Isavuconazonium Sulfate

1 INDICATIONS AND USAGE CRESEMBA ® is an azole antifungal indicated for the treatment of: Invasive aspergillosis ( 1.1 ) and Invasive mucormycosis ( 1.2 ) as follows: • CRESEMBA for injection : adults and pediatric patients 1 year of age and older • CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater 1.1 Invasive Aspergillosis CRESEMBA ® is indicated for the treatment of invasive aspergillosis as follows: CRESEMBA for injection : adults and pediatric patients 1 year of age and older [see Clinical Studies ( 14.1 ) and Clinical Pharmacology ( 12.4 )] CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater [see Dosage and Administration ( 2.3 ) Clinical Studies ( 14.1 ) and Clinical Pharmacology ( 12.4 )] 1.2 Invasive Mucormycosis CRESEMBA is indicated for the treatment of invasive mucormycosis as follows: CRESEMBA for injection : adults and pediatric patients 1 year of age and older [see Clinical Studies ( 14.1 ) and Clinical Pharmacology ( 12.3 , 12.4 )] CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kg and greater [see Dosage and Administration ( 2.3 )], Clinical Studies ( 14.1 ) and Clinical Pharmacology ( 12.3 , 12.4 )] 1.3 Usage Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. 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 Important Administration Instructions: • CRESEMBA for injection is intended for use in patients who are 1 year of age and older ( 2.1 , 2.3 ). • CRESEMBA for injection via nasogastric (NG) tube administration is intended for use by patients who are 6 years of age and older and weighing 16 kg and greater. ( 2.1 , 2.6 ). • CRESEMBA for injection must be administered through an in-line filter over a minimum of 1 hour. ( 2.1 , 2.5 ). • CRESEMBA capsules are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater ( 2.1 , 2.3 ). • CRESEMBA capsules can be taken with or without food. ( 2.1 ). Recommended Dosage in Adult Patients ( 2.2 ): Recommended Dosage for CRESEMBA in Adult Patients ( 2.2 ) Dosage Form Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose CRESEMBA for Injection, 372 mg/vial 372 mg of isavuconazonium sulfate per vial One reconstituted vial (372 mg) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg) intravenously once daily CRESEMBA Capsules, 186 mg 186 mg of isavuconazonium sulfate per capsule Two 186 mg capsules (372 mg) orally every 8 hours for 6 doses (48 hours) Two 186 mg capsules (372 mg) orally once daily CRESEMBA Capsules, 74.5 mg 74.5 mg of isavuconazonium sulfate per capsule Five 74.5 mg capsules (372 mg) orally every 8 hours for 6 doses (48 hours) Five 74.5 mg capsules (372 mg) orally once daily Recommended Dosage in Pediatric Patients ( 2.3 ): • The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA. ( 2.3 ) Recommended Dosage for CRESEMBA in Pediatric Patients ( 2.3 ) Dosage Form Age Body Weight (kg) Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose CRESEMBA for Injection, 372 mg/vial 372 mg of isavuconazonium sulfate per vial 1 to less than 3 years of age less than 18 kg 15 mg/kg intravenously every 8 hours for 6 doses (48 hours) 15 mg/kg intravenously once daily 3 to less than 18 years of age less than 37 kg 10 mg/kg intravenously every 8 hours for 6 doses (48 hours) 10 mg/kg intravenously once daily greater than or equal to 37 kg One reconstituted vial (372 mg) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg) intravenously once daily CRESEMBA Capsules, 74.5 mg 74.5 mg of isavuconazonium sulfate per capsule 6 to less than 18 years of age 16 kg to less than 18 kg Two capsules (149 mg) orally every 8 hours for 6 doses (48 hours) Two capsules (149 mg) orally once daily 18 kg to less than 25 kg Three capsules (223.5 mg) orally every 8 hours for 6 doses (48 hours) Three capsules (223.5 mg) orally once daily 25 kg to less than 32kg Four capsules (298 mg) orally every 8 hours for 6 doses (48 hours) Four capsules (298 mg) orally once daily greater than or equal to 32 kg Five 74.5 mg capsules (372 mg) orally every 8 hours for 6 doses (48 hours) Five 74.5 mg capsules (372 mg) orally once daily 2.1 Important Administration Instructions for CRESEMBA CRESEMBA for Injection • CRESEMBA for injection is intended for use in patients who are 1 year of age and older [see Dosage and Administration ( 2.2 and 2.3 )]. • Intravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron). • Infuse the intravenous formulation over a minimum of 1 hour in 250 mL of a compatible diluent, to reduce the risk for infusion-related reactions. Do not administer as an intravenous bolus injection. • Do not infuse CRESEMBA with other intravenous medications. • Flush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA. • After dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use a pneumatic transport system. Nasogastric Tube Administration of CRESEMBA for Injection • CRESEMBA for injection via nasogastric (NG) tube administration is intended for use by patients who are 6 years of age and older and weighing 16 kg and greater [see Dosage and Administration ( 2.2 , 2.3 and 2.6 ] . CRESEMBA Capsules • CRESEMBA capsules are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater [see Dosage and Administration ( 2.2 and 2.3 )]. • Switching between the intravenous and oral formulations of CRESEMBA is acceptable as bioequivalence has been demonstrated. Loading dose is not required when switching between formulations. • With oral administration, swallow CRESEMBA capsules whole. Do not chew, crush, dissolve, or open the capsules. CRESEMBA capsules can be taken with or without food. 2.2 Recommended Dosage and Administration in Adult Patients Recommended dosage and administration of CRESEMBA for injection and capsules in adult patients is described in Table 1 below. CRESEMBA (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Table 1. Recommended Dosage and Administration for CRESEMBA in Adult Patients Dosage Form Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose. CRESEMBA for Injection, 372 mg/vial 372 mg 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole. of isavuconazonium sulfate per vial One reconstituted vial (372 mg ) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg ) intravenously once daily CRESEMBA Capsules, 186 mg 186 mg 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole. of isavuconazonium sulfate per capsule Two 186 mg capsules (372 mg ) orally every 8 hours for 6 doses (48 hours) Two 186 mg capsules (372 mg ) orally once daily CRESEMBA Capsules, 74.5 mg 74.5 mg 74.5 mg of isavuconazonium sulfate is equivalent to 40 mg of isavuconazole. of isavuconazonium sulfate per capsule Five 74.5 mg capsules (372 mg ) orally every 8 hours for 6 doses (48 hours) Five 74.5 mg capsules (372 mg ) orally once daily 2.3 Recommended Dosage and Administration in Pediatric Patients Recommended dosage and administration of CRESEMBA for injection and CRESEMBA capsules in pediatric patients is described in Table 2 below [see Clinical Pharmacology ( 12.3 ) ] . The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA. Table 2. Recommended Dosage and Administration for CRESEMBA in Pediatric Patients Dosage Form Age Body Weight (kg) Loading Dose Maintenance Dose Start maintenance doses 12 to 24 hours after the last loading dose. CRESEMBA for Injection, 372 mg/vial 372 mg 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole. of isavuconazonium sulfate per vial 1 year to less than 3 years of age less than 18 kg 15 mg/kg intravenously every 8 hours for 6 doses (48 hours) 15 mg/kg intravenously once daily 3 years to less than 18 years of age less than 37 kg 10 mg/kg intravenously every 8 hours for 6 doses (48 hours) 10 mg/kg intravenously once daily greater than or equal to 37 kg One reconstituted vial (372 mg ) intravenously every 8 hours for 6 doses (48 hours) One reconstituted vial (372 mg ) intravenously once daily CRESEMBA Capsules, 74.5 mg 74.5 mg 74.5 mg of isavuconazonium sulfate is equivalent to 40 mg of isavuconazole. of isavuconazonium sulfate per capsule 6 to less than 18 years of age 16 kg to less than 18 kg Two capsules (149 mg) orally every 8 hours for 6 doses (48 hours) Two capsules (149 mg) orally once daily 18 kg to less than 25 kg Three capsules (223.5 mg) orally every 8 hours for 6 doses (48 hours) Three capsules (223.5 mg) orally once daily 25 kg to less than 32 kg Four capsules (298 mg) orally every 8 hours for 6 doses (48 hours) Four capsules (298 mg) orally once daily greater than or equal to 32 kg Five capsules Five 74.5 mg CRESEMBA capsules are equivalent to two 186 mg CRESEMBA capsules. (372 mg) orally every 8 hours for 6 doses (48 hours) Five capsules (372 mg) orally once daily 2.4 Reconstitution Instructions for the CRESEMBA for Injection Formulation Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in CRESEMBA or in the materials specified for reconstitution. CRESEMBA is water soluble, preservative-free, sterile, and nonpyrogenic. • Reconstitute one vial of CRESEMBA by adding 5 mL water for injection, USP to the vial. The resultant solution will be 74.4 mg/mL of isavuconazonium sulfate. • Gently shake to dissolve the powder completely. • Visually inspect the reconstituted solution for particulate matter and discoloration. Reconstituted CRESEMBA should be clear and free of visible particulate. • The reconstituted solution may be stored between 5°C to 25°C (41°F to 77°F) for a maximum of 1 hour prior to preparation of the patient intravenous infusion solution [see Dosage and Administration ( 2.5 )]. • For nasogastric tube administration, the reconstituted solution should be administered within 1 hour of reconstitution [see Dosage and Administration ( 2.6 )]. • Discard any unused portion of the reconstituted solution. 2.5 Dilution and Preparation Instructions for the Intravenous Administration of the CRESEMBA for Injection Formulation • Based on the adult or pediatric dosage regimen [see Dosage and Administration ( 2.2 and 2.3 )], remove the appropriate volume of the reconstituted solution (74.4 mg/mL of isavuconazonium sulfate) from the vial and add it to an infusion bag containing 250 mL of compatible diluent [see Dosage and Administration ( 2.7 )] . A smaller volume infusion bag of compatible diluent may be used as long as the final concentration does not exceed approximately 1.5 mg isavuconazonium sulfate per mL. • The diluted solution may show visible translucent to white particulates of isavuconazole (which will be removed by in-line filtration). • Use gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution. • Apply in-line filter with a microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag. • Do not use a pneumatic transport system. • The intravenous administration should be completed within 6 hours of dilution at room temperature. If this is not possible, immediately refrigerate (2°C to 8°C / 36°F to 46°F) the infusion solution after dilution and complete the infusion within 24 hours. Do not freeze the infusion solution. 2.6 Preparation Instructions for the Nasogastric Tube Administration of the CRESEMBA for Injection Formulation CRESEMBA for injection can be administered through a nasogastric tube as follows: • Utilizing aseptic technique, reconstitute one vial of CRESEMBA for injection (equivalent to 200 mg isavuconazole) with 5 mL of water for injection, USP [see Dosage and Administration ( 2.4 )] . • Based on the adult or pediatric (6 years of age to less than 18 years of age) CRESEMBA for injection dosage regimen [see Dosage and Administration ( 2.2 , 2.3 )] , withdraw the appropriate volume of the reconstituted solution (74.4 mg/mL of isavuconazonium sulfate) from the vial using an appropriate syringe and needle. Discard the needle and cap the syringe. • To administer, remove the cap from the syringe containing the reconstituted solution and connect the syringe to the nasogastric (NG) tube to deliver the dose. After administering the dose, administer three 5 mL rinses to the NG tube with water [see Clinical Pharmacology ( 12.3 )] . • Administer the reconstituted solution via the nasogastric tube within 1 hour of reconstitution. Discard any unused portion of the reconstituted solution. • Do not administer CRESEMBA capsules through a nasogastric tube. 2.7 Compatibility for the Injection Formulation CRESEMBA for injection should only be administered with the following diluents: • 0.9% sodium chloride injection, USP • 5% dextrose injection, USP

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hepatic Adverse Drug Reactions [see Warnings and Precautions ( 5.1 )] • Infusion-Related Reactions [see Warnings and Precautions ( 5.2 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] • Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.4 )] • Adult Patients: The most frequent adverse reactions in adult patients were nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain. ( 6.1 ) • Pediatric Patients: The most frequent adverse reactions in pediatric patients were diarrhea, abdominal pain, vomiting, elevated liver chemistry tests, rash, nausea, pruritus, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of CRESEMBA cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adult Patients A total of 403 adult patients were exposed to CRESEMBA in two clinical trials. The most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%). Serious adverse reactions occurred in 223/403 (55%) of patients and 56/403 (14%) of patients permanently discontinued treatment with CRESEMBA due to an adverse reaction in the two trials. The adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%). Patients in the clinical trials were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, graft-versus-host disease, and hematopoietic stem cell transplant. The patient population was 61% male, had a mean age of 51 years (range 17-92, including 85 patients aged greater than 65 years), and was 79% White and 3% Black. One hundred forty-four (144) patients had a duration of CRESEMBA therapy of greater than 12 weeks, with 52 patients receiving CRESEMBA for over six months. In Trial 1, a randomized, double-blind, active-controlled clinical trial for treatment of invasive aspergillosis, treatment‑emergent adverse reactions occurred in 247/257 (96%), and 255/259 (99%) patients in the CRESEMBA and voriconazole treatment groups, respectively. Adverse reactions resulting in permanent discontinuation were reported in 37 (14%) CRESEMBA-treated patients and 59 (23%) voriconazole-treated patients. Table 3 includes selected adverse reactions which were reported at an incidence of ≥ 5% during CRESEMBA therapy in Trial 1. In Trial 2, an open-label, non-comparative trial of CRESEMBA in patients with invasive aspergillosis and renal impairment or invasive mucormycosis, adverse reactions occurred in 139/146 (95%) of patients in the CRESEMBA treatment group. Adverse reactions resulting in permanent discontinuation were reported in 19 (13%) CRESEMBA‑treated patients. The frequencies and types of adverse reactions observed in CRESEMBA-treated patients were similar between Trial 1 and Trial 2. Table 3. Selected Adverse Reactions with Rates of 5% or Greater in CRESEMBA-treated Patients in Trial 1 System Organ Class Adverse Reactions Trial 1 CRESEMBA (N=257) n (%) Voriconazole (N=259) n (%) Gastrointestinal disorders Nausea 71 (27.6) 78 (30.1) Vomiting 64 (24.9) 73 (28.2) Diarrhea 61 (23.7) 60 (23.2) Abdominal pain 43 (16.7) 59 (22.8) Constipation 36 (14.0) 54 (20.8) Dyspepsia 16 (6.2) 14 (5.4) General disorders and administration site conditions Edema peripheral 39 (15.2) 46 (17.8) Fatigue 27 (10.5) 18 (6.9) Chest pain 23 (8.9) 16 (6.2) Injection site reaction 16 (6.2) 4 (1.5) Hepatobiliary disorders Elevated liver laboratory tests Elevated liver laboratory tests include reactions of increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, blood bilirubin, and gamma-glutamyl transferase. 44 (17.1) 63 (24.3) Metabolism and nutrition disorders Hypokalemia 49 (19.1) 58 (22.4) Decreased appetite 22 (8.6) 28 (10.8) Hypomagnesemia 14 (5.4) 27 (10.4) Musculoskeletal and connective tissue disorders Back pain 26 (10.1) 19 (7.3) Nervous system disorders Headache 43 (16.7) 38 (14.7) Psychiatric disorders Insomnia 27 (10.5) 25 (9.7) Delirium Delirium includes adverse reactions of agitation, confusional state, delirium, disorientation, and mental status changes. 22 (8.6) 30 (11.6) Anxiety 21 (8.2) 18 (6.9) Renal and urinary disorders Renal failure 26 (10.1) 21 (8.1) Respiratory, thoracic and mediastinal disorders Dyspnea 44 (17.1) 35 (13.5) Acute respiratory failure 19 (7.4) 22 (8.5) Skin and subcutaneous tissue disorders Rash 22 (8.6) 36 (13.9) Pruritus 21 (8.2) 15 (5.8) Vascular disorders Hypotension 21 (8.2) 28 (10.8) The following adverse reactions occurred in less than 5% of all CRESEMBA-treated patients in Trial 1 or 2. The list does not include reactions presented in Table 3 . This listing includes adverse reactions where a causal relationship to CRESEMBA cannot be ruled out or those which may help the physician in managing the risks to the patients. • Blood and lymphatic system disorders: agranulocytosis, leukopenia, pancytopenia • Cardiac disorders: atrial fibrillation, atrial flutter, bradycardia, reduced QT interval on electrocardiogram, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, cardiac arrest • Ear and labyrinth disorders: tinnitus, vertigo • Eye disorders: optic neuropathy • Gastrointestinal disorders: abdominal distension, gastritis, gingivitis, stomatitis • General disorders and administration site conditions: catheter thrombosis, malaise, chills • Hepatobiliary disorders: cholecystitis, cholelithiasis, hepatitis, hepatomegaly, hepatic failure • Immune system disorders: hypersensitivity • Injury, poisoning and procedural complications: fall • Metabolism and nutrition disorders: hypoalbuminemia, hypoglycemia, hyponatremia • Musculoskeletal and connective tissue disorders: myositis, bone pain, neck pain • Nervous system disorders: convulsion, dysgeusia, encephalopathy, hypoesthesia, migraine, peripheral neuropathy, paresthesia, somnolence, stupor, syncope, tremor • Psychiatric disorders: confusion, hallucination, depression • Renal and urinary disorders: hematuria, proteinuria • Respiratory, thoracic and mediastinal disorders: bronchospasm, tachypnea • Skin and subcutaneous tissue disorders: alopecia, dermatitis, exfoliative dermatitis, erythema, petechiae, urticaria • Vascular disorders: thrombophlebitis Laboratory Effects In Trial 1, elevated liver transaminases (alanine aminotransferase or aspartate aminotransferase) greater than three times the upper limit of normal were reported at the end of study treatment in 4.4% of patients who received CRESEMBA. Elevations of liver transaminases greater than ten times the upper limit of normal developed in 1.2% of patients who received CRESEMBA. Clinical Trials Experience in Pediatric Patients The clinical safety of CRESEMBA was assessed in 77 pediatric patients who received at least one dose of intravenous or oral CRESEMBA in two uncontrolled studies. Fifteen (19.5%) subjects were in the 1 to < 6 years old cohort, 30 subjects (39.0%) were in the 6 to < 12 years old cohort, and 32 subjects (41.6%) were in the 12 to < 18 years old cohort. The duration of treatment ranged from 1 to 181 days with a median duration of treatment of 15 days. The most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%) and headache (12%). In general, adverse reactions (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of CRESEMBA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Immune system disorders: anaphylactic reaction

12.3 Pharmacokinetics General Pharmacokinetics In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of CRESEMBA capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose proportional ( Table 6 ). Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (V ss ) was approximately 450 L following intravenous administration. Table 6. Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules Parameter CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37) CRESEMBA 186 mg 6 Capsules (n = 32) C max (mg/L) Mean SD CV % 7.5 1.9 25.2 20.0 3.6 17.9 t max (hr) Median Range 3.0 2.0 – 4.0 4.0 2.0 – 4.0 AUC (mg•hr/L) Mean SD CV % 121.4 35.8 29.5 352.8 72.0 20.4 Following oral administration of CRESEMBA capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg CRESEMBA capsules and five 74.5 mg CRESEMBA capsules exhibited a mean (SD) C max and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. Absorption After oral administration of CRESEMBA in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (C max ) 2 hours to 3 hours after single and multiple dosing. The absolute bioavailability of isavuconazole following oral administration of CRESEMBA is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. Following intravenous administration of CRESEMBA, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration. The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion. The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole. CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule ( Table 7 ). Table 7. Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions CRESEMBA IV Solution via NG Tube CRESEMBA Oral Capsules NG Tube/Oral Capsule Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI) C max (mg/L) 13 2.3 (23.6) 13 2.2 (26.7) 105.34 (89-124) AUC 0-72hr (mg·hr/L) 13 34.9 (22.1) 13 35.8 (24.6) 97.81 (93-103) AUC 0-∞ (mg·hr/L) 12 98.1 (44.5) 12 100.1 (46.8) 99.27 (93-106) GMR = Geometric least-squares mean ratio; CI = confidence interval Effect of Food Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C max by 9% and increased AUC by 9%. CRESEMBA can be taken with or without food. Distribution Isavuconazole is extensively distributed with a mean steady state volume of distribution (V ss ) of approximately 450 L. Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. Elimination Metabolism In in vitro studies isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Following single doses of [cyano 14 C] isavuconazonium and [pyridinylmethyl 14 C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a number of minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC greater than 10% of drug-related material. In vivo studies indicate that CYP3A4, CYP3A5 and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole. Excretion Following oral administration of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 46.1% of the total radioactive dose was recovered in the feces and 45.5% was recovered in the urine. Renal excretion of isavuconazole itself was less than 1% of the dose administered. The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites. Renal elimination of intact cleavage product was less than 1% of the total dose administered. Following intravenous administration of radio-labeled cleavage product, 95% of the total radioactive dose was excreted in the urine. Special populations Geriatric Patients The AUC of isavuconazole following a single oral dose of CRESEMBA equivalent to 200 mg isavuconazole in elderly subjects (65 years and older) was similar to that in younger volunteers (18 years to 45 years). The AUC was similar between younger female and male subjects and between elderly and younger males. Elderly female AUC estimates were 38% and 47% greater than AUC estimates obtained in elderly males and younger females, respectively. The pharmacokinetic difference in elderly females receiving CRESEMBA are not considered to be clinically significant. Therefore, no dose adjustment is required based on age and gender. Pediatric Patients The pharmacokinetics of isavuconazole were evaluated in two clinical studies (N = 73) in pediatric patients aged 1 to less than 18 years of age which included twenty-eight patients with at least possible invasive aspergillosis or possible invasive mucormycosis. Table 8. Derived Steady State Isavuconazole AUC (mg•hr/L) values in Pediatric Patients, by Age Group Dosage 15 mg/kg Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously. 10 mg/kg CRESEMBA for injection administered intravenously. 10 mg/kg or Maximum Dose of 372 mg CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally. Age Group 1 to < 3 years (n=5) 3 to < 6 years (n=10) 6 to < 12 years (n=29) 12 to < 18 years (n=29) Mean 80.2 103.3 97.3 104.2 Median 64.3 110.3 87.7 97.7 Minimum - Maximum 53.7 - 155 51.5 – 159.1 37.8– 153.8 35.5 – 215.6 Race A 2-compartment population pharmacokinetic model was developed to assess the pharmacokinetics of isavuconazole between healthy Western and Chinese subjects. Chinese subjects were found to have on average a 40% lower clearance compared to Western subjects (1.6 L/hr for Chinese subjects as compared to 2.6 L/hr for Western subjects) and therefore approximately 50% higher AUC than Western subjects. Body mass index (BMI) did not play a role in the observed differences. No dose adjustment is recommended for Chinese patients. Gender AUC estimates were similar between young female and male subjects (18 years to 45 years). There was a difference in AUC for elderly females (see Geriatric section above) . No dose adjustment is required based on gender. Patients with Renal Impairment Total isavuconazole AUC and C max were not affected to a clinically meaningful extent in subjects with mild, moderate and severe renal impairment relative to healthy controls. No dose adjustment is necessary in patients with renal impairment. Isavuconazole is not readily dialyzable. A dose adjustment is not warranted in patients with ESRD. Patients with Hepatic Impairment After a single-dose of CRESEMBA equivalent to 100 mg of isavuconazole was administered to 32 patients with mild (Child-Pugh Class A) hepatic impairment and 32 patients with moderate (Child-Pugh Class B) hepatic impairment (16 intravenous and 16 oral patients per Child-Pugh Class), the least squares mean systemic exposure (AUC) increased 64% and 84% in the Child-Pugh Class A group and the Child-Pugh Class B group, respectively, relative to 32 age and weight-matched healthy subjects with normal hepatic function. Mean C max was 2% lower in the Child-Pugh Class A group and 30% lower in the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy subjects and patients with mild and moderate hepatic impairment demonstrated that the mild and moderate hepatic impairment population had 40% and 48% lower isavuconazole clearance (CL) values, respectively, compared to the healthy population. It is recommended that the standard CRESEMBA loading dose and maintenance dose regimen be utilized in patients with mild to moderate hepatic disease. CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Drug Interaction Studies In Vitro Studies CYP450 Enzymes: Isavuconazole is a substrate of CYP3A4 and CYP3A5. Isavuconazole is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Isavuconazole is an inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9. Transporter Systems: Isavuconazole is an inhibitor of P-gp-, BCRP- and OCT2. Clinical Studies and Model-Informed Approaches The effect of coadministration of drugs on the pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of coadministered drugs were studied after single and multiple doses of isavuconazole in healthy subjects. The effects of ketoconazole, rifampin, lopinavir/ritonavir, and esomeprazole on isavuconazole are shown in Figure 1 . Ketoconazole: As a strong CYP3A4 inhibitor, ketoconazole increased the isavuconazole C max by 9% and isavuconazole AUC by 422% after multiple-dose administration of ketoconazole (200 mg twice daily) for 24 days and a single-dose of CRESEMBA equivalent to 200 mg of isavuconazole. Isavuconazole is a sensitive CYP3A4 substrate and use with strong CYP3A4 inhibitors are contraindicated per Section 4 and Figure 1 . Lopinavir/Ritonavir: Lopinavir/ritonavir (400 mg/100 mg twice daily) increased the C max and AUC of isavuconazole by 74% and 96%, respectively, with concurrent decreases in the mean AUCs of lopinavir and ritonavir by 27% and 31%, respectively. Rifampin: Rifampin (600 mg) decreased the mean C max and AUC of isavuconazole by 75% and 97%, respectively, when coadministered with multiple doses of CRESEMBA and thus, coadministration of CRESEMBA with strong CYP3A4 inducers is contraindicated. Figure 1. The Effect of Coadministered Drugs on Isavuconazole Exposure The effects of isavuconazole on ritonavir, lopinavir, prednisone, combined oral contraceptives (ethinyl estradiol and norethindrone), cyclosporine, atorvastatin, sirolimus, midazolam, and tacrolimus are shown in Figure 2 . CYP3A4 Substrates: CRESEMBA increased the systemic exposure of sensitive CYP3A4 substrates midazolam, sirolimus and tacrolimus approximately 2-fold, and therefore CRESEMBA is a moderate inhibitor of CYP3A4. Figure 2. The Effect of Isavuconazole on Coadministered CYP3A4 Substrate Medications The effects of isavuconazole on other CYP substrates: caffeine, bupropion, methadone, repaglinide, warfarin, omeprazole, and dextromethorphan, are shown in Figure 3 . Figure 3. The Effect of Isavuconazole on Exposure of Coadministered CYP Substrate Medications The effects of isavuconazole on the substrates of UGT and transporters: mycophenolate mofetil (MMF), methotrexate, metformin, and digoxin are shown in Figure 4 . Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters Vincristine: Vincristine (P-gp substrate) exposure is predicted to increase by less than 2-fold in pediatric and adult patients following concomitant administration with CRESEMBA. Figure 1. The Effect of Co-administered Drugs on Isavuconazole Exposure Figure 2. The Effect of Isavuconazole on Co-administered CYP3A4 Substrate Medications Figure 3. The Effect of Isavuconazole on Exposure of Co-administered CYP Substrate Medications Figure 4. The Effect of Isavuconazole on Exposure on the Substrates of UGT and Transporters