Voriconazole

Contraindications ( 4 ) 1/2021 Warnings and Precautions ( 5.5 ) 9/2020 Warnings and Precautions ( 5.8 ) 1/2021

1 INDICATIONS AND USAGE Voriconazole tablets are 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 Candida infections ( 1.2 ) Esophageal candidiasis ( 1.3 ) Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.4 ) 1.1 Invasive Aspergillosis 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 apergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus . There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus[see Clinical Studies (14.1, 14.5) and Microbiology (12.4) ]. 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections 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 Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2, 14.5) and Microbiology (12.4) ]. 1.3 Esophageal Candidiasis 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) ] 1.4 Scedosporiosis and Fusariosis Voriconazole tablets are indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. i ncluding 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) ]. 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. 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 .

2 DOSAGE AND ADMINISTRATION Dosage in Adults (2.3) Infection Loading dose Maintenance Dose Intravenous infusion Intravenous infusion Oral Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3-4 mg/kg every 12 hours 200 mg every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours 200 mg every 12 hours Esophageal Candidiasis Not Evaluated Not Evaluated 200 mg every 12 hours 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 tablets in pediatric patients with renal or hepatic impairment has not been established (2.5, 2.6) 2.1 Important Administration Instructions for Use in All Patients Administer voriconazole tablets at least one hour before or after a meal. 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 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) ]. 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. Esophageal Candidiasis See 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 a,b a Increase dose when voriconazole is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5) b 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 (12) . c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. d In a clinical study of IA, the median duration of intravenous voriconazole therapy was 10 days (range 2 to 85 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 232 days) (14.1) . e 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. f Not evaluated in patients with EC. Intravenous infusion Intravenous infusion Oral c Invasive Aspergillosis d 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg ever …

3 DOSAGE FORMS AND STRENGTHS Voriconazole tablets, 50 mg are white to off-white, round, biconvex film coated tablets debossed with “283” on one side and “S” on the other side. Voriconazole tablets, 200 mg are white to off-white, capsule shaped, biconvex film coated tablets debossed with “285” on one side and “S” on the other side. • Tablets: 50 mg, 200 mg ( 3 )

4 CONTRAINDICATIONS 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 tablets to patients with hypersensitivity to other azoles. Coadministration of cisapride, pimozide or quinidine with voriconazole tablets 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) and Clinical Pharmacology (12.3) ]. Coadministration of voriconazole tablets with sirolimus is contraindicated because voriconazole tablets significantly increases sirolimus concentrations [ see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. Coadministration of voriconazole tablets with rifampin, carbamazepine and long-acting barbiturates 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 tablets 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 tablets with rifabutin is contraindicated since voriconazole tablets 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 tablets with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole tablets may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [ see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. Coadministration of voriconazole tablets with St. John’s Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration [ see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. Coadministration of voriconazole tablets with naloxegol is contraindicated because voriconazole tablets may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. Coadministration of voriconazole tablets with tolvaptan is contraindicated because voriconazole tablets may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7) ]. Hypersensitivity to voriconazole or its excipients ( 4 ) Coadministration with cisapride, pimozide or quinidine, sirolimus due to risk of serious adverse reactions ( 4 , 7 ) Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St. John’s Wort due to risk of loss of efficacy ( 4 , 7 ) Coadministration with naloxegol due to risk of adverse reactions ( 4 , 7 ) Coadministration with tolvaptan due to risk of adverse reactions ( 4 , 7 )

6 ADVERSE REACTIONS 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 )] Adult Patients: The most common adverse reactions (incidence ≥2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AVKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.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. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 4) 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 [ see Warning and Precautions (5.1, 5.4) and Adverse Reactions (6.1) ]. 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 3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with voriconazole tablets for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy. Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions. Liver function tests should be evaluated at the start of and during the course of voriconazole tablets therapy. Patients who develop abnormal liver function tests during voriconazole tablets therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole tablets must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole tabl …

7 DRUG INTERACTIONS Voriconazole is metabolized by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products. CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust voriconazole tablets dosage and monitor for adverse reactions or lack of efficacy ( 4 , 7 ) Voriconazole may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions ( 4 , 7 ) Phenytoin or Efavirenz: With co-administration, increase maintenance oral dosage of voriconazole tablets ( 2.3 , 2.7 , 7 ) Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [ see Clinical Pharmacology ( 12.3 )] Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (C max and AUC after 200 mg every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects ** Results based on in vivo clinical 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 Rifampin* and Rifabutin* (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours)** (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (300 mg every 24 hours)** (CYP450 Induction) Slight Decrease in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours High-dose Ritonavir (400 mg every 12 hours)** (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg every 12 hours)** (CYP450 Induction) Reduced 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 Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin* (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg) Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John’s Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole. Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir In Vitro Studies Demonstrated P …

8 USE IN SPECIFIC POPULATIONS Pediatrics: Safety and effectiveness in patients younger than 2 years has not been established ( 8.4 ) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 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 . 8.1 Pregnancy Risk Summary Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of voriconazole 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 [ see Data] . 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 [ see Warnings and Precautions (5.9)] . 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. Data Animal Data 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 in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on mg/m 2 , and cleft palate at 60 mg/kg, approximately 2 times the RMD based on mg/m 2 . Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternbrae, 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 mg/m 2 ). 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. 8.2 Lactation Risk Summary No data are available regarding the presence of voriconazole in human milk, the effects of voriconazole on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for voriconazole tablets and any potential adverse effects on the breastfed child from voriconazole tablets or from the underlying maternal condition. 8.3 …

11 DESCRIPTION Voriconazole, an azole antifungal agent is available as 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-(1H-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 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 (corn), and a coating containing polyvinyl alcohol-part hydrolyzed, lactose monohydrate, titanium dioxide, macrogol/PEG and talc. image description

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Click here to enter How Supplied 16.1 How Supplied Voriconazole tablets, 50 mg are white to off-white, round, biconvex film coated tablets debossed with “283” on one side and “S” on the other side. Voriconazole tablets, 200 mg are white to off-white, capsule shaped, biconvex film coated tablets debossed with “285” on one side and “S” on the other side. NDC 50268-803-12 (10 tablets per card, 2 cards per card). Dispensed in Unit Dose Package. For Institutional Use Only. 16.2 Storage Voriconazole tablets should be stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].