Voriconazole

1 INDICATIONS AND USAGE Voriconazole tablets are an azole antifungal indicated for the treatment of adults and pediatric patients 2 years of age and older with: • Invasive aspergillosis ( 1.1 ) • Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) • Esophageal candidiasis ( 1.3 ) • Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.4 ) 1.1 Invasive Aspergillosis Voriconazole tablets are indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus . There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies ( 14.1 , 14.5 ) and Microbiology ( 12.4 )]. 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections Voriconazoletablets are indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies ( 14.2 , 14.5 ) and Microbiology ( 12.4 )]. 1.3 Esophageal Candidiasis Voriconazoletablets are indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) [see Clinical Studies ( 14.3 , 14.5 ) and Microbiology ( 12.4 )]. 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. including Fusarium solani , in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy [see Clinical Studies ( 14.4 ) and Microbiology ( 12.4 )]. 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.

2 DOSAGE AND ADMINISTRATION • Dosage in Adults ( 2.3 ) Infection Maintenance Dose Oral tablets Oral suspension Invasive Aspergillosis 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis 200 mg every 12 hours 5 mL 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 years of age and older ( 2.4 ) • For pediatric patients 2 to less than 12 years of age and 12 to 14 years of age weighing less than 50 kg see Table below. Infection Maintenance Dose Oral tablets Oral suspension Invasive Aspergillosis 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 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] • 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 of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously [see Clinical Pharmacology ( 12.3 )] . 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) a Increase dose when voriconazole tablets are 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 (AUCτ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUCτ) 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 w…

5 WARNINGS AND PRECAUTIONS • 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 ) • 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 tablets and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after voriconazole tablets 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 tablets ( 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 ) 5.1 Hepatic Toxicity 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 tablets 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 )]. 5.2 Arrhythmias and QT Prolongation Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and postmarketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes ), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as: • Congenital or acquired QT prolongation • Cardiomyopathy, in particular when heart failure is present • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant…

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 pimozide, quinidine or ivabradine 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 )]. • 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, long-acting barbiturates or 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 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 may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions ( 7 )]. • Coadministration of voriconazole tablets 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 tablets with tolvaptan is contraindicated because voriconazole may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions ( 7 )]. • Coadministration of voriconazole tablets 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 tablets 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 )]. • Coadministration of voriconazole tablets with finerenone is contraindicated since it may result in significant increases in finerenone exposure and the potential for serious adverse reactions [see Drug Interactions ( 7 )]. • Hypersensitivity to voriconazole or its excipients ( 4 ) • Coadministration with pimozide, quinidine, sirolimus or ivabradine due to risk of serious adverse reactions ( 4 , 7 ) • Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, rit…

7 DRUG INTERACTIONS 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 10 and 11 provide the clinically significant interactions between voriconazole and other medical products. 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 τ 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) Efavirenz (300 mg every 24 hours)** (CYP450 Induction) Significantly Reduced Slight Decrease in AUC τ Contraindicated 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) Low-dose Ritonavir (100 mg every 12 hours)** (CYP450 Induction) Significantly Reduced Reduced Contraindicated 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 (e.g., phenobarbital, mephobarbital) (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 reactions 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 reactions 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 In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors. Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and …

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 of the malformations hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the 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.

8.3 Females and Males of Reproductive Potential Contraception Advise females of reproductive potential to use effective contraception during treatment with voriconazole tablets. The coadministration of voriconazole with the oral contraceptive, Ortho-Novum ® (35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. Monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )].

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 )] 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 ) • 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 ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 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 <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 disco…