VECANZOL

(voriconazole), an azole antifungal agent is available as a lyophilized powder for solution for intravenous infusion.

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 an empirical formula of C 16 H 14 F 3 N 5 O and a molecular weight of 349.3.

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

I.V. is a white lyophilized powder containing nominally 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.

I.V. is intended for administration by intravenous infusion.

It is a single-dose, unpreserved product.

Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL VFEND and 160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium.

The resultant solution is further diluted prior to administration as an intravenous infusion.

• Invasive aspergillosis.

• Candidemia in non-neutropenics and other deep tissue Candida infections.

• Esophageal candidiasis.

• Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy 1.1 Invasive Aspergillosis VFEND 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. 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida.

Infections VFEND 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. 1.3 Esophageal Candidiasis VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) . 1.4 Scedosporiosis and Fusariosis VFEND 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. 1.5 Usage 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 is an antifungal drug. 12.2 Pharmacodynamics Exposure-Response Relationship for Efficacy and Safety In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively.

A pharmacokinetic-pharmacodynamic analysis of patient data from of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy.

However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances.

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole.

ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period.

The placebo-adjusted mean maximum increases in

QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec.

Females exhibited a greater increase in

QTc than males, although all mean changes were <10 msec.

Age was not found to affect the magnitude of increase in QTc.

No subject in any group had an increase in QTc of ≥60 msec from baseline.

No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown. 12.3 Pharmacokinetics 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 Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.

AUC 12 = area under the curve over 12 hour dosing interval, C max = maximum plasma concentration, C min = minimum plasma concentration.

CV = coefficient of variation. 6 mg/kg IV (loading dose) 3 mg/kg IV every 12 hours 4 mg/kg IV every 12 hours 400 mg Oral (loading dose) 200 mg Oral every 12 hours 300 mg Oral every 12 hours N 35 23 40 17 48 16 AUC 12 (μg∙h/mL) 13.9 13.7 33.9 9.31 12.4 34.0 C max (μg/mL) 3.13 3.03 4.77 2.30 2.31 4.74 C min (μg/mL) -

• 0.46 1.63 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 in the majority of subjects.

The pharmacokinetic properties of voriconazole are similar following administration by the intravenous and oral routes.

Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (CV 13%).

Maximum plasma concentrations (C max ) are achieved 1–2 hours after dosing.

When multiple doses of voriconazole are administered with high-fat meals, the mean C max and AUC τ are reduced by 34% and 24%, respectively when administered as a tablet and by 58% and 37% respectively when administered as the oral suspension.

In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues.

Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9–15 µg/mL).

Varying degrees of hepatic and renal impairment do not affect the protein binding of voriconazole.

In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4.

In vivo studies indicated that

CYP2C19 is significantly involved in the metabolism of voriconazole.

This enzyme exhibits genetic polymorphism.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma.

Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

After administration of a single radiolabelled dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine.

The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

As a result of non-linear pharmacokinetics, the terminal half-life of voriconazole is dose dependent and therefore not useful in predicting the accumulation or elimination of voriconazole.

In a multiple oral dose study, the mean C max and AUC τ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18–45 years), after tablet dosing.

In the same study, no significant differences in the mean C max and AUC τ were observed between healthy elderly males and healthy elderly females (>65 years).

In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males whereas the mean C max was comparable between genders.

The steady state trough voriconazole concentrations (C min ) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

In the clinical program, no dosage adjustment was made on the basis of gender.

The safety profile and plasma concentrations observed in male and female subjects were similar.

Therefore, no dosage adjustment based on gender is necessary.

Geriatric Patients In an oral multiple dose study the mean C max and AUC τ in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in young males (18–45 years).

No significant differences in the mean C max and AUC τ were observed between healthy elderly females (≥65 years) and healthy young females (18–45 years).

In the clinical program, no dosage adjustment was made on the basis of age.

An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical trials showed that the median voriconazole plasma concentrations in the elderly patients (>65 years) were approximately 80% to 90% higher than those in the younger patients (≤65 years) after either IV or oral administration.

However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly.

The recommended doses in pediatric patients were based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised pediatric patients aged to less than 12 years and 26 immunocompromised pediatric patients aged to less than 17 years.

A comparison of the pediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC 12 ) in pediatric patients aged to less than 12 years following administration of a 9 mg/kg intravenous loading dose was comparable to that in adults following a 6 mg/kg intravenous loading dose.

The predicted total exposures in pediatric patients aged to less than 12 years following intravenous maintenance doses of and 8 mg/kg twice daily were comparable to those in adults following and 4 mg/kg IV twice daily, respectively.

The predicted total exposure in pediatric patients aged to less than 12 years following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily.

An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose in pediatric patients aged to less than 12 years.

Voriconazole exposures in the majority of pediatric patients aged to less than 17 years were comparable to those in adults receiving the same dosing regimens.

However, lower voriconazole exposure was observed in some pediatric patients aged to less than 17 years with low body weight compared to adults.

Limited voriconazole trough plasma samples were collected in pediatric patients aged to less than 18 years with IA or invasive candidiasis including candidemia, and EC in two prospective, open-label, non-comparative, multicenter clinical studies.

In eleven pediatric patients aged to less than 12 years and aged to 14 years, with body weight less than 50 kg, who received 9 mg/kg intravenously every 12 hours as a loading dose on the first day of treatment, followed by 8 mg/kg every 12 hours as an intravenous maintenance dose, or 9 mg/kg every 12 hours as an oral maintenance dose, the mean trough concentration of voriconazole was 3.6 mcg/mL (range 0.3 to 10.7 mcg/mL).

In four pediatric patients aged to less than 12 years and aged to 14 years, with body weight less than 50 kg, who received 4 mg/kg intravenously every 12 hours, the mean trough concentration of voriconazole was 0.9 mcg/mL (range 0.3 to 1.6 mcg/mL) .

After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function.

There was no difference in mean peak plasma concentrations (C max ) between the groups.

When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared to controls.

In an oral multiple dose study, AUC τ was similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given the standard 200 mg twice daily maintenance dose.

The mean peak plasma concentrations (C max ) were 20% lower in the hepatically impaired group.

No pharmacokinetic data are available for patients with se.

The following serious adverse reactions are described elsewhere in the labeling: Hepatic Toxicity Arrhythmias and QT Prolongation Infusion Related Reactions Visual Disturbances Severe Cutaneous Adverse Reactions Photosensitivity Renal Toxicity.

• Adult Patients: The most common adverse reactions (incidence ≥2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations.

• Pediatric Patients: The most common adverse reactions (incidence ≥5%) were visual disturbances, pyrexia, vomiting, epistaxis, nausea, rash, abdominal pain, diarrhea, hypertension, hypokalemia, cough, headache, thrombocytopenia, ALT abnormal, hypotension, peripheral edema, hyperglycemia, tachycardia, dyspnea, hypocalcemia, hypophosphatemia, LFT abnormal, mucosal inflammation, photophobia, abdominal distention, constipation, dizziness, hallucinations, hemoptysis, hypoalbuminemia, hypomagnesemia, renal impairment, upper respiratory tract infection To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience 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.

The most frequently reported adverse reactions in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%).

The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances.

The data described in

Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies.

This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients.

This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies.

This patient population was 62% male, had a mean age of 46 years (range 11–90, including 51 patients aged 12–18 years), and was 78% White and 10% Black.

Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months.

Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%.

In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA.

The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients).

In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients).

The rate of discontinuation from voriconazole study medication due to adverse reactions was 19.5% out of 272 patients.

Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC.

The rate of discontinuation from voriconazole study medication in Study 305 due to adverse reactions was 7% (14/200 patients).

Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 4: Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602–608 Combined, or Study 305.

Possibly Related to Therapy or Causality Unknown Study 307/602: IA; Study 608: candidemia; Study 305: EC Therapeutic Studies Studies 303, 304, 305, 307, 309, 602, 603, 604, 608 Studies 307/602 and 608 (IV/ oral therapy) Study 305 (oral therapy) Voriconazole N=1655 Voriconazole N=468 Ampho B Amphotericin B followed by other licensed antifungal therapy N=185 Ampho B→ Fluconazole N=131 Voriconazole N=200 Fluconazole N=191 N (%) N (%) N (%) N (%) N (%) N (%) Special Senses See Warnings and Precautions Abnormal vision 310 63 1 0 31 8 Photophobia 37 8 0 0 5 2 Chromatopsia 20 2 0 0 2 0 Body as a Whole Fever 94 8 25 5 0 0 Chills 61 1 36 8 1 0 Headache 49 9 8 1 0 1 Cardiovascular System Tachycardia 39 6 5 0 0 0 Digestive System Nausea 89 18 29 2 2 3 Vomiting 72 15 18 1 2 1 Liver function tests abnormal 45 15 4 1 6 2 Cholestatic jaundice 17 8 0 1 3 0 Metabolic and Nutritional Systems Alkaline phosphatase increased 59 19 4 3 10 3 Hepatic enzymes increased 30 11 5 1 3 0 SGOT increased 31 9 0 1 8 2 SGPT increased 29 9 1 2 6 2 Hypokalemia 26 3 36 16 0 0 Bilirubinemia 15 5 3 2 1 0 Creatinine increased 4 0 59 10 1 0 Nervous System Hallucinations 39 13 1 0 0 0 Skin and Appendages Rash 88 20 7 1 3 1 Urogenital Kidney function abnormal 10 6 40 9 1 1 Acute kidney failure 7 2 11 7 0 0 Visual Disturbances VFEND treatment-related visual disturbances are common.

In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia.

Visual disturbances may be associated with higher plasma concentrations and/or doses.

The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina.

In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, VFEND caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception.

ERG measures electrical currents in the retina.

These effects were noted early in administration of VFEND and continued through the course of study drug treatment.

Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal.

Dermatological reactions were common in patients treated with VFEND.

The mechanism underlying these dermatologic adverse reactions remains unknown.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with VFEND.

Erythema multiforme has also been reported during treatment with VFEND.

VFEND has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus.

The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655).

This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients.

The list does not include events included in Table 4 above and does not include every event reported in the voriconazole clinical program.

Body as a

Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction, ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.

Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes ) .

Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.

Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.

Hemic and

Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.

Metabolic and

Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia.

Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.

System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.

System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngiti.

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.

• VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients.

There is no information regarding cross-sensitivity between VFEND and other azole antifungal agents.

Refer to the prescribing information for other azole antifungal agents.

• Concomittant use of VFEND 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 VFEND. 1.

• Ergot alkaloids (e.g., ergotamine, dihydroergotamine).

• 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.

• Voclosporin 2.

• Efavirenz Concomitant use with efavirenz dosages of 400 mg every 24 hours or higher is contraindicated.

• Long-acting barbiturates.

• 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 VFEND.

• Known hypersensitivity to voriconazole or its excipients.

• Concomitant use 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.

• Concomitant use 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.

• Dosage in Adults Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis Not Evaluated Not Evaluated 200 mg every 12 hours 5 mL every 12 hours o Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours o Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) o Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min).

• Dosage in Pediatric Patients 2 years of age and older o For pediatric patients to less than 12 years of age and to 14 years of age weighing less than 50 kg see Table below.

Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis 9 mg/kg every 12 hours for the first 24 hours 8 mg/kg every 12 hours after the first 24 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Candidemia in nonneutropenics and other deep tissue Candida infections Scedosporiosis and Fusariosis Esophageal Candidiasis Not Evaluated 4 mg/kg every 12 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] o For pediatric patients aged 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. o Dosage adjustment of VFEND in pediatric patients with renal or hepatic impairment has not been established.

• See full prescribing information for instructions on reconstitution of VFEND lyophilized powder for intravenous use and important administration instructions 2.1 Important Administration Instructions for Use in All Patients VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over to 3 hours.

Administer diluted VFEND

I.V. by intravenous infusion over to 3 hours only.

Do not administer as an

IV bolus injection. 2.2 Use of VFEND I.V. with Other Parenteral Drug Products Blood products and concentrated electrolytes VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas).

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

Intravenous solutions containing (non-concentrated) electrolytes VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN) VFEND I.V. can be infused at the same time as total parenteral nutrition, but must be infused in a separate line.

If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND I.V. 2.3 Recommended Dosing Regimen in Adults 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 VFEND 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 VFEND 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.

Candidemia in non-neutropenic patients and other deep tissue Candida infections See Table 1.

Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Table 1.

Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Table 1: Recommended Dosing Regimen (Adults) Infection Loading Dose Maintenance Dose Increase dose when VFEND is coadministered with phenytoin or efavirenz; Decrease dose in patients with hepatic impairment, In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 4 mg/kg intravenous infusion every 12 hours dose.

Intravenous infusion Intravenous infusion Oral tablets

Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.

Oral suspension Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous VFEND therapy was 10 days (range to 85 days).

The median duration of oral

VFEND therapy was 76 days (range to 232 days) . 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg every 12 hours for the first 24 hours 3–4 mg/kg every 12 hours In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy.

Appropriate dose should be based on the severity and nature of the infection. 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis Not Evaluated Not evaluated in patients with EC.

Evaluated 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Method for Adjusting the Dosing Regimen in Adults.

• If the patient's response is inadequate, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 200 mg (or 5 mL) every 12 hours to 300 mg (or 7.5 mL) every 12 hours.

• For adult patients weighing less than 40 kg, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 100 mg (or 2.5 mL) every 12 hours to 150 mg (or 3.75 mL) every 12 hours.

• If the patient is unable to tolerate 300 mg (or 7.5 mL) orally every 12 hours, reduce the oral maintenance dose of VFEND tablets or oral suspension by 50 mg (or 1.25 mL) steps to a minimum of 200 mg (or 5 mL) every 12 hours for adult patients weighing more than 40 kg or to 100 mg (or 2.5 mL) every 12 hours for adult patients weighing less than 40 kg.

• If the patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours. 2.4 Recommended Dosing Regimen in Pediatric Patients The recommended dosing regimen for pediatric patients to less than 12 years of age and to 14 years of age with body weight less than 50 kg is shown in Table 2.

For pediatric patients 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 VFEND.

Table 2: Recommended Dosing Regimen for Pediatric Patients to less than 12 years of age and to 14 years of age with body weight less than 50 kg Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged to less than 12 years of age and 26 immunocompromised pediatric patients aged to less than 17 years of age.

Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks.

Patients received

IV treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy. 9 mg/kg every 12 hours for the first 24 hours 8 mg/kg every 12 hours after the first 24 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Candidemia in nonneutropenics and other deep tissue Candida infections Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria.

For subjects with primary or salvage

ICC, VFEND 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 were treated for at least 7 days after the resolution of clinical signs and symptoms.

Scedosporiosis and Fusariosis Esophageal Candidiasis Not

Evaluated 4 mg/kg every 12 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] 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.

Oral bioavailability may be limited in pediatric patients to 12 years with malabsorption and very low body weight for age.

In that case, intravenous VFEND administration is recommended.

Method for Adjusting the Dosing Regimen in Pediatric Patients Pediatric Patients to less than 12 years of age and to 14 years of age with body weight less than 50 kg If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may be increased by 1 mg/kg steps.

If patient response is inadequate and the patient is able to tolerate the oral maintenance dose, the dose may be increased by 1 mg/kg (0.025 mL/kg) steps or 50 mg (1.25 mL) steps to a maximum of 350 mg (8.75 mL) every 12 hours.

If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps.

If patients are unable to tolerate the oral maintenance dose, reduce the dose by 1 mg/kg (0.025 mL/kg) or 50 mg (1.25 mL) steps.

Pediatric patients to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight: Use the optimal method for titrating dosage recommended for adults. 2.5 Dosage Modifications in Patients With Hepatic Impairment Adults The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit o.

I.V. for Injection is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

It does not contain preservatives and is not made with natural rubber latex.

Individually packaged vials of 200 mg VFEND I.V. (NDC 0049-4190-01) 16.2 Storage VFEND I.V. for Injection unreconstituted vials should be stored at 15°C to 30°C (59°F to 86°F) .

VFEND is a single dose unpreserved sterile lyophile.

From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F).

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36°F to 46°F).

This medicinal product is for single use only and any unused solution should be discarded.

Only clear solutions without particles should be used.

I.V. for Injection unreconstituted vials should be stored at 15°C to 30°C (59°F to 86°F) .

VFEND is a single dose unpreserved sterile lyophile.

From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F).

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36°F to 46°F).

This medicinal product is for single use only and any unused solution should be discarded.

Only clear solutions without particles should be used.

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

There are no available data on the use of VFEND in pregnant women.

In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits.

Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons).

In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis.

Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated populations is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20% respectively.

Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6–17) at 10, 30, and 60 mg/kg/day. Voriconazole was associated with increased incidences of the malformations hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons.

Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternebrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater.

There was no evidence of maternal toxicity at any dose.

Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7–19) at 10, 40, and 100 mg/kg/day. Voriconazole was associated with increased post-implantation loss and decreased fetal body weight, in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on body surface area comparisons).

Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day. In a peri.

• and postnatal toxicity study in rats, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.

The safety and effectiveness of

VFEND 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 to less than 12 [N=26] and aged to less than 18 [N=79] from two, non-comparative Phase 3 pediatric studies and eight adult therapeutic trials provided safety information for VFEND use in the pediatric population.

Safety and effectiveness in pediatric patients below the age of 2 years has not been established.

Therefore, VFEND 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.

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.

VFEND has not been studied in pediatric patients with hepatic or renal impairment.

Hepatic function and serum creatinine levels should be closely monitored in pediatric patients.

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.