL voriconazole. The inactive ingredients include anhydrous citric acid, colloidal silicon dioxide, natural orange flavor, sodium benzoate, sodium citrate dihydrate, sucrose, titanium dioxide, and xanthan gum.

Pancreatitis has been observed in patients undergoing treatment with voriconazole [see Adverse Reactions (6.1, 6.2)] Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole treatment.

The safety and effectiveness of voriconazole have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data.

A total of 105 pediatric patients aged 2 to less than 12 [N=26] and aged 12 to less than 18 [N=79] from two, non-comparative Phase 3 pediatric studies and eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, voriconazole is not recommended for pediatric patients less than 2 years of age.

A higher frequency of liver enzyme elevations was observed in the pediatric patients [see Dosage and Administration (2.4), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation [see Warnings and Precautions (5.6)].

Voriconazole has not been studied in pediatric patients with hepatic or renal impairment [see Dosage and Administration (2.4, 2.5)]. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.5) and Warnings and Precautions (5.1, 5.10)].

In multiple dose therapeutic trials of voriconazole, 9.2% of patients were ≥65 years of age and 1.8% of patients were ≥75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (C_max) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3)].

Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.5)].

Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

• •
  Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or its excipients [see Warnings and Precautions (5.5) and Adverse Reactions (6.1, 6.2)]. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Refer to the prescribing information for other azole antifungal agents.
• •
  Concomittant use of voriconazole with the interacting drugs described and listed below in this section are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with voriconazole.
  • 1.
    Concomitant use of voriconazole is contraindicated with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life‑threatening reactions [see Drug Interactions (7)]:
    • •
      Eplerenone
    • •
      Ergot alkaloids (e.g., ergotamine, dihydroergotamine)
    • •
      Finerenone
    • •
      Ivabradine
    • •
      Lurasidone
    • •
      Naloxegol
    • •
      Pimozide
    • •
      Quinidine
    • •
      Rifabutin [see Clinical Pharmacology (12.3)]
    • •
      Sirolimus [see Clinical Pharmacology (12.3)]
    • •
      Tolvaptan
    • •
      Venetoclax: Coadministration at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7)].
    • •
      Voclosporin
  • 2.
    Concomitant use of voriconazole is contraindicated with drugs and herbal products that induce CYP2C19, CYP2C9, and/or CYP3A4 and for which significantly reduced voriconazole plasma concentrations may be associated with loss of efficacy [see Drug Interactions (7)]:
    • •
      Carbamazepine
    • •
      Efavirenz
      
      Concomitant use with efavirenz dosages of 400 mg every 24 hours or higher is contraindicated [see Clinical Pharmacology (12.3)].
    • •
      Long-acting barbiturates
    • •
      Rifabutin
    • •
      Rifampin
    • •
      Ritonavir
      
      Concomitant use with high-dose ritonavir (400 mg every 12 hours) is contraindicated. Concomitant use with low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Clinical Pharmacology (12.3)]
    • •
      St. John’s Wort [see Clinical Pharmacology (12.3)]

The following serious adverse reactions are described elsewhere in the labeling:

Hepatic Toxicity [see Warnings and Precautions (5.1)]

Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

Infusion Related Reactions [see Warnings and Precautions (5.3)]

Visual Disturbances [see Warnings and Precautions (5.4)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.

Table 9 and Table 10 provide listings of clinically significant drug interactions, including contraindicated drugs [see Contraindications (4)]. Drugs listed in Table 9 and Table 10 are a guide and not considered a comprehensive list of all possible drugs and herbal products that are contraindicated or may interact with voriconazole.

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Adverse Reactions (6.1)].

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1)]. Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

Voriconazole has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen’s disease) and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued. In addition, voriconazole has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during voriconazole therapy.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Read this Instructions for Use before you start taking voriconazole and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

Important information:

• •
  Follow your healthcare provider's instructions for the dose of voriconazole to take.
• •
  Ask your healthcare provider or pharmacist if you are not sure how to take voriconazole.
• •
  Voriconazole for oral suspension is a liquid form of voriconazole. Your pharmacist will mix (reconstitute) the medicine before it is dispensed to you. If voriconazole is still in powder form, do not use it. Return it to your pharmacist.
• •
  Always use the oral dispenser provided with voriconazole to make sure you measure the right amount of voriconazole.
• •
  Shake the closed bottle of mixed (reconstituted) oral suspension well for about 10 seconds before each use.

Each pack contains:

How to prepare the bottle and take voriconazole:

Rinse the oral dispenser after each use.

• •
  Pull the plunger out of the oral dispenser and wash both parts with warm soapy water.
• •
  Rinse both parts with water and allow to air dry after each use.
• •
  After air drying, push the plunger back into the oral dispenser.
• •
  Store the oral dispenser with voriconazole oral suspension in a clean safe place.

How should I store voriconazole oral suspension?

• •
  Store voriconazole oral suspension at room temperature between 59°F to 86°F (15°C to 30°C).
• •
  Do not refrigerate or freeze.
• •
  Keep the bottle cap tightly closed.
• •
  Use voriconazole oral suspension within 14 days after it has been mixed (reconstituted) by the pharmacist. The pharmacist will write the expiration date on the bottle label (the expiration date of the oral suspension is 14 days from the date it was mixed (reconstituted) by the pharmacist). Throw away (discard) any unused voriconazole after the expiration date.
• •
  Keep voriconazole and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

LAB-1397-7.0

Revised: 8/2024

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUC_τ); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 11).

When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

CYP2C19, significantly involved in the metabolism of voriconazole, exhibits genetic polymorphism. Approximately 15–20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3–5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUC_τ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts [see Clinical Pharmacology (12.3)].

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

A total of 22 patients aged 12 to 18 years with IA were included in the adult therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg every 12 hours.

Fifty-three pediatric patients aged 2 to less than 18 years old were treated with voriconazole in two prospective, open-label, non-comparative, multicenter clinical studies.

One study was designed to enroll pediatric patients with IA or infections with rare molds (such as Scedosporium or Fusarium). Patients aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous voriconazole loading dose of 9 mg/kg every 12 hours for the first 24-hours followed by an 8 mg/kg intravenous maintenance dose every 12 hours. After completing 7 days of intravenous therapy patients had an option to switch to oral voriconazole. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg). All other pediatric patients aged 12 to less than 18 years received the adult voriconazole dosage regimen. Patients received voriconazole for at least 6 weeks and up to a maximum of 12 weeks.

The study enrolled 31 patients with possible, proven, or probable IA. Fourteen of 31 patients, 5 of whom were 2 to less than 12 years old and 9 of whom were 12 to less than 18 years old, had proven or probable IA and were included in the modified intent-to-treat (MITT) efficacy analyses. No patients with rare mold were enrolled. A successful global response was defined as resolution or improvement in clinical signs and symptoms and at least 50% resolution of radiological lesions attributed to IA. The overall rate of successful global response at 6 weeks in the MITT population is presented in Table 17 below.

The second study enrolled 22 patients with invasive candidiasis including candidemia (ICC) and EC requiring either primary or salvage therapy. Patients with ICC aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous voriconazole loading dose of 9 mg/kg every 12 hours for the first 24 hours followed by an 8 mg/kg intravenous maintenance dose every 12-hours. After completing 5 days of intravenous therapy patients had an option to switch to oral voriconazole. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg). All other pediatric patients aged 12 to less than 18 years received the adult voriconazole dosage regimen. Voriconazole was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted.

Patients with primary or salvage EC aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous voriconazole dose of 4 mg/kg every 12 hours followed by an oral VORICONAZOLE dose of 9 mg/kg every 12 hours (maximum dose of 350 mg) when criteria for oral switch were met. All other pediatric patients aged 12 to less than 18 years received the adult voriconazole dosage regimen. Voriconazole was administered for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.

For EC, study treatment was initiated without a loading dose of intravenous voriconazole. Seventeen of these patients had confirmed Candida infection and were included in the MITT efficacy analyses. Of the 17 patients included in the MITT analyses, 9 were 2 to less than 12 years old (7 with ICC and 2 with EC) and 8 were 12 to less than 18 years old (all with EC). For ICC and EC, a successful global response was defined as clinical cure or improvement with microbiological eradication or presumed eradication. The overall rate of successful global response at EOT in the MITT population is presented in Table 18 below.

Voriconazole is an azole antifungal indicated for the treatment of adults and pediatric patients 2 years of age and older with:

• •
  Invasive aspergillosis (1.1)
• •
  Candidemia in non-neutropenics and other deep tissue Candida infections (1.2)
• •
  Esophageal candidiasis (1.3)
• •
  Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy (1.4)

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been postmarketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [see Adverse Reactions (6.2)].

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients receiving voriconazole and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after voriconazole treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.

Voriconazole is an antifungal drug [see Microbiology (12.4)].

Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia, and embryomortality [see Use in Specific Populations (8.1)].

If voriconazole is used during pregnancy, or if the patient becomes pregnant while taking voriconazole, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole [see Use in Specific Populations (8.3)].

Voriconazole is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1, 14.5) and Microbiology (12.4)].

Voriconazole is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)].

• •
  Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during voriconazole therapy (5.1)
• •
  Arrhythmias and QT Prolongation: Correct potassium, magnesium, and calcium prior to use; caution patients with proarrhythmic conditions (5.2)
• •
  Infusion Related Reactions (including anaphylaxis): Stop the infusion (5.3)
• •
  Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days (5.4)
• •
  Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions (5.5)
• •
  Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
• •
  Adrenal Dysfunction: Carefully monitor patients receiving voriconazole and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after voriconazole treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency (5.8)
• •
  Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole (5.9, 8.1, 8.3)
• •
  Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur (5.12)
• •
  Clinically Significant Drug Interactions: Review patient's concomitant medications (5.13, 7)
• •
  Patients with Hereditary Galactose Intolerance, Lapp Lactase Deficiency or Glucose-Galactose Malabsorption: voriconazole tablets should not be given to these patients because it contains lactose (5.14)

Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

• •
  Tablets: 50 mg, 200 mg (3)
• •
  For Oral Suspension: 40 mg/mL (200 mg/5 mL) when reconstituted (3)

• •
  Pediatrics: Safety and effectiveness in patients younger than 2 years has not been established (8.4)

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.2)].

Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of EC was demonstrated in Study 150–305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven EC. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent-to-Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against EC, as presented in Table 15.

Microbiologic success rates by Candida species are presented in Table 16.

Voriconazole is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Visual Disturbances

Patients should be instructed that visual disturbances such as blurring and sensitivity to light may occur with the use of voriconazole.

Photosensitivity

• •
  Advise patients of the risk of photosensitivity (with or without concomitant methotrexate), accelerated photoaging, and skin cancer.
• •
  Advise patients that voriconazole can cause serious photosensitivity and to immediately contact their healthcare provider for new or worsening skin rash.
• •
  Advise patients to avoid exposure to direct sun light and to use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Embryo-Fetal Toxicity

• •
  Advise female patients of the potential risks to a fetus.
• •
  Advise females of reproductive potential to use effective contraception during treatment with voriconazole.

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and postmarketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• •
  Congenital or acquired QT prolongation
• •
  Cardiomyopathy, in particular when heart failure is present
• •
  Sinus bradycardia
• •
  Existing symptomatic arrhythmias
• •
  Concomitant medicinal product that is known to prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)]

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3)].

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with voriconazole. If a patient develops a severe cutaneous adverse reaction, voriconazole should be discontinued [see Adverse Reactions (6.1, 6.2)].

NDC 59762-0935-3

75 mL (when reconstituted)

GREENSTONE^® BRAND

voriconazole

for oral suspension

ORANGE FLAVORED

40 mg/mL*

Rx only

8716724

LOT:

EXP:

See Table 9 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 10 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].

NDC 59762-0935-3

75 mL (when reconstituted)

GREENSTONE^® BRAND

voriconazole

for oral suspension

ORANGE FLAVORED

40 mg/mL*

Oral Dispenser Included

Important: Read assembly instructions

carefully before dispensing.

Contains Small Parts -

Keep out of reach of children.

Rx only

NDC 59762-0934-1

30 Tablets

GREENSTONE^® BRAND

voriconazole

tablets

50 mg

Rx only

The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg is shown in Table 2. For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of voriconazole [see Dosage and Administration (2.2)].

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement. Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The oral dose recommendation for children is based on studies in which voriconazole was administered as the powder for oral suspension formulation. Bioequivalence between the voriconazole powder for oral suspension and voriconazole tablets has not been investigated in a pediatric population.

Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.

NDC 59762-0936-1

30 Tablets

GREENSTONE^® BRAND

voriconazole

tablets

200 mg

Rx only

Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6 times the RMD on a body surface area basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4, or 1.4 times the RMD on a body surface area basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (Unscheduled DNA Synthesis assay).

Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD.

The following adverse reactions have been identified during post-approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatological Reactions

Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

Administer Voriconazole Tablets or Oral Suspension at least one hour before or after a meal.

The maintenance dose of voriconazole should be increased when coadministered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.2)].

Voriconazole is indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2, 14.5) and Microbiology (12.4)].

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open-label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150–608 are presented in Table 14.

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intra-abdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.