CRESEMBA contains isavuconazonium sulfate, which is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazonium sulfate drug substance is an amorphous, white to yellowish-white powder. The chemical name of isavuconazonium sulfate is glycine, N -methyl-, [2-[[[1-[1-[(2 R ,3 R )-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4 H -1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1). The empirical formula is C 35 H 35 F 2 N 8 O 5 S·HSO 4 , the molecular weight is 814.84 and the structural formula is: CRESEMBA Capsules CRESEMBA (isavuconazonium sulfate) 74.5 mg capsules are available for oral administration. Each CRESEMBA capsule contains 74.5 mg isavuconazonium sulfate, equivalent to 40 mg isavuconazole. The inactive ingredients include black iron oxide, colloidal silicon dioxide, disodium edetate, gellan gum, hypromellose, magnesium citrate, microcrystalline cellulose, potassium acetate, potassium hydroxide, propylene glycol, purified water, red iron oxide, shellac, sodium lauryl sulfate, stearic acid, strong ammonia solution, talc and titanium dioxide. CRESEMBA (isavuconazonium sulfate) 186 mg capsules are available for oral administration. Each CRESEMBA capsule contains 186 mg isavuconazonium sulfate, equivalent to 100 mg isavuconazole. The inactive ingredients include black iron oxide, colloidal silicon dioxide, disodium edetate, gellan gum, hypromellose, magnesium citrate, microcrystalline cellulose, potassium acetate, potassium hydroxide, propylene glycol, purified water, red iron oxide, shellac, sodium lauryl sulfate, stearic acid, strong ammonia solution, talc and titanium dioxide. CRESEMBA for Injection CRESEMBA (isavuconazonium sulfate) for injection is available for intravenous administration. CRESEMBA for injection is a white to yellow sterile, lyophilized powder containing 372 mg isavuconazonium sulfate, equivalent to 200 mg isavuconazole, per vial. Inactive ingredients included in each vial are 96 mg mannitol and sulfuric acid for pH adjustment. Isavuconazonium sulfate Structural Formula

CRESEMBA ® is an azole antifungal indicated for the treatment of: Invasive aspergillosis and Invasive mucormycosis 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 CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater 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 CRESEMBA capsules : adults and pediatric patients 6 years of age and older who weigh 16 kg and greater , Clinical Studies 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.

CRESEMBA Capsules CRESEMBA 74.5 mg isavuconazonium sulfate (equivalent to 40 mg of isavuconazole) capsules are opaque and have a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a Swedish orange cap imprinted with “557” in black ink. CRESEMBA 186 mg isavuconazonium sulfate (equivalent to 100 mg of isavuconazole) capsules are opaque, elongated and have a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a white cap imprinted with “766” in black ink. CRESEMBA for Injection Each single-dose vial of CRESEMBA for injection contains 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole). CRESEMBA for injection is supplied in a single-dose vial as a sterile lyophilized white to yellow powder. • CRESEMBA for injection is supplied in a single-dose vial as a sterile lyophilized powder containing 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole). • CRESEMBA capsules: 74.5 mg of isavuconazonium sulfate (equivalent to 40 mg of isavuconazole), 186 mg of isavuconazonium sulfate (equivalent to 100 mg of isavuconazole).

Important Administration Instructions: • CRESEMBA for injection is intended for use in patients who are 1 year of age and older. • 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.. • CRESEMBA for injection must be administered through an in-line filter over a minimum of 1 hour.. • CRESEMBA capsules are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater. • CRESEMBA capsules can be taken with or without food.. Recommended Dosage in Adult Patients: Recommended Dosage 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 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: • The maximum of any individual loading or daily maintenance dose to be administered to any pediatric patient is 372 mg of CRESEMBA. Recommended Dosage 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 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 . • 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 . CRESEMBA Capsules • CRESEMBA capsules are intended for use in patients who are 6 years of age and older and weighing 16 kg and greater . • 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

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 . 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 . • For nasogastric tube administration, the reconstituted solution should be administered within 1 hour of reconstitution . • Discard any unused portion of the reconstituted solution

Dilution and Preparation Instructions for the Intravenous Administration of the CRESEMBA for Injection Formulation • Based on the adult or pediatric dosage regimen , 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 . 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

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 . • Based on the adult or pediatric (6 years of age to less than 18 years of age) CRESEMBA for injection dosage regimen , 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 . • 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

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

• Hepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy. • Infusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. • Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens-Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed. • Embryo-Fetal Toxicity: CRESEMBA may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective method of contraception. ( 5.4 , 8.1 , 8.3 ) • Drug Interactions: Review patient’s concomitant medications. Several drugs may significantly alter isavuconazole concentrations. Isavuconazole may alter concentrations of several drugs. ( 5.5 , 7 , 12.3 ) • Drug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter. 5.1 Hepatic Adverse Drug Reactions Hepatic adverse drug reactions (e.g., elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin) have been reported in clinical trials. The elevations in liver-related laboratory tests were generally reversible and did not require discontinuation of CRESEMBA. Cases of more severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy. Monitor patients who develop abnormal liver-related laboratory tests during CRESEMBA therapy for the development of more severe hepatic injury. Discontinue CRESEMBA if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA

Infusion-Related Reactions Infusion-related reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur

Hypersensitivity Reactions Anaphylactic Reactions Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Symptoms including dyspnea, hypotension, generalized erythema with flushing, and urticaria have been reported in such cases often soon after the initiation of treatment. Severe Skin Reactions Severe skin reactions, such as Stevens-Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if a patient develops an anaphylactic or severe cutaneous adverse reaction and initiate supportive treatment as needed. There is no information regarding cross-sensitivity between CRESEMBA and other azole antifungal agents though cross-sensitivity between other triazole agents has been reported. When prescribing CRESEMBA to patients with hypersensitivity to other azoles, monitor for signs and symptoms of hypersensitivity reactions

Embryo-Fetal Toxicity Based on findings from animal reproduction studies, CRESEMBA may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Perinatal mortality was significantly increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at 90 mg/kg/day (less than half the maintenance human dose based on AUC comparisons) during pregnancy through the weaning period. Isavuconazonium chloride administration was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, doses equivalent to about 0.2 and 0.1 of the human maintenance dose based on AUC comparisons. In rats, dose-related increases in the incidences of zygomatic arch fusion and supernumerary ribs/rudimentary supernumerary ribs were also noted at 30 mg/kg and above, equivalent to one fifth the maintenance human dose based on AUC comparisons . Advise females of reproductive potential to use an effective method of contraception during treatment with CRESEMBA and for 28 days after the final dose

Drug Interactions Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates is contraindicated

Drug Particulates Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter .

Isavuconazole is a sensitive substrate of CYP3A4. CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. Isavuconazole is a moderate inhibitor of CYP3A4, and a mild inhibitor of P-glycoprotein (P-gp), and organic cation transporter 2 (OCT2). Drug interaction studies were conducted to investigate the effect of coadministered drugs on the pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of coadministered drugs . Table 4. Drug(s) Affecting Pharmacokinetics of CRESEMBA Recommendation Comments Ketoconazole Contraindicate coadministration of all potent CYP3A4 inhibitors There is more than a 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole . Lopinavir/ritonavir 400 mg of lopinavir in combination with 100 mg of ritonavir. Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir . Rifampin Contraindicate coadministration of all potent CYP3A4 inducers There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin . Table 5. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs Recommendation Comments Lopinavir/ritonavir 400 mg of lopinavir in combination with 100 mg of ritonavir. Use with Caution Concomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy . Atorvastatin Use with Caution Caution should be used when atorvastatin is used with CRESEMBA due to a potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin . Cyclosporine Use with Caution Concomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed . Sirolimus Use with Caution Concomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed . Tacrolimus Use with Caution Concomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed . Midazolam Use with Caution Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered . Bupropion Use with Caution Concomitant administration of CRESEMBA and bupropion results in decrease in bupropion exposure. Dose increase of bupropion may be necessary when coadministered with CRESEMBA, but should not exceed the maximum recommended dose . Mycophenolate Mofetil Use with Caution Concomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities . Digoxin Use with Caution Concomitant administration of CRESEMBA and digoxin results in increase in digoxin exposure. Serum digoxin concentrations should be monitored and used for titration when dosed concurrently with CRESEMBA . Vincristine Avoid Concomitant Use Avoid concomitant use with CRESEMBA in pediatric and adult patients. CRESEMBA is predicted to have a less than 2‑fold increase in vincristine exposure in pediatric and adult patients , which may increase the risk of vincristine-related adverse reactions. • CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. • Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when coadministered with CRESEMBA. • Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA.