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

Invasive Aspergillosis and Serious Fungal Infections due to Fusariumspp . 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. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)] .

This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. October 2021

Contraindications ( 4) 9/2021

Warnings and Precautions,

Severe Cutaneous Adverse Reactions ( 5.5) 9/2020

Warnings and Precautions, Adrenal Dysfunction ( 5.8) 1/2021

Voriconazole 200 mg Tablet

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.

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 a film-coated tablets for oral administration. The structural formula is:

Voriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1 H-1,2,4-triazol-1-yl)-2-butanol with the molecular formula of C ₁₆H ₁₄F ₃N ₅O and a molecular weight of 349.31.

Voriconazole drug substance is a white to off-white 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.

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 aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to less than 18 [N=51] from 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 (2.5), 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 (2.5, 2.6)] . Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.6)and Warnings and Precautions (5.1, 5.10) ].

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 (2.6)] .

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 Aspergillusspp., Fusariumspp., and Scedosporiumspp.

• Voriconazole tablets are contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
• Coadministration of cisapride, pimozide, quinidine or ivabradine with voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7)].
• Coadministration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with rifampin, carbamazepine, long-acting barbiturates, and St. John’s Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and 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 Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7)] .
• Coadministration of voriconazole with naloxegol is contraindicated because voriconazole may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)] .
• Coadministration of voriconazole with tolvaptan is contraindicated because voriconazole may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions(7)] .
• Coadministration of voriconazole with venetoclax 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)].
• Coadministration of voriconazole with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions ( 7)] .

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.

Tables 10and 11provide the clinically significant interactions between voriconazole and other medical products.

*Results based on in vivoclinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects

**Results based on in vivoclinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects

***Non-Nucleoside Reverse Transcriptase Inhibitors

*Results based on in vivoclinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects

• **Results based on in vivoclinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects
• ***Results based on in vivoclinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg every 24 hours)

****Non-Steroidal Anti-Inflammatory Drug

*****Non-Nucleoside Reverse Transcriptase Inhibitors

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 (2.5)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 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. 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.

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 12).

• Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens

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 to 20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3 to 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.

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

Voriconazole tablets are an azole antifungal indicated for the treatment of adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight with:

• Invasive aspergillosis ( 1.1)
• Candidemia in non-neutropenics and other deep tissue Candidainfections ( 1.2)
• Esophageal candidiasis ( 1.3)
• Serious fungal infections caused by Scedosporium apiospermumand Fusariumspecies 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 post-marketing 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 tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) 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 Aspergillusother than A. fumigatus [see Clinical Studies (14.1, 14.5)and Microbiology (12.4)] .

Voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of esophageal candidiasis (EC) in adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight [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.

• Dosage in Adults ( 2.3)

• Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours
• Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5)
• Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6)
• Dosage in Pediatric Patients ( 2.4)
• For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4)
• Dosage adjustment of voriconazole in pediatric patients with renal or hepatic impairment has not been established. ( 2.5, 2.6)

Voriconazole tablets, 50 mg are white to off-white, round, biconvex, film coated tablets with 'SZ' debossed on one side and '132' debossed on the other side.

Voriconazole tablets, 200 mg are white to off-white, capsule shaped, biconvex, film coated tablets with 'SZ' debossed on one side and '133' debossed on the other side.

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

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 to 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 16.

Table 16: Success Rates in Patients Treated for Esophageal Candidiasis

*Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

^†PP (Per Protocol) patients had confirmation of Candidaesophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment).

^‡ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

Microbiologic success rates by Candidaspecies are presented in Table 17.

• Table 17: Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study-150-305)

*Some patients had more than one species isolated at baseline.

^†Patients with endoscopic and/or mycological assessment at end of therapy.

Voriconazole tablets are 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 (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) 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).

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 post-marketing 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)] .

Voriconazole tablets, 200 mg are white to off-white, capsule shaped, biconvex, film coated tablets with 'SZ' debossed on one side and '133' debossed on the other side.

NDC 72162-1198-03, Bottles of 30 Tablets

Voriconazole tablets should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Repackaged/Relabeled by:

Bryant Ranch Prepack, Inc.

Burbank, CA 91504

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)].

See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 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)] .

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 (2.3)] .

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.

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 mg/m ²basis. 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 mg/m ²basis. 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 vivoDNA 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.

Administer voriconazole tablets at least one hour before or after a meal.

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7)and Dosage and Administration (2.3)] .

Voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of candidemia in non-neutropenic patients and the following Candidainfections: 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 Candidaor 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 Candidaspecies in Study 150 to 608 are presented in Table 15.

• Table 15: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen ^*,†

*A few patients had more than one pathogen at baseline.

^†Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

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 Candidainfections. 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 Fusariumspp . 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. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)] .

This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. October 2021

Contraindications ( 4) 9/2021

Warnings and Precautions,

Severe Cutaneous Adverse Reactions ( 5.5) 9/2020

Warnings and Precautions, Adrenal Dysfunction ( 5.8) 1/2021

Voriconazole 200 mg Tablet

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.

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 a film-coated tablets for oral administration. The structural formula is:

Voriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1 H-1,2,4-triazol-1-yl)-2-butanol with the molecular formula of C ₁₆H ₁₄F ₃N ₅O and a molecular weight of 349.31.

Voriconazole drug substance is a white to off-white 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.

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 aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to less than 18 [N=51] from 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 (2.5), 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 (2.5, 2.6)] . Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.6)and Warnings and Precautions (5.1, 5.10) ].

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 (2.6)] .

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 Aspergillusspp., Fusariumspp., and Scedosporiumspp.

• Voriconazole tablets are contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
• Coadministration of cisapride, pimozide, quinidine or ivabradine with voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7)].
• Coadministration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with rifampin, carbamazepine, long-acting barbiturates, and St. John’s Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and 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 Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7)] .
• Coadministration of voriconazole with naloxegol is contraindicated because voriconazole may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)] .
• Coadministration of voriconazole with tolvaptan is contraindicated because voriconazole may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions(7)] .
• Coadministration of voriconazole with venetoclax 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)].
• Coadministration of voriconazole with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions ( 7)] .

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.

Tables 10and 11provide the clinically significant interactions between voriconazole and other medical products.

*Results based on in vivoclinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects

**Results based on in vivoclinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects

***Non-Nucleoside Reverse Transcriptase Inhibitors

*Results based on in vivoclinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects

• **Results based on in vivoclinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects
• ***Results based on in vivoclinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg every 24 hours)

****Non-Steroidal Anti-Inflammatory Drug

*****Non-Nucleoside Reverse Transcriptase Inhibitors

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 (2.5)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 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. 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.

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 12).

• Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens

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 to 20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3 to 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.

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

Voriconazole tablets are an azole antifungal indicated for the treatment of adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight with:

• Invasive aspergillosis ( 1.1)
• Candidemia in non-neutropenics and other deep tissue Candidainfections ( 1.2)
• Esophageal candidiasis ( 1.3)
• Serious fungal infections caused by Scedosporium apiospermumand Fusariumspecies 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 post-marketing 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 tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) 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 Aspergillusother than A. fumigatus [see Clinical Studies (14.1, 14.5)and Microbiology (12.4)] .

Voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of esophageal candidiasis (EC) in adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight [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.

• Dosage in Adults ( 2.3)

• Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours
• Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5)
• Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6)
• Dosage in Pediatric Patients ( 2.4)
• For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4)
• Dosage adjustment of voriconazole in pediatric patients with renal or hepatic impairment has not been established. ( 2.5, 2.6)

Voriconazole tablets, 50 mg are white to off-white, round, biconvex, film coated tablets with 'SZ' debossed on one side and '132' debossed on the other side.

Voriconazole tablets, 200 mg are white to off-white, capsule shaped, biconvex, film coated tablets with 'SZ' debossed on one side and '133' debossed on the other side.

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

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole). However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 to 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 16.

Table 16: Success Rates in Patients Treated for Esophageal Candidiasis

*Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

^†PP (Per Protocol) patients had confirmation of Candidaesophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment).

^‡ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

Microbiologic success rates by Candidaspecies are presented in Table 17.

• Table 17: Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study-150-305)

*Some patients had more than one species isolated at baseline.

^†Patients with endoscopic and/or mycological assessment at end of therapy.

Voriconazole tablets are 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 (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) 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).

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 post-marketing 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)] .

Voriconazole tablets, 200 mg are white to off-white, capsule shaped, biconvex, film coated tablets with 'SZ' debossed on one side and '133' debossed on the other side.

NDC 72162-1198-03, Bottles of 30 Tablets

Voriconazole tablets should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Repackaged/Relabeled by:

Bryant Ranch Prepack, Inc.

Burbank, CA 91504

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)].

See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 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)] .

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 (2.3)] .

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.

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 mg/m ²basis. 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 mg/m ²basis. 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 vivoDNA 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.

Administer voriconazole tablets at least one hour before or after a meal.

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7)and Dosage and Administration (2.3)] .

Voriconazole tablets are indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of candidemia in non-neutropenic patients and the following Candidainfections: 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 Candidaor 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 Candidaspecies in Study 150 to 608 are presented in Table 15.

• Table 15: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen ^*,†

*A few patients had more than one pathogen at baseline.

^†Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

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 Candidainfections. 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.